Medical coupling agent and preparation process thereof

Abstract

The invention relates to the technical field of couplants, and discloses a medical couplant and a preparation process thereof, the medical couplant comprises the following materials by weight: 0.8-1 part of Carbomer, 8-10 parts of glycerin, 5-7 parts of drug-loaded silica core-shell particles, 0.2-0.4 part of sodium hyaluronate, 0.5-1 part of ethylhexylglycerin, 0.1-0.3 part of polysorbate 80, 0.05-0.1 part of disodium ethylene diamine tetraacetate, and 82.5-83.5 parts of deionized water. According to the medical coupling agent and the preparation technology thereof, the gel transparency of the medical coupling agent is improved, and the long-term stability of the medical coupling agent in the storage process is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of coupling agents, and in particular to a medical coupling agent and a preparation process thereof. Background Art

[0002] As a key auxiliary material in ultrasound examination and diagnosis, medical coupling agents play an irreplaceable role in improving ultrasound image quality and ensuring diagnostic accuracy. Their performance directly impacts the effectiveness of ultrasound examinations and the patient experience. With the continuous advancement of medical technology and the increasing application of ultrasound diagnosis, higher requirements are being placed on the performance and preparation of medical coupling agents.

[0003] In actual production, some medical coupling agents exhibit low gel transparency. This is primarily due to uneven dispersion of the carbomer or high levels of impurities in the raw materials. Uneven carbomer dispersion can cause the gel to form tiny particles or clumps, which can affect light transmission and reduce the gel's transparency. Impurities can also interfere with light transmission, making the gel appear turbid. Low transparency not only affects the product's appearance but can also hinder the observation and analysis of ultrasound images. Some medical coupling agents are prone to poor long-term stability during storage, manifesting as changes in gel viscosity, delamination, or decreased preservative performance. This is primarily due to preservative failure or pH fluctuations. While preservatives inhibit microbial growth, their stability is affected by various factors, such as temperature and light. Preservative failure can allow microbial growth in the coupling agent, resulting in poor product quality. pH fluctuations can affect the structure and properties of ingredients like the carbomer, further impacting the gel's stability and viscosity. Coupling agents with poor long-term stability cannot guarantee consistent performance throughout their shelf life, leading to inconvenience and potential risks in clinical use. Based on this, the present invention provides a medical coupling agent and a preparation process thereof. Summary of the Invention

[0004] The purpose of the present invention is to provide a medical coupling agent and a preparation process thereof, thereby improving the gel transparency of the medical coupling agent and the long-term stability of the medical coupling agent during storage.

[0005] In one aspect, the present invention provides a medical coupling agent comprising the following materials in parts by weight: 0.8-1 parts of carbomer, 8-10 parts of glycerol, 5-7 parts of drug-loaded silica core-shell particles, 0.2-0.4 parts of sodium hyaluronate, 0.5-1 parts of ethylhexylglycerin, 0.1-0.3 parts of polysorbate 80, 0.05-0.1 parts of disodium edetate, and 82.5-83.5 parts of deionized water.

[0006] Furthermore, the preparation method of the drug-loaded silica core-shell particles includes: treating silica with 3-aminopropyltriethoxysilane to obtain amino silica, dissolving ibuprofen in a buffer solution, adding the amino silica, and oscillating and adsorbing to obtain drug-loaded silica; then dispersing the drug-loaded silica in a sodium alginate aqueous solution, adding it dropwise to a CaCl2 solution, stirring, centrifuging, washing, and freeze-drying to obtain the obtained product.

[0007] Furthermore, the preparation method of the drug-loaded silica core-shell particles includes: treating silica with 3-aminopropyltriethoxysilane to obtain amino silica, dissolving ibuprofen in PBS buffer with a pH of 6.0, adding amino silica, and oscillating and adsorbing at 40-50°C and 100-150 rpm for 20-24 hours to obtain drug-loaded silica; then dispersing the drug-loaded silica in a sodium alginate aqueous solution, adding it dropwise to a CaCl2 solution, stirring at 250-300 rpm for 20-30 minutes, centrifuging, washing, and freeze-drying to obtain the obtained product.

