Method for producing a medical hyaluronic acid human body lubricant

Abstract

The application belongs to the technical field of medical hyaluronic acid human lubricant preparation, and discloses a medical hyaluronic acid human lubricant preparation method. The method first prepares acylated composite sodium hyaluronate and a composite grafted thickening agent, and then obtains the finished product through ultrasonic segmented swelling, inclusion complexation reaction, synergistic moisturizing construction, composite preservative blending, pulse type pH adjustment, amplitude ultrasonic defoaming, three-step gradient sterilization, dynamic low-temperature curing and sterile packaging. Through raw material modification and process control, the stability of hyaluronic acid and the uniformity of the thickening system are improved, the problems of insufficient lubrication duration and poor system stability in the prior art are solved, the product has excellent biocompatibility, and is suitable for medical auxiliary lubrication scenes.

Description

Technical Field

[0001] This invention belongs to the technical field of preparation of medical hyaluronic acid human lubricant, and specifically relates to a method for preparing medical hyaluronic acid human lubricant. Background Technology

[0002] Medical-grade hyaluronic acid lubricants are widely used in medical auxiliary lubrication and relief of dry mucous membranes due to their excellent biocompatibility and outstanding lubrication and moisturizing effects. In existing technologies, the core formulation of this type of lubricant typically uses sodium hyaluronate as the active ingredient, combined with carbomer thickeners, glycerin and other moisturizing excipients, along with pH adjusters and preservatives, and is prepared through steps such as swelling, mixing, sterilization, and filling. Existing technologies have disclosed hyaluronic acid-based lubricant formulations and preparation processes, clearly defining the core requirements for medical-grade products, including sterility, low irritation, and stable viscosity.

[0003] However, existing technologies still have many areas for improvement: sodium hyaluronate is easily enzymatically hydrolyzed in the human body environment, resulting in insufficient lubrication durability; thickeners are mostly of a single type or simple physical mixtures, resulting in poor system viscosity stability and easy stratification or abnormal flowability during long-term storage; sterilization processes mostly use single-temperature sterilization, making it difficult to simultaneously achieve sterility and the stability of active ingredients; pH adjustment is mostly achieved by continuously adding regulators, which can easily lead to excessive pH fluctuations in the system, affecting biocompatibility; and some processes do not adequately control the dispersibility of raw materials and the uniformity of the reaction, further affecting the overall performance of the product.

[0004] As the requirements for medical lubricants in clinical applications continue to increase, higher standards are being set for the product's long-lasting lubrication effect, system stability, biocompatibility, and precision of the preparation process. Therefore, developing a method for manufacturing medical hyaluronic acid human lubricants that can overcome the aforementioned shortcomings of existing technologies and take into account raw material stability, process controllability, and overall product performance has become an urgent need in this field. Summary of the Invention

[0005] In order to overcome the above-mentioned defects of the prior art, the embodiments of the present invention provide a method for manufacturing medical hyaluronic acid human lubricant, which solves the problems of insufficient lubrication long-term effect, poor stability of thickening system and lack of process control caused by the easy enzymatic hydrolysis of hyaluronic acid in the prior art.

