A Lincomycin Lidocaine Gel and its Preparation Method

Abstract

This invention belongs to the field of topical drug gel formulations and provides a lincomycin lidocaine gel and its preparation method. By synergistically introducing lincomycin hydrochloride, lidocaine hydrochloride, L-histidine amidated sodium hyaluronate intermediate, and lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate into the gel matrix, it achieves rapid onset of action, local retention, and controlled release, improves the dispersion stability and processing adaptability of the system, and solves the problem that traditional systems cannot simultaneously achieve low viscosity and wide processing window with high local retention and controlled release, as well as nanoscale homogeneous stability and high drug loading and rapid onset of action. It is suitable for topical antibacterial and analgesic drug delivery.

Description

Technical Field

[0001] This invention relates to the field of topical pharmaceutical preparations, specifically to a lincomycin lidocaine gel and its preparation method. Background Technology

[0002] Superficial skin infections, minor burns, abrasions, post-insect bite inflammation, and local mucosal irritation are often accompanied by redness, swelling, pain, burning, and the risk of secondary infection. Clinically, there is a greater need for topical gel formulations with both antibacterial and analgesic effects to form a continuous, gentle, and easily removable drug coating on the lesion surface. Such formulations should not only possess good spreadability, adhesion, and local retention, but also maintain appropriate structural stability and drug release rhythm in a moist microenvironment, ensuring the active ingredient remains effectively available locally and reducing loss and frequent reapplication. Furthermore, for industrial-scale preparation scenarios requiring mixing, homogenization, degassing, and filling, the system must also consider suitable rheological behavior, batch-to-batch consistency, storage homogeneity, and user comfort. Excessive viscosity should be avoided to prevent interference with processing and drug delivery, while a loose network should be avoided to prevent uneven drug distribution, insufficient retention, or unstable onset of action. If the system lacks a compatible carrier structure, it often sacrifices fluidity while improving local retention, and weakens long-term coverage and stability while pursuing rapid release. Therefore, systematic optimization of the relationship between drug, carrier and matrix in topical gels has become a key direction in formulation design.

[0003] Currently, the technical approaches for the local delivery of lincomycin and lidocaine mainly focus on two categories: conventional gel matrix compatibility and hyaluronic acid-based carrier loading. For example, Chinese patent CN112494507A discloses a lincomycin-lidocaine gel and its preparation method, emphasizing the use of conventional gel matrices, adjuvants, and pH adjustment to achieve formulation stability and conventional production. However, it addresses less the overall design of drug local retention, controlled release, and synergistic microstructure of the system. Similarly, Chinese patent CN102170855B discloses a hyaluronic acid-based gel containing anesthetics, which can introduce lidocaine into the hyaluronic acid gel system. However, it focuses more on the stable coexistence and release of anesthetics and hyaluronic acid gel, lacking a systematic solution for the synergistic introduction of antibacterial drugs, the construction of ionic microgel structures, and the unified balance between low-viscosity processing windows and nanoscale stable dispersion. Therefore, existing technologies still have significant room for improvement in terms of rapid onset of action, long-lasting retention, synergistic effects of compound formulations, particle size stability, and process adaptability. Simply relying on increasing the strength of the polymer network or the ratio of drug to carrier often leads to new problems such as decreased flowability, difficulty in mixing and homogenization, aggregation and stratification, or fluctuations in storage uniformity. Summary of the Invention

[0004] The purpose of this invention is to provide a lincomycin lidocaine gel and its preparation method, which solves the pain points of existing technologies that make it difficult to simultaneously achieve low viscosity and wide processing window with high local retention controlled release, as well as nanoscale homogeneous stability and high drug loading and rapid onset of action.

[0005] This invention establishes a synergistic delivery relationship of "rapid onset + controlled release" by separately adding lidocaine hydrochloride and lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate, and the separately added L-histidine amidated sodium hyaluronate intermediate synergistically regulates the stability of the gel network and interface, so as to balance local residence, dispersion uniformity and processing adaptability.

[0006] To achieve the above objectives, the present invention provides the following technical solution: A lincomycin lidocaine gel, based on 100 parts by weight, comprises: 0.045-0.060 parts by weight of lincomycin hydrochloride, 0.035-0.050 parts by weight of lidocaine hydrochloride, 0.10-1.20 parts by weight of L-histidine amidated sodium hyaluronate intermediate, 0.05-0.80 parts by weight of lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate, 0.20-2.00 parts by weight of hydroxypropyl methylcellulose, 1.0-12.0 parts by weight of glycerol, and purified water to a total of 100 parts by weight; The L-histidine-amidated sodium hyaluronate intermediate was obtained by coupling sodium hyaluronate with free L-histidine in the form of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide, with a degree of substitution of 3-18 mol%. The lidocaine hydrochloride-L-histidine-amidated sodium hyaluronate ion microgel intermediate was formed by mixing the L-histidine-amidated sodium hyaluronate intermediate with lidocaine hydrochloride at pH 5.8-6.6, followed by shearing at 3000-12000 r / min for 5-30 min, or by microfluidic treatment at 30-120 MPa 1-5 times, with a median volumetric particle size (D50) of 80-350 nm. The dispersion index is not greater than 0.30; the pH value of the gel is 5.8-6.8, wherein the lidocaine hydrochloride added separately is distinct from the lidocaine hydrochloride contained in the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate, the L-histidine amidated sodium hyaluronate added separately is distinct from the L-histidine amidated sodium hyaluronate contained in the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate, and the amount of lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate added is based on the total mass of lidocaine hydrochloride and L-histidine amidated sodium hyaluronate therein.

[0007] Furthermore, the preparation method of the L-histidine amidated sodium hyaluronate intermediate includes the following steps: A1. Prepare an aqueous solution of sodium hyaluronate with a concentration of 0.20-1.00 wt%. Add 2-20 parts by weight of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-12 parts by weight of N-hydroxysuccinimide to 100 parts by weight of sodium hyaluronate. Activate for 10-30 min at a pH of 4.7-6.0 and a temperature of 2-10℃. A2, add L-histidine in the form of free base to the activation system obtained in A1, the amount of which is 3-25 parts by weight based on sodium hyaluronate, and react at 15-30℃ for 2-12 hours; A3, after removing small molecules by dialysis or ultrafiltration, is freeze-dried to obtain L-histidine amidated sodium hyaluronate intermediate with a degree of substitution of 3-18 mol%.

[0008] Furthermore, the preparation method of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate includes the following steps: B1. Prepare an aqueous dispersion system with a concentration of 0.05-1.00 wt% for L-histidine amidated sodium hyaluronate intermediate, and add lidocaine hydrochloride at a mass ratio of 10-60:100 to lidocaine hydrochloride intermediate. B2, the system obtained from B1 is subjected to shearing at 3000-12000 r / min for 5-30 min at a pH of 5.8-6.6, or treated with microfluidic jets at 30-120 MPa 1-5 times. B3, after standing and aging for 0.5-4 hours, yields a lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate with a median particle size D50 of 80-350 nm and a dispersion index of no more than 0.30.

[0009] Furthermore, the degree of substitution of the L-histidine amidated sodium hyaluronate intermediate is 5-15 mol%, and the molecular weight of the sodium hyaluronate is 2 × 10⁻⁶. 5 -1.8×10 6 .

[0010] Furthermore, the median particle size (D50) of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate is 100-250 nm, and the polymerization dispersion index is not greater than 0.20.

[0011] Furthermore, the pH value of the gel is 6.0-6.5.

[0012] Furthermore, the mass ratio of the L-histidine amidated sodium hyaluronate intermediate to the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate is 1:0.5-4.

[0013] Furthermore, the mass ratio of lincomycin hydrochloride to lidocaine hydrochloride added is 1:0.6-1.0.

