Riptacaine nano-cream and preparation method thereof

Abstract

The invention provides ripdicaine nano-cream and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. According to the riprodicaine nano-cream provided by the invention, the riprodicaine-entrapped nanoparticles are dispersed in the cream matrix, and the riprodicaine-entrapped nanoparticles can control lidocaine and prilocaine to have a stable proportion, and can enable the riprodicaine nano-cream to have a good slow-release effect; the transdermal permeability of lidocaine and prilocaine is improved by utilizing the effect of the cream matrix. The result of the embodiment shows that the riptacaine nano-cream provided by the invention has good stability, permeability and slow release effect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a lidocaine and prilocaine nanometer cream and a preparation method thereof. BACKGROUND

[0002] Emla cream, which is composed of lidocaine and prilocaine, is a compound local anesthetic and is widely used for local anesthesia in clinical operations such as skin puncture, laser therapy and superficial surgery. However, the existing commercially available lidocaine and prilocaine cream dosage forms have the following technical challenges in actual application: first, due to the physicochemical properties of lidocaine and prilocaine, the effective penetration of lidocaine and prilocaine on the skin is limited, which results in a relatively long onset time of Emla cream, usually 30-60 minutes, and problems such as incomplete anesthetic effect or insufficient action time, which makes it difficult to meet the needs of rapid and long-acting anesthesia in clinical practice. Second, high-concentration Emla cream applied to the skin surface for a long time can easily cause local irritation such as skin dryness, erythema, itching and swelling, thereby reducing the medication compliance and comfort of patients. Third, lidocaine and prilocaine are weakly basic drugs with limited solubility in aqueous media. During storage, the existing dosage forms have the risk of drug precipitation or degradation of active ingredients, which affects the product quality and shelf life, and has the problem of poor stability. Fourth, the release and penetration of drugs in traditional cream dosage forms are affected by multiple factors such as skin barrier function, administration method and individual differences, which leads to certain variability in drug bioavailability and affects the uniformity of clinical efficacy. Therefore, how to improve the permeability, sustained-release and stability of Emla cream is a technical problem to be solved in the field.

[0003] The application of nanotechnology in the field of pharmaceutical preparations provides an innovative approach to solving the solubilization, sustained-release, targeted delivery and improvement of bioavailability of poorly soluble drugs. Although nanotechnology has made significant progress in the medical field, the existing Emla cream in the prior art has poor stability, permeability and sustained-release effect in actual use, making it difficult for the drug to exert its efficacy. SUMMARY

[0004] The purpose of the present application is to provide a lidocaine and prilocaine nanometer cream with good stability, permeability and sustained-release effect and a preparation method thereof.

[0005] In order to achieve the above-mentioned purpose of the application, the present application provides the following technical solutions:

[0006] The present application provides a lidocaine and prilocaine nanometer cream, which comprises a cream base and lidocaine and prilocaine nanoparticles loaded in the cream base;

[0007] The mass ratio of lidocaine to prilocaine in the lidocaine and prilocaine nanoparticles is 1:(1±0.5).

[0008] The drug loading of lipracaine in the nanoparticles is 10-25%;

[0009] The mass percentage of lipofacaine in the lipofaca nano-emulsion is 1.0% to 4.0%.

[0010] Preferably, the average particle size of the lipofuscin-loaded nanoparticles is 50 nm to 150 nm; the polydispersity index is ≤0.2.

[0011] Preferably, the carrier material for encapsulating lipofusine nanoparticles includes one or more of polylactic acid-glycolic acid copolymer, polycaprolactone, polylactic acid, polyglycolic acid, polyhydroxyalkanoate, albumin, and chitosan.

[0012] Preferably, the cream base comprises a gel matrix, a solubilizing and moisturizing agent, a penetration enhancer, an emulsifier, a pH adjuster, a preservative, an oily excipient, and water; the emulsifier is composed of an oily emulsifier and an aqueous emulsifier.

[0013] Preferably, the gel matrix comprises one or more of carbomer 940, carbomer 934, carbomer 980, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose.

[0014] Preferably, the penetration enhancer includes one or more of sodium hyaluronate, laurocapram, azone, oleic acid, and cholesterol-PEG1500-biotin conjugate.

[0015] This invention also provides a method for preparing the lipofuscin nano-emulsion described in the above technical solution, comprising the following steps:

[0016] (1) Lidocaine, prilocaine and the carrier material are dissolved in an organic solvent to obtain an oil phase;

[0017] The emulsifier was dissolved in purified water to obtain an aqueous phase;

[0018] The oil phase and the aqueous phase are mixed and then emulsified to obtain an O / W primary emulsion.

[0019] The O / W colostrum was purified after removing the organic solvent to obtain lipoic acid nanoparticles.

[0020] (2) Mix the encapsulated levodiamine nanoparticles obtained in step (1) with the cream matrix to obtain levodiamine nanocream.

[0021] Preferably, the concentration of the carrier material in the oil phase of step (1) is 10-15 mg / mL.

[0022] Preferably, the mass concentration of the emulsifier in the aqueous phase of step (1) is 0.5-5.0%.

[0023] Preferably, the volume ratio of the oil phase to the water phase in step (1) is 1:(2-10).

[0024] This invention provides a lidocaine nano-emulsion, comprising an emulsion matrix and lidocaine-encapsulated nanoparticles dispersed in the emulsion matrix; the mass ratio of lidocaine to prilocaine in the lidocaine-encapsulated nanoparticles is 1:1; the lidocaine loading in the lidocaine-encapsulated nanoparticles is 10-25%; and the mass percentage of lidocaine in the lidocaine nano-emulsion is 1.0-4.0%. In the lidocaine nano-emulsion provided by this invention, the lidocaine-encapsulated nanoparticles are dispersed in the emulsion matrix, which allows for a stable ratio of lidocaine to prilocaine and enables the lidocaine nano-emulsion to have a good sustained-release effect. By dispersing the lidocaine-encapsulated nanoparticles in the emulsion matrix, this invention can utilize the effect of the emulsion matrix to improve the transdermal permeability of lidocaine and prilocaine. The results of the examples show that the lipoic acid nano-emulsion provided by the present invention has good stability, permeability and sustained-release effect. Attached Figure Description

[0025] Figure 1 This is a TEM image of the lipofuscin nano-emulsion prepared in Example 1 of the present invention;

[0026] Figure 2 The cumulative permeation curves of the in vitro transdermal permeation test of the lipoic acid nano-emulsion prepared in Example 1 of this invention and the comparative formulation are shown.

