Lidocaine ethosome gel

Abstract

The invention relates to the technical field of medicines, in particular to lidocaine ethosome gel as well as a preparation method and application thereof. The invention provides lidocaine ethosome gel. The lidocaine ethosome gel comprises the following components in percentage by weight: (a) 2-4% of lidocaine; (b) 5%-10% by weight of a film forming material; (c) 0.5%-2% by weight of a surfactant; (d) 0.01-1% by weight of an antioxidant; and (e) a solvent, wherein the solvent is selected from ethanol and water.

Description

1. Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a lidocaine liposome gel, its preparation method, and its uses. 2. Background Technology

[0002] Lidocaine is an amide-based local anesthetic, first synthesized and used as a local anesthetic by Lofgren in 1934. It produces a local anesthetic effect by stabilizing nerve cell membranes by blocking the ion flow required for nerve impulse generation and conduction. Currently, lidocaine is the most widely used local anesthetic in clinical practice, available in various dosage forms. Topical preparations include gels, creams, patches (gel patches), and plasters, and can be used for infiltration anesthesia, epidural anesthesia, surface anesthesia (including mucosal anesthesia during thoracoscopy, upper gastrointestinal endoscopy, transurethral examinations, or abdominal surgery), and nerve conduction blocks.

[0003]

[0004] According to the "Expert Consensus on Neonatal Pain Assessment and Analgesia Management (2020 Edition)," in the management of moderate pain, during intravenous and arterial punctures: ① If possible, plan the procedure and apply EMLA cream to the affected area with a bite bandage 60 minutes before puncture. This can replace commonly used medical adhesive tape, as its lower adhesiveness avoids pain during removal (2B). ② If possible, use a faster-acting anesthetic (such as 40g / L lidocaine liposome cream) (2B); preparations such as tetracaine cream are ineffective in newborns and are not recommended (4A). In the "Guidelines for the Operation and Management of Peripherally Inserted Central Venous Catheters in Newborns (2021)," pain caused by PICC falls into the category of moderate to severe pain. Recommendation 1 for pain management in this case recommends the use of local anesthetic creams (Level D evidence, strong recommendation). According to the *Good Practice in Postoperative and Procedural Pain Management*, 2nd Edition, 2012 (American Paediatric Anesthesia Association of Great Britain and Ireland, APA), it is recommended that patients with intravenous catheters use topical local anesthetic preparations (Grade A) and psychological strategies to reduce pain and anxiety (Grade A). According to the *Clinical Practice Guidelines for Peripherally Inserted Central Catheters (PICC) Placement (2014)*, the needle must penetrate the skin to enter the blood vessel during PICC placement. Furthermore, most adult needles are 16G or 18G, resulting in a larger contact area with the skin surface. Compared to conventional steel needles or indwelling needles, this causes greater tissue cutting and damage, leading to more severe pain during PICC placement. Painful stimuli can activate sympathetic nerve endings, releasing catecholamines, causing peripheral vasoconstriction or spasm, leading to puncture failure or difficulty in catheter insertion. Therefore, reducing puncture pain or achieving painless puncture is crucial for ensuring successful placement.

[0005] In various needle punctures and surgical anesthesia for skin and mucous membrane ablation, the commonly used drug is lidocaine cream (trade name: EMLA), which needs to be applied to the surgical site 60 minutes in advance and has a relatively slow onset time. Lidocaine liposome cream (trade name: LMX4) developed by Ferndale Laboratories has an onset time of 30 minutes when used for local anesthesia before intravenous catheterization or puncture and local skin treatment. This time has been greatly shortened, but the 30-minute waiting time is still relatively long, especially when used in children. The 30-minute waiting time can greatly reduce children's willingness to undergo treatment and reduce treatment compliance.

[0006] Therefore, there is an urgent need to develop a fast-acting drug that can be used for local anesthesia before intravenous catheterization or venipuncture, or for local skin treatment. 3. Summary of the Invention

[0007] To address the issue of slow onset of action in topical lidocaine preparations and improve patient compliance, especially in children, this invention provides a fast-acting lidocaine liposome gel.

[0008] This invention provides a lidocaine liposome gel, comprising:

[0009] (a) 2-4% lidocaine by weight;

[0010] (b) 5% to 10% by weight of film-forming material;

[0011] (c) 0.5% to 2% by weight of surfactant;

[0012] (d) 0.01–1% antioxidant by weight; and

[0013] (e) Solvent, wherein the solvent is selected from ethanol and water.

[0014] The present invention further provides a lidocaine liposome gel, comprising:

[0015] (a) 2-4% lidocaine by weight;

[0016] (b) 5% to 10% by weight of film-forming material;

[0017] (c) 0.5% to 2% by weight of surfactant;

[0018] (d) 0.01 to 1% antioxidant by weight;

[0019] (e) A solvent, wherein the solvent is selected from ethanol and water;

[0020] (f) 0.5% to 1% by weight of gelling agent;

[0021] (g) 1% to 2% by weight of an antibacterial agent; and

[0022] (h) 0.1 to 1% by weight of pH adjuster.

[0023] The film-forming material of this invention is selected from egg yolk lecithin, soybean phosphatidylcholine, cholesterol, dipalmitoylcholine, distearate, myristoyl phosphatidylcholine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol, stearamide cholesterol derivatives, etc., or a combination of one or more thereof. Egg yolk lecithin or cholesterol is preferred.

