Compound lidocaine cream and its preparation method

Abstract

The application provides a compound lidocaine cream and a preparation method thereof, and belongs to the technical field of external medicines. The compound lidocaine cream comprises the following components in percentage by mass: lidocaine-prilocaine co-crystal 5-10%, a surfactant 2-8%, diethylene glycol monoethyl ether 2-10%, a thickening agent 3-5%, white vaseline 15-35%, and water in an appropriate amount. The application takes lidocaine and prilocaine as active ingredients, and adopts a specific method to prepare the lidocaine-prilocaine co-crystal. The prepared compound lidocaine cream has a faster drug effect and a longer drug effect maintenance time compared with the lidocaine-prilocaine cream (EMLA cream) in the prior art.

Description

Technical Field

[0001] This invention relates to the field of topical medicine technology, specifically to compound lidocaine cream and its preparation method. Background Technology

[0002] A recent development in cutaneous anesthesia is the delivery of local anesthetics to dermal pain receptors via diffusion through the intact skin barrier. This is known as percutaneous local anesthesia, a concept first proposed by Monash. Unlike other percutaneous delivery systems, percutaneous local anesthesia requires a local skin effect rather than systemic absorption of the active agent. Ideally, percutaneous local anesthesia should provide rapid, deep, and relatively long-lasting anesthesia to the skin surface and underlying tissues with the minimum necessary anesthetic dose.

[0003] Lidocaine and prilocaine are currently the most widely used local anesthetics for skin anesthesia, possessing advantages such as rapid onset, strong and long-lasting effects, strong penetration, and a relatively wide safety margin. Lidocaine and prilocaine released from prilocaine cream penetrate the epidermis and dermis, accumulating near pain receptors and nerve endings in the dermis to achieve skin anesthesia. Both lidocaine and prilocaine stabilize nerve cell membranes by inhibiting the ion flux required for nerve impulse initiation and conduction, thereby producing local anesthesia; the anesthetic effect is dependent on the timing and dosage of administration.

[0004] In existing technologies, lidocaine and prilocaine have slow transdermal penetration rates, requiring prolonged administration to achieve the desired skin anesthetic effect, necessitating at least 1-2 hours of closed administration. Therefore, developing a surface anesthetic formulation with rapid transdermal penetration, fast onset of action, and long-lasting efficacy is of great significance. Summary of the Invention

[0005] To address the shortcomings of the existing technologies, this invention provides a compound lidocaine cream with rapid transdermal absorption, fast onset of action, and long duration of efficacy, as well as its preparation method.

[0006] To achieve the above objectives, the specific technical solution of the present invention is as follows:

[0007] Compound lidocaine cream comprises the following components by weight percentage: lidocaine-prilocaine cocrystal 5%~10%, surfactant 2%~8%, diethylene glycol monoethyl ether 2%~10%, thickener 3~5%, white petrolatum 15~35%, and appropriate amount of water.

[0008] The surfactants are sodium glycocholate and SPAN 40.

[0009] To address the problem of slow transdermal penetration in existing compound lidocaine topical medications, this invention uses lidocaine and prilocaine as active ingredients and prepares lidocaine-prilocaine cocrystals using a specific method. The compound lidocaine cream prepared from these lidocaine-prilocaine cocrystals, with the synergistic effect of sodium glycocholate and SPAN 40 in a specific ratio, has advantages such as rapid transdermal penetration, fast onset of action, and long duration of efficacy.

[0010] Preferably, the compound lidocaine cream comprises the following components in weight percentage: lidocaine-prilocaine 5%, surfactant 6%, diethylene glycol monoethyl ether 5%, thickener 5%, white petrolatum 25%, and water as needed.

[0011] Preferably, the compound lidocaine cream comprises the following components in weight percentage: lidocaine-prilocaine 5%, surfactant 6%, diethylene glycol monoethyl ether 5%, thickener 3%, white petrolatum 25%, and water as needed.

[0012] Preferably, the compound lidocaine cream comprises the following components in weight percentage: lidocaine-prilocaine 7.5%, surfactant 6%, diethylene glycol monoethyl ether 5%, thickener 3%, white petrolatum 25%, and water as needed.

[0013] Preferably, the compound lidocaine cream comprises the following components in weight percentage: 10% lidocaine-prilocaine, 6% surfactant, 5% diethylene glycol monoethyl ether, 3% thickener, 25% white petrolatum, and an appropriate amount of water.

[0014] Preferably, the compound lidocaine cream comprises the following components in weight percentage: lidocaine-prilocaine 7.5%, surfactant 2%, diethylene glycol monoethyl ether 5%, thickener 3%, white petrolatum 25%, and water as needed.

[0015] Preferably, the compound lidocaine cream comprises the following components in weight percentage: lidocaine-prilocaine 7.5%, surfactant 8%, diethylene glycol monoethyl ether 5%, thickener 3%, white petrolatum 25%, and water as needed.

[0016] Preferably, the mass ratio of sodium glycocholate to SPNA 40 is 1:2.