[0027] Figure 3 The in vitro release curves of the lipoic acid nano-emulsion prepared in Example 1 of this invention and the comparative formulation are shown. Detailed Implementation

[0028] This invention provides a levodiamine nanocream, comprising a cream matrix and levodiamine nanoparticles dispersed in the cream matrix;

[0029] The mass ratio of lidocaine to prilocaine in the lidocaine-encapsulated nanoparticles is 1:(1±0.5).

[0030] The drug loading of lipracaine in the nanoparticles is 10-25%;

[0031] The mass percentage of lipofacaine in the lipofaca nano-emulsion is 1.0% to 4.0%.

[0032] The lipoic acid nano-cream provided by this invention includes a cream base.

[0033] In this invention, the cream base preferably includes a gel matrix, a solubilizing and moisturizing agent, a penetration enhancer, an emulsifier, a pH adjuster, a preservative, an oily excipient, and water.

[0034] In this invention, the gel matrix preferably includes one or more of carbomer 940, carbomer 934, carbomer 980, hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose, more preferably carbomer 940. By selecting the above-mentioned gel matrix as a thickener, this invention exhibits good thixotropy and spreadability, and demonstrates superior thickening effect at pH 8.0–9.0.

[0035] In this invention, the gel matrix preferably comprises 0.8% to 2.5% of the mass of the lipopropylcaine nanoemulsion. As one embodiment of this invention, the gel matrix may comprise 0.8%, 1.0%, 1.5%, 2.0%, or 2.5% of the mass of the lipopropylcaine nanoemulsion.

[0036] In this invention, the solubilizing and moisturizing agent preferably includes one or more of propylene glycol, glycerin, butylene glycol, and polyethylene glycol 400, more preferably one or more of propylene glycol, glycerin, and butylene glycol, and even more preferably propylene glycol and / or glycerin. In this invention, when the solubilizing and moisturizing agent is propylene glycol and glycerin, the mass ratio of propylene glycol to glycerin is preferably 2-4:1, more preferably 3-4:1. This invention, by adding a solubilizing and moisturizing agent, can assist in drug dissolution and improve the moisturizing effect.

[0037] In this invention, the solubilizing and moisturizing agent preferably constitutes 8.0% to 18.0% of the mass percentage of the lipopropylcaine nanoemulsion. As one embodiment of this invention, the solubilizing and moisturizing agent may constitute 8.0%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 16.0%, 17.0%, or 18.0% of the mass percentage of the lipopropylcaine nanoemulsion.

[0038] In this invention, the penetration enhancer preferably includes one or more of sodium hyaluronate, laurocapram, azone, oleic acid, and cholesterol-PEG1500-Biotin conjugate, more preferably sodium hyaluronate and / or cholesterol-PEG1500-Biotin conjugate. In this invention, when the penetration enhancer is preferably sodium hyaluronate and cholesterol-PEG1500-Biotin conjugate, the mass ratio of sodium hyaluronate to cholesterol-PEG1500-Biotin conjugate is preferably 1 to 2:1. In this invention, the molecular weight of the cholesterol-PEG1500-Biotin conjugate is preferably 2000 to 2500 Da; this invention does not have a special limitation on the source of the cholesterol-PEG1500-Biotin conjugate, and conventional commercially available products or conventional preparation methods can be used. In this invention, the molecular weight of the sodium hyaluronate is preferably 50,000 to 500,000 Da. By adding the above-mentioned penetration enhancer, this invention can synergistically promote the drug penetration of liprocaine and improve skin affinity.

[0039] In this invention, the penetration enhancer preferably accounts for 0.8% to 3.0% of the mass percentage of the lipopropylcaine nanoemulsion. As one embodiment of this invention, the penetration enhancer may account for 0.8%, 1.0%, 1.5%, 2.0%, 2.5%, or 3.0% of the mass percentage of the lipopropylcaine nanoemulsion.

[0040] In this invention, the emulsifier is composed of an oil-based emulsifier and an aqueous emulsifier. Preferably, the oil-based emulsifier comprises polyoxyethylene lauryl ether; the aqueous emulsifier preferably comprises one or more of polyvinyl alcohol, polysorbate 80, and poloxamer 188, more preferably one or more of polyvinyl alcohol and polysorbate 80. Preferably, the molecular weight of the polyvinyl alcohol is 10,000–100,000 Da, more preferably 30,000–70,000 Da; the degree of hydrolysis of the polyvinyl alcohol is preferably 80–90%, more preferably 87–89%. When the emulsifier is polyoxyethylene lauryl ether and polysorbate 80, the mass ratio of polyoxyethylene lauryl ether to polysorbate 80 is preferably 2–3:1. This invention forms a stable O / W type emulsion system by adding an emulsifier.

[0041] In this invention, the emulsifier is preferably present in the form of 1.5% to 4.0% by mass of the lipopropylcaine nanoemulsion. As one embodiment of this invention, the emulsifier may be present in the form of 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, or 4.0% by mass.

[0042] In this invention, the pH adjuster preferably includes triethanolamine or sodium hydroxide solution, and the concentration of the sodium hydroxide solution is preferably 0.1–1.0 mol / L, more preferably 0.5 mol / L. This invention adjusts the pH value of the cream base by adding a pH adjuster. In this invention, the pH value of the cream base is preferably 8.0–9.0, more preferably 8.5. By controlling the pH value of the cream base within the above range, this invention helps to improve the stability and transdermal penetration of lidocaine and prilocaine free bases. This invention does not specifically limit the amount of the pH adjuster; it is sufficient to achieve a pH value of 8.0–9.0 for the cream base.

[0043] In this invention, the preservative preferably includes one or more of methylparaben, propylparaben, and phenoxyethanol, more preferably methylparaben and / or propylparaben. In this invention, when the preservative is preferably methylparaben and propylparaben, the mass ratio of methylparaben to propylparaben is preferably 5–10:1, more preferably 6–8:1.

[0044] In this invention, the preservative is preferably present in the following percentage by mass of the lipofuscin nanoemulsion: 0.1% to 0.3%. As one embodiment of this invention, the preservative may be present in the following percentage by mass of the lipofuscin nanoemulsion: 0.1%, 0.15%, 0.18%, 0.2%, 0.25%, or 0.3%.

[0045] In this invention, the oily excipients preferably include one or more of liquid paraffin, petrolatum, and vegetable oils. In this invention, the oily excipients provide good spreadability and lubricity to the cream matrix, which is beneficial for forming a stable emulsion system.

[0046] In this invention, the oily excipients preferably constitute 8-15% of the mass of the lipopropylcaine nanoemulsion. As one embodiment of this invention, the oily excipients may constitute 8%, 9%, 10%, 12%, or 15% of the mass of the lipopropylcaine nanoemulsion.

[0047] In this invention, the water is preferably purified water. In this invention, the water constitutes 35-70% of the mass percentage of the lipopropylcaine nano-emulsion, more preferably 35-65%.