[0024] The surfactants described in this invention are selected from higher fatty acid salts, such as alkali metal soaps, alkaline earth metal soaps, and organic amine soaps; sulfates, such as sulfated castor oil and sodium dodecyl sulfate; sulfonates, such as sodium dioctyl succinate, sodium dodecylbenzene sulfonate, and sodium glycocholate; cationic soaps, such as benzalkonium chloride and benzalkonium bromide; amphoteric surfactants, such as amino acid-type and betaine-type surfactants; alkyl glucosides, such as cocoyl glucoside, lauryl glucoside, and cetearyl glucoside; fatty acid glycerides, such as glyceryl monostearate; polyols, such as sucrose esters, fatty acid sorbitan 20, fatty acid sorbitan 60, polysorbate 80, polysorbate 60, and polysorbate 20; polyoxyethylene-polyoxypropylene copolymers, such as poloxamer 188, or combinations thereof, or combinations thereof. Polysorbate 80 is preferred.

[0025] The antioxidant described in this invention is selected from vitamin E, polyethylene glycol ester of vitamin E succinate, sodium sulfite, sodium bisulfite, sodium thiosulfate, sodium formaldehyde sulfoxylate, thiourea, cysteine, methionine, tert-butyl-p-hydroxyanisole, butylated cresol, tartaric acid, citric acid, ascorbic acid, disodium edetate, sodium calcium edetate, dimercaprol, etc., or a combination of one or more thereof. Vitamin E is preferred.

[0026] The gelling agent is selected from carbomer homopolymer type C, carbomer homopolymer type B, carbomer homopolymer type A, carbomer interpolymer, carbomer copolymer type A, carbomer copolymer type B, carbomer copolymer type C, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, chitosan, sodium alginate, calcium alginate, astragalus gum, xanthan gum, gelatin, starch, etc., or a combination of one or more thereof. Carbomer homopolymer type C is preferred.

[0027] The antibacterial agent is selected from benzyl alcohol, thimerosal, mercuric nitrate, benzalkonium chloride, benzalkonium bromide, chlorobutanol, methylparaben, ethylparaben, propylparaben, butylparaben, sorbic acid, potassium sorbate, sodium benzoate, benzoic acid, phenol, cresol, chlorocresol, p-hydroxybenzoate esters, etc., or a combination of one or more thereof. Benzyl alcohol is preferred.

[0028] The pH adjuster is selected from triethanolamine, sodium hydroxide, diethylamine, laurylamine, sodium bicarbonate, concentrated ammonia solution, hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, citric acid, sodium citrate, tartaric acid, potassium hydrogen tartrate, maleic acid, malic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, boric acid, etc., or a combination of one or more thereof. Triethanolamine is preferred.

[0029] The present invention further provides a lidocaine liposome gel, comprising:

[0030] (a) 2-4% lidocaine by weight;

[0031] (b) 5% to 10% by weight of film-forming material;

[0032] (c) 0.5% to 2% by weight of polysorbate 80;

[0033] (d) Vitamin E, 0.01–1% by weight;

[0034] (e) A solvent, wherein the solvent is selected from ethanol and water;

[0035] (f) 0.5% to 1% by weight of carbomer homopolymer type C;

[0036] (g) 1%–2% benzyl alcohol by weight; and

[0037] (h) 0.1-1% by weight of triethanolamine;

[0038] The film-forming material is selected from egg yolk lecithin and cholesterol. The present invention further provides a lidocaine liposome gel, comprising: (a) 2% lidocaine by weight;

[0039] (b) 5% by weight of egg yolk lecithin;

[0040] (c) 0.36% cholesterol by weight;

[0041] (d) 0.7% polysorbate 80 by weight;

[0042] (e) 0.1% vitamin E by weight;

[0043] (f) 0.7% by weight of carbomer homopolymer type C;

[0044] (g) 1.5% benzyl alcohol by weight;

[0045] (h) 0.8% triethanolamine by weight; and

[0046] (i) Ethanol and water.

[0047] The present invention further provides a lidocaine liposome gel comprising: (a) 3% lidocaine by weight;

[0048] (b) 6% by weight of egg yolk lecithin;

[0049] (c) 0.42% cholesterol by weight;

[0050] (d) 0.7% polysorbate 80 by weight;

[0051] (e) 0.02% vitamin E by weight;

[0052] (f) 0.7% by weight of carbomer homopolymer type C;

[0053] (g) 1.5% benzyl alcohol by weight;

[0054] (h) 0.6% by weight of triethanolamine; and

[0055] (i) Ethanol and water.

[0056] The present invention further provides a lidocaine liposome gel comprising: (a) 4% lidocaine by weight;

[0057] (b) 7% by weight of egg yolk lecithin;

[0058] (c) 0.5% cholesterol by weight;

[0059] (d) 1.4% by weight of polysorbate 80;

[0060] (e) 0.06% vitamin E by weight;

[0061] (f) 0.7% by weight of carbomer homopolymer type C;

[0062] (g) 1.5% benzyl alcohol by weight;

[0063] (h) 0.4% by weight of triethanolamine; and

[0064] (i) Ethanol and water.

[0065] The present invention further provides a lidocaine liposome gel, comprising:

[0066] (a) A single 200 mg dose of lidocaine;

[0067] (b) 7% egg yolk lecithin by weight

[0068] (c) 0.5% cholesterol by weight;

[0069] (d) 1.4% by weight of polysorbate 80;

[0070] (e) 0.06% antioxidant by weight;

[0071] (f) 0.7% by weight of carbomer homopolymer type C;

[0072] (g) 1.5% benzyl alcohol by weight;

[0073] (h) 0.4% by weight of triethanolamine; and

[0074] (i) Ethanol and water.

[0075] The lidocaine liposome gel of the present invention contains impurity A with a content of ≤0.04%, impurity B with a content of ≤0.2%, and a total impurity content of ≤1.0%. Impurity A is 2,6-dimethylaniline, and impurity B is a nitrogen oxide of lidocaine.

[0076]

[0077] The lidocaine liposome gel of the present invention has an encapsulation efficiency of ≥40%. Preferably, the encapsulation efficiency is ≥50%.

[0078] The lidocaine liposome gel of the present invention has an average particle size of 20-50 μm. Preferably, the average particle size of the lidocaine is 20-40 μm.

