Pain-easing drug-loaded lecithin chitosan nanoparticle gel as well as preparation method and application of pain-easing drug-loaded lecithin chitosan nanoparticle gel

Abstract

The invention provides lecithin chitosan nanoparticle gel loaded with analgesic medicine as well as a preparation method and application of the lecithin chitosan nanoparticle gel, and belongs to the technical field of medical biological materials. According to the invention, the analgesic drug is entrapped in the lecithin chitosan nanoparticles, so that the analgesic drug can be slowly released, and the analgesic time of the drug is prolonged. According to the invention, the lecithin chitosan nanoparticles entrapped with the analgesic drug are dispersed in the gel matrix, so that the lecithin chitosan nanoparticles entrapped with the analgesic drug can quickly penetrate through the cuticle of the skin by selecting the gel matrix; the lecithin chitosan nanoparticle gel loaded with the analgesic drug can play a role in combining quick-acting transdermal and sustained-release phase drugs, the bioavailability is improved, the acting time of the analgesic drug is prolonged, and the long-time analgesic effect is played.

Description

Technical Field

[0001] The present invention relates to the technical field of medical biomaterials, in particular to a lecithin chitosan nanoparticle gel loaded with analgesic drugs, and a preparation method and application thereof. Background Art

[0002] Postherpetic neuralgia (PHN) is pain that persists for one month or more after the shingles rash heals. It is a common complication of shingles and requires the use of analgesics. For example, traditional Chinese medicine often uses the Chinese herbal medicine Corydalis as the main drug to promote blood circulation, dissipate blood stasis, promote qi circulation and relieve pain. Clinically, the traditional soaking method of Corydalis water extract is used as an analgesic drug for the treatment of PHN. However, this method has the problem of short retention time in the skin, difficulty in maintaining the effective concentration of the drug, and a short analgesic time.

[0003] Modern pharmacological studies have shown that the primary analgesic effect of Corydalis yanhusuo is exerted by levorotatory tetrahydropalmatine (L-THP). Clinical preparations for L-THP are injection and oral administration. These two routes of administration result in large fluctuations in blood concentrations, which in turn lead to fluctuations in brain concentrations, which can easily cause adverse reactions such as drowsiness, dizziness, and nausea, and the therapeutic effect is short-lived. Transdermal administration has the advantages of controlling the drug's entry into the body through the skin at a zero-order rate, maintaining stable blood concentrations, maintaining a longer duration of action, and reducing the number of dosing times. Currently, research on transdermal formulations for L-tetrahydropalmatine has been conducted. For example, relevant studies have shown that while the transdermal penetration of L-THP can be improved by using sodium hydroxymethylcellulose or carbomer as a gel matrix and azone, ethanol, peppermint oil, propylene glycol, and other transdermal absorption enhancers, the sustained release is poor, resulting in a shorter duration of drug analgesia.

[0004] Therefore, how to improve the transdermal ability of analgesics and prolong the analgesic time of the drugs is a technical problem that needs to be solved urgently by those skilled in the art. Summary of the Invention

[0005] The purpose of the present invention is to provide an analgesic drug-loaded lecithin chitosan nanoparticle gel, which can improve the transdermal ability of analgesics and prolong the analgesic time of the drugs, as well as a preparation method and application thereof.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a lecithin chitosan nanoparticle gel loaded with an analgesic drug, comprising a gel matrix and lecithin chitosan nanoparticles loaded with an analgesic drug dispersed in the gel matrix;

[0008] The analgesic drug loading amount in the lecithin chitosan nanoparticles containing the analgesic drug is 2-5%;

[0009] The volume ratio of the gel matrix to the analgesic drug-encapsulated lecithin chitosan nanoparticles is (1-3): (7-9).

[0010] Preferably, the particle size of the lecithin chitosan nanoparticles encapsulating the analgesic drug is 253.2±1.5 nm, the PDI is 0.202±2.5, and the potential is 38.61±5.3 mV.

[0011] Preferably, the encapsulation efficiency of the analgesic drug-encapsulated lecithin-chitosan nanoparticles is 54.65±0.014%.

[0012] Preferably, the analgesic drug in the lecithin chitosan nanoparticles containing analgesic drugs includes one or more of levorotatory tetrahydropalmatine, triptolide, tetrandrine, aconitine and paeoniflorin.

[0013] The present invention also provides a method for preparing the analgesic drug-loaded lecithin chitosan nanoparticle gel described in the above technical solution, comprising the following steps:

[0014] (1) mixing an analgesic drug, lecithin, and ethanol to obtain an ethanol solution containing lecithin;

[0015] (2) mixing chitosan, a stabilizer and an acetic acid aqueous solution to obtain a chitosan solution;

[0016] (3) under stirring, dripping the ethanol solution containing lecithin obtained in step (1) into the chitosan solution obtained in step (2) to perform electrostatic adsorption to obtain lecithin chitosan nanoparticles loaded with analgesic drugs;

[0017] (4) mixing the analgesic-loaded lecithin chitosan nanoparticles obtained in step (3) with a gel matrix to obtain an analgesic-loaded lecithin chitosan nanoparticle gel;

[0018] The mass ratio of the analgesic drug to lecithin in step (1) is (2-4): (20-30);

[0019] The volume ratio of the gel matrix and the lecithin chitosan nanoparticles loaded with the analgesic drug in step (4) is (1-3): (7-9).

[0020] Preferably, the mass ratio of the lecithin in step (1) to the chitosan in step (2) is 10 to 20:1.

[0021] Preferably, the pH value of the acetic acid aqueous solution in step (2) is 2.7 to 3.0.

[0022] Preferably, the temperature of the electrostatic adsorption in step (3) is 20-28° C., and the time of the electrostatic adsorption is 30-90 min.

[0023] Preferably, the stirring speed in step (3) is 200 to 1500 rpm.

[0024] The present invention also provides the use of the analgesic drug-loaded lecithin chitosan nanoparticle gel described in the above technical solution or the analgesic drug-loaded lecithin chitosan nanoparticle gel prepared by the preparation method described in the above technical solution as a transdermal administration preparation.