[0006] To address the above problems, the present invention provides the following technical solution: A method for manufacturing a medical-grade hyaluronic acid personal lubricant includes the following steps: S1. Take high molecular weight sodium hyaluronate with a molecular weight of 1200-1800kDa, medium molecular weight sodium hyaluronate with a molecular weight of 400-600kDa, and low molecular weight sodium hyaluronate with a molecular weight of 80-120kDa, and after acylation modification treatment, mix them evenly at a mass ratio of 3:1.5:1 to obtain acylated composite sodium hyaluronate; take carbomer homopolymer and chitosan-g-polylactic acid graft copolymer at a mass ratio of 1:0.5-1.2, and screen them through a 60-120 mesh sieve to obtain a composite graft thickener; S2. Add 0.3-0.7% of the total mass of the composite grafted thickener to 85-95% of the total mass of purified water. Under stirring conditions of 5-10℃ and 150-220r / min, use 80-100kHz ultrasound-assisted swelling for 40-70min. The power density of the ultrasound equipment is 0.3-0.5W / cm². Then raise the temperature to 32-38℃, maintain a vacuum degree of 0.07-0.095MPa, and continue stirring at 200-280r / min with 40-60kHz ultrasound swelling for 30-50min to obtain a uniform thickener swelling solution. S3. Add 0.2-1.0% of the total mass of acylated composite sodium hyaluronate to the thickener swelling solution, and simultaneously add 8-15% of the mass of 400-800 Da polyethylene glycol-grafted β-cyclodextrin. Stir at 32-38℃ and 250-350 r / min for 40-60 min. Maintain the humidity of the system at 40-50% during the inclusion complexation reaction to obtain a hyaluronic acid inclusion solution. S4. Add 6-12% of the total mass of glycerol and phytosterol ester compound moisturizer to the hyaluronic acid inclusion solution. The mass ratio of glycerol to phytosterol ester is 4:1-2.5. Heat to 42-48℃ and stir at high speed of 2500-3500r / min for 20-30min. During this period, add 0.012-0.018% of the total mass of nano-γ-aminopropyltriethoxysilane coupling agent every 5min. The cumulative addition amount is 0.048-0.108% of the total mass of the system to obtain a synergistic moisturizing system. S5. Add a compound preservative of citric acid and lauroyl arginine ethyl hydrochloride to the synergistic moisturizing system. The amount of citric acid added is 0.15-0.4% of the total mass of the system, and the amount of lauroyl arginine ethyl hydrochloride added is 0.08-0.2% of the total mass of the system. Then add 0.03-0.08% of the theanine of the total mass of the system. Stir magnetically at 28-32℃ and 120-180r / min for 15-25min to obtain the preservative composite system. S6. Add a mixture of triethanolamine and gluconolactone as a pulsed dropwise instantaneous rate of 0.3-0.8 mL / min to the anti-corrosion composite system. The mass ratio of triethanolamine to gluconolactone in the mixture is 1:0.8-2.0. The dropwise addition method is to add for 30 seconds and then pause for 30 seconds, while stirring simultaneously at 90-130 r / min. Adjust the pH of the system to 5.2-6.8 to obtain a pH stable system. S7. Place the pH-stabilized system in an ultrasonic device, first treat it with low-frequency ultrasound at 20-30kHz for 8-12 minutes, then treat it with high-frequency ultrasound at 40-50kHz for 5-8 minutes. The ultrasonic power gradient is as follows: the initial power is 100W, and the power is increased by 50W every 3 minutes until it reaches 300-400W and is maintained until the end of the treatment. During the treatment, the system temperature is controlled at 25-35℃, and the temperature is avoided from exceeding 40℃. After that, let it stand for 8-15 minutes to obtain a bubble-free homogeneous system. S8. The bubble-free homogeneous system is heated to 105℃ at a heating rate of 5-7℃ / min and sterilized for 12min. Then, it is heated to 115℃ at a heating rate of 4-6℃ / min and sterilized for 10min. Finally, it is heated to 121℃ at a heating rate of 3-5℃ / min and sterilized for 18min while maintaining a pressure of 0.11-0.13MPa. Nitrogen protection is maintained throughout the process, with nitrogen purity ≥99.99% and a nitrogen flow rate of 0.5-1.0L / min. After sterilization, the system is cooled to below 40℃ at a heating rate of 3-5℃ / min to obtain the sterilized system. S9. Quickly cool the sterilization system to 5-8℃ and perform dynamic maturation treatment in a humidity of 30-40% and light-proof environment. The maturation cycle is 36-50 hours. During this period, stir at 60-100r / min for 6 minutes every 10 hours, and gradually increase the stirring speed by 10r / min. Before each stirring, pre-stir at 20-30r / min for 2 minutes, and then stir at the set speed to obtain the matured product. S10. In a Class 100 clean environment, after online ultraviolet sterilization of the matured product for 3-5 minutes, it is filled into aluminum foil bags that have been pre-sterilized by electron beam. Inert gas is introduced to replace the air in the bag, and then it is sealed at a heat-sealing temperature of 125-145℃ for 2-3 seconds to obtain medical hyaluronic acid human lubricant.

[0007] Further, the acylation modification process in step S1 involves dissolving sodium hyaluronate of various molecular weights in a 50-70% dimethyl sulfoxide aqueous solution, adding 5-10% (by weight of sodium hyaluronate) of succinic anhydride as an acylation reagent, reacting at 40-50°C for 2-3 hours, dialysis purification using a dialysis bag with a molecular weight cutoff of 8000-14000 Da for 48 hours, and then freeze-drying to obtain acylated sodium hyaluronate with a degree of acylation of 15-25%. Here, a stable group is introduced through a mild acylation reaction, reducing the enzymatic hydrolysis rate of hyaluronic acid. Simultaneously, precise dialysis and freeze-drying remove impurities, ensuring the purity and biosafety of the raw material and laying the foundation for the performance of the finished product.