[0008] Furthermore, the preparation steps of the amino-silica include: ultrasonically treating silica in ethanol, adding 3-aminopropyltriethoxysilane, refluxing and stirring, centrifuging, washing, and drying to obtain the silica.

[0009] Furthermore, the preparation steps of the amino-silica include: dispersing silica in ethanol under 300W ultrasound for 30 minutes, adding 3-aminopropyltriethoxysilane, reflux stirring at 55-65°C under nitrogen protection for 5-6 hours, centrifuging, washing, and drying to obtain the product.

[0010] Furthermore, the silica has a pore size of 3-5 nm and a specific surface area of ​​≥800 m 2 / g.

[0011] Furthermore, the usage ratio of the silicon dioxide, ethanol and 3-aminopropyltriethoxysilane is 80-90 g:450-550 mL:0.7-0.8 g.

[0012] Furthermore, in the preparation process of the drug-loaded silica, the usage ratio of ibuprofen, PBS buffer and amino-silica is 14-16 g: 180-220 mL: 80-88 g.

[0013] Furthermore, the sodium alginate aqueous solution is a 2-3 wt% sodium alginate aqueous solution; and the CaCl2 solution is a 0.4-0.6 wt% CaCl2 aqueous solution.

[0014] Furthermore, the dosage ratio of the drug-loaded silica, sodium alginate aqueous solution and CaCl2 solution is 10g:90-110mL:180-220mL.

[0015] On the other hand, the present invention provides a preparation process for a medical coupling agent, comprising the following steps: weighing raw materials according to a formula, mixing drug-loaded silica core-shell particles with glycerol, part of deionized water, and polysorbate 80, ultrasonically dispersing, and homogenizing with a microporous filter membrane; dispersing carbomer in the remaining deionized water for swelling, controlling the stirring speed and using a pH regulator to adjust the pH for gelation, adding the drug-loaded particle dispersion to a gel matrix, stirring, and vacuum degassing to obtain the medical coupling agent.

[0016] Furthermore, the present invention provides a preparation process for a medical coupling agent, comprising the following steps: weighing raw materials according to a formula, mixing drug-loaded silica core-shell particles with glycerol, 40-50% by weight of deionized water, and polysorbate 80, ultrasonically dispersing the particles at 30-40 kHz for 10-15 minutes, and homogenizing the mixture through a 200 nm microporous filter membrane; dispersing carbomer in residual deionized water at 55-60° C. for swelling for 3-4 hours, controlling the stirring speed to 50-100 rpm and adjusting the pH to 6.5±0.1 using a pH regulator for gelation, adding the drug-loaded particle dispersion to a gel matrix, stirring at a low speed of 3-4° C. and 80-120 rpm for 30-40 minutes, maintaining a vacuum of -0.09±0.01 MPa for 20-30 minutes, and controlling the residual bubble content to less than 0.1%.

[0017] Furthermore, the pH regulator is triethanolamine.

[0018] The beneficial effects of the present invention are:

[0019] The present invention uses amino-silica as a drug carrier. The surface of the silica is modified with 3-aminopropyltriethoxysilane to provide amino groups on its surface. The amino groups have strong basicity and can electrostatically interact with the carboxyl groups in the ibuprofen molecule, thereby significantly enhancing the adsorption capacity of ibuprofen on the silica surface. This chemical adsorption is more stable than physical adsorption, ensuring that the drug is not easily leaked during preparation and use, thereby achieving a stable drug loading.