[0079] The lidocaine liposome gel of the present invention has a pH value of 7.5 to 8.5.

[0080] The beneficial technical effects of this invention are as follows:

[0081] (1) The lidocaine oxosome gel of the present invention has an oxosome structure, which is a single-layer, nearly circular vesicle structure.

[0082] (2) The lidocaine protoplast gel of the present invention has good transdermal effect in vitro.

[0083] (3) The lidocaine protoplast gel of the present invention has excellent in vivo experimental results in animals: the onset time is faster than the positive control preparation (LMX4 and EMLA), the analgesic intensity is greater than the control preparation, and there are no obvious adverse reactions. Therefore, the prescription was finally confirmed to have good drug properties and significant efficacy.

[0084] (4) The lidocaine protoplast gel of the present invention has good safety. During the non-clinical observation period, no obvious adverse reactions were observed, no animals died, and the skin condition of the test site was normal.

[0085] (5) Acupuncture studies showed that the effect of the lidocaine liposome gel of the present invention at each time point was stronger than that of the two positive control groups (LMX4 and EMLA). At 40 min, the average effect of the lidocaine liposome gel of the present invention exceeded 50%. 4. Description of the attached drawings

[0086] Figure 1 The lidocaine liposome gel structure is shown in Example 1. 5. Detailed Implementation Methods

[0087] The specific embodiments of the present invention are described in detail below. It should be noted that the embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0088] Example 1: Lidocaine liposome gel

[0089] 1. Prescription Composition

[0090]

[0091] 2. Preparation process

[0092] 1) Organic phase dissolution: Weigh the prescribed amounts of anhydrous ethanol, lidocaine, cholesterol, polysorbate 80, vitamin E, and refined egg yolk lecithin, and dissolve by stirring at 45°C;

[0093] 2) Crude alcohol body: Weigh the amount of purified water prescribed under the alcohol body section, inject it into the organic phase, mix at 45°C with high-speed stirring (laboratory stirring rate is 700 rpm) for 20 min;

[0094] 3) Refining of alcohol body: Homogenize 6 times at room temperature using a microfluidic homogenizer at a homogenization pressure of 10000 Psi, and set aside for later use;

[0095] 4) Carbomer swelling: Weigh the amount of purified water and carbomer homopolymer C prescribed under the gel matrix section, and stir until swelling is complete;

[0096] 5) Mixing benzyl alcohol and triethanolamine: Weigh the prescribed amounts of benzyl alcohol and triethanolamine into the carbomer solution, stir and mix thoroughly, and set aside.

[0097] 6) Pour the alcohol intermediate into the gel matrix and stir to mix evenly.

[0098] 3. Structure

[0099] The prepared lidocaine glycosome gel possesses an glycosome structure, and under low-temperature transmission electron microscopy, it appears as a monolayer, nearly circular vesicle structure, such as... Figure 1 As shown.

[0100] Example 2: Lidocaine liposome gel

[0101] 1. Prescription Composition

[0102]

[0103] 2. Preparation process

[0104] 1) Organic phase dissolution: Weigh the prescribed amounts of anhydrous ethanol, lidocaine, cholesterol, polysorbate 80, vitamin E, and refined egg yolk lecithin, and dissolve by stirring at 45°C;

[0105] 2) Crude alcohol body: Weigh the amount of purified water prescribed under the alcohol body section, inject it into the organic phase, mix at 45°C with high-speed stirring (laboratory stirring rate is 700 rpm) for 20 min;

[0106] 3) Refining of alcohol body: Homogenize 6 times at room temperature using a microfluidic homogenizer at a homogenization pressure of 10000 Psi, and set aside for later use;

[0107] 4) Carbomer swelling: Weigh the amount of purified water and carbomer homopolymer C prescribed under the gel matrix section, and stir until swelling is complete;

[0108] 5) Mixing benzyl alcohol and triethanolamine: Weigh the prescribed amounts of benzyl alcohol and triethanolamine into the carbomer solution, stir and mix thoroughly, and set aside.

[0109] 6) Pour the alcohol intermediate into the gel matrix and stir to mix evenly.

[0110] Example 3: Lidocaine liposome gel

[0111] 1. Prescription Composition

[0112]

[0113]

[0114] 2. Preparation process

[0115] 1) Organic phase dissolution: Weigh the prescribed amounts of anhydrous ethanol, lidocaine, cholesterol, polysorbate 80, sodium lauryl sulfate, vitamin E, and refined egg yolk lecithin, and dissolve by stirring at 45°C;

[0116] 2) Crude alcohol body: Weigh the amount of purified water prescribed under the alcohol body section, inject it into the organic phase, mix at 45°C with high-speed stirring (laboratory stirring rate is 700 rpm) for 20 min;

[0117] 3) Refining of alcohol body: Homogenize 6 times at room temperature using a microfluidic homogenizer at a homogenization pressure of 10000 Psi, and set aside for later use;

[0118] 4) Carbomer swelling: Weigh the amount of purified water and carbomer homopolymer C prescribed under the gel matrix section, and stir until swelling is complete;

[0119] 5) Mixing benzyl alcohol and triethanolamine: Weigh the prescribed amounts of benzyl alcohol and triethanolamine into the carbomer solution, stir and mix thoroughly, and set aside.

[0120] 6) Pour the alcohol intermediate into the gel matrix and stir to mix evenly.