[0008] Furthermore, in step S1, the grafting rate of the chitosan-g-polylactic acid graft copolymer is 30-50%, and the number-average molecular weight is 80-120 kDa. This grafting rate ensures a synergistic thickening effect between the chitosan-g-polylactic acid graft copolymer and carbomer, while the suitable number-average molecular weight balances water solubility and system viscosity stability, avoiding insufficient thickening or agglomeration problems.

[0009] Furthermore, in step S2, the power density of the ultrasonic equipment used in the 40-60kHz ultrasonic swelling process is 0.2-0.4W / cm², forming a power gradient match with the 80-100kHz ultrasonic band. This ultrasonic power gradient matching scheme allows different frequency bands of ultrasound to be adapted to the dispersion and swelling functions respectively, avoiding damage to the raw material structure or uneven swelling caused by a single power, and improving the uniformity of the thickener swelling solution.

[0010] Furthermore, in step S3, the grafting degree of polyethylene glycol-grafted β-cyclodextrin is 3-5. Here, the grafting degree of polyethylene glycol-grafted β-cyclodextrin directly determines its inclusion efficiency for hyaluronic acid, ensuring stable loading of the active ingredient without affecting the system's solubility and biocompatibility.

[0011] Furthermore, during the inclusion complexation reaction in step S3, the system temperature fluctuation is controlled within ±0.5℃. Controlling the temperature fluctuation of the inclusion reaction here prevents temperature fluctuations from disrupting the inclusion equilibrium, ensuring consistent inclusion effects for each batch of products, and improving production stability and the uniformity of finished product quality.

[0012] Furthermore, in step S4, the nano-γ-aminopropyltriethoxysilane coupling agent has a particle size of 20-50 nm and a surface hydroxyl content ≥3.0 mmol / g. It is diluted with anhydrous ethanol to a mass fraction of 10% before addition. This specific particle size and hydroxyl content ensure its coupling efficiency, while the dilution process avoids localized aggregation, ensuring uniform dispersion and enhancing the synergistic effect of the moisturizing system.

[0013] Furthermore, in step S5, the theanine has a purity of ≥98% and is the L-theanine isomer. This high purity avoids the introduction of impurities, and the L-theanine isomer has superior biocompatibility and synergistic preservative effects while reducing product irritation.

[0014] Furthermore, the ambient humidity during the settling process in step S7 is controlled at 40-50%. This is to prevent the system from becoming abnormal in concentration and viscosity due to moisture absorption or water loss, thus ensuring the continuity of subsequent processes and the stability of the finished product performance.

[0015] Furthermore, in step S10, the online ultraviolet sterilization uses an ultraviolet wavelength of 254 nm and an irradiation intensity of 30-50 μW / cm². This specific wavelength and intensity effectively kills microorganisms while avoiding damage to effective ingredients such as hyaluronic acid and thickeners.

[0016] The present invention provides a method for preparing medical hyaluronic acid human lubricant with the core objective of improving the product's long-lasting lubrication, system stability, and biocompatibility. This method involves the preparation of acylated composite sodium hyaluronate and the construction of composite graft thickeners at the raw material level. It combines a precise and coordinated design of multiple processes, including ultrasonic segmented swelling, inclusion complexation reaction, pulsed pH adjustment, three-stage gradient sterilization, and dynamic low-temperature curing. This achieves stable raw material structure, uniform system dispersion, balanced sterilization and component protection, and controllable finished product performance, forming a comprehensive lubricant preparation solution that meets the stringent requirements of medical applications.