[0014] Furthermore, it also includes 0.05-0.40 parts by weight of 2-hydroxypropyl-β-cyclodextrin, and the purified water is made up to 100 parts by weight.

[0015] As a concept of this invention, a composite gel design is employed, synergistically constructed with lidocaine hydrochloride, L-histidine-amiditized sodium hyaluronate intermediate, and a lidocaine hydrochloride-L-histidine-amiditized sodium hyaluronate ionic microgel intermediate. This design primarily enhances the retention and controlled-release performance, rapid onset of action, and dispersion stability of the local drug delivery system. Lincomycin hydrochloride provides local antibacterial function, while the separately added lidocaine hydrochloride facilitates the rapid establishment of an available drug concentration at the initial stage of administration. The lidocaine hydrochloride-L-histidine-amiditized sodium hyaluronate ionic microgel intermediate forms a nanoscale drug storage structure through ionic interactions, promoting a more gradual release of lidocaine at the lesion site. Simultaneously, the separately added L-histidine-amiditized sodium hyaluronate intermediate and hydroxypropyl methylcellulose participate in the gel network construction, maintaining system homogeneity while avoiding excessive thickening. Thus, the gel achieves a comprehensive improvement in local antibacterial, analgesic, retention, and stability without sacrificing mixing homogeneity and filling compatibility.

[0016] This invention also discloses a method for preparing lincomycin lidocaine gel, comprising the following steps: S1 provides an L-histidine amidated sodium hyaluronate intermediate with a degree of substitution of 3-18 mol% obtained by coupling sodium hyaluronate with L-histidine in the form of free base via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide. S2, the L-histidine amidated sodium hyaluronate intermediate obtained in S1 was prepared into an aqueous dispersion system with a concentration of 0.05-1.00wt%. Lidocaine hydrochloride was added at a mass ratio of 10-60:100 to lidocaine hydrochloride. Under the conditions of pH 5.8-6.6, the mixture was sheared at 3000-12000 r / min for 5-30 min, or treated with microfluidic jet at 30-120 MPa 1-5 times. After standing and aging for 0.5-4 h, lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ionic microgel intermediate was obtained. S3, add 0.20-2.00 parts by weight of hydroxypropyl methylcellulose to a portion of purified water, and swell at 15-35℃ for 0.5-6 hours to obtain a gel-based solution; S4, dissolve 0.045-0.060 parts by weight of lincomycin hydrochloride in some purified water and then add it to the gel base solution obtained in S3; S5, add 1.0-12.0 parts by weight of glycerol and 0.05-0.80 parts by weight of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate obtained in S2 to the system obtained in S4, as well as 0.035-0.050 parts by weight of lidocaine hydrochloride and 0.10-1.20 parts by weight of the L-histidine amidated sodium hyaluronate ion microgel intermediate, respectively; wherein, the amount of lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate added is based on the ratio of lidocaine hydrochloride to L... Based on the total mass of histidine-amiditized sodium hyaluronate, when the formulation contains 2-hydroxypropyl-β-cyclodextrin, add 0.05-0.40 parts by weight of 2-hydroxypropyl-β-cyclodextrin; then add purified water to 100 parts by weight, mix and homogenize at 500-3000 r / min for 10-40 min, degas under vacuum of 0.03-0.09 MPa for 5-20 min, and fill into single-dose tubular or pump-type packages at 10-30℃ to obtain lincomycin lidocaine gel with a pH of 5.8-6.8.

[0017] Furthermore, the lidocaine hydrochloride added separately is distinguished from the lidocaine hydrochloride contained in the ion microgel intermediate, and the L-histidine amidated sodium hyaluronate added separately is distinguished from the L-histidine amidated sodium hyaluronate contained in the ion microgel intermediate.

[0018] Furthermore, the amount of ion microgel intermediate added is based on the total mass of lidocaine hydrochloride and L-histidine amidated sodium hyaluronate contained therein.

[0019] Furthermore, the degree of substitution is calculated based on the molar amount of sodium hyaluronate carboxyl groups.

[0020] Furthermore, the molecular weight of the sodium hyaluronate is the weight-average molecular weight Mw, expressed in Da.

[0021] Furthermore, the degree of substitution was determined using hydrogen nuclear magnetic resonance (NMR).

[0022] Furthermore, the median particle size D50 was determined using laser particle size distribution method, and the aggregation and dispersion index was determined using dynamic light scattering method.

[0023] Furthermore, in steps A1, B2, and the final preparation process, pH adjustment is performed using 0.1-1 mol / L hydrochloric acid solution or sodium hydroxide solution.

[0024] Furthermore, the L-histidine added in step A2 is in the form of a free base.

[0025] Furthermore, in step A3, dialysis is performed using a dialysis bag with a molecular weight cutoff of 3500-14000 Da, or ultrafiltration is performed using an ultrafiltration membrane with a molecular weight cutoff of 3000-10000 Da.

[0026] Furthermore, in step A3, the freeze-drying process involves pre-freezing at -40°C to -20°C for 2-8 hours, and the vacuum degree during freeze-drying is less than 0.00002 MPa.

[0027] Furthermore, in step B3, the intermediate is aged at 10-30°C for 0.5-4 hours. The resulting ionic microgel intermediate is formed by the ionic interaction between lidocaine hydrochloride and L-histidine amidated sodium hyaluronate intermediate.

[0028] Furthermore, in step S4, lincomycin hydrochloride is dissolved in purified water accounting for 5-20% of the total purified water volume and then added to the gel base solution.

[0029] Furthermore, when the formulation contains 2-hydroxypropyl-β-cyclodextrin, the 2-hydroxypropyl-β-cyclodextrin and lidocaine hydrochloride are pre-mixed and then added to the system.

[0030] As another concept of the present invention, the present invention adopts a step-by-step preparation design of "preconstruction of L-histidine amidated sodium hyaluronate intermediate - formation of lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate - preparation of gel base liquid - final homogenization and degassing", which is mainly used to enhance the structural controllability, batch-to-batch consistency and industrial processing adaptability of lincomycin lidocaine gel. By first constructing an L-histidine amidated sodium hyaluronate intermediate, and then forming a lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ionic microgel intermediate under controlled pH conditions, the disorderly competition between the drug and the carrier during the final formulation process can be reduced, and the stability of the nano-dispersion state can be improved. Subsequently, a gel base liquid is formed with hydroxypropyl methylcellulose, and lincomycin hydrochloride, glycerol, lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ionic microgel intermediate, lidocaine hydrochloride and L-histidine amidated sodium hyaluronate intermediate are introduced in sequence. This helps to maintain the local residence, controlled release and rapid onset of action of the finished product while ensuring uniform mixing, smooth defoaming and filling operability.

[0031] The separately added lidocaine hydrochloride focuses on rapidly establishing a locally available drug concentration at the initial stage of administration, directly improving the onset of action and early analgesia. The lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate focuses on forming a stable drug storage structure through ion interactions and nanoscale dispersion, which is more crucial for improving local retention, delaying release, and inhibiting aggregation and stratification. The former addresses the issue of "timely onset of action," while the latter addresses the issue of "durability of action and system stability." When the two work synergistically in the same gel network, the risk of instability caused by simply increasing the proportion of separately added lidocaine hydrochloride or simply increasing matrix viscosity can be reduced, resulting in a more balanced unity of rapid onset of action, sustained analgesia, and formulation processability.

[0032] Beneficial technical effects 1. By forming a synergistic delivery relationship between lidocaine hydrochloride and lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate, the gel can rapidly provide available local anesthetic drugs in the early stage of drug administration, while relying on the ion microgel intermediate to achieve subsequent slow release, thus taking into account both rapid analgesia and sustained effect.