[0121] Example 4: Lidocaine liposome gel

[0122] 1. Prescription Composition

[0123]

[0124] 2. Preparation process

[0125] 1) Organic phase dissolution: Weigh the prescribed amounts of anhydrous ethanol, lidocaine, cholesterol, polysorbate 80, vitamin E, and refined egg yolk lecithin, and dissolve by stirring at 45°C;

[0126] 2) Crude alcohol body: Weigh the amount of purified water prescribed under the alcohol body section, inject it into the organic phase, mix at 45°C with high-speed stirring (laboratory stirring rate is 700 rpm) for 20 min;

[0127] 3) Refining of alcohol body: Homogenize 6 times at room temperature using a microfluidic homogenizer at a homogenization pressure of 10000 Psi, and set aside for later use;

[0128] 4) Carbomer swelling: Weigh the amount of purified water and carbomer homopolymer C prescribed under the gel matrix section, and stir until swelling is complete;

[0129] 5) Mixing benzyl alcohol and triethanolamine: Weigh the prescribed amounts of benzyl alcohol and triethanolamine into the carbomer solution, stir and mix thoroughly, and set aside.

[0130] 6) Pour the alcohol intermediate into the gel matrix and stir to mix evenly.

[0131] Example 5: Lidocaine liposome gel

[0132] 1. Prescription Composition

[0133]

[0134] 2. Preparation process

[0135] 1) Organic phase dissolution: Weigh the prescribed amounts of anhydrous ethanol, lidocaine, cholesterol, polysorbate 80, vitamin E, refined egg yolk lecithin, and soybean phosphatidylcholine, and dissolve by stirring at 45°C;

[0136] 2) Crude alcohol body: Weigh the amount of purified water prescribed under the alcohol body section, inject it into the organic phase, mix at 45°C with high-speed stirring (laboratory stirring rate is 700 rpm) for 20 min;

[0137] 3) Refining of alcohol body: Homogenize 6 times at room temperature using a microfluidic homogenizer at a homogenization pressure of 10000 Psi, and set aside for later use;

[0138] 4) Carbomer swelling: Weigh the amount of purified water and carbomer homopolymer C prescribed under the gel matrix section, and stir until swelling is complete;

[0139] 5) Mixing benzyl alcohol and triethanolamine: Weigh the prescribed amounts of benzyl alcohol and triethanolamine into the carbomer solution, stir and mix thoroughly, and set aside.

[0140] 6) Pour the alcohol intermediate into the gel matrix and stir to mix evenly.

[0141] Example 6: Lidocaine liposome gel

[0142] 1. Prescription Composition

[0143]

[0144] 2. Preparation process

[0145] 1) Organic phase dissolution: Weigh the prescribed amounts of anhydrous ethanol, lidocaine, cholesterol, polysorbate 80, vitamin E, and refined egg yolk lecithin, and dissolve by stirring at 45°C;

[0146] 2) Crude alcohol body: Weigh the amount of purified water prescribed under the alcohol body section, inject it into the organic phase, mix at 45°C with high-speed stirring (laboratory stirring rate is 700 rpm) for 20 min;

[0147] 3) Refining of alcohol body: Homogenize 6 times at room temperature using a microfluidic homogenizer at a homogenization pressure of 10000 Psi, and set aside for later use;

[0148] 4) Carbomer swelling: Weigh the amount of purified water and carbomer homopolymer C prescribed under the gel matrix section, and stir until swelling is complete;

[0149] 5) Mixing benzyl alcohol and triethanolamine: Weigh the prescribed amounts of benzyl alcohol and triethanolamine into the carbomer solution, stir and mix thoroughly, and set aside.

[0150] 6) Pour the alcohol intermediate into the gel matrix and stir to mix evenly.

[0151] Example 7: Lidocaine liposome gel

[0152] 1. Prescription Composition

[0153]

[0154]

[0155] 2. Preparation process

[0156] 1) Organic phase dissolution: Weigh the prescribed amounts of anhydrous ethanol, lidocaine, cholesterol, polysorbate 80, vitamin E, and egg yolk lecithin, and dissolve by stirring at 45°C;

[0157] 2) Crude alcohol body: Weigh the amount of purified water prescribed under the alcohol body section, inject it into the organic phase, mix at 45°C with high-speed stirring (laboratory stirring rate is 700 rpm) for 20 min;

[0158] 3) Refining of alcohol body: Homogenize 6 times at room temperature using a microfluidic homogenizer at a homogenization pressure of 10000 Psi, and set aside for later use;

[0159] 4) Carbomer swelling: Weigh the amount of purified water and carbomer homopolymer C prescribed under the gel matrix section, and stir until swelling is complete;

[0160] 5) Mixing benzyl alcohol and triethanolamine: Weigh the prescribed amounts of benzyl alcohol and triethanolamine into the carbomer solution, stir and mix thoroughly, and set aside.

[0161] 6) Pour the alcohol intermediate into the gel matrix and stir to mix evenly.

[0162] Example 8: Lidocaine liposome gel

[0163] 1. Prescription Composition

[0164]

[0165] 2. Preparation process

[0166] 1) Organic phase dissolution: Weigh the prescribed amounts of anhydrous ethanol, lidocaine, cholesterol, polysorbate 80, vitamin E, and egg yolk lecithin, and dissolve by stirring at 45°C;

[0167] 2) Crude alcohol body: Weigh the amount of purified water prescribed under the alcohol body section, inject it into the organic phase, mix at 45°C with high-speed stirring (laboratory stirring rate is 700 rpm) for 20 min;

[0168] 3) Refining of alcohol body: Homogenize 6 times at room temperature using a microfluidic homogenizer at a homogenization pressure of 10000 Psi, and set aside for later use;

[0169] 4) Carbomer swelling: Weigh the amount of purified water and carbomer homopolymer C prescribed under the gel matrix section, and stir until swelling is complete;

[0170] 5) Mixing benzyl alcohol and triethanolamine: Weigh the prescribed amounts of benzyl alcohol and triethanolamine into the carbomer solution, stir and mix thoroughly, and set aside.

[0171] 6) Pour the alcohol intermediate into the gel matrix and stir to mix evenly.

[0172] Example 9: Encapsulation efficiency of lidocaine liposome gel

[0173] Experimental method: Encapsulation efficiency was determined by column chromatography. An appropriate amount of the formulation was loaded onto the sample, washed with 20 times the volume of purified water, and the washings were used for sample analysis. The liquid chromatography method was consistent with the content determination method.