[0048] The levodiamine nano-cream provided by the present invention comprises levodiamine nanoparticles dispersed in the cream matrix.

[0049] In this invention, the mass ratio of lidocaine to prilocaine in the lidocaine-loaded nanoparticles is 1:(1±0.5), preferably 1:1. By controlling the mass ratio of lidocaine to prilocaine in the lidocaine-loaded nanoparticles to 1:(1±0.5), lidocaine has a relatively rapid onset of action, while prilocaine provides better anesthetic depth. The combination of the two complements each other, providing a more comprehensive and prolonged anesthetic effect.

[0050] In this invention, the lepromazine loading in the lepromazine-encapsulated nanoparticles is 10-25%. As one embodiment of this invention, the lepromazine loading in the lepromazine-encapsulated nanoparticles can be 10%, 15%, 20%, or 25%. In this invention, the lepromazine loading in the lepromazine-encapsulated nanoparticles refers to the percentage by mass of lepromazine in the lepromazine-encapsulated nanoparticles. By controlling the lepromazine loading in the lepromazine-encapsulated nanoparticles within the above-mentioned range, this invention achieves efficient drug delivery, enabling the lepromazine nano-emulsion to exert its optimal efficacy.

[0051] In this invention, the mass percentage of liprocaine in the liprocaine nanoemulsion is 1.0% to 4.0%. In this invention, the mass percentage of liprocaine in the liprocaine nanoemulsion is simply referred to as the drug loading in the liprocaine nanoemulsion. As one embodiment of this invention, the drug loading in the liprocaine nanoemulsion can be 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, or 4.0%. By controlling the drug loading in the liprocaine nanoemulsion within the above range, this invention enables the liprocaine nanoemulsion to exert a better therapeutic effect.

[0052] In this invention, the encapsulation efficiency of lidocaine and prilocaine in the lidocaine-loaded nanoparticles is independently ≥90%, more preferably ≥92%. By controlling the encapsulation efficiency of lidocaine and prilocaine in the lidocaine-loaded nanoparticles within the above range, this invention can improve the sustained-release effect of the drug.

[0053] In this invention, the average particle size of the lidocaine-encapsulated nanoparticles is preferably 50 nm to 150 nm, and the polydispersity index is preferably ≤0.2. As one embodiment of this invention, the average particle size of the lidocaine-encapsulated nanoparticles can be 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, or 150 nm; the polydispersity index can be 0.2, 0.15, or 0.1. By controlling the average particle size of the lidocaine-encapsulated nanoparticles within the above range, this invention is more conducive to improving the solubility and uniform dispersion of lidocaine and prilocaine in lidocaine nano-emulsions, and can also improve the onset speed of lidocaine nano-emulsions.

[0054] In this invention, the zeta potential of the leuprolide nanoparticles is preferably -15mV to +15mV, more preferably -8.7mV to +8.7mV. By controlling the zeta potential of the leuprolide nanoparticles within the above range, this invention enables the leuprolide nanoparticles to possess better stability.

[0055] In this invention, the carrier material for encapsulating lipofusine nanoparticles preferably includes one or more of polylactic acid-glycolic acid copolymer, polycaprolactone, polylactic acid, polyglycolic acid, polyhydroxy fatty acid ester, albumin, and chitosan, and more preferably polylactic acid-glycolic acid copolymer or polycaprolactone.

[0056] This invention also provides a method for preparing the lipofuscin nano-emulsion described in the above technical solution, comprising the following steps:

[0057] (1) Lidocaine, prilocaine and the carrier material are dissolved in an organic solvent to obtain an oil phase;

[0058] The emulsifier was dissolved in purified water to obtain an aqueous phase;

[0059] The oil phase and the aqueous phase are mixed and then emulsified to obtain an O / W primary emulsion.

[0060] The O / W colostrum was purified after removing the organic solvent to obtain lipoic acid nanoparticles.

[0061] (2) Mix the encapsulated levodiamine nanoparticles obtained in step (1) with the cream matrix to obtain levodiamine nanocream.

[0062] This invention involves dissolving lidocaine, prilocaine, and a carrier material in an organic solvent to obtain an oil phase.

[0063] In this invention, the mass ratio of lidocaine, prilocaine and carrier material is preferably 1:1:4 to 8, more preferably 1:1:6.

[0064] In this invention, the carrier material preferably includes one or more of polylactic acid-glycolic acid copolymer, polycaprolactone, polylactic acid, polyglycolic acid, polyhydroxyalkanoate, albumin, and chitosan, more preferably polylactic acid-glycolic acid copolymer (PLGA) or polycaprolactone (PCL). In this invention, when the carrier material is preferably PLGA, the molecular weight of the PLGA can range from 10,000 to 50,000 Da, and the mass ratio of lactic acid to glycolide is preferably 50:50 to 85:15, more preferably 75:25. In this invention, when the carrier material is PCL, the molecular weight of the PCL can range from 10,000 to 80,000 Da.

[0065] In this invention, the organic solvent preferably includes ethyl acetate, dichloromethane, or chloroform.

[0066] In this invention, the concentration of the carrier material in the oil phase is preferably 10-15 mg / mL, more preferably 12-13 mg / mL.

[0067] The present invention does not specifically limit the method of dissolving lidocaine, prilocaine and the carrier material in an organic solvent, as long as the lidocaine, prilocaine and the carrier material can be completely dissolved in the organic solvent.

[0068] This invention dissolves an emulsifier in purified water to obtain an aqueous phase.

[0069] In this invention, the emulsifier is composed of an oil-based emulsifier and an aqueous emulsifier. Preferably, the oil-based emulsifier comprises polyoxyethylene lauryl ether; the aqueous emulsifier preferably comprises one or more of polyvinyl alcohol, polysorbate 80, and poloxamer 188, more preferably one or more of polyvinyl alcohol and polysorbate 80. Preferably, the molecular weight of the polyvinyl alcohol is 10,000–100,000 Da, more preferably 30,000–70,000 Da; the degree of hydrolysis of the polyvinyl alcohol is preferably 80–90%, more preferably 87–89%. When the emulsifier is polyoxyethylene lauryl ether and polysorbate 80, the mass ratio of polyoxyethylene lauryl ether to polysorbate 80 is preferably 2–3:1. This invention forms a stable O / W type emulsion system by adding an emulsifier.

[0070] In this invention, the emulsifier mass concentration in the aqueous phase is preferably 0.5-5.0%, more preferably 1.0-4.0%. In this invention, the emulsifier mass concentration in the aqueous phase refers to the ratio of the mass of the emulsifier to the volume of water.