[0020] To prepare the drug-loaded silica core-shell microparticles, the aminated silica and ibuprofen solution are first oscillated and adsorbed to ensure that the ibuprofen is fully loaded onto the surface and pores of the aminated silica. Subsequently, a calcium alginate encapsulation layer is formed on the surface of the drug-loaded silica through a cross-linking reaction between sodium alginate and CaCl₂. This encapsulation layer not only protects the drug, preventing premature release during storage and use, but also further controls its release rate. When the coupling agent is applied to the skin, the calcium alginate encapsulation layer gradually degrades under the physiological conditions of the skin surface, allowing the ibuprofen to be slowly and continuously released, thus achieving a sustained-release effect.

[0021] Ibuprofen also has a certain bactericidal effect, and its sustained-release properties allow the drug to maintain an effective bactericidal concentration for a longer period of time, enhancing the durability and broad-spectrum of its bactericidal properties. The amino-silica core-shell drug delivery system, through the synergistic effect of drug loading and encapsulation technology, achieves stable drug storage, controlled release, and efficient bactericidal properties, endowing the medical coupling agent with excellent antibacterial properties.

[0022] In the process of preparing drug-loaded silica core-shell particles, the drug-loaded silica is dispersed in a sodium alginate aqueous solution, and then added dropwise to a CaCl2 aqueous solution. The carboxyl groups in the sodium alginate molecules react with the CaCl2 aqueous solution. 2+ An ionic cross-linking reaction occurs, forming a calcium alginate gel network structure that encapsulates the drug-loaded silica. This cross-linked encapsulation structure has multiple functions. On the one hand, it provides a stable microenvironment for the drug-loaded silica, protecting the drug from external environmental factors such as light, heat, and oxygen, thereby improving the drug's stability. On the other hand, the calcium alginate gel network has a certain pore structure and permeability, which can regulate the drug release rate. Drug molecules can be gradually released from the gel network through diffusion, and their release rate is affected by factors such as the pore size and cross-linking degree of the gel network. By rationally controlling the concentration of sodium alginate and CaCl2, the cross-linking degree of the gel network can be adjusted, thereby achieving precise control of the drug release rate.

[0023] In terms of fungal killing, the calcium alginate encapsulation layer not only controls the release of ibuprofen but also forms a protective film on the skin surface, preventing fungal invasion and reproduction. Furthermore, as the encapsulation layer gradually degrades, the released ibuprofen can directly act on fungal cells, interfering with the synthesis and function of their cell membranes and destroying their integrity, thereby achieving the purpose of killing fungi. The sodium alginate and CaCl2 cross-linking encapsulation technology synergizes with the bactericidal effect of ibuprofen, enhancing the fungal killing effectiveness of the medical coupling agent.

[0024] The present invention utilizes the synergistic effect of glycerol and carbomer to jointly adjust the rheological properties of a medical coupling agent. To prepare the medical coupling agent, drug-loaded silica core-shell microparticles are first mixed with glycerol, a portion of deionized water, and polysorbate 80. Glycerol penetrates the surface of the drug-loaded microparticles, forming a lubricating film that reduces friction and aggregation between the microparticles and improves their dispersion stability. Glycerol also absorbs moisture from the air, maintaining the wettability of the coupling agent and preventing it from drying out and clumping during use. Subsequently, the carbomer is dispersed in the remaining deionized water and allowed to swell, forming a uniform gel matrix. The carbomer gel network structure has high viscosity and elasticity, providing excellent skeletal support for the coupling agent. The drug-loaded microparticle dispersion is added to the gel matrix, where glycerol interacts with the carbomer to further adjust the viscosity and fluidity of the coupling agent. Glycerol lowers the glass transition temperature of the carbomer gel, allowing it to maintain good flexibility and fluidity at relatively low temperatures, making it easier to apply and use.

[0025] From the perspective of acoustic coupling, an ideal medical coupling agent should possess appropriate viscosity and acoustic impedance to effectively eliminate air gaps and enable efficient transmission of ultrasonic energy into human tissue. The synergistic thickening effect of glycerin and carbomer gives the coupling agent an appropriate viscosity, allowing it to adhere tightly to the skin surface, reducing the formation of air gaps, while also ensuring that it does not flow or fall off during ultrasound probe movement. Furthermore, by properly controlling the dosage of glycerin and carbomer, the acoustic impedance of the coupling agent can be adjusted to match that of human tissue, further improving ultrasound transmission efficiency and achieving excellent acoustic coupling. DETAILED DESCRIPTION

[0026] The following is a clear and complete description of the technical solution of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0027] Carbomer: Carbomer-941. Sodium Hyaluronate: -CWS sodium hyaluronate, Bloomage Biopharm.