[0033] 2. By adding L-histidine amidated sodium hyaluronate intermediate, lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate, and hydroxypropyl methylcellulose to construct a composite network, the formulation can form a more stable coating layer on the local surface, which is beneficial to improving lesion retention and local effective utilization of lincomycin hydrochloride.

[0034] 3. By synergistically controlling the formation conditions of ionic microgels and the final pH, the system is more likely to maintain a uniform nanoscale dispersion, which can reduce the risk of aggregation and stratification and uneven storage, and improve the appearance consistency, dispersion stability and long-term reliability of the finished product.

[0035] 4. By distributing local residence, controlled release, and rheological regulation to different structural units, this invention can achieve comprehensive performance without simply relying on increasing matrix viscosity. Therefore, it is more conducive to mixing and homogenization, degassing, filling, and scale-up production, and combines formulation performance with process adaptability. Attached Figure Description

[0036] Figure 1 The image shows the infrared spectra of three samples from Example 1, Comparative Example 9, and Comparative Example 3.

[0037] Figure 2 These are magnified images of the fingerprint areas of Example 1, Comparative Example 9, and Comparative Example 3.

[0038] Figure 3 The image shows the particle size distribution overlays of Example 1, Comparative Example 2, and Comparative Example 4.

[0039] Figure 4 The cumulative particle size distribution diagrams are for Example 1, Comparative Example 2, and Comparative Example 4.

[0040] Figure 5 The scatter plots of D50 and PDI dual Y-axis are for Example 1, Comparative Example 2, and Comparative Example 4.

[0041] Figure 6 The above is a superimposed graph of the upward and downward flow curves of Example 1, Comparative Example 8, and Comparative Example 9.

[0042] Figure 7 The graphs show the retention rates of Example 1, Comparative Example 8, and Comparative Example 9.

[0043] Figure 8 The graphs show the transmittance of Example 1, Comparative Example 8, and Comparative Example 9.

[0044] Figure 9 This is a superimposed diagram of the DSC heat flow curves of Example 1 and Comparative Example 10.

[0045] Figure 10 The image shows a comparison of the characteristic peak integrals of Example 1 and Comparative Example 10.

[0046] Figure 11 This is a composite image of the 0-30 min local magnification release curves of Example 1 and Comparative Example 10.

[0047] Figure 12 The image shows the initial slope fitting plots for Example 1 and Comparative Example 10.

[0048] Figure 13 Macroscopic photograph of the lincomycin lidocaine gel prepared in Example 1.

[0049] Figure 14 Scanning electron microscope image of the lincomycin lidocaine gel freeze-dried sample prepared in Example 1.

[0050] Figure 14 (a) is a low-magnification scanning electron microscope image of the lincomycin lidocaine gel freeze-dried sample prepared in Example 1.

[0051] Figure 14 (b) is a scanning electron microscope image of the lympic lincomycin lidocaine gel freeze-dried sample prepared in Example 1.

[0052] Figure 14 (c) is a scanning electron microscope image of the lympic lincomycin lidocaine gel freeze-dried sample prepared in Example 1.

[0053] Figure 14 (d) is a high-power scanning electron microscope image of the lincomycin lidocaine gel freeze-dried sample prepared in Example 1.

[0054] Figure 15 Transmission electron microscopy image of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate prepared in step B3 of Example 1.

[0055] Figure 15 (a) is a bright-field transmission electron microscopy image of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate prepared in step B3 of Example 1.

[0056] Figure 15 (b) is a high-resolution transmission electron microscopy image of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate prepared in step B3 of Example 1.

[0057] Figure 15 (c) is a high-resolution transmission electron microscopy image of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate prepared in step B3 of Example 1.

[0058] Figure 15 (d) is the selected area electron diffraction pattern of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate prepared in step B3 of Example 1. Detailed Implementation

[0059] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0060] Example 1 I. Preparation of L-histidine amidated sodium hyaluronate intermediate A1. The weight-average molecular weight Mw is 2 × 10⁻⁶. 5 Sodium hyaluronate was prepared into an aqueous solution with a concentration of 0.20 wt%. 100 parts by weight of sodium hyaluronate were added to 2 parts by weight of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1 part by weight of N-hydroxysuccinimide. The pH value was adjusted to 4.7 with 0.1 mol / L hydrochloric acid solution and activated at 2℃ for 10 min. A2. Add L-histidine in the form of free base to the activation system obtained in A1, the amount of which is 3 parts by weight based on sodium hyaluronate, and react at 15°C for 2 hours. A3. After removing small molecules by dialysis using a dialysis bag with a molecular weight cutoff of 3500 Da, the product was pre-frozen at -40℃ for 2 hours and then freeze-dried under a vacuum of less than 0.00002 MPa to obtain an L-histidine amidated sodium hyaluronate intermediate with a degree of substitution of 3 mol%. The degree of substitution was determined by proton nuclear magnetic resonance (NMR) and calculated based on the molar amount of the carboxyl group in sodium hyaluronate.

[0061] II. Preparation of lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate B1. Prepare an aqueous dispersion system with a concentration of 0.05 wt% using the L-histidine amidated sodium hyaluronate intermediate obtained in step A3, and add lidocaine hydrochloride at a mass ratio of 10:100 to lidocaine hydrochloride. B2. The pH of the system obtained in B1 was adjusted to 5.8 using 0.1 mol / L sodium hydroxide solution, and then sheared at 3000 r / min for 5 min. B3. After standing and aging at 10℃ for 0.5 h, a lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate with a median volumetric particle size (D50) of 80 nm and a dispersion index of 0.30 was obtained. The median volumetric particle size (D50) was determined by laser particle size distribution, and the dispersion index was determined by dynamic light scattering. The ion microgel intermediate obtained in this example was formed by the ionic interaction between lidocaine hydrochloride and the L-histidine amidated sodium hyaluronate intermediate.

[0062] III. Preparation of Lincomycin Lidocaine Gel S3. Add 0.20 parts by weight of hydroxypropyl methylcellulose to a portion of purified water and swell at 15°C for 0.5 h to obtain a gel-based solution; S4. Dissolve 0.045 parts by weight of lincomycin hydrochloride in purified water accounting for 5% of the total amount of purified water, and then add it to the gel base solution obtained in S3. S5. Add 1.0 parts by weight of glycerol and 0.05 parts by weight of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate obtained in step B3 to the system obtained in S4, along with 0.035 parts by weight of lidocaine hydrochloride and 0.10 parts by weight of the L-histidine amidated sodium hyaluronate intermediate, and simultaneously add 0.05 parts by weight of 2-hydroxypropyl-β-cyclodextrin. In this embodiment, the lidocaine hydrochloride added separately is distinguished from the lidocaine hydrochloride contained in the ion microgel intermediate, and the L-histidine amidated sodium hyaluronate intermediate added separately is distinguished from the L-histidine amidated sodium hyaluronate contained in the ion microgel intermediate. The amount of the ion microgel intermediate added is based on the total mass of lidocaine hydrochloride and L-histidine amidated sodium hyaluronate contained therein. Purified water was then added to bring the total weight to 100 parts, and the mixture was homogenized at 500 rpm for 10 min. The pH was adjusted to 5.8 using 0.1 mol / L hydrochloric acid solution or sodium hydroxide solution. The mixture was degassed under a vacuum of 0.03 MPa for 5 min and then filled into single-dose tubular packages at 10°C to obtain lincomycin lidocaine gel with a pH of 5.8.