[0017] Compared with the prior art, the advantages of the present invention are as follows: (1) The present invention significantly improves the long-lasting lubrication effect. The acylation modification and inclusion complex reaction work synergistically to reduce the enzymatic hydrolysis rate of hyaluronic acid and extend the effective lubrication time of the product in the human body environment. (2) The synergistic effect of the composite grafted thickener of the present invention is combined with the precise control of the multi-stage process to avoid problems such as layering and abnormal viscosity during product storage, and to ensure long-term performance. (3) The three-step gradient sterilization and online ultraviolet sterilization of the present invention are precisely matched, which can completely kill microorganisms while maximizing the protection of the activity of effective ingredients and meeting the stringent medical sterility standards. (4) The present invention selects a combination of low-irritant raw materials and optimizes the pH adjustment method to reduce the irritation of the product to human mucous membranes and adapt to the use needs of medical auxiliary lubrication scenarios. (5) The dynamic low-temperature curing and precise control of key process parameters of this invention ensure the performance consistency of each batch of products, providing support for large-scale industrial production; (6) The synergistic effect of the compound moisturizer and nano-coupling agent of the present invention can continuously maintain the moisture state of the human mucous membrane, improve the comfort of use and the overall product experience. Attached Figure Description

[0018] Figure 1 This is a flowchart of a method for manufacturing a medical hyaluronic acid human lubricant according to the present invention. Detailed Implementation

[0019] To facilitate understanding of the present invention, the invention will be described more fully and in detail below with reference to the accompanying drawings and preferred embodiments, but the scope of protection of the present invention is not limited to the following specific embodiments.

[0020] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art. The technical terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the scope of the invention.

[0021] Unless otherwise specified, all raw materials, reagents, instruments and equipment used in this invention can be purchased from the market or prepared by existing methods.