[0071] After obtaining the oil phase and the aqueous phase, the present invention mixes the oil phase and the aqueous phase and performs emulsification treatment to obtain an O / W primary emulsion.

[0072] In this invention, the volume ratio of the oil phase to the water phase is preferably 1:(2-10). As one embodiment of this invention, the volume ratio of the oil phase to the water phase can be 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10. By controlling the volume ratio of the oil phase to the water phase within the above range, this invention is more conducive to obtaining encapsulated lipofaine nanoparticles with small particle size and good uniformity.

[0073] In this invention, the emulsification process preferably includes: adding the oil phase dropwise to the aqueous phase, and obtaining an O / W primary emulsion through high-speed shearing or ultrasound. This invention uses high-speed shearing or ultrasound to thoroughly mix the oil and aqueous phases, forming emulsion particles with small and uniform particle size.

[0074] In this invention, the dropping rate is preferably 0.5–2.0 mL / min, more preferably 1.0–1.5 mL / min. Controlling the dropping rate within this range in this invention is more conducive to a more uniform mixing of the oil and water phases.

[0075] In this invention, the high-speed shearing or ultrasonication is preferably performed at room temperature, which is preferably 20-30°C, more preferably 23-25°C.

[0076] In this invention, the ultrasonic power is preferably 200-400W, more preferably 300-350W; the ultrasonic duration is preferably 5-15 minutes, more preferably 10-15 minutes. In an embodiment of this invention, the ultrasonic treatment is preferably performed at a power of 300W, with ultrasonic treatment lasting 5 seconds followed by a 2-second pause, for a total ultrasonic duration of 10 minutes. This invention does not impose any particular limitation on the ultrasonic device; any conventional ultrasonic device can be used. In an embodiment of this invention, the ultrasonic device can be an ultrasonic disruptor.

[0077] After obtaining the O / W colostrum, the present invention removes the organic solvent from the O / W colostrum and then purifies it to obtain leuprolide nanoparticles.

[0078] This invention does not specifically limit the method for removing organic solvents; conventional solvent evaporation methods can be used to sufficiently remove the organic solvents. In this invention, the preferred method for removing organic solvents is rotary evaporation or dialysis. In this invention, the preferred temperature for rotary evaporation is 30–45°C, and the preferred pressure for rotary evaporation is 50–150 mbar, more preferably 100–120 mbar; the rotary evaporation time can be 2 hours. In this invention, the preferred molecular weight cutoff of the dialysis bag used for dialysis is 1,000–10,000 Da; the preferred dialysis time is 1–4 hours.

[0079] In this invention, the purification process preferably includes: centrifuging, ultrafiltration or permeation purification of the nanoparticle suspension obtained after removing the organic solvent, washing the precipitate obtained by centrifugation, ultrafiltration or permeation purification with purified water to obtain a concentrated solution containing nanoparticles.

[0080] This invention does not impose any particular limitation on the centrifugation and washing methods; conventional centrifugation and washing methods are acceptable. In this invention, the centrifugation speed is preferably 15,000–25,000 rpm, more preferably 20,000 rpm; the centrifugation time is preferably 15–30 min, more preferably 20–25 min. In this invention, the washing process can be performed 2–3 times.

[0081] In this invention, the concentration of nanoparticles in the concentrated solution containing nanoparticles is preferably 10-50 mg / mL, more preferably 20-30 mg / mL.

[0082] The present invention preferably dries the concentrated solution containing nanoparticles obtained from the purification process to obtain nanoparticles loaded with levodopamine.

[0083] In this invention, the drying method is preferably freeze-drying or spray-drying. This invention does not specifically limit the freeze-drying or spray-drying method; any conventional freeze-drying or spray-drying method that yields dried leptin nanoparticles is acceptable. In this invention, a protective agent may be added during freeze-drying to protect the structure of the leptin nanoparticles. In this invention, the protective agent is preferably trehalose, mannitol, or lactose; the mass ratio of the protective agent to the volume of the nanoparticle-containing concentrate is preferably 5–15% (w / v), more preferably 5–10% (w / v). In an embodiment of this invention, the freeze-drying method may be: pre-freezing at -40°C for 24 hours; primary drying at -20°C for 48 hours; and secondary drying at 25°C for 12 hours.

[0084] After obtaining the levodopacaine nanoparticles, the present invention mixes the levodopacaine nanoparticles with a cream matrix to obtain a levodopacaine nanocream.

[0085] In this invention, the cream matrix is ​​the same as the cream matrix described in the above technical solution, and will not be repeated here.

[0086] In this invention, the method for preparing the cream base preferably includes:

[0087] The gel matrix is ​​mixed with water to obtain a gelled matrix;

[0088] The gelled matrix is ​​mixed with a solubilizing and moisturizing agent, a penetration enhancer and an aqueous emulsifier to obtain an aqueous gel;

[0089] Oily excipients, oily emulsifiers, and preservatives are mixed to obtain an oil phase solution;

[0090] The oil phase solution and the aqueous phase gel are mixed to obtain the cream matrix.

[0091] In this invention, the gel matrix is ​​preferably mixed with water to obtain a gelled matrix. The method for mixing the gel matrix with water preferably includes: mixing the gel matrix with water at a temperature of 70-75°C and then stirring. This invention achieves thorough hydration and gelation of the gel matrix through stirring.

[0092] After obtaining the gelled matrix, the present invention preferably mixes the gelled matrix with a solubilizing and moisturizing agent, a penetration enhancer, and an aqueous emulsifier to obtain an aqueous gel. In the present invention, the method of mixing the gelled matrix with the solubilizing and moisturizing agent, the penetration enhancer, and the aqueous emulsifier is preferably stirring. The present invention promotes the dissolution of the solubilizing and moisturizing agent, the penetration enhancer, and the aqueous emulsifier in the gelled matrix by stirring.

[0093] This invention preferably involves mixing an oily excipient, an oily emulsifier, and a preservative to obtain an oil-phase solution. In this invention, the method for mixing the oily excipient, oily emulsifier, and preservative preferably includes: heating the oily excipient to 70–75°C, and then mixing the oily emulsifier and preservative with the heated oily excipient. This mixing method improves mixing efficiency.

[0094] After obtaining the oil phase solution and the aqueous phase gel, the present invention preferably mixes the oil phase solution and the aqueous phase gel to obtain the cream matrix.

[0095] In this invention, the method of mixing the oil phase solution and the aqueous phase gel preferably includes: adding the oil phase solution to the aqueous phase gel at 70-75°C, and then emulsifying it using high-speed shearing to obtain a cream matrix.

[0096] In this invention, the rotational speed of the high-speed shearing is preferably 1500–3000 rpm, more preferably 2000–2500 rpm; the high-speed shearing time is preferably 20–30 min, more preferably 25–30 min. In this invention, the device for the high-speed shearing can be a high-speed shearing machine. This invention, through high-speed shearing, enables the oil phase solution and aqueous phase gel to form a stable O / W type cream matrix.

