Injection-grade medical chitosan and sodium glycerophosphate gel capable of being subjected to moist heat sterilization and preparation method of injection-grade medical chitosan and sodium glycerophosphate gel

Abstract

The invention discloses injection-grade medical chitosan and sodium glycerophosphate gel capable of being sterilized in a moist heat manner and a preparation method of the injection-grade medical chitosan and sodium glycerophosphate gel. The core is characterized in that a composite formula based on an acid solvent system and sodium glycerophosphate is developed, and the stability of chitosan under the high-temperature and high-pressure sterilization condition is achieved through the synergistic effect and concentration optimization of all the components. An acid solvent system is introduced in the gel preparation process, the acid solvent system is composed of sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate, sodium chloride and hydrochloric acid, and the solubility of chitosan is remarkably improved; the chitosan is prepared according to the conventional chitosan product concentration, raw materials are easy to obtain, the method is high in reference, the production cost is reduced, and popularization and implementation in the field are facilitated. Meanwhile, sodium glycerophosphate powder is dissolved in a phosphate buffer solution to obtain a sodium glycerophosphate solution, and the precooled sodium glycerophosphate solution is slowly dropwise added into the chitosan gel in cooperation with the ice-water bath condition, so that precipitation in the gelling process is prevented.

Description

Technical Field

[0001] This invention relates to a method for preparing a sterilizable gel, and more particularly to an injectable medical-grade chitosan and sodium glycerophosphate gel that can be sterilized by moist heat and its preparation method. Background Technology

[0002] Chitosan is a linear polysaccharide composed of randomly distributed β-(1→4)-linked D-glucosamine (deacetylated units) and N-acetyl-D-glucosamine (acetylated units). It is produced by treating shrimp shells, crab shells, and chitin powder from other crustaceans with alkaline substances.

[0003] Chitosan, as a multifunctional biopolymer material, has a variety of commercial and potential biomedical applications and has shown significant application value in multiple technological fields. In the biomedical field: Chitosan can (1) serve as a key functional component of hemostatic dressings, which can significantly improve the hemostatic effect of wounds; (2) serve as a broad-spectrum antibacterial material, which exhibits excellent microbial inhibition properties; and (3) serve as a drug carrier in transdermal drug delivery systems, which can significantly improve the transdermal penetration efficiency of active ingredients.

[0004] To date, high-temperature moist heat sterilization remains considered one of the safest and most practical methods for sterilizing medical devices and liquids. While it achieves terminal sterilization, it causes chitosan molecular chain breakage, significantly reducing molecular weight and degree of deacetylation, thus disrupting its fundamental antibacterial structure. Simultaneously, it significantly reduces viscosity (viscosity can decrease by more than 50% after degradation), weakening chitosan's ability to form and affecting the product's sustained-release function. Currently, commercially available medical chitosan products generally use filtration sterilization, which suffers from incomplete sterilization, limited solution concentration (usually below 2%), and a lack of terminal sterilization assurance, leading to potential biosafety risks and low reliability in clinical applications. Summary of the Invention

[0005] This invention aims to overcome the technical defects of existing chitosan moist heat sterilization methods and provides an injectable medical-grade chitosan and sodium glycerophosphate gel that can be moist heat sterilized, along with its preparation method. This method significantly reduces the loss of chitosan molecular weight during traditional moist heat sterilization by optimizing the initial dissolution formulation, effectively inhibiting the degradation of chitosan molecular chains, thereby maintaining its inherent physicochemical properties and biological activity.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0007] This invention discloses a method for preparing injectable medical-grade chitosan and sodium glycerophosphate gel that can be sterilized by moist heat, comprising the following steps:

[0008] Step 1: Dissolve chitosan powder in an acidic solvent system and stir until homogeneous to obtain chitosan gel; the acidic solvent system consists of sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate, sodium chloride, and hydrochloric acid;

[0009] Step 2: Dissolve sodium glycerophosphate powder in phosphate buffer to obtain sodium glycerophosphate solution, and keep it in a refrigerator for later use; the phosphate buffer consists of sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate, and sodium chloride.