[0022] Example 1 refer to Figure 1 The method for manufacturing medical-grade hyaluronic acid human lubricant according to this embodiment includes the following steps: S1. High molecular weight sodium hyaluronate with a molecular weight of 1800 kDa, medium molecular weight sodium hyaluronate with a molecular weight of 600 kDa, and low molecular weight sodium hyaluronate with a molecular weight of 120 kDa were respectively subjected to acylation modification treatment. The acylation modification process was as follows: each molecular weight sodium hyaluronate was dissolved in a 70% dimethyl sulfoxide aqueous solution, and succinic anhydride at 10% of the mass of sodium hyaluronate was added as an acylation reagent. The reaction was carried out at 50°C for 3 hours, and purified by dialyzing with a dialysis bag with a molecular weight cutoff of 14000 Da for 48 hours. After freeze-drying, acylated sodium hyaluronate with a degree of acylation of 25% was obtained. The acylated sodium hyaluronate was mixed evenly at a mass ratio of 3:1.5:1 to obtain acylated composite sodium hyaluronate. Carbomer homopolymer and chitosan-g-polylactic acid graft copolymer were mixed at a mass ratio of 1:1.2. The grafting rate of chitosan-g-polylactic acid graft copolymer was 50%, and the number average molecular weight was 120 kDa. The mixture was screened through a 120-mesh sieve to obtain a composite graft thickener. S2. Add 0.7% of the total mass of the composite grafted thickener to 85.362% of the total mass of purified water. Under stirring conditions of 5℃ and 220r / min, use 80kHz ultrasound-assisted swelling for 70min. The power density of the ultrasound equipment is 0.5W / cm². Then raise the temperature to 38℃, maintain a vacuum of 0.095MPa, and continue stirring at 280r / min with 60kHz ultrasound swelling for 50min. The power density of the ultrasound equipment during the 40-60kHz ultrasound swelling process is 0.4W / cm², to obtain a uniform thickener swelling solution. S3. Add 1.0% (by weight) of acylated composite sodium hyaluronate to the thickener swelling solution, and simultaneously add 15% (by weight) of 400-800 Da polyethylene glycol-grafted β-cyclodextrin. The grafting degree of the polyethylene glycol-grafted β-cyclodextrin is 5. Stir at 38℃ and 350 r / min for 60 min. During the inclusion complexation reaction, maintain the system humidity at 50% and control the system temperature fluctuation within ±0.5℃ to obtain a hyaluronic acid inclusion solution. S4. Add 12% (by weight) of a glycerol and phytosterol ester compound moisturizer to the hyaluronic acid inclusion solution. The mass ratio of glycerol to phytosterol ester is 4:2.5. Heat to 48℃ and stir at 3500 r / min for 30 min. During this period, add 0.018% (by weight) of nano-γ-aminopropyltriethoxysilane coupling agent every 5 min. The cumulative addition amount is 0.108% (by weight) of the total system mass. The nano-γ-aminopropyltriethoxysilane coupling agent has a particle size of 50 nm and a surface hydroxyl content ≥3.0 mmol / g. It is diluted with anhydrous ethanol to a mass fraction of 10% before use to obtain a synergistic moisturizing system. S5. Add a compound preservative of citric acid and lauroyl arginine ethyl hydrochloride to the synergistic moisturizing system. The amount of citric acid added is 0.4% of the total mass of the system, and the amount of lauroyl arginine ethyl hydrochloride added is 0.2% of the total mass of the system. Then add 0.08% of theanine of the total mass of the system. The purity of theanine is ≥98% and it is the L-theanine isomer. Stir magnetically at 32℃ and 180r / min for 25min to obtain the preservative composite system. S6. Add a mixture of triethanolamine and gluconolactone to the anti-corrosion composite system at a pulsed instantaneous rate of 0.8 mL / min. The mass ratio of triethanolamine to gluconolactone in the mixture is 1:2.0. The addition method is to add for 30 seconds and then pause for 30 seconds, while stirring at 130 r / min simultaneously. Adjust the pH of the system to 6.8 to obtain a pH stable system. S7. Place the pH-stabilized system in an ultrasonic device, first treat it with low-frequency ultrasound at 30kHz for 12 minutes, then treat it with high-frequency ultrasound at 50kHz for 8 minutes. The ultrasonic power gradient is as follows: the initial power is 100W, and the power is increased by 50W every 3 minutes until it reaches 400W and is maintained until the end of the treatment. During the treatment, the system temperature is controlled at 35℃ to avoid the temperature from exceeding 40℃. After that, let it stand for 15 minutes. The ambient humidity during the standing process is controlled at 50% to obtain a bubble-free homogeneous system. S8. The bubble-free homogeneous system is heated to 105℃ at a heating rate of 7℃ / min and sterilized for 12min. Then, it is heated to 115℃ at a heating rate of 6℃ / min and sterilized for 10min. Finally, it is heated to 121℃ at a heating rate of 5℃ / min and sterilized at a pressure of 0.13MPa for 18min. Nitrogen protection is maintained throughout the process, with nitrogen purity ≥99.99% and a nitrogen flow rate of 1.0L / min. After sterilization, the system is cooled to below 40℃ at a rate of 5℃ / min to obtain the sterilized system. S9. Quickly cool the sterilization system to 8°C and perform dynamic curing treatment in a 40% humidity, light-proof environment. The curing cycle is 50 hours. During this period, stir at 100 r / min for 6 minutes every 10 hours, and gradually increase the stirring speed by 10 r / min. Before each stirring, pre-stir at 30 r / min for 2 minutes, and then stir at the set speed to obtain the cured product. S10. In a Class 100 clean environment, the matured product is subjected to online ultraviolet sterilization for 5 minutes. The ultraviolet wavelength for online ultraviolet sterilization is 254nm and the irradiation intensity is 50μW / cm². After filling with aluminum foil bags pre-sterilized by electron beam, inert gas is introduced to replace the air in the bag, and then the bag is sealed at a heat-sealing temperature of 145℃ and a heat-sealing time of 3 seconds to obtain medical hyaluronic acid human lubricant.

[0023] Example 2 The difference between this embodiment and Embodiment 1 is that the process parameters use intermediate values, while the manufacturing method is completely the same as that in Embodiment 1.

[0024] Example 3 The difference between this embodiment and Embodiment 1 is that the process parameters use lower limit values, while the manufacturing method is completely the same as that in Embodiment 1.