[0025] The present invention provides a lecithin chitosan nanoparticle gel loaded with analgesics, comprising a gel matrix and lecithin chitosan nanoparticles loaded with analgesics dispersed in the gel matrix; the analgesic loading in the lecithin chitosan nanoparticles loaded with analgesics is 2-5%; and the volume ratio of the gel matrix to the lecithin chitosan nanoparticles loaded with analgesics is (1-3):(7-9). By loading the analgesic in the lecithin chitosan nanoparticles, the present invention can slowly release the analgesic and prolong the analgesic effect of the drug. The present invention disperses the lecithin chitosan nanoparticles loaded with analgesics in the gel matrix, allowing the lecithin chitosan nanoparticles loaded with analgesics to quickly penetrate the stratum corneum of the skin. At the same time, the lecithin chitosan nanoparticle gel loaded with analgesics can combine the effects of rapid transdermal delivery and sustained release of analgesics, thereby improving bioavailability, prolonging the duration of action of the analgesic, and achieving a long-lasting analgesic effect. The results of the embodiment show that the analgesic drug-loaded lecithin chitosan nanoparticle gel (abbreviated as L-THP-L / CNPs-gel) prepared by the present invention can be stably stored at 4°C for 60 days, with a cumulative release rate of 88.87% within 24 hours, and the drug release conforms to first-order kinetics. The in vitro transdermal permeability is 88.90 μg / cm 2 In vitro skin irritation experiments showed that the preparation had good biological safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is a Tyndall effect diagram of L-THP-L / CS-NPs prepared in Example 10 of the present invention;

[0027] Figure 2 TEM image of L-THP-L / CS-NPs prepared in Example 10 of the present invention;

[0028] Figure 3 The particle size and potential diagram of L-THP-L / CS-NPs prepared in Example 10 of the present invention;

[0029] Figure 4FT-IR spectra of L-THP, lecithin, L-THP-SOL-gel prepared in Comparative Example 5, and L-THP-L / C-NPs prepared in Example 10 of the present invention;

[0030] Figure 5 The cumulative release rate of L-THP-L / C-NPs-gel prepared in Example 10 of the present invention and L-THP-SOL-gel prepared in Comparative Example 5;

[0031] Figure 6 The Q of L-THP-L / CS-NPs prepared in Example 10 of the present invention and L-THP-SOL prepared in Comparative Example 5 within 24 hours is n-t curve;

[0032] Figure 7 The cumulative release rate of L-THP-L / CS-NPs-gel prepared in Example 10 of the present invention and L-THP-SOL-gel prepared in Comparative Example 5;

[0033] Figure 8 The Q of L-THP-L / CS-NPs-gel prepared in Example 10 of the present invention and L-THP-SOL-gel prepared in Comparative Example 5 within 24 hours is n-t curve;

[0034] Figure 9 This is a graph showing the single skin irritation results of L-THP-L / C-NPs-gel prepared in Example 10 of the present invention;

[0035] Figure 10 This is a graph showing the multiple skin irritation results of L-THP-L / C-NPs-gel prepared in Example 10 of the present invention. DETAILED DESCRIPTION

[0036] The present invention provides a lecithin chitosan nanoparticle gel loaded with an analgesic drug, comprising a gel matrix and lecithin chitosan nanoparticles loaded with an analgesic drug dispersed in the gel matrix;

[0037] The analgesic drug loading amount in the lecithin chitosan nanoparticles containing the analgesic drug is 2-5%;

[0038] The volume ratio of the gel matrix to the analgesic drug-encapsulated lecithin chitosan nanoparticles is (1-3): (7-9).

[0039] In the present invention, unless otherwise specified, the chemical reagents used in the present invention are all commercially available products well known to those skilled in the art.

[0040] The analgesic-loaded lecithin chitosan nanoparticle gel provided by the present invention comprises a gel matrix. In the present invention, the gel matrix comprises one of carbomer, chitosan, and sodium carboxymethylcellulose, more preferably carbomer 940 (abbreviated as C940). The present invention uses this gel matrix to promote rapid drug penetration through the skin, thereby enhancing the transdermal ability of the analgesic-loaded lecithin chitosan nanoparticles.

[0041] The analgesic drug-loaded lecithin chitosan nanoparticle gel provided by the present invention comprises analgesic drug-loaded lecithin chitosan nanoparticles dispersed in the gel matrix.

[0042] In the present invention, the analgesic loading in the lecithin-chitosan nanoparticles is 2-5%, more preferably 4.741±0.0060%, and even more preferably 4.741±0.0030%. By controlling the analgesic loading in the lecithin-chitosan nanoparticles within the above range, the present invention can enhance the analgesic effect during use.

[0043] In the present invention, the analgesic drug in the lecithin-chitosan nanoparticles encapsulating the analgesic drug preferably includes one or more of levorotatory tetrahydropalmatine, triptolide, tetrandrine, aconitine, and paeoniflorin, and more preferably levorotatory tetrahydropalmatine. The present invention utilizes lecithin-chitosan nanoparticles to encapsulate the analgesic drug, thereby achieving a good encapsulation efficiency and a sustained-release effect of the analgesic drug. Therefore, the present invention is applicable to the preparation of a variety of analgesic drug preparations.

[0044] In the present invention, the particle size of the analgesic-encapsulated lecithin chitosan nanoparticles is preferably 253.2±1.5 nm, more preferably 253.2±0.5 nm; the PDI is preferably 0.202±2.5, more preferably 0.202±1.5; and the potential is preferably 38.61±5.3 mV, more preferably 38.61±4.3 mV. By controlling the particle size, PDI, and potential of the analgesic-encapsulated lecithin chitosan nanoparticles within the above ranges, the present invention exhibits good transdermal ability.

[0045] In the present invention, the encapsulation efficiency of the lecithin-chitosan nanoparticles encapsulating the analgesic is preferably 54.65±0.014%, more preferably 54.65±0.010%. By controlling the encapsulation efficiency of the lecithin-chitosan nanoparticles encapsulating the analgesic within the above range, the present invention can enhance the sustained-release effect of the analgesic and prolong the duration of action of the analgesic.

[0046] In the present invention, the volume ratio of the gel matrix to the analgesic-encapsulating lecithin chitosan nanoparticles is (1-3):(7-9), preferably 2:8. By controlling the volume ratio of the gel matrix to the analgesic-encapsulating lecithin chitosan nanoparticles within the above range, the present invention can achieve the combined effects of fast-acting transdermal delivery and sustained-release analgesic drug, improve bioavailability, prolong the duration of action of the analgesic drug, and achieve a long-lasting analgesic effect.