[0174] Experimental results:

[0175] sample Example 1 Example 7 Example 8 Control formulation (LMX4) Encapsulation rate 54.2％ 42.3％ 46.1％ 41.6％

[0176] Experimental conclusion: According to the experimental results, the self-made lidocaine liposome gel had a higher encapsulation rate than the control formulation, indicating that liposomes can better improve the encapsulation rate of the formulation compared with ordinary liposomes, thus playing a positive role in promoting the skin penetration of the formulation.

[0177] Example 10: Lidocaine liposome gel stability

[0178] pH detection method:

[0179] Test method: pH value determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0631)

[0180] Specific experimental procedures: The lidocaine liposome gel from Example 1 was examined according to the law, and the pH value was 7.5-8.5.

[0181] Content detection method: HPLC method (General Chapter 0512, Chinese Pharmacopoeia 2020 Edition)

[0182] Test conditions:

[0183] Chromatographic conditions: High performance liquid chromatograph, UV detector (detection wavelength 230 nm)

[0184] Column: Waters Xterra RP18, 150mm × 3.9mm, 5μm or equivalent performance column.

[0185] Mobile phase: pH 8.0 phosphate solution (dissolve 4.85g of potassium dihydrogen phosphate in 1000ml of water, and adjust the pH to 8.0 with 5mol / L sodium hydroxide solution) - acetonitrile (60:40)

[0186] Flow rate: 1.0 ml / min

[0187] Column temperature: 30℃

[0188] Injection volume: 20 μl

[0189] Running time: 8 minutes

[0190] System suitability test requirements: In the chromatogram of the reference solution, the theoretical plate number calculated based on the lidocaine peak should not be less than 2000.

[0191] Specific experimental procedures:

[0192] Test solution: Take an appropriate amount of lidocaine liposome gel from Example 1 (approximately equivalent to 25 mg of lidocaine), place it in a 50 ml volumetric flask, add 5 ml of 5 mol / L sodium hydroxide solution, sonicate to disperse, add 5 ml of 5 mol / L hydrochloric acid solution to neutralize, dilute to the mark with the mobile phase, shake well, filter, and collect the filtrate.

[0193] Reference solution: Weigh an appropriate amount of lidocaine reference standard accurately, dissolve and quantitatively dilute it with the mobile phase to prepare a solution containing approximately 0.5 mg of lidocaine per 1 ml.

[0194] System suitability test: Take 20 μl of the reference solution, inject it into the liquid chromatograph, record the chromatogram, and the theoretical plate number calculated based on the lidocaine peak should not be less than 2000.

[0195] Accurately measure 20 μl each of the test solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the result by peak area using the external standard method.

[0196] Viscosity testing methods:

[0197] According to the standard operating procedure of the rheometer (HAKKE MARS 40), rotor 20 was selected, the Rot mode was selected, the time scan mode was selected, the CR mode was set, the shear rate was set to 0.100 1 / s, the time was set to 300s, the data acquisition mode was set to #100, and the temperature was set to 25℃. Time-viscosity curves were measured, and the average value was calculated using rheological data processing software (HAAKE RheoWin Data Manager) to determine the viscosity.

[0198] Related substances detection method: HPLC method (Chinese Pharmacopoeia 2020 General Chapter 0512)

[0199] Experimental conditions: High performance liquid chromatograph, UV detector (detection wavelength 210 nm)

[0200] Column: Agilent Elipse XDB-C18 4.6mm × 150mm 5μm or equivalent performance column

[0201] Mobile phase: Mobile phase A: Phosphate solution (dissolve 4.85g of potassium dihydrogen phosphate in 1000ml of water, and adjust the pH to 8.0 with 5mol / L sodium hydroxide solution) - Acetonitrile (70:30)

[0202] Mobile phase B: Phosphate solution (dissolve 4.85 g of potassium dihydrogen phosphate in 1000 ml of water, and adjust the pH to 8.0 with 5 mol / L sodium hydroxide solution) - acetonitrile (60:40)

[0203] Linear gradient elution conditions

[0204]

[0205] Flow rate: 1.0 ml / min

[0206] Column temperature: 30℃

[0207] Injection volume: 20 μl

[0208] Specific experimental procedures:

[0209] Blank excipient solution: Weigh approximately 1.3g of the blank excipient of this product accurately, place it in a 50ml volumetric flask, add 5ml of 5mol / L sodium hydroxide to disperse it, sonicate for 10 minutes, add 5ml of 5mol / L hydrochloric acid solution to neutralize, add an appropriate amount of mobile phase B, sonicate for 10 minutes, dilute to the mark with mobile phase B, shake well, filter, and collect the filtrate.

[0210] Test solution: Take an appropriate amount of lidocaine liposome gel from Example 1 (approximately equivalent to 50 mg of lidocaine), accurately weigh it, place it in a 50 ml volumetric flask, add 5 ml of 5 mol / L sodium hydroxide to disperse it, sonicate for 10 minutes, add 5 ml of 5 mol / L hydrochloric acid solution to neutralize it, add an appropriate amount of mobile phase B, sonicate for 10 minutes, dilute to the mark with mobile phase B, shake well, filter, and collect the filtrate.

[0211] Reference solution: Weigh an appropriate amount of lidocaine reference standard accurately, dissolve it in mobile phase B and dilute quantitatively to prepare a solution containing approximately 2 μg of lidocaine per 1 ml.

[0212] Sensitivity solution: Accurately measure 2 ml of the reference solution and place it in a 10 ml volumetric flask. Dilute to the mark with mobile phase B and shake well.

[0213] System suitability test: Take 20 μl of the reference solution and the sensitivity solution and inject them into the liquid chromatograph respectively. In the chromatogram of the reference solution, the theoretical plate number based on the lidocaine peak should not be less than 5000 and the tailing factor should not exceed 2.0. In the chromatogram of the sensitivity solution, the signal-to-noise ratio of the main component peak should not be less than 10.