[0010] Step 3: Under ice-water bath conditions, slowly add sodium glycerophosphate solution dropwise to the dissolved chitosan gel; filter the mixed gel with silk cloth to obtain the filtered chitosan gel.

[0011] Step 4: Perform terminal moist heat sterilization on the filtered chitosan gel.

[0012] As a further improvement, in step 1 of the present invention, the concentrations of sodium dihydrogen phosphate (NaH2PO4·H2O) in the acidic solvent system are 0.03 mg / mL to 0.09 mg / mL, the concentrations of disodium hydrogen phosphate (Na2HPO4) are 0.06 mg / mL to 0.2 mg / mL, the concentrations of sodium chloride (NaCl) are 0.6 mg / mL to 1.6 mg / mL, and the concentrations of hydrochloric acid (HCl) are 0.07 M to 0.12 M.

[0013] As a further improvement, the concentration of chitosan after dissolution in step 1 of this invention is 1 mg / mL-50 mg / mL.

[0014] As a further improvement, in step 2 of the present invention, the concentration of sodium dihydrogen phosphate hydrate (NaH2PO4·H2O) in the phosphate buffer is 0.3 mg / mL-0.9 mg / mL, the concentration of disodium hydrogen phosphate (Na2HPO4) is 0.6 mg / mL-2 mg / mL, and the concentration of sodium chloride (NaCl) is 6 mg / mL-16 mg / mL.

[0015] As a further improvement, the concentration of the sodium glycerophosphate solution in step 2 of the present invention is 10 mg / mL to 160 mg / mL.

[0016] As a further improvement, step 3 of the present invention specifically involves using a ratio of sodium glycerophosphate solution to chitosan gel of 0.8:1 to 1.2:1 under ice-water bath conditions.

[0017] The beneficial effects of this invention are as follows:

[0018] This invention provides a method for preparing injectable medical-grade chitosan and sodium glycerophosphate gel that can be sterilized by moist heat. The core innovation of this invention lies in the development of a composite formulation based on an acidic solvent system and sodium glycerophosphate. Through the synergistic effect of each component and concentration optimization, the stability of chitosan under high temperature and high pressure sterilization conditions is achieved. Specifically, this invention introduces an acidic solvent system in the gel preparation process. The acidic solvent system consists of sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate, sodium chloride, and hydrochloric acid, which significantly improves the solubility of chitosan. The formulation uses the concentration of conventional chitosan products, the raw materials are readily available, and the method has strong reference value. It does not rely on high-concentration or specially modified chitosan raw materials, which helps to reduce production costs and facilitates its promotion and implementation in this field. At the same time, by dissolving sodium glycerophosphate powder in phosphate buffer to obtain a sodium glycerophosphate solution, the phosphate buffer consists of sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate, and sodium chloride. The pre-cooled sodium glycerophosphate solution is slowly added dropwise to the chitosan gel under ice-water bath conditions, which effectively prevents precipitation during the gelation process. By rationally designing the concentrations of each component in the acidic solvent system—with sodium dihydrogen phosphate (NaH₂PO₄·H₂O) at 0.03 mg / mL–0.09 mg / mL, disodium hydrogen phosphate (Na₂HPO₄) at 0.06 mg / mL–0.2 mg / mL, sodium chloride (NaCl) at 0.6 mg / mL–1.6 mg / mL, and hydrochloric acid (HCl) at 0.07 M–0.12 M—the system's osmotic pressure after sterilization meets injection requirements, overcoming the problem of excessively low osmotic pressure caused by insufficient salt concentration and improving the product's biocompatibility and safety. Ultimately, this allows injection-grade chitosan to withstand 121°C moist heat sterilization, solving the technical challenge of traditional chitosan solutions being unable to undergo compliant terminal sterilization due to poor thermal stability. The retention rate of chitosan molecular weight after sterilization is significantly improved, avoiding performance degradation caused by molecular chain degradation. The entire process is controllable, highly repeatable, and suitable for industrial production, providing a reliable technical path for the terminal sterilization of chitosan-based medical gels. Attached Figure Description

[0019] Figure 1 The graph shows the changes in molecular weight and dynamic viscosity of chitosan samples in Examples 1, 12, and 13 after moist heat sterilization under different conditions. The dynamic viscosity data is calculated at a shear rate of 0.1 s⁻¹. -1 The measurements were taken under specific conditions and expressed in millipascal-seconds (mPa·s).