[0063] Features of Example 1: This example uses a design scheme close to the lower limit of the range of each formulation component. The amounts of 0.045 parts by weight of lincomycin hydrochloride, 0.035 parts by weight of lidocaine hydrochloride, 0.10 parts by weight of L-histidine amidated sodium hyaluronate intermediate, 0.05 parts by weight of ion microgel intermediate, 0.20 parts by weight of hydroxypropyl methylcellulose, and 1.0 part by weight of glycerol are all in the low range. The intermediate preparation process also uses conditions biased towards the lower limit, including a sodium hyaluronate molecular weight of 2 × 10⁻⁶. 5 The process involved a 3 mol% substitution degree, a low concentration of 0.20 wt% aqueous solution, a low amount of coupling agent, activation at 2°C, a short activation time of 10 min, and a 2-hour reaction. Ionic microgels were prepared using a low concentration of 0.05 wt% dispersion system, a low mass ratio of 10:100, a low pH of 5.8, low shearing at 3000 rpm for 5 min, and a short aging time of 0.5 h, resulting in microgels with a small particle size of 80 nm and a high polymerization dispersion index of 0.30. The final formulation process involved swelling at 15°C for 0.5 h, homogenization at 500 rpm for 10 min, degassing under low vacuum of 0.03 MPa for 5 min, and filling at 10°C, achieving a final pH of 5.8. This embodiment is suitable for applications requiring low irritation and a gentle formulation, such as the treatment of mild inflammation in sensitive skin.

[0064] Example 2 I. Preparation of L-histidine amidated sodium hyaluronate intermediate A1. The weight-average molecular weight Mw is 1.8 × 10⁻⁶. 6 Sodium hyaluronate was prepared into an aqueous solution with a concentration of 1.00 wt%. 100 parts by weight of sodium hyaluronate were added to 20 parts by weight of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 12 parts by weight of N-hydroxysuccinimide. The pH value was adjusted to 6.0 with 0.5 mol / L hydrochloric acid solution and activated at 10℃ for 30 min. A2. Add L-histidine in the form of free base to the activation system obtained in A1. The amount of L-histidine is 25 parts by weight based on sodium hyaluronate. React at 30°C for 12 hours. A3. After removing small molecules using an ultrafiltration membrane with a molecular weight cutoff of 14000 Da, the product was pre-frozen at -20℃ for 8 hours and then freeze-dried under a vacuum of less than 0.00002 MPa to obtain an L-histidine-substituted sodium hyaluronate intermediate with a degree of substitution of 18 mol%. The degree of substitution was determined by proton nuclear magnetic resonance (NMR) and calculated based on the molar amount of the carboxyl group in sodium hyaluronate.

[0065] II. Preparation of lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate B1. Prepare an aqueous dispersion system with a concentration of 1.00 wt% using the L-histidine amidated sodium hyaluronate intermediate obtained in step A3, and add lidocaine hydrochloride at a mass ratio of 60:100 to lidocaine hydrochloride. B2. The pH of the system obtained in B1 was adjusted to 6.6 using 1 mol / L sodium hydroxide solution, and then treated 5 times with a microfluidic jet at 120 MPa. B3. After standing and aging at 30℃ for 4 hours, a lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate with a median volumetric particle size (D50) of 350 nm and a dispersion index of 0.28 was obtained. The median volumetric particle size (D50) was determined by laser particle size distribution, and the dispersion index was determined by dynamic light scattering. The ion microgel intermediate obtained in this example was formed by the ionic interaction between lidocaine hydrochloride and the L-histidine amidated sodium hyaluronate intermediate.

[0066] III. Preparation of Lincomycin Lidocaine Gel S3. Add 2.00 parts by weight of hydroxypropyl methylcellulose to a portion of purified water and swell at 35°C for 6 hours to obtain a gel-based solution; S4. Dissolve 0.060 parts by weight of lincomycin hydrochloride in purified water that accounts for 20% of the total amount of purified water, and then add it to the gel base solution obtained in S3. S5. Add 12.0 parts by weight of glycerol and 0.80 parts by weight of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate obtained in step B3 to the system obtained in S4, along with 0.050 parts by weight of lidocaine hydrochloride and 1.20 parts by weight of the L-histidine amidated sodium hyaluronate intermediate. Simultaneously, add 0.40 parts by weight of 2-hydroxypropyl-β-cyclodextrin to the system after pre-mixing with the lidocaine hydrochloride. In this embodiment, the lidocaine hydrochloride added separately is distinguished from the lidocaine hydrochloride contained in the ion microgel intermediate, and the L-histidine amidated sodium hyaluronate intermediate added separately is distinguished from the L-histidine amidated sodium hyaluronate contained in the ion microgel intermediate. The amount of the ion microgel intermediate added is based on the total mass of lidocaine hydrochloride and L-histidine amidated sodium hyaluronate contained therein. Purified water was then added to bring the total weight to 100 parts, and the mixture was homogenized at 3000 r / min for 40 min. The pH was adjusted to 6.8 using 1 mol / L hydrochloric acid solution or sodium hydroxide solution. The mixture was degassed under a vacuum of 0.09 MPa for 20 min and then filled into pump-type packaging at 30°C to obtain lincomycin lidocaine gel with a pH of 6.8.

[0067] Features of Example 2: This embodiment employs an optimized design close to the upper limit of the range for each formulation component. The components—0.060 parts by weight of lincomycin hydrochloride, 0.050 parts by weight of lidocaine hydrochloride, 1.20 parts by weight of L-histidine amidated sodium hyaluronate intermediate, 0.80 parts by weight of ion microgel intermediate, 2.00 parts by weight of hydroxypropyl methylcellulose, 12.0 parts by weight of glycerol, and 0.40 parts by weight of 2-hydroxypropyl-β-cyclodextrin—are all within the high-range of their respective values, and the mass ratio of cyclodextrin to lidocaine hydrochloride reaches 8:1. The intermediates were prepared using high molecular weight 1.8 × 10⁻⁶... 6 Sodium hyaluronate, a high-substitution-degree (18 mol%), a high-concentration (1.00 wt%) aqueous solution, a high amount of coupling agent, a relatively high pH of 6.0, and activation at 10°C for 30 min, followed by a reaction at 30°C for 12 h. Ionic microgels were prepared using a high-concentration (1.00 wt%) dispersion system, a mass ratio of 60:100, a high pH of 6.6, five cycles of high-pressure (120 MPa) microfluidic treatment, and a long aging time of 4 h, resulting in microgels with a relatively large particle size of 350 nm and an oligomerization dispersion index of 0.28. The final formulation process involved swelling at 35°C for 6 h, homogenization at 3000 r / min for 40 min, degassing at 0.09 MPa for 20 min, and filling at 30°C, achieving a final pH of 6.8. This embodiment is suitable for applications requiring high drug loading and potent anti-inflammatory and analgesic effects, such as the treatment of moderate to severe skin infections accompanied by pain.

[0068] Example 3 I. Preparation of L-histidine amidated sodium hyaluronate intermediate: A1. Prepare intermediates with a weight-average molecular weight Mw of 8 × 10⁻⁶. 5 Sodium hyaluronate was prepared into an aqueous solution with a concentration of 0.60 wt%. 100 parts by weight of sodium hyaluronate were added to 12 parts by weight of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 6 parts by weight of N-hydroxysuccinimide. The pH value was adjusted to 5.5 with 0.5 mol / L hydrochloric acid solution and activated at 6℃ for 20 min. A2. Add L-histidine in the form of free base to the activation system obtained in A1. The amount of L-histidine is 15 parts by weight based on sodium hyaluronate. React at 25°C for 6 hours. A3. After removing small molecules by dialysis using a dialysis bag with a molecular weight cutoff of 10000 Da, the intermediate was pre-frozen at -30℃ for 4 hours and then freeze-dried under a vacuum of less than 0.00002 MPa to obtain an L-histidine amidated sodium hyaluronate intermediate with a degree of substitution of 15 mol%. The degree of substitution was determined by proton nuclear magnetic resonance (NMR) and calculated based on the molar amount of the carboxyl group in sodium hyaluronate.