[0214] Under the condition that the system suitability test meets the above requirements, accurately measure 20 μl each of the test solution, reference solution, and blank excipient solution, and inject them separately into the liquid chromatograph, recording the chromatograms. For the chromatogram of the test solution, excluding the solvent peak and the blank excipient peak, calculate the peak area of ​​the main peak in the reference solution using the external standard method. Impurity B (relative retention time approximately 0.11) should not exceed 0.2%, impurity A (relative retention time approximately 0.41) should not exceed 0.04%, other individual impurities should not exceed 0.2%, and the total impurities should not exceed 1.0%.

[0215] Table 1. Stability of lidocaine oxogel

[0216]

[0217]

[0218] The experimental results show that the related substances, content, and pH of the self-made lidocaine liposome gel changed slightly, but the changes were small and within acceptable ranges. The viscosity increased to some extent with increasing temperature, but this did not affect the application of the formulation and was also acceptable. In summary, the lidocaine liposome gel of the present invention has good stability.

[0219] Example 11: In vitro transdermal test of lidocaine liposome gel

[0220] Test method:

[0221] Particle size determination: Take about 1 ml of ethanol intermediate and measure its particle size using a potentiometric particle size analyzer (model: Zetasizer AdvanceSeries Pro Blue). The measurement temperature is 25℃. Select the DTS0012 plastic sample cell. Repeat the measurement three times to obtain the particle size.

[0222] In vitro transdermal assay (Franz diffusion cell):

[0223] Test method: Vertical diffusion cell assay <United States Pharmacopeia 43rd Edition 1724>

[0224] HPLC method (General Chapter 0512, Chinese Pharmacopoeia 2020 Edition)

[0225] Experimental conditions: 18 ml of phosphate buffer (pH 7.4) was used as the diffusion medium; the diffusion speed was 300 rpm; and the receiving area was 3.14 cm². 2 The sample loading amount was 0.05g, the test temperature was 32℃, the skin barrier was Bama miniature pig, and the procedure was performed according to the law. Samples were taken at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours, with a sample volume of 1.5ml and a replenishment volume of 1.5ml.

[0226] Chromatographic conditions: High performance liquid chromatograph, UV detector (detection wavelength 230 nm)

[0227] Column: Waters Xterra RP18, 150mm × 3.9mm, 5μm or equivalent performance column.

[0228] Mobile phase: pH 8.0 phosphate solution (dissolve 4.85g of potassium dihydrogen phosphate in 1000ml of water, and adjust the pH to 8.0 with 5mol / L sodium hydroxide solution) - acetonitrile (60:40)

[0229] Flow rate: 1.0 ml / min

[0230] Column temperature: 30℃

[0231] Injection volume: 20 μl

[0232] Running time: 8 minutes

[0233] System suitability test requirements: In the chromatogram of the reference solution, the theoretical plate number calculated based on the lidocaine peak should not be less than 2000.

[0234] Specific experimental procedures:

[0235] In vitro transdermal permeation solution: Take 0.05 g of the test sample and perform the vertical diffusion cell assay <United States Pharmacopeia 43rd Edition 1724>, using 18 ml of phosphate buffer (pH 7.4) as the diffusion medium, a rotation speed of 300 rpm, and a receiving area of ​​3.14 cm². 2 The sample loading amount was 0.4g, the test temperature was 32℃, the artificial membrane was a polypropylene membrane, and the operation was carried out according to the law. Samples were taken at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours, with a sample volume of 1.5ml and a replenishment volume of 1.5ml.

[0236] Donor compartment solution: Immediately after the transdermal test, remove the skin, dry the skin surface of the receiving compartment with filter paper, and then rinse the skin surface of the donor compartment with about 30 ml of phosphate buffer (pH 7.4). The rinsing solution is poured into a 50 ml volumetric flask, and the skin surface of the donor compartment is wiped 3 times with a cotton swab. The cotton swab is then placed into the above 50 ml volumetric flask, diluted to the mark with phosphate buffer (pH 7.4), sonicated for 60 minutes, shaken well, filtered, and the filtrate is collected.

[0237] Skin residue solution: After rinsing and drying the skin, cut it into small pieces and put it into a vial. Add 5 ml of phosphate buffer (pH 7.4) and sonicate for 1 hour. Pour out the extract. Repeat 3 times. Combine the extracts and transfer them to a 20 ml volumetric flask. Dilute to the mark with phosphate buffer (pH 7.4), shake well, filter, and collect the filtrate.

[0238] Reference solution: Weigh an appropriate amount of lidocaine reference standard accurately, dissolve it in diffusion medium and dilute quantitatively to prepare a solution containing approximately 0.2 mg of lidocaine per 1 ml.

[0239] System suitability test: Take 20 μl of the reference solution, inject it into the liquid chromatograph, record the chromatogram, and the theoretical plate number calculated based on the lidocaine peak should not be less than 2000.

[0240] Calculation formula

[0241]

[0242] Cumulative permeation (μg) = X 原n +(X 原1 +X 原2 +…+X 原n-1 )×1.5 / 18

[0243] Cumulative transmittance per unit area (μg / cm²) 2 = Cumulative transmittance / 3.14

[0244]

[0245]

[0246] In the formula W 对 The sample weight of the reference standard is in mg.

[0247] H 对 This refers to the content of the reference standard.

[0248] A 对 The peak area of ​​the main peak in the chromatogram of the reference solution;

[0249] A 样1 The peak area of ​​the main peak in the chromatogram of transdermal permeate;

[0250] 18 represents the volume of the diffusion medium;

[0251] N 对 This is the dilution factor of the reference solution;

[0252] 1.5 is the sampling volume;

[0253] 3.14 represents the receiving area;

[0254] A 样2 The peak area of ​​the main peak in the chromatogram of the donor chamber solution;

[0255] N 样1 This refers to the dilution factor of the solution in the donor chamber.