[0020] Figure 2 The graph shows the changes in molecular weight and dynamic viscosity of the chitosan sample in Example 2 after moist heat sterilization. The dynamic viscosity data is based on a shear rate of 0.1 s⁻¹. -1 The measurements were taken under specific conditions and expressed in millipascal-seconds (mPa·s).

[0021] Figure 3 This is a graph showing the change in molecular weight of chitosan samples from different batches of raw materials in Comparative Examples 14 and 15 of Example 3 after moist heat sterilization.

[0022] Figure 4 The graph shows the changes in molecular weight and osmotic pressure of the chitosan sample in Comparative Example 3 after it was dissolved in an equal amount of purified water instead of the acidic solvent system containing hydrated sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium chloride.

[0023] Figure 5 This is a comparison chart of the osmotic pressure of chitosan samples in Example 1 and Comparative Example 3 under different formulation treatments. Detailed Implementation

[0024] To further understand the present invention, the following detailed description, in conjunction with embodiments, provides an injectable medical-grade chitosan and sodium glycerophosphate gel capable of being sterilized by moist heat, and its preparation method. The present invention specifically includes the following steps:

[0025] Chitosan powder was dissolved in an acidic solvent system and stirred until homogeneous to obtain chitosan gel; the acidic solvent system consisted of sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate, sodium chloride, and hydrochloric acid;

[0026] Preferably, the concentrations of sodium dihydrogen phosphate (NaH2PO4·H2O) in the acidic solvent system are 0.03 mg / mL to 0.09 mg / mL, disodium hydrogen phosphate (Na2HPO4) is 0.06 mg / mL to 0.2 mg / mL, sodium chloride (NaCl) is 0.6 mg / mL to 1.6 mg / mL, and hydrochloric acid (HCl) is 0.07 M to 0.12 M.

[0027] Preferably, the concentration of chitosan after dissolution is 1 mg / mL to 50 mg / mL.

[0028] Dissolve sodium glycerophosphate powder in phosphate buffer to obtain sodium glycerophosphate solution, and keep it in a refrigerator for later use; the phosphate buffer consists of sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate, and sodium chloride.

[0029] Preferably, the concentrations of sodium dihydrogen phosphate (NaH2PO4·H2O) in the phosphate buffer solution are 0.3 mg / mL to 0.9 mg / mL, the concentrations of disodium hydrogen phosphate (Na2HPO4) are 0.6 mg / mL to 2 mg / mL, and the concentrations of sodium chloride (NaCl) are 6 mg / mL to 16 mg / mL.

[0030] Preferably, the concentration of the sodium glycerophosphate solution is 10 mg / mL to 160 mg / mL.

[0031] Under ice-water bath conditions, the sodium glycerophosphate solution was slowly added dropwise to the dissolved chitosan gel; the mixed gel was then filtered through silk cloth.

[0032] Specifically, under ice-water bath conditions, the ratio of sodium glycerophosphate solution to chitosan gel is 0.8:1 to 1.2:1.

[0033] Preferably, the mixed gel is filtered using silk cloth.

[0034] The filtered chitosan gel was then subjected to terminal moist heat sterilization.

[0035] Example 1

[0036] Weigh out 0.041 g of sodium dihydrogen phosphate hydrate, 0.09 g of disodium hydrogen phosphate, and 0.78 g of sodium chloride, respectively, and add them to 1000 mL of purified water. Stir until homogeneous to obtain a solvent system. Take 10.8 mL of 1M hydrochloric acid solution and add it to 109.2 mL of the above solvent system. Stir until homogeneous to obtain an acidic solvent system with a hydrochloric acid concentration of 0.09M. Weigh out 2.7 g of chitosan and add it to the above acidic solvent system. Stir until the chitosan is completely dissolved, resulting in a chitosan concentration of 22.5 mg / mL.