[0097] In this invention, the method of mixing the cream matrix and the encapsulated levodiamine nanoparticles preferably includes: dispersing the encapsulated levodiamine nanoparticles in water to obtain a levodiamine nanoparticle suspension; mixing the levodiamine nanoparticle suspension, the cream matrix, and the pH adjuster; and then adjusting the volume with water to obtain a levodiamine nanocream.

[0098] This invention, by dispersing levodiamine nanoparticles in water, facilitates the uniform dispersion of the levodiamine nanoparticles within the cream matrix. This invention does not impose a specific limit on the concentration of the levodiamine nanoparticle suspension; adjustments are made to prevent clumping of the nanoparticles.

[0099] The present invention does not have a special limitation on the amount of pH adjuster used; the pH value of the lipoic acid nano-emulsion can be made to reach 8.0 to 9.0.

[0100] This invention achieves uniform quality of lipofuscin nano-emulsion through volume control.

[0101] In this invention, the total amount of water used to obtain the gel matrix, the water in the suspension containing lipofuscin nanoparticles, and the water used for volume adjustment is the same as the amount of water used in the cream matrix.

[0102] This invention, through the above-described preparation method, enables the thorough dispersion of lidocaine-encapsulated nanoparticles within a cream matrix. The preparation method provided by this invention is a two-step process. First, it ensures the efficient encapsulation of lidocaine and prilocaine and the stability of the encapsulated lidocaine nanoparticles. Then, it combines these nanoparticles with the cream matrix, effectively solving the problems of low penetration efficiency, poor stability, and strong skin irritation associated with lidocaine in conventional dosage forms.

[0103] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0104] Example 1

[0105] A levodiamine nano-cream, comprising a cream matrix and levodiamine nanoparticles encapsulated in the cream matrix;

[0106] The mass ratio of lidocaine to prilocaine in the lidocaine-encapsulated nanoparticles is 1:1.

[0107] The particle size of the lidocaine-encapsulated nanoparticles is 115.3 nm (PDI = 0.18). The zeta potential is -8.7 mV; the encapsulation efficiency of lidocaine in the lidocaine-encapsulated nanoparticles is 93.2%, and the encapsulation efficiency of prilocaine is 91.8%; the drug loading of lidocaine in the lidocaine-encapsulated nanoparticles is 22.1%; the mass percentage of lidocaine in the lidocaine nanoemulsion is 2.5%.

[0108] The preparation method of the lipoic acid nano-cream is as follows:

[0109] (1) 1.25 g of lidocaine, 1.25 g of prilocaine and 7.5 g of PLGA (LA:GA = 75:25, MW 3,000 Da) were dissolved in 50 mL of dichloromethane to obtain the oil phase;

[0110] 2.5 g of polyvinyl alcohol (PVA, MW 30,000–70,000 Da, degree of hydrolysis 87–89%) was dissolved in 100 mL of purified water to form a 2.5% (w / v) aqueous phase.

[0111] The oil phase was added dropwise to the aqueous phase at a rate of 1.0 mL / min, and simultaneously ultrasonically emulsified for 10 min under ice bath conditions using an ultrasonic disruptor (300W power, intermittent operation, 5 seconds of operation, 2 seconds of pause) to form an O / W type primary emulsion.

[0112] The O / W type colostrum was evaporated under reduced pressure for 2 hours at 40°C and 100 mbar on a rotary evaporator to remove dichloromethane, yielding a nanoparticle suspension. The nanoparticle suspension was centrifuged at 20,000 rpm for 20 minutes, the supernatant was discarded, and the precipitate was washed twice with a small amount of purified water and resuspended in 25 mL of purified water. The nanoparticle suspension was mixed with an equal volume of 5% (w / v) trehalose solution, dispensed, and then freeze-dried (pre-freeze at -40°C for 24 hours; main dry at -20°C for 48 hours; secondary dry at 25°C for 12 hours) to obtain white, fluffy nanoparticles loaded with lipofusine.

[0113] (2) Heat 50g of purified water to 75°C, add 1.5g of carbomer 940, stir to hydrate carbomer 940 and form a gel matrix; add 12.0g of propylene glycol, 6.0g of glycerol, 1.0g of sodium hyaluronate (molecular weight 200,000 Da) and 1.0g of polysorbate 80 to the gel matrix in sequence, stir to dissolve and obtain an aqueous gel, and keep warm.

[0114] 12.0g of liquid paraffin was heated to 75℃, and 2.5g of polyoxyethylene (23) lauryl ether, 0.15g of methylparaben, 0.03g of propylparaben and 1.0g of cholesterol-PEG1500-biotin conjugate were added. The mixture was stirred and dissolved to obtain an oil phase solution, which was then kept warm.

[0115] At 75°C, the oil phase solution was added to the aqueous phase gel and emulsified for 20 minutes using a high-speed shear mixer (2000 rpm) to form a stable O / W type cream matrix.

[0116] Under continuous stirring, the cream matrix was cooled to 38°C. 2.5g of the levodopacaine-loaded nanoparticles prepared in step (1) were dispersed in 5g of purified water to form a levodopacaine-loaded nanoparticle suspension. This suspension was added to the cream matrix and stirred until homogeneous. The pH of the cream was adjusted to 8.5 using triethanolamine. Finally, purified water was added to a final volume of 100g, stirred until homogeneous, and defoamed to obtain the levodopacaine nano-cream.

[0117] Example 2

[0118] A levodiamine nano-cream, comprising a cream matrix and levodiamine nanoparticles encapsulated in the cream matrix;

[0119] The mass ratio of lidocaine to prilocaine in the lidocaine-encapsulated nanoparticles is 1:1.

[0120] The average particle size of the lidocaine-loaded nanoparticles is 80.5 nm (PDI = 0.15). The zeta potential is -5.2 mV; the encapsulation efficiency of lidocaine in the lidocaine-loaded nanoparticles is 92.5%, and the encapsulation efficiency of prilocaine is 91.0%; the drug loading of lidocaine in the lidocaine-loaded nanoparticles is 15.0%; the mass percentage of lidocaine in the lidocaine nanoemulsion is 1.0%.

[0121] The preparation method of the lipoic acid nano-cream is as follows:

[0122] (1) Dissolve 0.5g lidocaine, 0.5g prilocaine and 5.67g PLGA (LA:GA=75:25, MW 30,000Da) in 50mL dichloromethane to obtain an oil phase (carrier material concentration is about 113mg / mL, ensuring drug loading of 15%).