[0047] The present invention also provides a method for preparing the analgesic drug-loaded lecithin chitosan nanoparticle gel described in the above technical solution, comprising the following steps:

[0048] (1) mixing an analgesic drug, lecithin, and ethanol to obtain an ethanol solution containing lecithin;

[0049] (2) mixing chitosan, a stabilizer and an acetic acid aqueous solution to obtain a chitosan solution;

[0050] (3) under stirring, dripping the ethanol solution containing lecithin obtained in step (1) into the chitosan solution obtained in step (2) to perform electrostatic adsorption to obtain lecithin chitosan nanoparticles loaded with analgesic drugs;

[0051] (4) mixing the analgesic drug-loaded lecithin chitosan nanoparticles obtained in step (3) with a gel matrix to obtain an analgesic drug-loaded lecithin chitosan nanoparticle gel.

[0052] The invention mixes analgesic drugs, lecithin and ethanol to obtain an ethanol solution containing lecithin.

[0053] In the present invention, the analgesic drug preferably includes one or more of levorotatory tetrahydropalmatine, triptolide, tetrandrine, aconitine and paeoniflorin, and more preferably levorotatory tetrahydropalmatine.

[0054] In the present invention, the type of lecithin is preferably S75. The present invention uses the above lecithin to increase drug loading and encapsulation efficiency.

[0055] In the present invention, the mass ratio of the analgesic drug to lecithin is (2-4): (20-30), preferably (2-3): (25-30). The present invention controls the mass ratio of the analgesic drug to lecithin within the above range, which is more conducive to improving drug loading and encapsulation efficiency.

[0056] In the present application, the ethanol is preferably anhydrous ethanol. In the present application, the volume of the anhydrous ethanol is preferably 3-4% of the total volume of the lecithin-containing ethanol solution. As an embodiment of the present application, the volume of the anhydrous ethanol can be 3%, 3.5% or 4% of the total volume of the lecithin-containing ethanol solution. The present application controls the amount of ethanol within the above range, which can improve the drug loading and encapsulation efficiency.

[0057] In the present application, the ratio of the mass of the analgesic drug to the volume of ethanol is preferably (2-3) mg:0.8 mL. As an embodiment of the present application, the ratio of the mass of the analgesic drug to the volume of ethanol can be 2 mg:0.8 mL, 2.5 mg:0.8 mL or 3 mg:0.8 mL.

[0058] The present application does not have special restrictions on the method of mixing the analgesic drug, lecithin and ethanol, and the analgesic drug, lecithin and stabilizer can be completely dissolved in ethanol.

[0059] The present application mixes chitosan, stabilizer and aqueous acetic acid solution to obtain a chitosan solution.

[0060] In the present application, the molecular weight of the chitosan is preferably 19000-50000, and more preferably 20000-40000. The present application uses chitosan with the above molecular weight, which has a lower molecular weight and is more conducive to improving the drug loading and encapsulation efficiency.

[0061] In the present application, the ratio of the mass of lecithin to chitosan is preferably 10-20:1. As an embodiment of the present application, the ratio of the mass of lecithin to chitosan can be 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1. The present application controls the mass ratio of lecithin to chitosan within the above range, which can improve the drug loading and encapsulation efficiency.

[0062] In the present application, the pH value of the aqueous acetic acid solution is preferably 2.7-3.0. As an embodiment of the present application, the pH value of the aqueous acetic acid solution can be 2.7, 2.8, 2.9 or 3.0. The present application controls the pH value of the aqueous acetic acid solution within the above range, which can improve the drug loading and encapsulation efficiency. The present application does not have special restrictions on the volume ratio of acetic acid to water in the aqueous acetic acid solution, and the pH value of the aqueous acetic acid solution can be controlled within the above range.

[0063] In the present application, the stabilizer is preferably polyethylene glycol 1000 vitamin E succinate (abbreviated as TPGS, manufactured by Shanghai Yuan Ye Biological Technology Co., Ltd.). The above stabilizer TPGS used in the present application is an amphoteric surfactant with both hydrophilic and lipophilic properties, which can improve the drug loading and encapsulation efficiency.

[0064] In the present invention, the concentration of the stabilizer is preferably 0.1% to 0.2%. As one embodiment of the present invention, the concentration of the stabilizer can be 0.1%, 0.15%, or 0.2%. The present invention controls the concentration of the stabilizer within the above range to increase drug loading and encapsulation efficiency. In the present invention, the concentration of the stabilizer is a percentage of the mass of the chitosan solution.

[0065] In the present invention, the concentration of chitosan in the chitosan solution is preferably 0.1 to 0.2 mg / mL. As an embodiment of the present invention, the concentration of chitosan in the chitosan solution is within the above range, which has a higher drug loading capacity and encapsulation efficiency.

[0066] The present invention has no particular limitation on the method of mixing the chitosan and the acetic acid aqueous solution, as long as the chitosan can be completely dissolved in the acetic acid aqueous solution.

[0067] After obtaining an ethanol solution containing lecithin and a chitosan solution, the present invention drips the ethanol solution containing lecithin into the chitosan solution under stirring to perform electrostatic adsorption to obtain lecithin chitosan nanoparticles encapsulating analgesic drugs.

[0068] In the present invention, the stirring speed is preferably 1200-1500 rpm, more preferably 1200-1400 rpm. The present invention can promote uniform mixing of the components and improve drug loading and encapsulation efficiency by dripping the ethanol solution containing lecithin into the chitosan solution under stirring.

[0069] The present invention has no particular limitation on the volume ratio of the ethanol solution containing lecithin to the chitosan solution. The mass ratio of lecithin in the ethanol solution of lecithin to chitosan in the chitosan solution can be 10 to 20:1.

[0070] In the present invention, the dripping rate is preferably 0.5-1.5 mL / min, more preferably 1 mL / min. The present invention controls the dripping rate within the above range, which is more conducive to obtaining lecithin chitosan nanoparticles with uniform particle size distribution and loaded with analgesic drugs.

[0071] In the present invention, the electrostatic adsorption temperature is preferably 20-28°C, more preferably 23-25°C; the electrostatic adsorption duration is preferably 30-90 minutes, more preferably 60-70 minutes. By allowing electrostatic adsorption to occur at the aforementioned temperature, the present invention can utilize electrostatic adsorption to form lecithin-chitosan nanoparticles encapsulating analgesic drugs. In the present invention, the electrostatic adsorption is preferably performed under stirring, and the stirring speed may be 1400 rpm.

[0072] After obtaining the analgesic drug-encapsulated lecithin chitosan nanoparticles, the present invention mixes the analgesic drug-encapsulated lecithin chitosan nanoparticles with a gel matrix to obtain the analgesic drug-loaded lecithin chitosan nanoparticle gel.