[0037] Weigh out 0.041 g of sodium dihydrogen phosphate hydrate, 0.09 g of disodium hydrogen phosphate and 0.78 g of sodium chloride respectively, add 100 mL of purified water and stir well to obtain phosphate buffer.

[0038] Weigh 2.8g of sodium glycerophosphate and dissolve it in 35mL of the above phosphate buffer solution. The concentration of the resulting sodium glycerophosphate solution is 80mg / mL. Keep it in the refrigerator for later use.

[0039] Under ice-water bath conditions, take 34.29 mL of sodium glycerophosphate solution at a ratio of 7:2 and slowly add it dropwise to the dissolved chitosan gel, stirring for 20 minutes.

[0040] Filter the gel using silk cloth.

[0041] All vials were filled and terminally sterilized by moist heat at 1 mL / vial. The sterilization conditions were F0≈8.

[0042] Example 2

[0043] Weigh out 0.041 g of sodium dihydrogen phosphate hydrate, 0.09 g of disodium hydrogen phosphate, and 0.78 g of sodium chloride, respectively, and add them to 1000 mL of purified water. Stir until homogeneous to obtain a solvent system. Take 10.8 mL of 1M hydrochloric acid solution and add it to 109.2 mL of the above solvent system. Stir until homogeneous to obtain an acidic solvent system with a hydrochloric acid concentration of 0.09M. Weigh out 2.7 g of chitosan and add it to the above acidic solvent system. Stir until the chitosan is completely dissolved, resulting in a chitosan concentration of 22.5 mg / mL.

[0044] Weigh out 0.041 g of sodium dihydrogen phosphate hydrate, 0.09 g of disodium hydrogen phosphate and 0.78 g of sodium chloride respectively, add 100 mL of purified water and stir well to obtain phosphate buffer.

[0045] Weigh 2.625 g of sodium glycerophosphate and dissolve it in 35 mL of the above phosphate buffer solution. The concentration of the resulting sodium glycerophosphate solution is 75 mg / mL. Keep it in the refrigerator for later use.

[0046] Under ice-water bath conditions, take 34.29 mL of sodium glycerophosphate solution at a ratio of 7:2 and slowly add it dropwise to the dissolved chitosan gel, stirring for 20 minutes.

[0047] Filter the gel using silk cloth.

[0048] All samples were filled and terminally sterilized by moist heat at 1 mL / vial. The sterilization conditions were F0≈8. The changes in molecular weight and dynamic viscosity of the chitosan samples after moist heat sterilization are shown in the attached figure. Figure 2 As shown, the dynamic viscosity data is at a shear rate of 0.1 s⁻¹. -1 The results were measured under the specified conditions and expressed in millipascals per second (mPa·s). After moist heat sterilization, the chitosan samples within the formulation range of this invention retained up to 92.9% of their molecular weight and maintained stable dynamic viscosity. This demonstrates that moist heat sterilization under the specific formulation system described in this invention can effectively inhibit chain breakage or degradation of chitosan molecules, thereby maintaining the integrity of its molecular structure at a high level.

[0049] Example 3

[0050] Weigh out 0.041 g of sodium dihydrogen phosphate hydrate, 0.09 g of disodium hydrogen phosphate, and 0.78 g of sodium chloride, respectively, and add them to 1000 mL of purified water. Stir until homogeneous to obtain a solvent system. Take 12 mL of 1M hydrochloric acid solution and add it to 108 mL of the above solvent system. Stir until homogeneous to obtain an acidic solvent system with a hydrochloric acid concentration of 0.1M. Weigh out 2.7 g of chitosan and add it to the above acidic solvent system. Stir until the chitosan is completely dissolved, resulting in a chitosan concentration of 22.5 mg / mL.

[0051] Weigh out 0.041 g of sodium dihydrogen phosphate hydrate, 0.09 g of disodium hydrogen phosphate and 0.78 g of sodium chloride respectively, add 100 mL of purified water and stir well to obtain phosphate buffer.