[0069] II. Preparation of lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate B1. Prepare an aqueous dispersion system with a concentration of 0.50 wt% using the L-histidine amidated sodium hyaluronate intermediate obtained in step A3, and add lidocaine hydrochloride at a mass ratio of 35:100 to lidocaine hydrochloride. B2. The pH of the system obtained in B1 was adjusted to 6.2 using 0.5 mol / L sodium hydroxide solution, and sheared at 12000 r / min for 30 min. B3. After standing and aging at 20℃ for 2 hours, a lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate with a median volumetric particle size (D50) of 100 nm and a dispersion index of 0.20 was obtained. The median volumetric particle size (D50) was determined by laser particle size distribution, and the dispersion index was determined by dynamic light scattering. The ion microgel intermediate obtained in this example was formed by the ionic interaction between lidocaine hydrochloride and the L-histidine amidated sodium hyaluronate intermediate.

[0070] III. Preparation of Lincomycin Lidocaine Gel S3. Add 1.00 parts by weight of hydroxypropyl methylcellulose to a portion of purified water and swell at 25°C for 3 hours to obtain a gel-based solution; S4. Dissolve 0.050 parts by weight of lincomycin hydrochloride in purified water that accounts for 10% of the total amount of purified water, and then add it to the gel base solution obtained in S3. S5. Add 6.0 parts by weight of glycerol and 0.80 parts by weight of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate obtained in step B3 to the system obtained in S4, as well as 0.050 parts by weight of lidocaine hydrochloride and 0.20 parts by weight of the L-histidine amidated sodium hyaluronate intermediate. In this embodiment, the lidocaine hydrochloride added separately is different from the lidocaine hydrochloride contained in the ion microgel intermediate, and the L-histidine amidated sodium hyaluronate intermediate added separately is different from the L-histidine amidated sodium hyaluronate contained in the ion microgel intermediate. The amount of the ion microgel intermediate added is based on the total mass of lidocaine hydrochloride and L-histidine amidated sodium hyaluronate contained therein. Purified water was then added to bring the total weight to 100 parts, and the mixture was homogenized at 1500 r / min for 25 min. The pH was adjusted to 6.0 using 0.5 mol / L hydrochloric acid solution or sodium hydroxide solution. The mixture was degassed under a vacuum of 0.06 MPa for 12 min and then filled into single-dose tubular packages at 20°C to obtain lincomycin lidocaine gel with a pH of 6.0.

[0071] Features of Example 3: This example is suitable for applications requiring fine particle size control and highly uniform microgel systems, such as inflammatory analgesia treatment with precise release control.

[0072] Example 4 I. Preparation of L-histidine amidated sodium hyaluronate intermediate: A1. Prepare intermediates with a weight-average molecular weight Mw of 5 × 10⁻⁶. 5 Sodium hyaluronate was prepared into an aqueous solution with a concentration of 0.40 wt%. 100 parts by weight of sodium hyaluronate were added to 8 parts by weight of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4 parts by weight of N-hydroxysuccinimide. The pH value was adjusted to 5.2 with 0.5 mol / L hydrochloric acid solution and activated at 8℃ for 15 min. A2. Add L-histidine in the form of free base to the activation system obtained in A1, the amount of which is 10 parts by weight based on sodium hyaluronate, and react at 22°C for 8 hours. A3. After removing small molecules using an ultrafiltration membrane with a molecular weight cutoff of 10000 Da, the product was pre-frozen at -30℃ for 5 hours and then freeze-dried under a vacuum of less than 0.00002 MPa to obtain an L-histidine amidated sodium hyaluronate intermediate with a degree of substitution of 5 mol%. The degree of substitution was determined by proton nuclear magnetic resonance (NMR) and calculated based on the molar amount of the carboxyl group in sodium hyaluronate.

[0073] II. Preparation of lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate B1. Prepare an aqueous dispersion system with a concentration of 0.30 wt% for the L-histidine amidated sodium hyaluronate intermediate obtained in step A3, and add lidocaine hydrochloride at a mass ratio of 25:100 to lidocaine hydrochloride. B2. The pH of the system obtained in B1 was adjusted to 6.0 using 0.5 mol / L sodium hydroxide solution, and then treated once with a microfluidic jet at 30 MPa. B3. After standing and aging at 20℃ for 1 hour, a lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate with a median volumetric particle size (D50) of 250 nm and a dispersion index of 0.15 was obtained. The median volumetric particle size (D50) was determined by laser particle size distribution, and the dispersion index was determined by dynamic light scattering. The ion microgel intermediate obtained in this example was formed by the ionic interaction between lidocaine hydrochloride and the L-histidine amidated sodium hyaluronate intermediate.

[0074] III. Preparation of Lincomycin Lidocaine Gel S3. Add 1.50 parts by weight of hydroxypropyl methylcellulose to a portion of purified water and swell at 22°C for 2 hours to obtain a gel-based solution. S4. Dissolve 0.058 parts by weight of lincomycin hydrochloride in purified water accounting for 12% of the total amount of purified water, and then add it to the gel base solution obtained in S3. S5. Add 8.0 parts by weight of glycerol and 0.20 parts by weight of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate obtained in step B3 to the system obtained in S4, along with 0.035 parts by weight of lidocaine hydrochloride and 0.40 parts by weight of the L-histidine amidated sodium hyaluronate intermediate. Simultaneously, add 0.28 parts by weight of 2-hydroxypropyl-β-cyclodextrin to the lidocaine hydrochloride intermediate after pre-mixing with the lidocaine hydrochloride intermediate. In this embodiment, the lidocaine hydrochloride intermediate added separately is distinguished from the lidocaine hydrochloride contained in the ion microgel intermediate, and the L-histidine amidated sodium hyaluronate intermediate added separately is distinguished from the L-histidine amidated sodium hyaluronate contained in the ion microgel intermediate. The amount of the ion microgel intermediate added is based on the total mass of lidocaine hydrochloride and L-histidine amidated sodium hyaluronate. Purified water was then added to bring the total weight to 100 parts, and the mixture was homogenized at 2000 r / min for 20 min. The pH was adjusted to 6.5 using 0.5 mol / L hydrochloric acid solution or sodium hydroxide solution. The mixture was degassed under a vacuum of 0.05 MPa for 10 min and then filled into single-dose tubular packages at 20°C to obtain lincomycin lidocaine gel with a pH of 6.5.

[0075] Example 4 Features: This example employs a design scheme combining optimized scope and gap filling. The mass ratio of 0.058 parts by weight of lincomycin hydrochloride to 0.035 parts by weight of lidocaine hydrochloride is approximately 1:0.6. The mass ratio of 0.40 parts by weight of L-histidine amidated sodium hyaluronate intermediate to 0.20 parts by weight of ion microgel intermediate is 1:0.5. The intermediate preparation is preferably selected with a lower substitution degree of 5 mol% and a medium molecular weight of 5 × 10⁻⁶. 5 Sodium hyaluronate, moderate concentration, and dosage parameters. The ionic microgel was prepared using a gentle microfluidic treatment at 30 MPa once, resulting in a microgel with a preferred upper limit particle size of 250 nm and an oligomerization dispersion index of 0.15, balancing particle size and distribution uniformity. The final formulation process parameters were moderate, with a final pH of 6.5, which is at the upper limit of the preferred range. This embodiment is suitable for applications requiring a balance between drug loading and mild irritation, and seeking an optimal pH range, such as mild anti-inflammatory and analgesic treatment in daily skin care.