[0028] Example 1

[0029] This embodiment provides a medical coupling agent, comprising the following materials in parts by weight: 0.9 parts of carbomer, 9 parts of glycerol, 6 parts of drug-loaded silica core-shell particles, 0.3 parts of sodium hyaluronate, 0.7 parts of ethylhexylglycerin, 0.2 parts of polysorbate 80, 0.08 parts of disodium edetate, and 83 parts of deionized water;

[0030] The preparation method of drug-loaded silica core-shell particles includes: 85g of silica with an average pore size of 4nm and a specific surface area of ​​800m 2 / g of silica was dispersed in 500mL of ethanol under 300W ultrasonication for 30min, 0.75g of 3-aminopropyltriethoxysilane was added, and the mixture was refluxed at 60°C for 5.5h under nitrogen protection, centrifuged at 10000rpm for 10min, washed with ethanol three times, and dried in vacuo at 60°C for 12h to obtain amino silica;

[0031] 15 g of ibuprofen was dissolved in 200 mL of PBS buffer (pH 6.0), 84 g of amino-silica was added, and the mixture was shaken and adsorbed at 45°C and 120 rpm for 22 h to obtain drug-loaded silica; then 10 g of drug-loaded silica was dispersed in 100 mL of 2.5 wt% sodium alginate aqueous solution, added dropwise to 200 mL of 0.5 wt% CaCl2 aqueous solution, stirred at 280 rpm for 25 min, centrifuged at 8000 rpm for 5 min, washed three times with deionized water, and freeze-dried at -50°C and 0.1 mbar for 24 h.

[0032] The preparation process of the medical coupling agent includes the following steps: weighing raw materials according to a formula, mixing drug-loaded silica core-shell particles with glycerol, 45% by weight of deionized water, and polysorbate 80, performing ultrasonic dispersion at 35 kHz for 12 minutes, and homogenizing through a 200 nm microporous filter membrane; dispersing carbomer in residual deionized water at 58° C. for swelling for 3.5 hours, controlling the stirring speed to 80 rpm and adjusting the pH to 6.5 with triethanolamine for gelation, adding the drug-loaded particle dispersion to a gel matrix, stirring at a low speed of 3.5° C. and 100 rpm for 35 minutes, maintaining a vacuum of -0.09 MPa for 25 minutes, and controlling the residual bubble content to less than 0.1% to obtain the medical coupling agent.

[0033] Example 2

[0034] This embodiment provides a medical coupling agent comprising the following materials in parts by weight: 0.8 parts of carbomer, 8 parts of glycerol, 5 parts of drug-loaded silica core-shell particles, 0.2 parts of sodium hyaluronate, 0.5 parts of ethylhexylglycerin, 0.1 parts of polysorbate 80, 0.05 parts of disodium edetate, and 82.5 parts of deionized water;

[0035] The preparation method of drug-loaded silica core-shell particles includes: 80g of silica core-shell particles with an average pore size of 4nm and a specific surface area of ​​800m 2 / g of silica was dispersed in 450mL of ethanol under 300W ultrasonication for 30min, 0.7g of 3-aminopropyltriethoxysilane was added, and the mixture was refluxed at 55°C for 5h under nitrogen protection, centrifuged at 10000rpm for 10min, washed with ethanol three times, and dried in vacuo at 60°C for 12h to obtain amino silica;

[0036] 14 g of ibuprofen was dissolved in 180 mL of PBS buffer (pH 6.0), 80 g of amino-silica was added, and the mixture was shaken and adsorbed at 40°C and 100 rpm for 20 h to obtain drug-loaded silica; then 10 g of drug-loaded silica was dispersed in 90 mL of 2 wt% sodium alginate aqueous solution, added dropwise to 180 mL of 0.4 wt% CaCl2 aqueous solution, stirred at 250 rpm for 20 min, centrifuged at 8000 rpm for 5 min, washed three times with deionized water, and freeze-dried at -50°C and 0.1 mbar for 24 h to obtain the obtained product.