[0052] Weigh 2.8g of sodium glycerophosphate and dissolve it in 35mL of the above phosphate buffer solution. The concentration of the resulting sodium glycerophosphate solution is 80mg / mL. Keep it in the refrigerator for later use.

[0053] Under ice-water bath conditions, take 34.29 mL of sodium glycerophosphate solution at a ratio of 7:2 and slowly add it dropwise to the dissolved chitosan gel, stirring for 20 minutes.

[0054] Filter the gel using silk cloth.

[0055] All vials were filled and terminally sterilized by moist heat at 1 mL / vial. The sterilization conditions were F0≈8.

[0056] Set up raw material batches A, B, and C to compare the differences in chitosan raw materials between different batches.

[0057] Comparative Example 1

[0058] The only difference in this comparative example is that the concentrations of sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate, and sodium chloride in the acidic solvent system are twice those in Example 1; all other technical features are the same as in Example 1.

[0059] Comparative Example 2

[0060] The only difference in this comparative example is that the concentrations of sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate, and sodium chloride in the acidic solvent system are 1.25 times that of Example 1; all other technical features are the same as in Example 1.

[0061] Comparative Example 3

[0062] This comparative example differs from Example 1 only in that an equal volume of purified water is used instead of the acidic solvent system. All other technical features are the same. The test results for the comparative example are attached. Figure 4 As shown, when purified water is used to replace sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate, and sodium chloride in the acidic solvent system of this invention in equal amounts, although the chitosan molecular weight retention rate is 93.3%, the osmotic pressure of the system decreases significantly, and its value is lower than the normal physiological range of the human body. Further comparative analysis is attached. Figure 5 As shown, the formulation of the present invention in Example 1 differs significantly from the alternative formulation in Comparative Example 3 in terms of osmotic pressure, with the alternative formulation showing an osmotic pressure reduction of up to 29%. This result demonstrates that the components of the system are crucial for maintaining a suitable osmotic pressure, and their absence will result in the final product failing to meet the osmotic pressure requirements for clinical applications.

[0063] Comparative Example 4

[0064] The only difference in this comparative example is that the acidic solvent system consists of hydrated sodium dihydrogen phosphate, disodium hydrogen phosphate, and hydrochloric acid, without the addition of sodium chloride. All other technical features are the same as in Example 1.

[0065] Comparative Example 5

[0066] This comparative example differs only in that the acidic solvent system consists of sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate, and hydrochloric acid, without the addition of sodium chloride, and the sodium chloride in Example 1 is replaced with sodium dihydrogen phosphate hydrate in equal mass. All other technical features are the same as in Example 1.

[0067] Comparative Example 6

[0068] This comparative example differs only in that the acidic solvent system consists of hydrated sodium dihydrogen phosphate, disodium hydrogen phosphate, and hydrochloric acid, without the addition of sodium chloride, and the sodium chloride in Example 1 is replaced with disodium hydrogen phosphate in equal mass. All other technical features are the same as in Example 1.

[0069] Comparative Example 7

[0070] The only difference in this comparative example is that the acidic solvent system consists of hydrated sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium chloride, without the addition of hydrochloric acid, and an equal amount of purified water is used instead of hydrochloric acid. All other technical features are the same as in Example 1.

[0071] Comparative Example 8

[0072] The only difference in this comparative example is that an equal volume of purified water was used instead of phosphate buffer; all other technical features are the same as in Example 1.

[0073] Comparative Example 9

[0074] The only difference between this comparative example and Example 1 is that the ratio of sodium glycerophosphate solution to chitosan gel is 1.4:1.

[0075] Comparative Example 10

[0076] This comparative example differs only in that the sodium glycerophosphate solution was slowly added dropwise to the dissolved chitosan gel at room temperature; all other technical features are the same as in Example 1.

[0077]

[0078] Example 1 demonstrates that when the composition and process parameters of the acidic solvent system are strictly controlled and kept within the optimized range defined in this patent, the degradation of chitosan molecular chains during traditional moist heat sterilization can be effectively inhibited, significantly reducing molecular weight loss and thus ensuring the stability of product performance.