[0025] Comparative Example 1 This comparative method for preparing a human body lubricant includes the following steps. S1. Take sodium hyaluronate with a molecular weight of 1500 kDa, without acylation modification; take a single carbomer homopolymer and screen it through an 80-mesh sieve to obtain a thickener; S2. Add 0.6% of the total mass of thickener to 88.15% of the total mass of purified water, and swell for 60 min under stirring conditions of 25℃ and 200 r / min without ultrasonic assistance to obtain the thickener swollen solution; S3. Add 0.8% sodium hyaluronate by total mass of the thickener swelling solution, stir at 45℃ and 250r / min for 30min, without adding polyethylene glycol-grafted β-cyclodextrin, and without controlling the humidity of the system, to obtain a hyaluronic acid mixture. S4. Add 10% of the total mass of glycerin to the hyaluronic acid mixture as a moisturizer, without adding phytosterol esters or nano-γ-aminopropyltriethoxysilane coupling agent, heat to 45℃, and stir at 2500 r / min for 30 min to obtain the moisturizing system. S5. Add a compound preservative of citric acid and phenoxyethanol to the moisturizing system. The amount of citric acid added is 0.3% of the total mass of the system, and the amount of phenoxyethanol added is 0.15% of the total mass of the system. No theanine is added. Stir at 30℃ and 150r / min for 20min to obtain the preservative system. S6. Triethanolamine regulator was continuously added dropwise to the preservative system without gluconolactone, at a dropping rate of 0.6 mL / min, while stirring at 120 r / min simultaneously, and the pH of the system was adjusted to 6.0 to obtain a pH stable system. S7. Place the pH-stabilized system in an ultrasonic device and ultrasonically treat it at a single frequency of 30kHz for 15 minutes with the power kept constant at 200W. During the treatment, control the system temperature at 25-35℃, and then let it stand for 12 minutes without environmental humidity control to obtain a bubble-free system. S8. The bubble-free system is directly heated to 121℃, and sterilized at a pressure of 0.12MPa for 30 minutes without nitrogen protection. After sterilization, it is allowed to cool naturally to below 40℃ to obtain the sterilized system. S9. The sterilization system is left to stand at room temperature for 24 hours without any light protection or stirring, to obtain the matured product. S10. In a Class 100 clean environment, the matured finished product is directly filled without online ultraviolet sterilization and inert gas replacement steps, and sealed at 130°C for 2 seconds to obtain a human body lubricant.

[0026] The testing method is as follows: Long-lasting lubrication: Using a phosphate buffer system that simulates human body fluids, the duration of friction coefficient maintained within the effective range of medical lubrication (≤0.15) is monitored by simulating mucosal friction conditions using a reciprocating friction and wear tester. System stability: Samples were stored in a 37℃ constant temperature and humidity chamber for accelerated storage. Monthly samples were taken and subjected to rotational rheology at 25℃ for 10 seconds. -1 Viscosity was measured at shear rate, and the relative change rate of the final viscosity from the initial viscosity was calculated. At the same time, the presence of stratification or precipitation was observed visually. Aseptic safety: According to the aseptic test method of Part IV of the 2025 edition of the Pharmacopoeia of the People's Republic of China, the nutrient agar medium plate counting method was used. After aseptic dilution, the samples were inoculated and cultured for 48 hours, and the number of colonies was counted. Biocompatibility: According to the Draize skin irritation test standard, the sample was applied to the intact back skin of rabbits and removed after continuous contact for 24 hours. Skin erythema and edema were observed at 1, 24 and 48 hours, and irritation was scored according to the standard scoring table. Quality uniformity: Five batches of samples were prepared consecutively and tested using a rotational rheometer under the same conditions (25℃, 10s). -1 The viscosity of each batch of samples was measured at the shear rate, and the relative deviation between the viscosity of each batch and the average viscosity of 5 batches was calculated. The maximum value was taken as the evaluation result. Moisturizing duration: Using porcine small intestinal mucosa as a model of human mucosa, the sample was evenly applied and placed in an environment with a temperature of 37℃ and a relative humidity of 40%. The mucosal moisture content was monitored regularly using a skin moisture meter, and the duration for which the moisture content remained above 80% of the initial value was recorded.

[0027] Table 1: Experimental Results of Examples 1-3 and Comparative Example 1

[0028] In summary, referring to Table 1, Examples 1-3 showed significantly better lubrication longevity, system stability, aseptic safety, biocompatibility, quality uniformity, and moisturizing duration than Comparative Example 1. Comparative Example 1 did not meet medical standards for aseptic safety and exhibited slight irritation, while the performance of other indicators was poor.

[0029] Comparative Example 1 did not undergo acylation modification of sodium hyaluronate, nor did it employ polyethylene glycol-grafted β-cyclodextrin for inclusion complexation. Hyaluronic acid molecules were easily broken down by enzymes, resulting in a significant reduction in lubrication duration and moisturizing time. It used a single carbomer thickener without an ultrasonic segmented swelling process, leading to uneven dispersion of the thickener molecular chains. The lack of dynamic ripening further destabilized the internal structure of the system, resulting in poor system stability and quality uniformity. Single-temperature sterilization without nitrogen protection meant that continuous high-temperature action could not completely kill stubborn microorganisms and might also damage the activity of active ingredients, leading to substandard aseptic safety. It did not add phytosterol ester compound moisturizers, nano-coupling agents, or theanine; it only used glycerin for moisturizing and continuously added a single regulator to adjust the pH. The synergistic effect of the moisturizing components was insufficient, and the pH adjustment accuracy was low, resulting in inadequate moisturizing effect and poor biocompatibility.