[0123] 2.5 g of polyvinyl alcohol (PVA, MW 30,000–70,000 Da, degree of hydrolysis 87–89%) was dissolved in 100 mL of purified water to form a 2.5% (w / v) aqueous phase.

[0124] The oil phase was added dropwise to the aqueous phase at a rate of 1.0 mL / min, and simultaneously ultrasonically emulsified for 10 min under ice bath conditions using an ultrasonic disruptor (300W power, intermittent operation, 5 seconds of operation, 2 seconds of pause) to form an O / W type primary emulsion.

[0125] The O / W type colostrum was evaporated under reduced pressure for 2 hours at 40°C and 100 mbar on a rotary evaporator to remove dichloromethane, yielding a nanoparticle suspension. The nanoparticle suspension was centrifuged at 20,000 rpm for 20 minutes, the supernatant was discarded, and the precipitate was washed twice with a small amount of purified water and resuspended in 25 mL of purified water. The nanoparticle suspension was mixed with an equal volume of 5% (w / v) trehalose solution, dispensed, and then freeze-dried (pre-freeze at -40°C for 24 hours; main dry at -20°C for 48 hours; secondary dry at 25°C for 12 hours) to obtain white, fluffy nanoparticles loaded with lipofusine.

[0126] (2) Heat 50g of purified water to 75°C, add 1.5g of carbomer 940, stir to hydrate carbomer 940 and form a gel matrix; add 12.0g of propylene glycol, 6.0g of glycerol, 1.0g of sodium hyaluronate (molecular weight 200,000 Da) and 1.0g of polysorbate 80 to the gel matrix in sequence, stir to dissolve and obtain an aqueous gel, and keep warm.

[0127] 12.0g of liquid paraffin was heated to 75℃, and 2.5g of polyoxyethylene (23) lauryl ether, 0.15g of methylparaben, 0.03g of propylparaben and 1.0g of cholesterol-PEG1500-biotin conjugate (average molecular weight about 2200Da) were added. The mixture was stirred and dissolved to obtain an oil phase solution, which was then kept warm.

[0128] At 75°C, the oil phase solution was added to the aqueous phase gel and emulsified for 20 minutes using a high-speed shear mixer (2000 rpm) to form a stable O / W type cream matrix.

[0129] Under continuous stirring, the cream matrix was cooled to 38°C. 6.67 g of the liprocaine-loaded nanoparticles prepared in step (1) (based on a drug loading of 15% to achieve a drug content of 1.0% in the cream) was dispersed in 5 g of purified water to form a liprocaine-loaded nanoparticle suspension. This liprocaine-loaded nanoparticle suspension was added to the cream matrix and stirred until homogeneous. The pH of the cream was adjusted to 8.5 with triethanolamine. Finally, purified water was added to a final volume of 100 g, stirred until homogeneous, and defoamed to obtain the liprocaine nano-cream.

[0130] The levodiamine nano-emulsion prepared in this embodiment is a milky white, uniform cream with a fine texture and no visible particles; its pH value is 8.5; and its viscosity, measured by a Brookfield viscometer at 25°C, is 45,000–60,000 mPa·s. The nanoparticles are well dispersed in the cream matrix, with a particle size distribution concentrated around 80 nm, and no obvious agglomeration.

[0131] Example 3

[0132] A levodiamine nano-cream, comprising a cream matrix and levodiamine nanoparticles encapsulated in the cream matrix;

[0133] The mass ratio of lidocaine to prilocaine in the lidocaine-encapsulated nanoparticles is 1:1.

[0134] The average particle size of the lidocaine-loaded nanoparticles is 140.2 nm (PDI = 0.19). The zeta potential is -10.1 mV; the encapsulation efficiency of lidocaine in the lidocaine-loaded nanoparticles is 90.8%, and the encapsulation efficiency of prilocaine is 90.2%; the drug loading of lidocaine in the lidocaine-loaded nanoparticles is 25.0%; the mass percentage of lidocaine in the lidocaine nanoemulsion is 4.0%.

[0135] The preparation method of the lipoic acid nano-cream is as follows:

[0136] (1) Dissolve 2.0 g of lidocaine, 2.0 g of prilocaine and 12.0 g of PLGA (LA:GA = 75:25, MW 30,000Da) in 50 mL of dichloromethane to obtain an oil phase (carrier material concentration of about 240 mg / mL, ensuring drug loading of 25%).

[0137] 2.5 g of polyvinyl alcohol (PVA, MW 30,000–70,000 Da, degree of hydrolysis 87–89%) was dissolved in 100 mL of purified water to form a 2.5% (w / v) aqueous phase.

[0138] The oil phase was added dropwise to the aqueous phase at a rate of 1.0 mL / min, and simultaneously ultrasonically emulsified for 10 min under ice bath conditions using an ultrasonic disruptor (300W power, intermittent operation, 5 seconds of operation, 2 seconds of pause) to form an O / W type primary emulsion.

[0139] The O / W type colostrum was evaporated under reduced pressure for 2 hours at 40°C and 100 mbar on a rotary evaporator to remove dichloromethane, yielding a nanoparticle suspension. The nanoparticle suspension was centrifuged at 20,000 rpm for 20 minutes, the supernatant was discarded, and the precipitate was washed twice with a small amount of purified water and resuspended in 25 mL of purified water. The nanoparticle suspension was mixed with an equal volume of 5% (w / v) trehalose solution, dispensed, and then freeze-dried (pre-freeze at -40°C for 24 hours; main dry at -20°C for 48 hours; secondary dry at 25°C for 12 hours) to obtain white, fluffy nanoparticles loaded with lipofusine.

[0140] (2) Heat 35g of purified water to 75°C, add 1.5g of carbomer 940, stir to hydrate carbomer 940 and form a gel matrix; add 12.0g of propylene glycol, 6.0g of glycerol, 1.0g of sodium hyaluronate (molecular weight 200,000 Da) and 1.0g of polysorbate 80 to the gel matrix in sequence, stir to dissolve and obtain an aqueous gel, and keep warm.

[0141] 12.0g of liquid paraffin was heated to 75℃, and 2.5g of polyoxyethylene (23) lauryl ether, 0.15g of methylparaben, 0.03g of propylparaben and 1.0g of cholesterol-PEG1500-biotin conjugate (average molecular weight about 2200Da) were added. The mixture was stirred and dissolved to obtain an oil phase solution, which was then kept warm.

[0142] At 75°C, the oil phase solution was added to the aqueous phase gel and emulsified for 20 minutes using a high-speed shear mixer (2000 rpm) to form a stable O / W type cream matrix.