[0079] Furthermore, Comparative Examples 1 and 2 show that if the acid concentration in the acidic solvent system exceeds the suitable range, it will lead to a decrease in the solubility of chitosan, resulting in incomplete dissolution or even precipitation after sterilization, seriously affecting the uniformity of the formulation and the feasibility of subsequent testing. Comparative Example 3 reveals that completely replacing the acidic solvent system with purified water will cause a significant decrease in the system's osmotic pressure, with a decrease of up to 29%, resulting in the final product's osmotic pressure being lower than the normal physiological range for humans, failing to meet the requirements for clinical application. Comparative Example 4 further verifies that even with the absence of sodium chloride in the acidic solvent system, a significant decrease in osmotic pressure also occurs, with a decrease of up to 18.3%, indicating that this component plays an irreplaceable role in maintaining the appropriate osmotic pressure of the system. In Comparative Example 5, replacing the missing sodium chloride with an equal amount of sodium dihydrogen phosphate still could not effectively maintain the required osmotic pressure, with a significant decrease in osmotic pressure, reaching 24.1%, indicating that the components in the system have a specific function in maintaining osmotic pressure, which is not solely determined by the total solids content, further highlighting the rationality and necessity of the solvent system design of this invention. Furthermore, Comparative Example 8 shows that using purified water instead of phosphate buffer causes the pH of the system to deviate from the control range, thereby affecting the stability and applicability of chitosan. This further confirms the synergistic effect and key technical value of the acidic solvent system used in this invention in maintaining suitable pH and osmotic pressure.

[0080] Comparative Example 11

[0081] The only difference in this comparative example is the use of irradiation sterilization; all other technical features are the same as in Example 1.

[0082] Comparative Example 12

[0083] The only difference between this comparative example and Example 1 is that the terminal moist heat sterilization condition is F0≈12. All other technical features are the same.

[0084] Comparative Example 13

[0085] The only difference in this comparative example is that the terminal moist heat sterilization condition is F0≈15; all other technical features are the same as in Example 1. The molecular weight and dynamic viscosity of the chitosan samples in Example 1, Comparative Example 12, and Comparative Example 13 after moist heat sterilization under different conditions are shown in the following figures. Figure 1 As shown. The dynamic viscosity data is at a shear rate of 0.1 s⁻¹. -1 The results were measured under the specified conditions and expressed in millipascal-seconds (mPa·s). The chitosan molecular weight retention rate in Example 1 was 88.2%, higher than that of Comparative Example 12 (85.6%) and Comparative Example 13 (80.1%). Further parallel experiments confirmed that the peak molecular weight retention rate of chitosan could be achieved when the F0 value of moist heat sterilization was adjusted to around 8.

[0086]

[0087] Comparative Example 14

[0088] The only difference between this comparative example and Example 3 is that the terminal moist heat sterilization condition is F0≈12.

[0089] Comparative Example 15

[0090] The only difference in this comparative example is that the terminal moist heat sterilization condition is F0≈15; all other technical features are the same as in Example 3. The molecular weight and dynamic viscosity of the chitosan samples in Example 3, Comparative Example 14, and Comparative Example 15 after moist heat sterilization under different conditions are shown below. Figure 3 As shown, it is also confirmed that when the F0 value of moist heat sterilization is adjusted to around 8, the molecular weight retention rate of chitosan can reach its peak.

[0091]

[0092] Based on parallel experiments of Examples 1 and 3, the chitosan molecular weight retention rate reached its peak when the F0 value of moist heat sterilization was adjusted to approximately 8. Meanwhile, compared to Example 1, irradiation sterilization in Comparative Example 11 resulted in liquefaction of the chitosan sample. These comparative experiments fully demonstrate that only moist heat sterilization under the formulation system defined in this patent can maximize the retention of chitosan molecular weight.