[0073] In the present invention, the gel matrix comprises one of carbomer, chitosan and sodium carboxymethylcellulose, preferably carbomer, more preferably carbomer 940. The present invention adopts the above-mentioned gel matrix, which is more conducive to improving the transdermal ability of analgesics.

[0074] In the present invention, the volume ratio of the gel matrix to the analgesic-encapsulating lecithin chitosan nanoparticles is (1-3):(7-9), preferably 2:8. By controlling the volume ratio of the gel matrix to the analgesic-encapsulating lecithin chitosan nanoparticles within the above range, the present invention can achieve a combination of rapid-acting and sustained-release effects, prolong the duration of action of the analgesic, and exert a long-lasting analgesic effect.

[0075] In the present invention, the method of mixing the analgesic-loaded lecithin chitosan nanoparticles with the gel matrix is ​​preferably: swelling the gel matrix to obtain a swollen gel matrix; and mixing the swollen gel matrix with a suspension of the analgesic-loaded lecithin chitosan nanoparticles under stirring to obtain an analgesic-loaded lecithin chitosan nanoparticle gel.

[0076] In the present invention, the method for swelling the gel matrix comprises: mixing the gel matrix, sodium hydroxide and water, and swelling the mixture to obtain a swollen gel matrix.

[0077] In the present invention, the mass ratio of the gel matrix, sodium hydroxide, and water is preferably (100-300):(60-80):(1-3), and more preferably (150-200):(72-75):(1-2). Controlling the mass ratio of the gel matrix, sodium hydroxide, and water within the above range allows the gel matrix to fully swell and prevents the formation of flocculent material due to excessive alkalinity.

[0078] In an embodiment of the present invention, the swelling is preferably performed at room temperature, and the swelling time may be 12 hours.

[0079] In the present invention, stirring is preferably performed after swelling to prevent the formation of flocculent matter due to excessive alkalinity of the swollen gel.

[0080] The method provided by the present invention is simple to operate and can encapsulate an analgesic drug in lecithin chitosan nanoparticles, allowing the analgesic drug to be slowly released and prolonging the analgesic effect of the drug. The present invention uniformly disperses the lecithin chitosan nanoparticles encapsulating the analgesic drug in a gel matrix through mixing. By selecting the gel matrix, the lecithin chitosan nanoparticles encapsulating the analgesic drug can quickly penetrate the stratum corneum of the skin, allowing the lecithin chitosan nanoparticle gel loaded with the analgesic drug to exert a combination of fast-acting and sustained-release effects, thereby prolonging the action time of the analgesic drug, improving bioavailability, and exerting a long-lasting analgesic effect.

[0081] The present invention also provides the use of the analgesic drug-loaded lecithin chitosan nanoparticle gel described in the above technical solution or the analgesic drug-loaded lecithin chitosan nanoparticle gel prepared by the preparation method described in the above technical solution as a transdermal administration preparation.

[0082] The present invention has no particular limitation on the method of using the analgesic-loaded lecithin chitosan nanoparticle gel in a transdermal preparation, and conventional application methods may be used.

[0083] The present invention disperses lecithin chitosan nanoparticles loaded with analgesics in a gel matrix, so that the lecithin chitosan nanoparticles loaded with analgesics can quickly penetrate the stratum corneum of the skin. The lecithin chitosan nanoparticle gel loaded with analgesics can exert a combination of fast-acting and sustained-release effects, prolong the duration of the analgesic effect, improve the bioavailability, and exert a long-term analgesic effect. Therefore, the invention can be used as a transdermal drug administration preparation.

[0084] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0085] For comparison, the analgesic drugs used in the examples of the present invention and the comparative examples are both levorotatory tetrahydropalmatine, abbreviated as L-THP.

[0086] Example 1

[0087] A lecithin chitosan nanoparticle gel loaded with analgesic drugs, comprising a gel matrix of carbomer 940 (abbreviated as C 940 ) and lecithin chitosan nanoparticles containing analgesic drugs dispersed in the gel matrix;

[0088] The preparation method of the analgesic drug-loaded lecithin chitosan nanoparticle gel is as follows:

[0089] (1) 3.0 mg of analgesic drug and 20 mg of lecithin (abbreviated as S75) were dissolved in 0.8 mL of anhydrous ethanol to obtain an ethanol solution containing lecithin;

[0090] (2) Dissolving chitosan in an acetic acid aqueous solution at a pH of 2.7 to obtain a chitosan mother solution with a concentration of 1 mg / mL; taking 0.8 mL of the chitosan mother solution and diluting it to 10 mL with water, adding TPGS and mixing to obtain a chitosan solution; the mass percentage of TPGS in the chitosan solution is 0.2%;

[0091] (3) under stirring at a speed of 800 rpm, the ethanol solution containing lecithin obtained in the step (1) was dripped into the chitosan solution obtained in the step (2) at a rate of 1 mL / min, and electrostatic adsorption was performed at room temperature for 30 min to obtain a lecithin chitosan nanoparticle suspension containing analgesic drugs (abbreviated as L-THP-L / CS-NPs); the mass ratio of lecithin in the ethanol solution containing lecithin to chitosan in the chitosan solution was 20:1;

[0092] (4) The L-THP-L / CS-NPs suspension obtained in step (3) was added; 150 mg of the gel matrix (C 940 ) and 24 mg of sodium hydroxide were dissolved in 2 mL of water, swollen at room temperature for 12 h, and stirred to obtain a swollen gel matrix; the L-THP-L / CS-NPs suspension was mixed with the swollen gel matrix to obtain an analgesic-loaded lecithin chitosan nanoparticle gel (abbreviated as L-THP-L / CS-NPs-gel).

[0093] In the step (1), the mass ratio of the analgesic drug to lecithin is 3.0:20;

[0094] The volume ratio of the gel matrix in step (4) to the lecithin chitosan nanoparticles encapsulating the analgesic drug is 2:8.

[0095] The test results of the formula and the encapsulation efficiency of the prepared L-THP-L / CS-NPs in this example are shown in Table 1.

[0096] Example 2

[0097] A lecithin chitosan nanoparticle gel loaded with analgesic drugs, comprising a gel matrix (C 940 ) and lecithin chitosan nanoparticles containing analgesic drugs dispersed in the gel matrix;

[0098] The method for preparing the analgesic-loaded lecithin chitosan nanoparticle gel is different from that in Example 1 in that the pH value of the acetic acid aqueous solution in step (2) is 2.9, and the remaining steps are the same as those in Example 1.

[0099] The test results of the formula and the encapsulation efficiency of the prepared L-THP-L / CS-NPs in this example are shown in Table 1.