[0143] Under continuous stirring, the cream matrix was cooled to 38°C. 16.0 g of the liprocaine-loaded nanoparticles prepared in step (1) (based on a drug loading of 25% to achieve a drug content of 4.0% in the cream) was dispersed in 5 g of purified water to form a liprocaine-loaded nanoparticle suspension. This liprocaine-loaded nanoparticle suspension was added to the cream matrix and stirred until homogeneous. The pH of the cream was adjusted to 8.5 with triethanolamine. Finally, purified water was added to a final volume of 100 g, stirred until homogeneous, and defoamed to obtain the liprocaine nano-cream.

[0144] The levodiamine nano-emulsion prepared in this embodiment is a milky white, uniform cream with a fine texture and no visible particles; its pH value is 8.5; and its viscosity, measured by a Brookfield viscometer at 25°C, is 60,000–75,000 mPa·s. The nanoparticles are well dispersed in the cream matrix, with a particle size distribution concentrated at around 140 nm, and no obvious agglomeration is observed.

[0145] Comparative Example 1

[0146] The domestically available liposome cream was used as the reference drug for this product, with batch number 100209 and licensee Aspen Pharma Trading Limited.

[0147] Test case

[0148] The performance of the lipoic acid nano-emulsion prepared in Example 1 and the commercially available lipoic acid cream in Comparative Example 1 (hereinafter referred to as the reference formulation) are compared as follows:

[0149] (1) The lipoic acid nano-cream prepared in Example 1 is a milky white, uniform cream with a fine texture and no visible particles; the reference preparation is a milky white cream.

[0150] (2) The pH value of the lipoic acid nano-emulsion prepared in Example 1 was 8.5;

[0151] Viscosity: 50,000–70,000 mPa·s at 25°C, measured by a Brookfield viscometer.

[0152] (3) TEM image of the lipoic acid nano-emulsion prepared in Example 1 is shown below. Figure 1 As shown. From Figure 1 It can be seen that the morphology of the levodopacaine nanoparticles loaded in the levodopacaine nanoemulsion prepared by the present invention is a uniform spherical structure with a particle size distribution concentrated at about 100 nm and no obvious agglomeration phenomenon, indicating that the nanoparticle preparation process is stable and has good dispersibility.

[0153] Particle size analysis of the nanoparticles in the cream was performed using laser diffraction or dynamic light scattering. The average particle size of the liprocaine nano-cream prepared in Example 1 remained within the range of 120–150 nm across multiple batches of testing, with a PDI of less than 0.25, indicating that the liprocaine-loaded nanoparticles were well dispersed in the cream matrix without significant aggregation. In contrast, the drug or oil droplet particles in the reference formulation were typically in the micrometer range, and microscopic observation revealed significant particle overlap.

[0154] (4) Franz diffusion cell in vitro transdermal permeation test using isolated pig ear skin:

[0155] In vitro transdermal assays were conducted using a modified Franz diffusion cell. Pre-saturated ex vivo skin was fixed between the donor and receiver cells, with the stratum corneum facing the donor cell. Approximately 0.3 g of cream was applied, and approximately 12 mL of release medium was used as the receiver solution. The diffusion cell was placed under constant temperature conditions of 32℃ ± 0.5℃, and electromagnetic stirring was activated at a speed of 600 r / min. At 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, and 20 h, 10 mL of the receiver solution was collected, and an equal volume and temperature of receiver solution were immediately added. The receiver solution was filtered through a 0.45 μm PP microporous membrane, and the filtrate was analyzed by HPLC.

[0156] The release medium is PBS buffer at pH 7.4;

[0157] The skin used for extraction is from piglets that are 30 days old.

[0158] The chromatographic column was a Phenomen Titank C18 (150 mm × 4.6 mm, 3 μm).

[0159] The mobile phase was phosphate buffer (pH 7.2)-acetonitrile (35:65);

[0160] The detection wavelength is 232nm;

[0161] The flow rate was 1.0 mL per minute;

[0162] Column temperature: 30℃;

[0163] Injection volume: 10 μL;

[0164] After the in vitro percutaneous penetration test is terminated, immediately scrape off the residual ointment from the pigskin surface, place it in a 50mL volumetric flask, add 2.5mL of 5mol / L sodium hydroxide solution to disperse the ointment evenly, add 2.5mL of 5mol / L hydrochloric acid solution, dissolve and dilute to the mark with water-acetonitrile (80:20), filter (it is recommended to use a 0.45μm filter head made of PP material), and take the filtrate for HPLC determination to obtain the surface residue;

[0165] Immediately after the in vitro percutaneous penetration test was terminated, any residual ointment on the pigskin surface was scraped off. The pigskin was rinsed with physiological saline, the skin was dried with filter paper, and excess skin was trimmed off, leaving approximately 1.76 cm² of skin in contact with the ointment. 2 The skin was minced and transferred to a 10 mL centrifuge tube. 0.9 mL of receiving solution was added, followed by 8.1 mL of acetonitrile. The mixture was extracted by sonication for 40 min, centrifuged at 4000 r / min for 15 min, and the supernatant was collected. The supernatant was filtered through a 0.45 μm PP membrane, and 1 mL of the filtrate was transferred to a 10 mL volumetric flask. The filtrate was diluted to the mark with water-acetonitrile (80:20) to obtain the retention rate sample. The intradermal retention was determined by HPLC. The cumulative permeation curves of the in vitro transdermal permeation test of the liprocaine nano-emulsion prepared in Example 1 and the comparative formulation are shown below. Figure 2 As shown.

[0166] from Figure 2 It can be seen that, after 6 hours, the cumulative lidocaine penetration of the lidocaine nano-emulsion prepared in Example 1 was 185 μg / cm³. 2 The cumulative penetration of prilocaine was 160 μg / cm³. 2 Permeation rate: lidocaine 30 μg / (cm³) 2 ·h), prilocaine 25μg / (cm 2 •h). The cumulative permeation of the reference formulation, lidocaine, was 105 μg / cm³. 2 The cumulative penetration of prilocaine was 90 μg / cm³. 2 Permeation rate: lidocaine 17.5 μg / (cm³) 2 ·h), prilocaine 15μg / (cm 2 ·h).

[0167] Within 24 hours, the cumulative penetration of the lipofuscin nano-emulsion prepared in Example 1 reached 250 μg / cm³. 2 The cumulative penetration of prilocaine reached 220 μg / cm³. 2 The cumulative permeation of the reference formulation, lidocaine, was 150 μg / cm³. 2 The cumulative penetration of prilocaine was 130 μg / cm³. 2 .

[0168] These results indicate that, under the same dosage and penetration time, the transdermal penetration efficiency of the lipoic acid nano-emulsion prepared in this invention is significantly higher than that of the reference formulation, with an increase of more than 30%.