[0093] This invention relates to an injectable-grade medical chitosan and sodium glycerophosphate gel that can be sterilized by moist heat, and its preparation method. The key feature is the use of a composite formulation system composed of phosphate buffer and sodium glycerophosphate solution, achieving a chitosan molecular weight retention rate of ≥75% under high-temperature sterilization at 121℃. (Phosphate ions) With protonated amino groups on the chitosan molecular chain Electrostatic interactions are formed, and simultaneously, the hydroxyl groups of the chitosan form hydrogen bonds with the hydroxyl / amino groups of the chitosan. This physical cross-linking constructs a dynamic three-dimensional network structure. During moist heat sterilization, the cross-linked network encapsulates the chitosan chains, reducing the probability of direct attack on glycosidic bonds by high-temperature water molecules and mitigating the risk of violent vibrations and hydrolysis of the chitosan molecular chains at high temperatures.

[0094] This method precisely controls the formulation concentration within the patented optimized range, ensuring complete chitosan dissolution while avoiding the drawback of insufficient osmotic pressure due to excessively low salt concentration after sterilization. Experimental data shows that only by performing moist heat sterilization within the formulation range defined in this invention can the retention of chitosan molecular weight be maximized. Parallel experiments determined that the optimal chitosan molecular weight retention rate was achieved when the F0 value was adjusted to approximately 8. This technology overcomes the technical bottleneck of traditional chitosan solutions being unable to withstand terminal sterilization, achieving compliance with sterilization methods while maintaining the inherent chitosan molecular weight of the material.

[0095] It should be noted that the specific embodiments listed in this specification are merely preferred examples of the technical solutions of the present invention, and their purpose is to more clearly illustrate the technical features and implementation methods of the present invention. Those skilled in the art, having fully understood the technical solutions of the present invention, can implement the present invention through equivalent substitutions, combinations, or reasonable modifications of the implementation methods, without departing from the scope of protection and technical essence defined by the claims. Any modifications, equivalent substitutions, or substantial improvements made based on the basic technical concept of the present invention are within the scope of protection of the patent rights of this invention.

[0096] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for preparing a moisture-heat sterilizable injection-grade medical chitosan and sodium glycerophosphate gel, characterized in that, Includes the following steps: Step 1: Dissolve chitosan powder in an acidic solvent system and stir until homogeneous to obtain chitosan gel; the acidic solvent system consists of sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate, sodium chloride, and hydrochloric acid; Step 2: Dissolve sodium glycerophosphate powder in phosphate buffer to obtain sodium glycerophosphate solution, and keep it in a refrigerator for later use; the phosphate buffer is composed of sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate, and sodium chloride. Step 3: Under ice-water bath conditions, the sodium glycerophosphate solution is slowly added dropwise to the dissolved chitosan gel to obtain a mixed gel; the mixed gel is filtered through silk cloth to obtain the filtered chitosan gel. Step 4: Perform terminal moist heat sterilization on the filtered chitosan gel.

2. The preparation method according to claim 1, characterized in that, In step 1, the concentrations of sodium dihydrogen phosphate (NaH2PO4·H2O) in the acidic solvent system are 0.03 mg / mL to 0.09 mg / mL, disodium hydrogen phosphate (Na2HPO4) is 0.06 mg / mL to 0.2 mg / mL, sodium chloride (NaCl) is 0.6 mg / mL to 1.6 mg / mL, and hydrochloric acid (HCl) is 0.07 M to 0.12 M.

3. The preparation method according to claim 1, characterized in that, In step 1, the concentration of chitosan after dissolution is 1 mg / mL to 50 mg / mL.

4. The preparation method according to claim 1, 2, or 3, characterized in that, In step 2, the concentrations of sodium dihydrogen phosphate (NaH2PO4·H2O) in the phosphate buffer solution are 0.3 mg / mL to 0.9 mg / mL, disodium hydrogen phosphate (Na2HPO4) is 0.6 mg / mL to 2 mg / mL, and sodium chloride (NaCl) is 6 mg / mL to 16 mg / mL.

5. The preparation method according to claim 4, characterized in that, In step 2, the concentration of the sodium glycerophosphate solution is 10 mg / mL to 160 mg / mL.

6. The preparation method according to claim 1, 2, 3, or 5, characterized in that, Step 3 specifically involves using a ratio of sodium glycerophosphate solution to chitosan gel of 0.8:1 to 1.2:1 under ice-water bath conditions.

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