[0256] N 样2 This refers to the dilution factor for the residual solution on the skin.

[0257]

[0258] In the formula, the sample loading amount is the amount of lidocaine loaded.

[0259] Plot the in vitro transdermal permeability curve using the cumulative permeability per unit area against time, and the in vitro transdermal flux curve using the cumulative permeability per unit area per unit time against time. Calculate the 24-hour cumulative permeability (AMT) and maximum flux (Jmax). The material recovery rate should be in the range of 90% to 110%.

[0260] Limit: AMT ≥ *μg / cm 2 Jmax ≥ *μg / cm 2 / h.

[0261] Table 2 Results of in vitro transdermal assay

[0262]

[0263] Experimental conclusion: Comparing the particle size and transdermal results of the liposome gel in Example 1 and Example 6, it can be seen that increasing the amount of surfactant can make the liposome particle size smaller and the in vitro transdermal results better. This indicates that increasing the amount of surfactant can optimize the transdermal effect of the liposome gel, making its drug efficacy more rapid.

[0264] The in vitro transdermal test results of Examples 1-8, following the method described above, are shown in Table 3 below.

[0265] Table 3 Results of in vitro transdermal assay

[0266]

[0267]

[0268] Experimental Conclusion: A comparison of the in vitro transdermal results from Examples 1-8 shows that the dosage of pH adjuster, type of surfactant, amount of cholesterol, and type and dosage of phospholipids all have a certain impact on the transdermal effect of the formulation. This invention optimizes the transdermal effect of the formulation by adjusting the dosage of the above-mentioned influencing factors. The in vitro transdermal effects of formulations of different specifications prepared into liposome gels showed little difference.

[0269] Table 4. Results of in vitro transdermal assays of the present invention and the control formulation (LMX4)

[0270]

[0271] Example 12: Analgesic effect of lidocaine liposome gel

[0272] Needles: Acupuncture needles with a diameter of 0.35mm.

[0273] The time interval between the two times is 3-5 seconds.

[0274] Four groups of animals were subjected to needle stimulation of the skin at the test site. A positive reaction was indicated by a contraction of the skin at the stimulation site or a hissing sound in the guinea pig; otherwise, it was considered a negative reaction.

[0275] The drug administration site was marked with an ink circle, and the test site was evenly divided into 9 small square areas. A point was taken in the center of each small square for acupuncture testing.

[0276] The specific timing and number of acupuncture sessions are shown in Table 5. The final timing of acupuncture sessions will be determined based on the results of the acupuncture.

[0277] Table 5 Animal Needle Prick Test Protocol

[0278]

[0279] Calculate the negative reaction rate at each point (= number of negative reactions / 9 * 100%), plot the negative reaction rate-time curve, calculate the area under the curve (AUEC) using the trapezoidal method, and compare the differences in AUEC among the groups.

[0280] Experimental results:

[0281] In the acupuncture test before drug administration, all guinea pigs showed no negative response, meaning the baseline number of negative responses was 0. There was no difference in the baseline pain-free response rate among the groups of guinea pigs.

[0282] If the number of negative reactions during acupuncture is greater than 0, the treatment is considered effective; if the number of negative reactions is 0, the treatment is considered ineffective.

[0283] The analgesic intensity is the negative reaction rate (=number of negative reactions / 9 * 100%).

[0284] In this experiment, all blank control groups showed negative reactions, suggesting the feasibility of using acupuncture negative reactions to measure analgesic (anesthetic) effects.

[0285] Table 6. Onset time (min) for each group

[0286]

[0287] Note: G1: Lidocaine liposome gel of Example 1; G2: Lidocaine cream; G3: Lidocaine liposome cream; G4: Blank gel. Note: For ease of comparison, in this calculation of the mean, except for the blank control group, if the target intensity is not achieved within 120 minutes, the mean is calculated as 240 minutes, and no difference analysis is performed.

[0288] According to the results of the onset time test in Table 6, under the experimental conditions, the median onset time for pain intensity >0% and the onset time for pain intensity >50% in the experimental group (lidocaine liposome gel group) were 30 min and 40 min, respectively, both of which were better than the positive control group (60 / 120 min; 60 / 240 min). The two positive control groups were liposome cream (EMLA) and lidocaine liposome cream (LMX4). The average number of negative tests at a single time point in each group was calculated to obtain the average number of negative tests at that time point for each group. The average painless response rate was obtained from the average number of negative tests, and the intensity of the effect was quantified by the painless response rate.

[0289] Table 7. Area under the effect-time curve (AUEC, min)

[0290]

[0291] Note: AUEC was calculated using the trapezoidal rule. *: Compared with group G1, p < 0.05.

[0292] According to the results of the effect-time curve area under the curve (AUEC, min) in Table 7, under the experimental conditions, the effect (AUEC) of the experimental group (lidocaine liposome gel group) was significantly stronger than that of the control group (lidocaine cream (EMLA) and lidocaine liposome cream (LMX4)) (P<0.05).

[0293] Experimental conclusion:

[0294] Compared to commercially available liposome cream and lidocaine liposome gel, the lidocaine liposome gel prepared in this invention has a faster onset of action and a stronger effect, which is beneficial to improving the compliance of patients, especially children, with local anesthesia before intravenous catheterization or venipuncture and local skin treatment.