[0169] (5) In vitro release: In vitro release test using a Franz diffusion cell:

[0170] The DHC-6TD vertical diffusion cell was used as the experimental setup, the filter membrane used was PTFE membrane, the experimental temperature was 32℃, and the sampling times were 0h, 4h, 8h, 90min, 12h, 16h, 20h and 24h.

[0171] Pre-saturate the PTFE filter membrane with freshly prepared PBS 7.2 buffer for 30 min. Remove surface moisture from the pre-saturated filter membrane with absorbent paper. Place the quantitative loop on top of the filter membrane and load the sample of lipoprotein dicaine cream (300-350 mg) onto the quantitative loop. Scrape off any excess sample from the surface with a spatula and assemble the quantitative loop and diffusion cell.

[0172] Take 1500mL of freshly prepared degassed PBS 7.2 buffer and transfer it into the media bottle. Place the media bottle in a constant temperature water bath at 32±0.5℃ to preheat.

[0173] Complete the installation according to the instrument requirements and begin the experiment. Take 1 mL of sample from each sampling point and inject it into a liquid chromatography vial. Use high-performance liquid chromatography (HPLC) to determine the release amounts of lidocaine and prilocaine in the release medium and plot the release curves. The in vitro release curves of the lidocaine-prilocaine nano-cream prepared in Example 1 and the comparative formulation are shown below. Figure 3 As shown.

[0174] from Figure 3 It can be seen that, after 4 hours, the cumulative release rate of lidocaine in the lidocaine nanoemulsion prepared in Example 1 was 45%, and the cumulative release rate of prilocaine was 40%. In contrast, the cumulative release rate of lidocaine in the reference formulation was 90%, and the cumulative release rate of prilocaine was 85%.

[0175] Over 24 hours, the lidocaine-prilocaine nanoemulsion prepared in Example 1 exhibited a cumulative lidocaine release rate of 85% and a prilocaine release rate of 80%. In contrast, the reference formulation showed a cumulative lidocaine release rate of 96% and a prilocaine release rate of 94%.

[0176] During 48 hours, the cumulative release rate of lidocaine in the lidocaine nanoemulsion prepared in Example 1 was 95%, and the cumulative release rate of prilocaine was 92%. The cumulative release rate of lidocaine in the reference formulation was 98%, and the cumulative release rate of prilocaine was 96%. These data demonstrate the in vitro release characteristics of lidocaine and prilocaine in the lidocaine nanoparticle sustained-release nanoemulsion prepared in this invention. During the 48-hour observation period, the drug release exhibited a stable zero-order or first-order sustained-release kinetic curve with no obvious burst release phenomenon, and the cumulative release rate remained at 80-85% up to 24 hours, far lower than the high release rate of commercially available immediate-release formulations in a short period, demonstrating excellent sustained-release effect.

[0177] (6) Stability: Accelerated stability test (40℃ / 75%RH, 6 months): The lidocaine nanoemulsion prepared in Example 1 had a lidocaine content of 98.5% and a prilocaine content of 98.2%. The nanoparticle size change rate was less than 5%, the encapsulation efficiency change rate was less than 3%, and there were no significant changes in appearance or pH value, with no drug precipitation. In contrast, the reference formulation had a lidocaine content of 96.5% and a prilocaine content of 95.8%, exhibiting slight precipitation and stratification, and a significant decrease in drug content.

[0178] Long-term stability test (25℃ / 60%RH, 12 months): The lidocaine nanoemulsion prepared in Example 1 had a lidocaine content of 99.2% and a prilocaine content of 99.0%. The nanoparticle size, encapsulation efficiency, appearance, and pH value remained stable. In contrast, the reference formulation had a lidocaine content of 97.5% and a prilocaine content of 97.0%, with slight precipitation.

[0179] The results above demonstrate that the liprocaine nanoparticle sustained-release nanoemulsion prepared in this invention significantly outperforms commercially available reference formulations in terms of precise drug particle size control, in vitro transdermal penetration efficiency, in vitro release characteristics, and physical and chemical stability. Furthermore, due to its sustained-release properties, it effectively reduces local irritation, thereby improving patient comfort and compliance.

[0180] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A lipofuscin nano-cream, characterized in that, Includes a cream matrix and encapsulated lipofuscin nanoparticles dispersed in the cream matrix; The mass ratio of lidocaine to prilocaine in the lidocaine-encapsulated nanoparticles is 1:(1±0.5). The drug loading of lipracaine in the nanoparticles is 10-25%; The mass percentage of lipofacaine in the lipofaca nano-emulsion is 1.0% to 4.0%.

2. The lipofuscin nano-emulsion according to claim 1, characterized in that, The average particle size of the nanoparticles loaded with levodopacaine is 50 nm to 150 nm; the polydispersity index is ≤0.

2.

3. The lipofuscin nano-emulsion according to claim 1, characterized in that, The carrier material for encapsulating levodopacaine nanoparticles includes one or more of polylactic acid-glycolic acid copolymer, polycaprolactone, polylactic acid, polyglycolic acid, polyhydroxyalkanoate, albumin, and chitosan.

4. The lipofuscin nano-emulsion according to claim 1, characterized in that, The cream base includes a gel base, a solubilizing and moisturizing agent, a penetration enhancer, an emulsifier, a pH adjuster, a preservative, an oily excipient, and water; the emulsifier is composed of an oily emulsifier and an aqueous emulsifier.

5. The lipofuscin nano-emulsion according to claim 4, characterized in that, The gel matrix includes one or more of carbomer 940, carbomer 934, carbomer 980, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose.

6. The lipofuscin nano-emulsion according to claim 4, characterized in that, The penetration enhancer includes one or more of sodium hyaluronate, laurocapram, azone, oleic acid, and cholesterol-PEG1500-biotin conjugate.

7. A method for preparing the lipofuscin nano-emulsion according to any one of claims 1 to 6, comprising the following steps: (1) Lidocaine, prilocaine and the carrier material are dissolved in an organic solvent to obtain an oil phase; The emulsifier was dissolved in purified water to obtain an aqueous phase; The oil phase and the aqueous phase are mixed and then emulsified to obtain an O / W primary emulsion. The O / W colostrum was purified after removing the organic solvent to obtain lipoic acid nanoparticles. (2) Mix the encapsulated levodiamine nanoparticles obtained in step (1) with the cream matrix to obtain levodiamine nanocream.

8. The preparation method according to claim 7, characterized in that, The concentration of the carrier material in the oil phase in step (1) is 10-15 mg / mL.

9. The preparation method according to claim 7, characterized in that, In step (1), the mass concentration of the emulsifier in the aqueous phase is 0.5-5.0%.

10. The preparation method according to claim 7, characterized in that, In step (1), the volume ratio of the oil phase to the water phase is 1:(2-10).

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