[0076] Comparative Example 1: It is basically the same as Example 1, except that in step A2, the amount of L-histidine used is 1.5 parts by weight based on sodium hyaluronate, and the reaction is carried out at 15°C for 2 hours. In step A3, L-histidine amidated sodium hyaluronate intermediate with a degree of substitution of 1 mol% is obtained, and other conditions remain unchanged.

[0077] Comparative Example 2: It is basically the same as Example 1, except that in step B1, lidocaine hydrochloride is added at a mass ratio of 70:100 to lidocaine hydrochloride and L-histidine amidated sodium hyaluronate intermediate, while other conditions remain unchanged.

[0078] Comparative Example 3: It is basically the same as Example 1, except that the pH value is adjusted to 5.4 in step B2, while other conditions remain unchanged.

[0079] Comparative Example 4: Basically the same as Example 1, except that in step B2, the shearing was performed at 1500 r / min for 5 min, while other conditions remained unchanged.

[0080] Comparative Example 5: It is basically the same as Example 1, except that the amount of hydroxypropyl methylcellulose added in step S3 is 0.10 parts by weight, and other conditions remain unchanged.

[0081] Comparative Example 6: It is basically the same as Example 1, except that 0.060 parts by weight of lidocaine hydrochloride is added in step S5, and other conditions remain unchanged.

[0082] Comparative Example 7: Basically the same as Example 1, except that the pH value of the gel was adjusted to 7.2 at the end of step S5, while other conditions remained unchanged.

[0083] Comparative Example 8: This example is essentially the same as Example 1, except that in step S5, 0.10 parts by weight of the separately added L-histidine amidated sodium hyaluronate intermediate are not added; only 0.05 parts by weight of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate are retained. Other conditions remain unchanged. This comparative example is used to verify the synergistic effect of the separately added L-histidine amidated sodium hyaluronate intermediate and the ion microgel intermediate.

[0084] Comparative Example 9: Essentially the same as Example 1, except that in step S5, 0.05 parts by weight of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate were not added; only 0.10 parts by weight of the L-histidine amidated sodium hyaluronate intermediate and 0.035 parts by weight of lidocaine hydrochloride were retained, with other conditions unchanged. This comparative example was used to verify the synergistic effect of the separately added L-histidine amidated sodium hyaluronate intermediate and the ion microgel intermediate.

[0085] Comparative Example 10: Essentially the same as Example 1, except that in step S5, 0.05 parts by weight of 2-hydroxypropyl-β-cyclodextrin was replaced with 0.05 parts by weight of β-cyclodextrin, while other conditions remained unchanged. This comparative example was used to verify the synergistic effect of 2-hydroxypropyl-β-cyclodextrin and lidocaine hydrochloride, which were added separately.

[0086] Performance testing: The lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate and final gel diluent obtained in step B3 were analyzed using laser diffraction inversion volume distribution to verify the nanoscale D50 and particle size drift after storage. Samples were diluted with purified water to a suitable opacity and then circulated for dispersion. D10, D50, and D90 were measured at 25℃, with each sample repeated three times. The final output was the mean ± standard deviation of D50 and the 30-day particle size retention rate.

[0087] The hydrodynamic particle size and distribution width of the aqueous dispersion system of the ion-microgel intermediate were determined using dynamic light scattering (DLS) to evaluate the uniformity of PDI and submicron dispersion. After 0.22 μm pre-filtration, the samples were equilibrated at 25 °C. Z-average and PDI were continuously measured at a scattering angle of 173°, with each sample measured three times. The mean ± standard deviation of PDI was output, and a dispersion stability threshold was established.

[0088] The final lincomycin lidocaine gel was prepared, and the shear rate-apparent viscosity relationship was obtained through rotational viscosity testing to evaluate its low viscosity, wide processing window, shear thinning behavior, and recovery ability. Samples that had been standing for 5 minutes at 25°C were subjected to rotational viscosity tests ranging from 0.1 to 50 seconds. -1 Up / down scan, record for 10 seconds -1 Apparent viscosity, thixotropic ring area, and recovery rate were measured three times for each sample. The mean ± standard deviation was output, and the homogeneity and filling fit range were determined.

[0089] The rapid onset and controlled release levels of lidocaine hydrochloride and lincomycin hydrochloride in the final gel were evaluated using an in vitro drug release method with a vertical diffusion cell. The experiment used a Franz diffusion cell and a regenerated cellulose membrane. Under constant dosage, diffusion area, and stirring rate at 37°C, samples were taken at regular intervals up to 8 hours, and the concentrations of both drugs were measured simultaneously. The experiment was repeated 6 times, and the cumulative release rates at 0.5 hours and 8 hours were calculated, and release curves were plotted.

[0090] The distribution behavior of the final gel on isolated skin was evaluated by quantifying transdermal drug transport and intradermal retention within a diffusion cell, assessing local retention capacity and transdermal migration trend. Ex vivo porcine skin was used in a Franz cell at 32°C with a concentration of 5 mg / cm³. 2 Twenty-four hours after administration, the amount of drug in the receptor fluid, skin flushing fluid, and skin tissue was measured, and the results were repeated six times. The 24-hour skin retention and cumulative permeation were output and analyzed in conjunction with the drug release data.

[0091] The time-kill method was used to compare the changes in viable bacterial count before and after contact in the gel eluent and drug-bacterial contact system to evaluate the sustained antibacterial ability in a long-acting analgesic and antibacterial setting. Staphylococcus aureus and Propionibacterium acnes were sampled and counted at 0.5, 2, and 8 hours, with the initial bacterial count controlled at 10⁻⁶. 5 -106 CFU / mL, incubated at 37℃, repeated 3 times, output log decrease value and plot bactericidal kinetic curve.

[0092] The finished gel was evaluated for particle size, pH, viscosity, and release consistency over its shelf life according to long-term / accelerated stability testing protocols. D50, PDI, pH, and 10s were measured at fixed points at 0, 1, 2, and 3 months under both long-term (25℃ / 60%RH) and accelerated (40℃ / 75%RH) conditions. -1 Apparent viscosity and 0.5-hour release rate were measured, and each measurement was repeated three times to calculate retention rate, slope of change, and instability warning point.

[0093] Figure 1 The superimposed infrared spectra of three samples from Example 1, Comparative Example 9, and Comparative Example 3 are shown. Fourier transform infrared spectroscopy was used to characterize the overall chemical processes of the samples. Compared to Comparative Example 9, which lacked the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate, and Comparative Example 3, where the pH of ion microgel formation deviated to 5.4, Example 1 showed more coordinated changes in the absorption bands of the carboxyl group, amide group, and broad peak region. This indicates that under pH 5.8 conditions, lidocaine hydrochloride and the L-histidine amidated sodium hyaluronate intermediate can form more stable ionic and hydrogen bonding interactions, which is the basis for obtaining a stable ion microgel structure.

[0094] Figure 2 The images shown are magnified views of the fingerprint regions in Examples 1, 9, and 3. Fourier transform infrared spectroscopy was used to perform local analysis of the characteristic peaks in the fingerprint regions. Figure 1 Based on the confirmation of the existence of overall interaction, Example 1 showed more consistent synergistic characteristics in terms of characteristic peak shift, peak shape change and relative intensity, while Comparative Example 9 was closer to simple superposition, and Comparative Example 3 had insufficient association due to pH deviation. This indicates that the ion association in this scheme is not an accidental mixing effect, but a stable assembly process regulated by the pH window.

[0095] Figure 3 The particle size distribution overlays for Examples 1, 2, and 4 are shown. The particle size and volume distribution of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate were determined using laser particle size distribution method. In Example 1, when the mass ratio of lidocaine hydrochloride to L-histidine amidated sodium hyaluronate intermediate was 10:100 and the shearing speed was 3000 r / min, the main distribution peak was located in the nanoscale region. However, in Comparative Example 2, when the drug loading ratio was increased to 70:100, and in Comparative Example 4, when the shearing speed was reduced to 1500 r / min, the distribution peak shifted significantly to the right and broadened. This indicates that a reasonable drug loading ratio and sufficient shear strength are key conditions for the formation of stable nanoscale ion microgels.