[0037] The preparation process of the medical coupling agent includes the following steps: weighing raw materials according to a formula, mixing drug-loaded silica core-shell particles with glycerol, 40% by weight of deionized water and polysorbate 80, dispersing them ultrasonically at 30 kHz for 10 minutes, and homogenizing them through a 200 nm microporous filter membrane; dispersing carbomer in residual deionized water at 55° C. for swelling for 3 hours, controlling the stirring speed to 50 rpm and adjusting the pH to 6.5 with triethanolamine for gelation, adding the drug-loaded particle dispersion to a gel matrix, stirring at a low speed of 3° C. and 80 rpm for 30 minutes, maintaining a vacuum of -0.09 MPa for 20 minutes, and controlling the residual bubble content to less than 0.1% to obtain the coupling agent.

[0038] Example 3

[0039] This embodiment provides a medical coupling agent comprising the following materials in parts by weight: 1 part carbomer, 10 parts glycerin, 7 parts drug-loaded silica core-shell particles, 0.4 parts sodium hyaluronate, 1 part ethylhexylglycerin, 0.3 parts polysorbate 80, 0.1 parts disodium edetate, and 83.5 parts deionized water;

[0040] The preparation method of drug-loaded silica core-shell particles includes: 90g of silica core-shell particles with an average pore size of 4nm and a specific surface area of ​​800m 2 / g of silica was dispersed in 550mL of ethanol under 300W ultrasound for 30min, 0.8g of 3-aminopropyltriethoxysilane was added, and the mixture was refluxed at 65°C for 6h under nitrogen protection, centrifuged at 10000rpm for 10min, washed with ethanol three times, and dried in vacuo at 60°C for 12h to obtain amino silica;

[0041] 16 g of ibuprofen was dissolved in 220 mL of PBS buffer (pH 6.0), 88 g of amino-silica was added, and the mixture was shaken and adsorbed at 50°C and 150 rpm for 24 h to obtain drug-loaded silica. Subsequently, 10 g of drug-loaded silica was dispersed in 110 mL of a 3 wt% sodium alginate aqueous solution, added dropwise to 220 mL of a 0.6 wt% CaCl2 aqueous solution, stirred at 300 rpm for 30 min, centrifuged at 8000 rpm for 5 min, washed three times with deionized water, and freeze-dried at -50°C and 0.1 mbar for 24 h.

[0042] The preparation process of the medical coupling agent includes the following steps: weighing raw materials according to a formula, mixing drug-loaded silica core-shell particles with glycerol, 50% by weight of deionized water and polysorbate 80, dispersing them ultrasonically at 40 kHz for 15 minutes, and homogenizing them through a 200 nm microporous filter membrane; dispersing carbomer in residual deionized water at 60° C. for swelling for 4 hours, controlling the stirring speed to 100 rpm and adjusting the pH to 6.5 with triethanolamine for gelation, adding the drug-loaded particle dispersion to a gel matrix, stirring at a low speed of 4° C. and 120 rpm for 40 minutes, maintaining a vacuum of -0.09 MPa for 30 minutes, and controlling the residual bubble content to less than 0.1% to obtain the medical coupling agent.

[0043] Comparative Example 1

[0044] Different from Example 1, the drug-loaded silica core-shell particles in this comparative example were replaced by blank silica.

[0045] Comparative Example 2

[0046] Different from Example 1, in this comparative example, the silica was not amino-modified during the preparation of the drug-loaded silica core-shell microparticles, and blank silica was directly used to load the drug.