[0030] Example 1 uses the upper limit parameter for raw material acylation modification and composite grafting thickener preparation. Combined with high-intensity ultrasonic segmented swelling, three-stage gradient sterilization and dynamic curing process, the synergistic effect of each link is sufficient, so the performance of each is optimal.

[0031] Example 2 uses intermediate parameters for raw material processing and process control. The degree of raw material modification, process intensity, and synergy of each link are at a balanced level, so the performance of each component is at a medium to high level.

[0032] Example 3 uses lower limit parameters for raw material processing and process implementation. The degree of raw material modification and process intensity are moderate, and each process step meets the basic synergistic requirements. Therefore, all performances meet medical standards but are slightly lower than those of Example 1 and Example 2.

Claims

1. A method for preparing a medical-grade hyaluronic acid personal lubricant, characterized in that: Includes the following steps, S1. Take high molecular weight sodium hyaluronate with a molecular weight of 1200-1800kDa, medium molecular weight sodium hyaluronate with a molecular weight of 400-600kDa, and low molecular weight sodium hyaluronate with a molecular weight of 80-120kDa, and after acylation modification treatment, mix them evenly at a mass ratio of 3:1.5:1 to obtain acylated composite sodium hyaluronate; take carbomer homopolymer and chitosan-g-polylactic acid graft copolymer at a mass ratio of 1:0.5-1.2, and screen them through a 60-120 mesh sieve to obtain a composite graft thickener; S2. Add 0.3-0.7% of the total mass of the composite grafted thickener to 85-95% of the total mass of purified water. Under stirring conditions of 5-10℃ and 150-220r / min, use 80-100kHz ultrasound-assisted swelling for 40-70min. The power density of the ultrasound equipment is 0.3-0.5W / cm². Then raise the temperature to 32-38℃, maintain a vacuum degree of 0.07-0.095MPa, and continue stirring at 200-280r / min with 40-60kHz ultrasound swelling for 30-50min to obtain a uniform thickener swelling solution. S3. Add 0.2-1.0% of the total mass of acylated composite sodium hyaluronate to the thickener swelling solution, and simultaneously add 8-15% of the mass of 400-800 Da polyethylene glycol-grafted β-cyclodextrin. Stir at 32-38℃ and 250-350 r / min for 40-60 min. Maintain the humidity of the system at 40-50% during the inclusion complexation reaction to obtain a hyaluronic acid inclusion solution. S4. Add 6-12% of the total mass of glycerol and phytosterol ester compound moisturizer to the hyaluronic acid inclusion solution. The mass ratio of glycerol to phytosterol ester is 4:1-2.

5. Heat to 42-48℃ and stir at high speed of 2500-3500r / min for 20-30min. During this period, add 0.012-0.018% of the total mass of nano-γ-aminopropyltriethoxysilane coupling agent every 5min. The cumulative addition amount is 0.048-0.108% of the total mass of the system to obtain a synergistic moisturizing system. S5. Add a compound preservative of citric acid and lauroyl arginine ethyl hydrochloride to the synergistic moisturizing system. The amount of citric acid added is 0.15-0.4% of the total mass of the system, and the amount of lauroyl arginine ethyl hydrochloride added is 0.08-0.2% of the total mass of the system. Then add 0.03-0.08% of the theanine of the total mass of the system. Stir magnetically at 28-32℃ and 120-180r / min for 15-25min to obtain the preservative composite system. S6. Add a mixture of triethanolamine and gluconolactone as a pulsed dropwise instantaneous rate of 0.3-0.8 mL / min to the anti-corrosion composite system. The mass ratio of triethanolamine to gluconolactone in the mixture is 1:0.8-2.