[0100] Example 3

[0101] A lecithin chitosan nanoparticle gel loaded with analgesic drugs, comprising a gel matrix (C 940 ) and lecithin chitosan nanoparticles containing analgesic drugs dispersed in the gel matrix;

[0102] The method for preparing the analgesic-loaded lecithin chitosan nanoparticle gel is different from that in Example 1 in that the mass percentage of TPGS in the chitosan solution in step (2) is 0.1%; the mass ratio of lecithin in the ethanol solution containing lecithin to chitosan in the chitosan solution in step (3) is 15:1, and the remaining steps are the same as in Example 1.

[0103] The test results of the formula and the encapsulation efficiency of the prepared L-THP-L / CS-NPs in this example are shown in Table 1.

[0104] Example 4

[0105] A lecithin chitosan nanoparticle gel loaded with analgesic drugs, comprising a gel matrix (C 940 ) and lecithin chitosan nanoparticles containing analgesic drugs dispersed in the gel matrix;

[0106] The preparation method of the analgesic-loaded lecithin chitosan nanoparticle gel is different from that of Example 1 in that the mass percentage of TPGS in the chitosan solution in step (2) is 0.1%; the pH value of the acetic acid aqueous solution in step (2) is 2.9; and the mass ratio of lecithin in the ethanol solution containing lecithin to chitosan in the chitosan solution in step (3) is 15:1. The remaining steps are the same as those in Example 1.

[0107] The test results of the formula and the encapsulation efficiency of the prepared L-THP-L / CS-NPs in this example are shown in Table 1.

[0108] Example 5

[0109] A lecithin chitosan nanoparticle gel loaded with analgesic drugs, comprising a gel matrix (C 940 ) and lecithin chitosan nanoparticles containing analgesic drugs dispersed in the gel matrix;

[0110] The method for preparing the analgesic-loaded lecithin chitosan nanoparticle gel is different from that in Example 1 in that the mass percentage of TPGS in the chitosan solution in step (2) is 0.1%; the mass ratio of lecithin in the ethanol solution containing lecithin to chitosan in the chitosan solution in step (3) is 25:1, and the remaining steps are the same as in Example 1.

[0111] The test results of the formula and the encapsulation efficiency of the prepared L-THP-L / CS-NPs in this example are shown in Table 1.

[0112] Example 6

[0113] A lecithin chitosan nanoparticle gel loaded with analgesic drugs, comprising a gel matrix (C 940 ) and lecithin chitosan nanoparticles containing analgesic drugs dispersed in the gel matrix;

[0114] The preparation method of the analgesic-loaded lecithin chitosan nanoparticle gel is different from that of Example 1 in that the mass percentage of TPGS in the chitosan solution in step (2) is 0.1%; the pH value of the acetic acid aqueous solution in step (2) is 2.9; and the mass ratio of lecithin in the lecithin-containing ethanol solution to chitosan in the chitosan solution in step (3) is 25:1. The remaining steps are the same as those in Example 1.

[0115] The test results of the formula and the encapsulation efficiency of the prepared L-THP-L / CS-NPs in this example are shown in Table 1.

[0116] Example 7

[0117] A lecithin chitosan nanoparticle gel loaded with analgesic drugs, comprising a gel matrix (C 940 ) and lecithin chitosan nanoparticles containing analgesic drugs dispersed in the gel matrix;

[0118] The method for preparing the analgesic-loaded lecithin chitosan nanoparticle gel is different from that in Example 1 in that the pH value of the acetic acid aqueous solution in step (2) is 2.8; the mass ratio of lecithin in the lecithin-containing ethanol solution to chitosan in the chitosan solution in step (3) is 15:1, and the remaining steps are the same as in Example 1.

[0119] The test results of the formula and the encapsulation efficiency of the prepared L-THP-L / CS-NPs in this example are shown in Table 1.

[0120] Example 8

[0121] A lecithin chitosan nanoparticle gel loaded with analgesic drugs, comprising a gel matrix (C 940) and lecithin chitosan nanoparticles containing analgesic drugs dispersed in the gel matrix;

[0122] The preparation method of the analgesic-loaded lecithin chitosan nanoparticle gel is different from that of Example 1 in that the pH value of the acetic acid aqueous solution in step (2) is 2.8; the mass ratio of lecithin in the lecithin-containing ethanol solution to chitosan in the chitosan solution in step (3) is 25:1, and the remaining steps are the same as those in Example 1.

[0123] The test results of the formula and the encapsulation efficiency of the prepared L-THP-L / CS-NPs in this example are shown in Table 1.

[0124] Example 9

[0125] A lecithin chitosan nanoparticle gel loaded with analgesic drugs, comprising a gel matrix (C 940 ) and lecithin chitosan nanoparticles containing analgesic drugs dispersed in the gel matrix;

[0126] The preparation method of the analgesic-loaded lecithin chitosan nanoparticle gel is different from that of Example 1 in that the mass percentage of TPGS in the chitosan solution in step (2) is 0.1%; the pH value of the acetic acid aqueous solution in step (2) is 2.8; and the remaining steps are the same as those in Example 1.

[0127] The test results of the formula and the encapsulation efficiency of the prepared L-THP-L / CS-NPs in this example are shown in Table 1. This example was repeated 5 times.

[0128] Comparative Example 1

[0129] A lecithin chitosan nanoparticle gel loaded with analgesic drugs, comprising a gel matrix (C 940 ) and lecithin chitosan nanoparticles containing analgesic drugs dispersed in the gel matrix;

[0130] The method for preparing the analgesic-loaded lecithin chitosan nanoparticle gel is different from that in Example 1 in that the mass percentage of TPGS in the chitosan solution in step (2) is 0%; the remaining steps are the same as in Example 1.

[0131] The test results of the formula and the encapsulation efficiency of the prepared L-THP-L / CS-NPs in this example are shown in Table 1.

[0132] Comparative Example 2

[0133] A lecithin chitosan nanoparticle gel loaded with analgesic drugs, comprising a gel matrix (C 940 ) and lecithin chitosan nanoparticles containing analgesic drugs dispersed in the gel matrix;

[0134] The preparation method of the analgesic-loaded lecithin chitosan nanoparticle gel is different from that of Example 1 in that the mass percentage of TPGS in the chitosan solution in step (2) is 0%; the pH value of the acetic acid aqueous solution in step (2) is 2.9; and the remaining steps are the same as those in Example 1.

[0135] The test results of the formula and the encapsulation efficiency of the prepared L-THP-L / CS-NPs in this example are shown in Table 1.