[0047] Comparative Example 3

[0048] The difference from Example 1 is that the ibuprofen loading in this comparative example is halved.

[0049] Comparative Example 4

[0050] The difference from Example 1 is that in this comparative example, glycerol is replaced by an equal amount of propylene glycol.

[0051] Comparative Example 5

[0052] The difference from Example 1 is that the amount of carbomer in this comparative example is reduced to 0.3 parts.

[0053] Comparative Example 6

[0054] Different from Example 1, the concentration of the sodium alginate aqueous solution in this comparative example was reduced to 1.0 wt %.

[0055] Comparative Example 7

[0056] The difference from Example 1 is that in this comparative example, silicon dioxide is replaced by an equal amount of mesoporous hydroxyapatite with a specific surface area of ​​≈750 m 2 / g.

[0057] Comparative Example 8

[0058] Different from Example 1, in this comparative example, sodium alginate is replaced by 2.5 wt % chitosan in acetic acid solution, wherein the solvent is 1 wt % acetic acid aqueous solution, and the CaCl 2 aqueous solution is replaced by 0.5 wt % sodium tripolyphosphate aqueous solution.

[0059] Comparative Example 9

[0060] The difference from Example 1 is that in this comparative example, ethylhexylglycerin is replaced by phenoxyethanol.

[0061] Test Example 1: The following tests were performed on the medical coupling agents prepared in the examples and comparative examples respectively;

[0062] Sound velocity test: refer to "WG-C type medical ultrasonic coupling agent performance and test" for testing;

[0063] Viscosity test: Viscosity test was performed using NDJ-97 rotary viscometer;

[0064] Bactericidal effect test, skin irritation test, allergy test: Tested in accordance with the "Medical Standard of the People's Republic of China YY0299-2008".

[0065] Table 1 Test results

[0066]

[0067]

[0068] Based on the foregoing, Example 1 performs best in terms of acoustic performance, viscosity, broad-spectrum bactericidal rate, and biosafety. The amino-silica core-shell drug delivery system ensures sustained drug release and efficient bactericidal efficacy. Cross-linking encapsulation with sodium alginate and CaCl2 ensures particle stability and fungicidal efficacy. Glycerol and carbomer provide synergistic thickening to achieve ideal rheological properties.

[0069] In Comparative Example 1, the blank silica had no sustained-release drug function, and the sterilization rate plummeted to below 30%. In Comparative Example 2, the unmodified silica had a significantly lower drug loading (sterilization rate ≤ 45%), demonstrating that amination enhances ibuprofen adsorption. In Comparative Example 3, halving the ibuprofen content resulted in a 40% drop in sterilization rate, confirming that Example 1 exhibited the optimal drug loading ratio.

[0070] In Comparative Example 4, after glycerol was replaced with propylene glycol, the viscosity decreased by 25% and caused skin irritation, affecting the acoustic coupling effect and safety.

[0071] When the amount of carbomer in Comparative Example 5 was reduced to 0.3 parts, the viscosity was less than 40% of the standard value, resulting in a decrease in acoustic performance.

[0072] In Comparative Example 6, when the sodium alginate concentration was reduced to 1.0 wt %, the sterilization rate of Candida albicans dropped to 85%, indicating that insufficient encapsulation resulted in drug leakage.

[0073] The drug loading efficiency of hydroxyapatite in Comparative Example 7 was low, the bactericidal rate was ≤70%, and the acoustic impedance was increased, deviating from the ideal range of 1.55-1.59 MRayl.

[0074] The chitosan-sodium tripolyphosphate system of Comparative Example 8 caused a 30% decrease in viscosity, a reduced sterilization rate of Candida albicans, and induced allergies, verifying that calcium cross-linking is safer and more efficient.

[0075] Although phenoxyethanol in comparative example 9 maintained the bactericidal rate, it caused moderate skin irritation, proving that ethylhexylglycerin has both high efficiency and low irritation.