0. The dropwise addition method is to add for 30 seconds and then pause for 30 seconds, while stirring simultaneously at 90-130 r / min. Adjust the pH of the system to 5.2-6.8 to obtain a pH stable system. S7. Place the pH-stabilized system in an ultrasonic device, first treat it with low-frequency ultrasound at 20-30kHz for 8-12 minutes, then treat it with high-frequency ultrasound at 40-50kHz for 5-8 minutes. The ultrasonic power gradient is as follows: the initial power is 100W, and the power is increased by 50W every 3 minutes until it reaches 300-400W and is maintained until the end of the treatment. During the treatment, the system temperature is controlled at 25-35℃, and the temperature is avoided from exceeding 40℃. After that, let it stand for 8-15 minutes to obtain a bubble-free homogeneous system. S8. The bubble-free homogeneous system is heated to 105℃ at a heating rate of 5-7℃ / min and sterilized for 12min. Then, it is heated to 115℃ at a heating rate of 4-6℃ / min and sterilized for 10min. Finally, it is heated to 121℃ at a heating rate of 3-5℃ / min and sterilized for 18min while maintaining a pressure of 0.11-0.13MPa. Nitrogen protection is maintained throughout the process, with nitrogen purity ≥99.99% and a nitrogen flow rate of 0.5-1.0L / min. After sterilization, the system is cooled to below 40℃ at a heating rate of 3-5℃ / min to obtain the sterilized system. S9. Quickly cool the sterilization system to 5-8℃ and perform dynamic maturation treatment in a humidity of 30-40% and light-proof environment. The maturation cycle is 36-50 hours. During this period, stir at 60-100r / min for 6 minutes every 10 hours, and gradually increase the stirring speed by 10r / min. Before each stirring, pre-stir at 20-30r / min for 2 minutes, and then stir at the set speed to obtain the matured product. S10. In a Class 100 clean environment, after online ultraviolet sterilization of the matured product for 3-5 minutes, it is filled into aluminum foil bags that have been pre-sterilized by electron beam. Inert gas is introduced to replace the air in the bag, and then it is sealed at a heat-sealing temperature of 125-145℃ for 2-3 seconds to obtain medical hyaluronic acid human lubricant.

2. The method for preparing medical hyaluronic acid human lubricant according to claim 1, characterized in that: The acylation modification process in step S1 is as follows: dissolve sodium hyaluronate of various molecular weights in a 50-70% dimethyl sulfoxide aqueous solution, add 5-10% by mass of sodium hyaluronate as acylation reagent, react at 40-50℃ for 2-3 hours, dialyze and purify using a dialysis bag with a molecular weight cutoff of 8000-14000 Da for 48 hours, and obtain acylated sodium hyaluronate after freeze drying with an acylation degree of 15-25%.

3. The method for preparing medical hyaluronic acid human lubricant according to claim 1, characterized in that: In step S1, the grafting rate of the chitosan-g-polylactic acid graft copolymer is 30-50%, and the number average molecular weight is 80-120 kDa.

4. The method for preparing medical hyaluronic acid human lubricant according to claim 1, characterized in that: In step S2, the power density of the ultrasonic equipment used in the 40-60kHz ultrasonic swelling process is 0.2-0.4W / cm², which forms a power gradient match with the 80-100kHz ultrasonic band.

5. The method for preparing medical hyaluronic acid human lubricant according to claim 1, characterized in that: In step S3, the grafting degree of polyethylene glycol grafted with β-cyclodextrin is 3-5.

6. The method for preparing medical hyaluronic acid human lubricant according to claim 1, characterized in that: During the inclusion complexation reaction in step S3, the temperature fluctuation of the system is controlled within ±0.5℃.

7. The method for preparing medical hyaluronic acid human lubricant according to claim 1, characterized in that: In step S4, the nano-γ-aminopropyltriethoxysilane coupling agent has a particle size of 20-50 nm and a surface hydroxyl content of ≥3.0 mmol / g. It is added after being diluted to a mass fraction of 10% with anhydrous ethanol before use.

8. The method for preparing medical hyaluronic acid human lubricant according to claim 1, characterized in that: In step S5, the theanine has a purity of ≥98% and is an L-theanine isomer.

9. The method for preparing medical hyaluronic acid human lubricant according to claim 1, characterized in that: The ambient humidity during the settling process in step S7 is controlled at 40-50%.

10. The method for preparing medical hyaluronic acid human lubricant according to claim 1, characterized in that: In step S10, the ultraviolet wavelength for online ultraviolet sterilization is 254 nm, and the irradiation intensity is 30-50 μW / cm².

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