[0096] Figure 4The cumulative particle size distribution diagrams for Example 1, Comparative Example 2, and Comparative Example 4 are shown. The cumulative volume distribution of particle size was analyzed using laser particle size analysis. The cumulative curve for Example 1 shows a steeper rise and a more prominent median particle size, indicating better particle size concentration. The cumulative rise intervals for Comparative Example 2 and Comparative Example 4 are significantly wider, reflecting dispersed particle distribution and insufficient system homogeneity. These results further demonstrate that this scheme does not merely pursue small particle size, but achieves a balance between particle size concentration and stable dispersion under controlled process conditions.

[0097] Figure 5 The scatter plots of D50 and PDI along the dual Y-axis for Examples 1, 2, and 4 are shown. D50 and PDI were measured using laser particle size distribution and dynamic light scattering methods, respectively. In Example 1, the D50 was 80±4 nm and the PDI was 0.30±0.01, falling within the nanoscale dispersion range required by this scheme. In Comparative Examples 2 and 4, the D50 increased to 460±22 nm and 520±25 nm, respectively, and the PDI increased to 0.48±0.03 and 0.52±0.03, respectively. This demonstrates that the small particle size and good uniformity obtained in Example 1 have a clear process basis, proving that this scheme can stably achieve nanoscale uniform dispersion, rather than being a result of accidental local optimization.

[0098] Figure 6 The image shows a superimposed graph of the upward and downward flow curves of Example 1, Comparative Example 8, and Comparative Example 9. The relationship between shear rate and apparent viscosity was obtained using rotational viscosity testing. The samples were subjected to a rotational viscosity test at 25°C for 0.1-50 s. -1 Scan. Example 1 exhibits clearer shear-thinning behavior, and within 10 seconds... -1 The apparent viscosity remained at 42±3 Pa·s, which was higher than that of the weaker Comparative Examples 8 and 9, but did not enter the high viscosity region that was difficult to homogenize and fill. This indicates that the synergistic effect of the L-histidine amidated sodium hyaluronate intermediate and the ionic microgel intermediate can improve the structural integrity of the system without significantly sacrificing the processing window.

[0099] Figure 7 The retention curves for Example 1, Comparative Example 8, and Comparative Example 9 were obtained by measuring the retention behavior of the samples in the skin using an isolated porcine skin Franz cell at 32°C and 5 mg / cm³. 2 Local retention capacity was assessed under drug administration conditions. Example 1 showed a higher and more stable skin retention trend throughout the entire study period, with a 24-hour skin retention amount reaching 18.5 ± 0.9 μg·cm³. -2 It was significantly higher than that of Comparative Example 8, which was 14.0 ± 0.7 μg·cm⁻¹. -2 Compared with Comparative Example 9, it was 9.6 ± 0.6 μg·cm⁻¹. -2This indicates that retaining only a single structural unit is insufficient to balance coverage and retention, while the dual-unit collaborative network constructed in this scheme is more conducive to the continuous retention of drugs in local tissues.

[0100] Figure 8 The permeation curves for Example 1, Comparative Example 8, and Comparative Example 9 are shown. The transdermal migration behavior of the drug was determined using an ex vivo porcine skin Franz cell. Compared to the faster migration of free drug in Comparative Example 9 and the limited release of single-ion microgels in Comparative Example 8, the cumulative permeation growth rate of Example 1 was more gradual, demonstrating a better balance between local retention and transdermal migration. These results are consistent with... Figure 7 The evidence corroborates each other, indicating that this approach does not simply delay release, but rather ensures effective local concentration while preventing excessive drug loss.

[0101] Figure 9 The DSC heat flow curves of Example 1 and Comparative Example 10 are overlayed, and the thermal behavior of the samples was characterized by differential scanning calorimetry. Example 1 used 2-hydroxypropyl-β-cyclodextrin, and Comparative Example 10 used β-cyclodextrin; other conditions were essentially the same. Compared to Comparative Example 10, the endothermic characteristic peaks related to lidocaine hydrochloride in Example 1 were significantly weakened and shifted, indicating that 2-hydroxypropyl-β-cyclodextrin can more effectively participate in drug solubilization and microscopic interactions, thereby reducing the proportion of free crystalline drug and providing a structural basis for subsequent early release enhancement.

[0102] Figure 10 The image shows a comparison of the characteristic peak integrals of Example 1 and Comparative Example 10. Differential scanning calorimetry was used to perform integral analysis on the relevant characteristic peaks of lidocaine hydrochloride. Figure 9 Based on the changes in thermal behavior, the characteristic peak integral of Example 1 further decreased, indicating that the dispersion state of lidocaine hydrochloride in the matrix was more reasonable, and the free crystalline portion was further weakened. This result proves that the introduction of 2-hydroxypropyl-β-cyclodextrin is not a simple excipient replacement, but can effectively improve the state of the drug in the system.

[0103] Figure 11 The image shows a superimposed plot of the localized release curves from 0 to 30 minutes for Example 1 and Comparative Example 10. The early cumulative release rate was evaluated using a regenerated cellulose membrane at 37°C using the Franz diffusion cell in vitro drug release method. Example 1 showed more complete release and a smoother curve in the 0-30 minute phase. The cumulative release rate of lidocaine hydrochloride at 0.5 h was 31.2 ± 1.4%, higher than the 24.6 ± 1.2% of Comparative Example 10. This indicates that 2-hydroxypropyl-β-cyclodextrin can increase the early available drug amount without significant burst release, which is beneficial for establishing a faster and more stable initial local drug concentration.

[0104] Figure 12The initial slope fitting plots for Example 1 and Comparative Example 10 show that early release data were used to perform linear fitting on the initial stage and the drug release rates were compared. Example 1 showed a higher and more stable fitting slope, indicating that it could enhance the initial drug release driving force while maintaining the overall stability of the system. Combined with... Figures 9 to 11 This forms a complete chain of evidence, namely that 2-hydroxypropyl-β-cyclodextrin first improves the dispersion and solubility of lidocaine hydrochloride, then translates into better early release performance, ultimately supporting the design goal of this scheme to balance rapid onset of action and subsequent sustained effect.

[0105] Figure 13 The image shows a macroscopic photograph of the lincomycin lidocaine gel prepared in Example 1. The sample is a white, semi-transparent gel with a smooth and uniform surface. No phase separation or precipitation was observed. The sample exhibits good flowability and extrudability, demonstrating that a low-concentration hydroxypropyl methylcellulose combined with an ionic microgel system can form a stable three-dimensional network structure. The vacuum degassing and low-temperature filling process effectively ensures the uniformity and morphological stability of the gel.

[0106] Figure 14 This is a scanning electron microscope image of the lyophilized lincomycin lidocaine gel sample prepared in Example 1. Figure 14 (a) Low-magnification image shows a uniform three-dimensional porous network covering the entire area. Figure 14 The magnified images in (b, c) reveal an irregular pore structure with a pore size distribution ranging from 0.5 to 5 micrometers and nanoparticles attached to the pore wall surface. Figure 14 (d) High magnification images show that spherical ionic microgels are uniformly dispersed in the polymer matrix, proving that low-substitution degree L-histidine amidation modification combined with low-temperature short-time aging process can accurately construct a high-porosity network, avoid excessive aggregation and achieve stable loading of microgels.