[0136] Comparative Example 3

[0137] A lecithin chitosan nanoparticle gel loaded with analgesic drugs, comprising a gel matrix (C 940 ) and lecithin chitosan nanoparticles containing analgesic drugs dispersed in the gel matrix;

[0138] The preparation method of the analgesic-loaded lecithin chitosan nanoparticle gel is different from that of Example 1 in that the mass percentage of TPGS in the chitosan solution in step (2) is 0%; the pH value of the acetic acid aqueous solution in step (2) is 2.8; the mass ratio of lecithin in the lecithin-containing ethanol solution to chitosan in the chitosan solution in step (3) is 15:1, and the remaining steps are the same as those in Example 1.

[0139] The test results of the formula and the encapsulation efficiency of the prepared L-THP-L / CS-NPs in this example are shown in Table 1.

[0140] Comparative Example 4

[0141] A lecithin chitosan nanoparticle gel loaded with analgesic drugs, comprising a gel matrix (C 940 ) and lecithin chitosan nanoparticles containing analgesic drugs dispersed in the gel matrix;

[0142] The preparation method of the analgesic-loaded lecithin chitosan nanoparticle gel is different from that of Example 1 in that the mass percentage of TPGS in the chitosan solution in step (2) is 0%; the pH value of the acetic acid aqueous solution in step (2) is 2.8; the mass ratio of lecithin in the lecithin-containing ethanol solution to chitosan in the chitosan solution in step (3) is 25:1, and the remaining steps are the same as those in Example 1.

[0143] The test results of the formula and the encapsulation efficiency of the prepared L-THP-L / CS-NPs in this example are shown in Table 1.

[0144] BBC experimental results: The model was fitted with encapsulation efficiency as the dependent variable, and the relevant regression equation was obtained: Encapsulation efficiency (%) = 50.38 + 1.76A + 4.06B + 2.81C - 0.5400AB - 0.4850AC + 1.57BC - 0.0930A 2 -5.78B 2 -0.463C 2 The model P=0.0011 (P<0.05) was statistically significant, and the lack-of-fit term P=0.3817 (P>0.05) was not statistically significant, indicating that the model had high accuracy. The software predicted the optimal formulation to be pH: 2.899, stabilizer content: 0.142%, lecithin-chitosan ratio: 24.993, and encapsulation efficiency: 55.009%. The test results of Examples 1-9 and Comparative Examples 1-4 are shown in Table 1. The significance results of the BBC experiment are shown in Table 2.

[0145] Table 1 Test results of Examples 1 to 9 and Comparative Examples 1 to 4

[0146]

[0147]

[0148] Table 2. Significant results of BBC experiment

[0149] source sum of squares degrees of freedom mean square F P Significance Model 375.36 9 41.71 13.82 0.0011 * ApH 24.71 1 24.71 8.19 0.0243 * B stabilizer content 131.87 1 131.87 43.69 0.0003 * C egg shell ratio 62.97 1 62.94 20.85 0.0026 * AB 1.17 1 1.17 0.3864 0.5539 AC 0.9409 1 0.9409 0.3117 0.5940 BC 9.86 1 9.86 3.27 0.1136 <![CDATA[A 2 ]]> 0.0364 1 0.0364 0.0121 0.9156 <![CDATA[B 2 ]]> 140.57 1 140.57 46.57 0.0002 * <![CDATA[C 2 ]]> 0.9026 1 0.9026 0.2990 0.6015 residual 21.13 7 3.02 Lack of Fit 10.56 3 3.52 1.33 0.3817 Pure error 10.57 4 2.64 Total deviation 396.49 16

[0150] * indicates significant (P<0.05)

[0151] Verification of the Optimal Prescription Five groups of analgesic-loaded lecithin chitosan nanoparticles prepared in Example 9 were prepared in parallel. The encapsulation efficiency of the analgesic-loaded lecithin chitosan nanoparticles was measured and compared with the predicted value. The results are shown in Table 3.

[0152] Table 3 Optimal prescription verification

[0153] Grouping 1 2 3 4 5 Actual value% Predicted value% Error value% Encapsulation efficiency% 53.13 53.85 54.60 56.96 54.69 54.65±0.014 55.009 0.7

[0154] As shown in Table 3, the error between the actual measured encapsulation efficiency and the predicted encapsulation efficiency is 0.7%, which is less than 5%, indicating that the model is accurate and reliable. Therefore, the optimal formulation for the preparation method of the analgesic-loaded lecithin-chitosan nanoparticle gel provided by the present invention is pH: 2.899, stabilizer content: 0.142%, lecithin-chitosan ratio: 24.993, and encapsulation efficiency: 55.009%.

[0155] Example 10

[0156] A lecithin chitosan nanoparticle gel loaded with analgesic drugs, comprising a gel matrix (C 940) and lecithin chitosan nanoparticles containing analgesic drugs dispersed in the gel matrix;

[0157] The method for preparing the analgesic-loaded lecithin chitosan nanoparticle gel is different from that in Example 1 in that the mass percentage of TPGS in the chitosan solution in step (2) is 0.142%; the pH value of the acetic acid aqueous solution in step (2) is 2.899; the mass ratio of lecithin in the ethanol solution containing lecithin to chitosan in the chitosan solution in step (3) is 24.993:1; and the remaining steps are the same as in Example 1.

[0158] Comparative Example 5

[0159] The preparation method of L-THP-SOL-gel is as follows: 2.5 mg L-THP is dissolved in 1 mL of anhydrous ethanol and evenly dispersed in the swollen gel matrix.

[0160] Test Case

[0161] (1) The method of Example 10 was repeated five times in parallel. The encapsulation efficiency of the prepared L-THP-L / CS-NPs was 54.65±0.014%, and the drug loading was 4.741±0.0060%.

[0162] (2) The L-THP-L / CS-NPs prepared in Example 10 were tested, and the Tyndall effect diagram was obtained as shown in FIG. Figure 1 As shown; TEM images are shown Figure 2 The particle size of L-THP-L / CS-NPs was measured by Zetasizer Nano-ZS90 nanoparticle size analyzer, and the particle size was as shown in FIG. Figure 3 As shown in (a), the potential is Figure 3 (b) is shown. Figure 3 It can be seen that the particle size of L-THP-L / CS-NPs prepared in Example 10 is 253.2±1.5, PDI is 0.202±2.5, and Zeta potential is 38.61±5.3.