Claims

1. A lidocaine ethosome gel, characterized in that: include: (a) 2 to 4% by weight of lidocaine; (b) 5% to 10% by weight of a film-forming material, wherein the film-forming material is selected from egg yolk lecithin, soybean phosphatidylcholine, cholesterol, dipalmitoylcholine, distearoylcholine, dimyristoylphosphatidylcholine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol, stearylamide cholesterol derivatives, or a combination thereof; (c) 0.5% to 2% by weight of a surfactant, wherein the surfactant is selected from higher fatty acid salts, including alkali metal soaps, alkaline earth metal soaps, and organic amine soaps; sulfates, including sulfated castor oil and sodium dodecyl sulfate; sulfonates, including sodium dioctyl succinate sulfonate, sodium dodecylbenzene sulfonate, and sodium glycocholate; cationic soaps, including benzalkonium chloride and benzalkonium bromide; zwitterions, including amino acid type and betaine type; alkyl glucosides, including coconut oil glucoside, lauryl glucoside, and cetearyl glucoside; fatty acid glycerides, including monostearate glyceryl; polyols, including sucrose esters, fatty acid sorbitan 20, fatty acid sorbitan 60, polysorbate 80, polysorbate 60, and polysorbate 20; polyoxyethylene-polyoxypropylene copolymers, including poloxamer 188; or a combination of one or more thereof; (d) 0.01-1% by weight of an antioxidant, wherein the antioxidant is selected from vitamin E, vitamin E succinate polyethylene glycol ester, sodium sulfite, sodium bisulfite, sodium thiosulfate, sodium formaldehyde sulfoxylate, thiourea, cysteine, methionine, butylated p-hydroxyanisole, dibutylcresol, tartaric acid, citric acid, ascorbic acid, disodium edetate, sodium calcium edetate, dimercaprol, or a combination thereof; and (e) A solvent selected from ethanol and water.

2. The lidocaine ethosome gel according to claim 1, characterized in that Also includes: (f) 0.5% to 1% by weight of a gelling agent, wherein the gelling agent is selected from carbomer homopolymer type C, carbomer homopolymer type B, carbomer homopolymer type A, carbomer interpolymer, carbomer copolymer type A, carbomer copolymer type B, carbomer copolymer type C, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, chitosan, sodium alginate, calcium alginate, tragacanth, xanthan gum, gelatin, starch, or a combination thereof; (g) 1% to 2% by weight of an antibacterial agent, wherein the antibacterial agent is selected from benzyl alcohol, thimerosal, mercuric nitrate, benzalkonium chloride, benzalkonium bromide, chlorobutanol, methylparaben, ethylparaben, propylparaben, butylparaben, sorbic acid, potassium sorbate, sodium benzoate, benzoic acid, phenol, cresol, chlorocresol, parahydroxybenzoic acid esters, or a combination thereof; (h) 0.1-1% by weight of a pH adjuster, wherein the pH adjuster is selected from triethanolamine, sodium hydroxide, diethylamine, laurylamine, sodium bicarbonate, concentrated ammonia solution, hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, citric acid, sodium citrate, tartaric acid, potassium hydrogen tartrate, maleic acid, malic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, boric acid, or a combination thereof.

3. The lidocaine alcohol gel according to claim 2, characterized in that: include: (a) 2 to 4% by weight of lidocaine; (b) 5% to 10% by weight of film-forming material; (c) 0.5% to 2% by weight of polysorbate 80; (d) 0.01 to 1% by weight of vitamin E; (e) a solvent, wherein the solvent is selected from ethanol and water; (f) 0.5% to 1% by weight of carbomer homopolymer type C; (g) 1-2% by weight of benzyl alcohol; and (h) 0.1 to 1% by weight of triethanolamine; Wherein, the film-forming material is selected from egg yolk lecithin and cholesterol.

4. The lidocaine ethosome gel according to claim 2, characterized in that include: (a) 2% by weight of lidocaine; (b) 5% by weight of egg yolk lecithin; (c) 0.36% by weight of cholesterol; (d) 0.7% by weight of polysorbate 80; (e) 0.1% by weight of vitamin E; (f) 0.7% by weight of carbomer homopolymer type C; (g) 1.5% by weight of benzyl alcohol; (h) 0.8% by weight of triethanolamine; and (i) Ethanol and water.

5. The lidocaine ethosome gel according to claim 2, characterized in that include: (a) 3% by weight of lidocaine; (b) 6% by weight of egg yolk lecithin; (c) 0.42% by weight of cholesterol; (d) 0.7% by weight of polysorbate 80; (e) 0.02% by weight of vitamin E; (f) 0.7% by weight of carbomer homopolymer type C; (g) 1.5% by weight of benzyl alcohol; (h) 0.6% by weight of triethanolamine; and (i) Ethanol and water.

6. The lidocaine ethosome gel according to claim 2, characterized in that include: (a) 4% by weight of lidocaine; (b) 7% by weight of egg yolk lecithin; (c) 0.5% by weight of cholesterol; (d) 1.4% by weight of polysorbate 80; (e) 0.06% by weight of vitamin E; (f) 0.7% by weight of carbomer homopolymer type C; (g) 1.5% by weight of benzyl alcohol; (h) 0.4% by weight of triethanolamine; and (i) Ethanol and water.

7. The lidocaine ethosome gel according to claim 2, characterized in that include: (a) 200 mg single dose of lidocaine; (b) 7% by weight of egg yolk lecithin; (c) 0.5% by weight of cholesterol; (d) 1.4% by weight of polysorbate 80; (e) 0.06% by weight of an antioxidant; (f) 0.7% by weight of carbomer homopolymer type C; (g) 1.5% by weight of benzyl alcohol; (h) 0.4% by weight of triethanolamine; and (i) Ethanol and water.

8. The lidocaine ethosome gel according to any one of claims 1 to 7, characterized in that in, The content of impurity A is ≤0.04%, the content of impurity B is ≤0.2%, and the total amount of impurities is ≤1.0%.

9. The lidocaine ethosome gel according to any one of claims 1 to 7, characterized in that in, The pH value is 7.5~8.

5.

10. The lidocaine ethosome gel according to any one of claims 1 to 7, characterized in that in, The average particle size of lidocaine is 20 to 50 μm.

Images