[0076] Test Example 2: Anti-inflammatory effect

[0077] After depilation and disinfection, the pigskin was fixed with the epidermis facing upward between the receptor and donor chambers of the diffusion cell. The receptor chamber was filled with 37°C release medium (pH 7.4 PBS mixed with 0.1% Tween 80);

[0078] Ultrasound equipment: therapeutic grade ultrasound machine, 3MHz, 1W / cm 2 ;

[0079] Group A was designed to use drug-loaded coupling agent combined with ultrasound, and the coupling agent of Example 1 was coated at 0.5 g / cm 2 , ultrasound for 5 minutes; Group B was free drug combined with ultrasound, coated with blank coupling agent containing equal amount of ibuprofen, ultrasound for 5 minutes; Group C was blank control, no drug coupling agent

[0080] At 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 12 hours, 0.5 mL of the receptor fluid was taken and replaced with an equal amount of medium. The ibuprofen concentration was determined by HPLC and the cumulative transdermal dose was calculated as: Q = C n ×V+∑(C i × Vs); where Q is the cumulative transdermal dose (μg / cm 2 );C n : drug concentration in the receptor compartment at the time of the nth sampling; V: volume of the receptor compartment (15 mL); C i : drug concentration at the time of sampling for the i-th time; V s : sampling volume (0.5 mL); A: diffusion area (1.77 cm 2 );∑:The total amount of historical sampled drugs. The test results are shown in Table 2.

[0081] Table 2: Test results

[0082] <![CDATA[C i (μg / mL)]]> 1h 2h 4h 6h 8h 12h 24h(end point) Group A 5.2 9.8 14.3 15.5 15.8 28.7 32.5 Group B 13.9 16.9 21.5 24.3 25.9 27.8 29.1 Group C 0 0 0 0 0 0 0

[0083] According to the results, the concentration of group A increased slowly and continued to release after 8 hours, while the concentration of group B was high at the beginning and had a sudden release effect, but increased slowly in the later period, proving that it had no sustained release ability.

[0084] Table 3: Cumulative scalp volume

[0085] 2h cumulative transdermal dose 8h cumulative transdermal dose 24h cumulative transdermal amount Group A <![CDATA[64.8μg / cm 2 ]]> <![CDATA[146.8μg / cm 2 ]]> <![CDATA[293.6μg / cm 2 ]]> Group B <![CDATA[146.8μg / cm 2 ]]> <![CDATA[240.8μg / cm 2 ]]> <![CDATA[293.6μg / cm 2 ]]> Group C 0 0 0

[0086] According to the results, the cumulative transdermal dose of group A in 24 hours was 293.6 μg / cm 2 ; The transdermal dose per unit area is 165.9μg / cm 2 ; The time for group A to reach 50% effective concentration was 8 hours, which was 4 times longer than 2 hours in group B, indicating that the sustained-release effect of group A was prolonged.

[0087] Test Example 3: Anti-inflammatory effect

[0088] Animal model: SD rats (200 ± 20 g), 10 per group, were injected subcutaneously with 0.1 mL of 1% carrageenan as the inflammatory agent into the paw. Pedal volume was measured using a 0.01 mL precision paw volume meter.

[0089] Group E was designed to use the drug-loaded coupling agent in Example 1. Immediately after inflammation was induced, 0.3 g of the coupling agent in Example 1 was applied at 3 MHz and 1 W / cm 2 Ultrasound was performed for 5 minutes. Group F was treated with a common coupling agent (no raw material drug-loaded silica core-shell particles were added based on Example 1). Immediately after inflammation was induced, 0.3 g of the coupling agent was applied, along with oral administration of 20 mg / kg of ibuprofen. Group G was a positive control, where inflammation was induced without treatment. Group H was a blank carrier control, where 0.3 g of the coupling agent of the blank particles in Comparative Example 1 was applied immediately after inflammation was induced. The ultrasound was performed at 3 MHz and 1 W / cm 2 Ultrasound for 5 minutes;

[0090] The baseline foot volume (V0) was measured before inflammation; the foot volume (V t ); Calculate the swelling inhibition rate (%): [1-(V t -V0) 治疗组 / (V t -V0)G 组 )]×100; the results are shown in Table 4 below.