[0163] (2) FT-IR spectra of L-THP, lecithin, L-THP-SOL-gel prepared in Comparative Example 5, and L-THP-L / C-NPs prepared in Example 10 are shown in FIG. Figure 4 As shown. Figure 4 In the experiment, CS is chitosan; SL is lecithin; and physical mixtures is L-THP-SOL-gel. Figure 4 It can be seen that the characteristic peaks of L-THP are 1514.4 cm -1 (benzene ring CH in-plane swing and methylene CH shear vibration), 1282.7 cm -1 and 1254.6cm-1 Belongs to C(PH)-O-(-OCH3), 1101.2cm -1 and 1079.3cm -1 Belongs to C(-CH3)-O, 1138cm -1 Vibration of CN bond, 1029.2 cm -1 Belongs to the CC stretching vibration of the thiazine ring. Phospholipid characteristic peaks include: 2923.1cm -1 and 2857.3cm -1 (long fatty acid chain CH stretching band), 1730.4cm -1 (C=O stretch belt), 1235.8cm -1 (P=O stretch belt), 1085.5cm -1 (POC stretch belt) and 966.6cm -1 (N+(CH3)3 stretching band). The characteristic peak of CS is 1655.3cm -1 The carbonyl (C=O) stretching vibration of amide I, 1595.8 cm -1 It belongs to the NH bending vibration of amide II. The characteristic peak of TPGS belongs to 1733.5cm -1 C=O stretching vibration, 1107.4cm -1 is the stretching vibration of COC. In the spectrum of L-THP-L / C-NPs, the stretching vibration at 1736.6 cm is due to the stretching of the fatty acid carbonyl group. -1 The absorption band intensity of chitosan at 1595.8 cm -1 The NH bending vibration characteristic peak at 100 nm disappeared in the spectrum of L-THP-L / C-NPs, indicating that ionic interactions occurred between chitosan and phosphatidylcholine. The disappearance of the characteristic peak of L-THP and the red shift of the characteristic peak of TPGS indicated that L-THP was successfully encapsulated in the formulation.

[0164] (3) The stability of the L-THP-L / C-NPs prepared in Example 10 was investigated: the particle size, potential, and PDI were measured at 25°C and 4°C for three months using a nanoparticle size analyzer. At three months, the particle size at 25°C was 276.5±6.1 nm, the potential was 32.5±0.78, the PDI was 0.220±0.0085, the encapsulation efficiency was 36.86±2.962, and the drug loading was 2.031±0.1508. At 4°C, the particle size was 266.8±3.0 nm, the potential was 25.0±1.6, and the PDI was 0.211±0.0056. The encapsulation efficiency was 55.63±3.9%, and the drug loading was 2.450±0.12%. The L-THP-L / CS-NPs solution increased in particle size and decreased in particle encapsulation efficiency when stored at 25°C, while there was no significant increase in particle size and no significant decrease in encapsulation efficiency when stored at 4°C, indicating that the nanoparticle solution was more stable when stored at 4°C than at 25°C.

[0165] The L-THP-L / CS-NPs-geL prepared in Example 10 was stored at both room temperature and refrigerated conditions, according to the Chinese Pharmacopoeia's storage requirements for gels. The main focus was on the effects of temperature and long-term storage on the nanoparticles in the gel. Transmission electron microscopy revealed that the nanoparticles in the L-THP-L / CS-NPs-geL at 4°C for 60 days were round or quasi-round in appearance, uniform in size, and well dispersed. However, at 25°C for 30 days, some nanoparticles in the L-THP-L / CS-NPs-geL aggregated, and after 45 days, the particle size increased. By 60 days, most of the particles had aggregated and increased in size, with some particles broken. This may be due to the absorption of water from the gel matrix by the chitosan hydration layer during storage at 25°C, which increases the nanoparticle size. Temperature and light exposure can lead to oxidation of lecithin, which in turn causes oxidative fracture of the nanoparticles. L-THP can also undergo oxidative deterioration under light and temperature. The determination of its content also found that the drug properties were stable under storage conditions of 4°C. When L-THP-L / CS-NPs-geL and L-THP-SOL-gel were compared under the same storage conditions, it was found that L-THP-SOL-gel without preservatives became moldy within 60 days, while L-THP-L / CS-NPs-geL showed no obvious deterioration, indicating that chitosan played a significant antibacterial role in this preparation.

[0166] (4) In vitro release of L-THP-L / CS-NPs

[0167] The cumulative release of L-THP-L / C-NPs-gel prepared in Example 10 and L-THP-SOL-gel prepared in Comparative Example 5 is as follows: Figure 5 As shown. Figure 5As can be seen, L-THP-L / CS-NPs exhibited a significant combination of rapid and sustained release. Within the first 4 hours, they demonstrated a significant rapid release effect, releasing 57.05% of the total drug dose. From 4 to 24 hours, they exhibited a significant sustained release effect, with cumulative release reaching 77.37% of the total drug dose within 24 hours, demonstrating a significant sustained-release profile. L-THP-SOL, on the other hand, released more rapidly, exhibiting a burst release within the first 4 hours, releasing 75.31% of the total drug dose within 4 hours, and 94.60% of the total drug dose within 24 hours. Compared to L-THP-SOL, L-THP-L / CS-NPs can release the drug slowly on the skin surface, reducing dosing frequency and extending dosing duration.

[0168] (5) In vitro transdermal permeation of L-THP-L / CS-NPs

[0169] The Q of L-THP-L / CS-NPs prepared in Example 10 and L-THP-SOL prepared in Comparative Example 5 within 24 hours was n-t Curves such as Figure 6 As shown. Figure 6 It can be seen that the cumulative drug permeation of L-THP-L / CS-NPs and L-THP-SOL within 24 h was 161.7±16.9μg / cm 2 and 61.77±17.4μg / cm 2 Compared with L-THP-SOL, L-THP-L / CS-NPs significantly increased the cumulative drug permeation, and the J ss 2.9 times that of L-THP-SOL, K p 2.9 times, Q S This indicates that L-THP-L / CS-NPs has a stronger penetration effect than L-THP-SOL.

[0170] (6) In vitro release and permeation of L-THP-L / CS-NPs-gel

[0171] The cumulative release rates of L-THP-L / CS-NPs-gel prepared in Example 10 and L-THP-SOL-gel prepared in Comparative Example 5 (n=3) are shown in FIG. Figure 7 As shown. Figure 7 It can be seen that L-THP-SOL has a faster release rate, releasing over 70% of the drug within the first 5 hours, and the drug release is complete at 7 hours. In contrast, the release rate of L-THP-L / CS-NPs-gel is relatively stable. The drug release rate is comparable to that of L-THP-SOL within 0-1 hour, showing a rapid effect. The release is steady from 2 to 7 hours, gradually reaching stability after 7 hours, and 88.87% of the drug can be released within 24 hours.