[0107] Figure 15 This is a transmission electron microscopy image of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate prepared in step B3 of Example 1. Figure 15 (a) Bright-field plots show uniform spherical particles with a diameter concentrated between 70 and 100 nm. Figure 15 (b, c) The high-resolution images show the characteristics of an amorphous polymer network without obvious lattice fringes. Figure 15 (d) Selected area electron diffraction results show a diffuse halo ring, further confirming the amorphous structure. This demonstrates that electrostatic self-assembly combined with moderate shear mixing at low pH values ​​can form a size-controllable ionic complex nanocarrier, providing a stable nano-reservoir unit for drug sustained release.

[0108] Table 1 Summary of performance of examples and comparative examples As can be seen from the performance of the examples and comparative examples in Table 1, simply reducing the amount of hydroxypropyl methylcellulose or disassembling the synergistic unit can reduce the viscosity of the system, but it will simultaneously weaken the 24-hour skin retention, antibacterial persistence, and particle size retention. Simply increasing the amount of lidocaine hydrochloride or significantly increasing the drug loading ratio of the microgel can increase the release rate by 0.5 h, but it is easy to lead to an increase in D50, an increase in PDI, and a decrease in storage stability. Example 3 achieves the best balance between 100 nm, PDI 0.20, moderate apparent viscosity, high early release, and the highest skin retention. Example 4 shows outstanding performance in terms of lower PDI and higher particle size retention, indicating that the intermediates added separately, the ionic microgel intermediates combined with the free lidocaine / cyclodextrin solubilization combination can simultaneously take into account processing, efficacy, controlled release, and stability.

[0109] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that any equivalent structural transformations made under the concept of the present invention and using the contents of the specification and drawings of the present invention should be covered within the scope of protection of the claims of the present invention.

Claims

1. A lincomycin lidocaine gel, characterized in that, Based on 100 parts by weight, the following are included: 0.045-0.060 parts by weight of lincomycin hydrochloride, 0.035-0.050 parts by weight of lidocaine hydrochloride, 0.10-1.20 parts by weight of L-histidine amidated sodium hyaluronate intermediate, 0.05-0.80 parts by weight of lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate, 0.20-2.00 parts by weight of hydroxypropyl methylcellulose, 1.0-12.0 parts by weight of glycerol, 0.05-0.40 parts by weight of 2-hydroxypropyl-β-cyclodextrin, and purified water to a final volume of 100 parts by weight. The L-histidine-amidated sodium hyaluronate intermediate is obtained by coupling sodium hyaluronate with free base L-histidine via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide, with a degree of substitution of 3-18 mol%; the lidocaine hydrochloride-L-histidine-amidated sodium hyaluronate ion microgel intermediate is formed by mixing the L-histidine-amidated sodium hyaluronate intermediate with lidocaine hydrochloride at pH 5.8-6.6, followed by shearing at 3000-12000 r / min for 5-30 min, or by microfluidic treatment at 30-120 MPa 1-5 times, with a median particle size (D50) of 80-350 nm and a dispersion index not greater than 0.30; the pH of the gel is 5.8-6.

8. The mass ratio of the L-histidine amidated sodium hyaluronate intermediate to lidocaine hydrochloride is 10-60:

100.

2. The lincomycin lidocaine gel according to claim 1, characterized in that, The preparation method of the L-histidine amidated sodium hyaluronate intermediate includes the following steps: A1. Prepare an aqueous solution of sodium hyaluronate with a concentration of 0.20-1.00 wt%. Add 2-20 parts by weight of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-12 parts by weight of N-hydroxysuccinimide to 100 parts by weight of sodium hyaluronate. Activate for 10-30 min at a pH of 4.7-6.0 and a temperature of 2-10℃. A2, add L-histidine in the form of free base to the activation system obtained in A1, the amount of which is 3-25 parts by weight based on sodium hyaluronate, and react at 15-30℃ for 2-12 hours; A3, after removing small molecules by dialysis or ultrafiltration, is freeze-dried to obtain L-histidine amidated sodium hyaluronate intermediate with a degree of substitution of 3-18 mol%.

3. The lincomycin lidocaine gel according to claim 1 or 2, characterized in that, The preparation method of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate includes the following steps: B1. Prepare an aqueous dispersion system with a concentration of 0.05-1.00 wt% for L-histidine amidated sodium hyaluronate intermediate, and add lidocaine hydrochloride at a mass ratio of 10-60:100 to lidocaine hydrochloride intermediate. B2, the system obtained from B1 is subjected to shearing at 3000-12000 r / min for 5-30 min at a pH of 5.8-6.6, or treated with microfluidic jets at 30-120 MPa 1-5 times. B3, after standing and aging for 0.5-4 hours, yields a lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate with a median particle size D50 of 80-350 nm and a dispersion index of no more than 0.

30.

4. The lincomycin lidocaine gel according to claim 1 or 2, characterized in that, The degree of substitution of the L-histidine amidated sodium hyaluronate intermediate is 5-15 mol%, and the molecular weight of the sodium hyaluronate is 2 × 10⁻⁶. 5 -1.8×10 6 .

5. The lincomycin lidocaine gel according to claim 1, characterized in that, The median particle size (D50) of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate is 100-250 nm, and the aggregation dispersibility index is not greater than 0.

20.

6. The lincomycin lidocaine gel according to claim 1, characterized in that, The pH value of the gel is 6.0-6.

5.

7. The lincomycin lidocaine gel according to claim 1, characterized in that, The mass ratio of the L-histidine amidated sodium hyaluronate intermediate to the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate is 1:0.5-4.

8. The lincomycin lidocaine gel according to claim 1, characterized in that, The mass ratio of lincomycin hydrochloride to lidocaine hydrochloride added is 1:0.6-1.

0.

9. A method for preparing lincomycin lidocaine gel as described in any one of claims 1-8, characterized in that, Includes the following steps: S1 provides an L-histidine amidated sodium hyaluronate intermediate with a degree of substitution of 3-18 mol% obtained by coupling sodium hyaluronate with L-histidine in the form of free base via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide. S2, the L-histidine amidated sodium hyaluronate intermediate obtained in S1 was prepared into an aqueous dispersion system with a concentration of 0.05-1.00wt%. Lidocaine hydrochloride was added at a mass ratio of 10-60:100 to lidocaine hydrochloride. Under the conditions of pH 5.8-6.6, the mixture was sheared at 3000-12000 r / min for 5-30 min, or treated with microfluidic jet at 30-120 MPa 1-5 times. After standing and aging for 0.5-4 h, lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ionic microgel intermediate was obtained. S3, add 0.20-2.00 parts by weight of hydroxypropyl methylcellulose to a portion of purified water, and swell at 15-35℃ for 0.5-6 hours to obtain a gel-based solution; S4, dissolve 0.045-0.060 parts by weight of lincomycin hydrochloride in some purified water and then add it to the gel base solution obtained in S3; S5, add 1.0-12.0 parts by weight of glycerol and 0.05-0.80 parts by weight of the lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate obtained in S2 to the system obtained in S4, as well as 0.035-0.050 parts by weight of lidocaine hydrochloride and 0.10-1.20 parts by weight of the L-histidine amidated sodium hyaluronate ion microgel intermediate, respectively; wherein, the amount of lidocaine hydrochloride-L-histidine amidated sodium hyaluronate ion microgel intermediate added is based on the ratio of lidocaine hydrochloride to L... Based on the total mass of histidine-amiditized sodium hyaluronate, when the formulation contains 2-hydroxypropyl-β-cyclodextrin, add 0.05-0.40 parts by weight of 2-hydroxypropyl-β-cyclodextrin; then add purified water to 100 parts by weight, mix and homogenize at 500-3000 r / min for 10-40 min, degas under vacuum of 0.03-0.09 MPa for 5-20 min, and fill into single-dose tubular or pump-type packages at 10-30℃ to obtain lincomycin lidocaine gel with a pH of 5.8-6.8.

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