[0091] Table 4: Test results

[0092]

[0093]

[0094] The results showed that the 6h inhibition rate of group E was significantly higher than that of group F (p<0.01), proving that the drug-loaded coupling agent prolonged the drug action time. The inhibition rate of group H (blank particles) was ≈10%, excluding the anti-inflammatory interference of the carrier itself.

[0095] Finally, it should be noted that the above embodiments are only used to illustrate the present invention and are not intended to limit the technical solutions described in the present invention. Those skilled in the art should understand that the present invention can still be modified or replaced by equivalents. All technical solutions and improvements that do not depart from the spirit and scope of the present invention should be included in the scope of the claims of the present invention.

Claims

1. A medical coupling agent, characterized in that: The invention comprises the following materials in parts by weight: 0.8-1 parts of carbomer, 8-10 parts of glycerol, 5-7 parts of drug-loaded silica core-shell particles, 0.2-0.4 parts of sodium hyaluronate, 0.5-1 parts of ethylhexylglycerin, 0.1-0.3 parts of polysorbate 80, 0.05-0.1 parts of disodium edetate, and 82.5-83.5 parts of deionized water.

2. The medical coupling agent according to claim 1, characterized in that: The preparation method of the drug-loaded silica core-shell particles comprises: treating silica with 3-aminopropyltriethoxysilane to obtain amino silica; dissolving ibuprofen in a buffer solution; adding the amino silica; and performing oscillation adsorption to obtain the drug-loaded silica; subsequently dispersing the drug-loaded silica in a sodium alginate aqueous solution, adding the solution dropwise to a CaCl2 solution, stirring, centrifuging, washing, and freeze-drying to obtain the drug-loaded silica.

3. The medical coupling agent according to claim 2, characterized in that: The preparation steps of the amino silicon dioxide include: ultrasonically treating silicon dioxide in ethanol, adding 3-aminopropyltriethoxysilane, refluxing and stirring, centrifuging, washing, and drying to obtain the product.

4. The medical coupling agent according to claim 3, characterized in that: The silica has a pore size of 3-5 nm and a specific surface area of ​​≥800 m 2 / g.

5. The medical coupling agent according to claim 3, characterized in that: The usage ratio of the silicon dioxide, ethanol and 3-aminopropyltriethoxysilane is 80-90 g:450-550 mL:0.7-0.8 g.

6. The medical coupling agent according to claim 2, characterized in that: In the preparation process of the drug-loaded silica, the usage ratio of ibuprofen, PBS buffer and amino-silica is 14-16 g: 180-220 mL: 80-88 g.

7. The medical coupling agent according to claim 2, characterized in that: The sodium alginate aqueous solution is a 2-3 wt % sodium alginate aqueous solution; the CaCl 2 solution is a 0.4-0.6 wt % CaCl 2 aqueous solution.

8. The medical coupling agent according to claim 7, characterized in that: The dosage ratio of the drug-loaded silica, sodium alginate aqueous solution and CaCl2 solution is 10g:90-110mL:180-220mL.

9. A process for preparing the medical coupling agent according to any one of claims 1 to 8, characterized in that the steps include: The raw materials are weighed according to the formula, and the drug-loaded silica core-shell particles are mixed with glycerol, part of the deionized water and polysorbate 80, and ultrasonically dispersed and homogenized with a microporous filter membrane; carbomer is dispersed in the remaining deionized water for swelling, and the stirring speed is controlled and the pH is adjusted using a pH regulator for gelation. The drug-loaded particle dispersion is added to the gel matrix, stirred, and vacuum degassed to obtain the product.

10. The preparation process of a medical coupling agent according to claim 9, characterized in that: The pH regulator is triethanolamine.

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