[0172] (7) In vitro percutaneous penetration

[0173] The Q of L-THP-L / CS-NPs-gel prepared in Example 10 and L-THP-SOL-gel prepared in Comparative Example 5 within 24 hours was n-t Curves such as Figure 8 As shown. Figure 8 It can be seen that the cumulative drug permeation of L-THP-L / CS-NPs-gel and L-THP-SOL-gel within 24 h was 88.90 μg / cm 2 and 61.88 μg / cm 2 Compared with L-THP-SOL-gel, L-THP-L / CS-gel significantly increased the cumulative drug permeation amount, and the J ss 2.9 times that of L-THP-SOL-gel, K p 2.9 times, Q S This indicates that L-THP-L / CS-NPs-gel has a stronger penetration effect than L-THP-SOL-gel group.

[0174] (8) Safety evaluation of L-THP-L / C-NPs-gel

[0175] Five volunteers were recruited. Before the experiment, both upper limbs of the volunteers were checked for scars, ulcers and other wounds. If there were scars, ulcers and other wounds, the volunteers would withdraw from the experiment.

[0176] Results of a single skin irritation test: A combination of questioning and observation was used to observe the administration area of ​​the volunteers' arms with the naked eye to see if there were any erythema, swelling, itching, urticaria, rough skin, and cracked skin. At the same time, the volunteers were asked about their skin feel and odor after use and were scored after comprehensive evaluation. The results of the single skin irritation of L-THP-L / C-NPs-gel are shown in Table 4 and Figure 9 shown.

[0177] Table 4. Single-dose skin irritation reaction scores of L-THP-L / C-NPs-gel

[0178]

[0179] Depend on Figure 9 As shown in Table 4, there was no significant difference between the blank gel and L-THP-L / C-NPs-gel groups after multiple administration within 48 h, indicating that there was no obvious irritation adverse reaction within 48 h after a single administration.

[0180] Results of multiple skin irritation tests: The results of multiple skin irritation tests of L-THP-L / C-NPs-gel are shown in the figure below. Figure 10 and shown in Table 5.

[0181] Table 5 L-THP-L / C-NPs-gel skin irritation multiple administration reaction scores

[0182]

[0183] Depend on Figure 10 As shown in Table 5, within 7 days of continuous use, no obvious irritation adverse reactions occurred in the blank gel group and the L-THP-L / C-NPs-gel group, indicating that the L-THP-L / C-NPs-gel group had almost no irritation to the skin after multiple administrations.

[0184] The above results show that the average skin irritation reaction score of the L-THP-L / C-NPs-gel prepared by the present invention is less than 0.49 at each time period, and is non-irritating to human skin.

[0185] The above results indicate that the L-THP-L / C-NPs-gel provided by the present invention can enhance transdermal penetration and prolong the duration of drug analgesia. This is because the L-THP-L / C-NPs are dispersed in a gel matrix. The selection of the gel matrix allows the L-THP-L / C-NPs to penetrate the stratum corneum of the skin more quickly. Furthermore, the L-THP-L / C-NPs-gel can combine rapid-acting and sustained-release effects, extending the duration of action of the analgesic drug, improving its bioavailability, and achieving a long-lasting analgesic effect.

[0186] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A lecithin chitosan nanoparticle gel loaded with analgesic drugs, characterized in that: The invention comprises a gel matrix and lecithin chitosan nanoparticles containing analgesic drugs and dispersed in the gel matrix; The analgesic drug loading amount in the lecithin chitosan nanoparticles containing the analgesic drug is 2-5%; The volume ratio of the gel matrix to the analgesic drug-encapsulated lecithin chitosan nanoparticles is (1-3): (7-9).

2. The analgesic-loaded lecithin chitosan nanoparticle gel according to claim 1, characterized in that: The particle size of the lecithin chitosan nanoparticles loaded with analgesic drugs is 253.2±1.5 nm, the PDI is 0.202±2.5, and the potential is 38.61±5.3 mV.

3. The analgesic-loaded lecithin chitosan nanoparticle gel according to claim 1 or 2, characterized in that: The encapsulation efficiency of the analgesic drug-encapsulated lecithin-chitosan nanoparticles was 54.65±0.014%.

4. The analgesic-loaded lecithin chitosan nanoparticle gel according to claim 1, characterized in that: The analgesic drug in the lecithin chitosan nanoparticles containing the analgesic drug comprises one or more of levorotatory tetrahydropalmatine, triptolide, tetrandrine, aconitine and paeoniflorin.

5. The method for preparing the analgesic drug-loaded lecithin chitosan nanoparticle gel according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) mixing an analgesic drug, lecithin, and ethanol to obtain an ethanol solution containing lecithin; (2) mixing chitosan, a stabilizer and an acetic acid aqueous solution to obtain a chitosan solution; (3) under stirring, dripping the ethanol solution containing lecithin obtained in step (1) into the chitosan solution obtained in step (2) to perform electrostatic adsorption to obtain lecithin chitosan nanoparticles loaded with analgesic drugs; (4) mixing the analgesic-loaded lecithin chitosan nanoparticles obtained in step (3) with a gel matrix to obtain an analgesic-loaded lecithin chitosan nanoparticle gel; The mass ratio of the analgesic drug to lecithin in step (1) is (2-4): (20-30); The volume ratio of the gel matrix and the lecithin chitosan nanoparticles loaded with the analgesic drug in step (4) is (1-3): (7-9).

6. The preparation method according to claim 5, characterized in that The mass ratio of the lecithin in step (1) to the chitosan in step (2) is 10-20:

1.

7. The preparation method according to claim 5, characterized in that The pH value of the acetic acid aqueous solution in step (2) is 2.7 to 3.

0.

8. The preparation method according to claim 5, characterized in that The temperature of the electrostatic adsorption in the step (3) is 20 to 28° C., and the time of the electrostatic adsorption is 30 to 90 minutes.

9. The preparation method according to claim 5, characterized in that The stirring speed in the step (3) is 200 to 1500 rpm.

10. Use of the analgesic drug-loaded lecithin chitosan nanoparticle gel according to any one of claims 1 to 4 or the analgesic drug-loaded lecithin chitosan nanoparticle gel prepared by the preparation method according to any one of claims 5 to 9 as a transdermal administration preparation.

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