[0017] Preferably, the method for preparing the lidocaine-prilocaine cocrystal includes the following steps: mixing lidocaine, prilocaine, propylene glycol and a solvent, then heating the mixture and cooling it to obtain the lidocaine-prilocaine cocrystal.

[0018] Preferably, the mass ratio of docaine, prilocaine, and propylene glycol is (1~3):1:(0.1~0.5).

[0019] More preferably, the mass ratio of docaine, prilocaine, and propylene glycol is 3:1:0.3.

[0020] Preferably, the heat treatment is performed at a temperature of 50-70°C for 1-3 hours.

[0021] Preferably, the thickener is one or more of glyceryl monostearate, glyceryl monostearate, beeswax, cetyl alcohol, and octadecyl alcohol.

[0022] More preferably, the thickener is glyceryl mono- and di-stearyl esters.

[0023] Preferably, the compound lidocaine cream further comprises dimethicone oil.

[0024] Preferably, the dimethicone oil has a mass percentage of 3% to 5%.

[0025] This invention also provides a method for preparing the compound lidocaine cream, comprising the following steps:

[0026] S1. Melt white petrolatum, thickener, and SPNA 40 at 60 ℃~80 ℃ and mix them evenly to obtain mixture I;

[0027] S2. Add lidocaine-prilocaine eutectic to mixture I, mix thoroughly to obtain mixture II;

[0028] S3. Dissolve sodium glycocholate and diethylene glycol monoethyl ether in water to obtain mixture III;

[0029] S4. Heat mixture III to 50 ℃~60 ℃, add mixture II, and emulsify by shearing to obtain mixture IV;

[0030] S5. Cool the mixture IV to room temperature to obtain compound lidocaine cream.

[0031] Preferably, the rotation speed of the shear emulsification is 1000~1500 cm / s, and the time is 10~30 min.

[0032] More preferably, the rotation speed of the shear emulsification is 1200 cm / s, and the time is 20 min.

[0033] Compared with the prior art, the advantages of the present invention are:

[0034] The compound lidocaine cream provided by this invention has a faster transdermal rate, faster onset of action, and longer duration of effect, solving the problems of slow transdermal rate and long administration time of lidocaine and prilocaine in the prior art. Detailed Implementation

[0035] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0036] This invention provides a compound lidocaine cream comprising the following components by weight percentage: lidocaine-prilocaine cocrystal 5%~10%, surfactant 2%~8%, diethylene glycol monoethyl ether 2%~10%, thickener 3~5%, white petrolatum 15~35%, and appropriate amount of water;

[0037] The surfactants are sodium glycocholate and SPAN 40.

[0038] The method for preparing the lidocaine-prilocaine cocrystal includes the following steps: mixing lidocaine, prilocaine, propylene glycol and a solvent, then heating the mixture and cooling it to obtain the lidocaine-prilocaine cocrystal.

[0039] In some examples, the mass ratio of docaine, prilocaine, and propylene glycol is (1~3):1:(0.1~0.5).

[0040] In some examples, the heat treatment is performed at a temperature of 50–70 °C for a duration of 1–3 h.

[0041] In some examples, the thickener is one or more of glyceryl monostearate, glyceryl monostearate, beeswax, cetyl alcohol, and octadecanol.

[0042] Examples 1-5

[0043] Compound lidocaine cream comprises the following components by weight percentage: lidocaine-prilocaine cocrystal 5%, surfactant 6%, diethylene glycol monoethyl ether 5%, glyceryl mono- and distearate 5%, white petrolatum 25%, and water 54%; wherein the surfactant is sodium glycocholate and SPNA 40, and the mass ratio of sodium glycocholate to SPNA 40 is 1:2.

[0044] The lidocaine-prilocaine cocrystal is prepared as follows: lidocaine, prilocaine, 1,2-propanediol and ethanol are mixed evenly (the mass-volume ratio of lidocaine to ethanol is 1:2 g / mL), heated in an open container at 60°C for 1 h, and cooled to obtain lidocaine-prilocaine cocrystal. The mass ratio of lidocaine, prilocaine and 1,2-propanediol is shown in Table 1.

[0045] The preparation method of the compound lidocaine cream is as follows:

[0046] S1. Melt white petrolatum, glyceryl monostearate and glyceryl distearate, and SPAN 40 at 70 °C and mix them evenly to obtain mixture I;

[0047] S2. Add lidocaine-prilocaine eutectic to mixture I, mix thoroughly to obtain mixture II;

[0048] S3. Dissolve sodium glycocholate and diethylene glycol monoethyl ether in water to obtain mixture III;

[0049] S4. Heat mixture III to 60 °C, add mixture II, and emulsify by shearing to obtain mixture IV;

[0050] S5. Cool the mixture IV to room temperature to obtain compound lidocaine cream.

[0051] Table 1: Mass ratio of lidocaine, prilocaine, and 1,2-propanediol in compound lidocaine creams of Examples 1-5

[0052]

[0053] Examples 6-10

[0054] Compound lidocaine cream comprises the following components by weight percentage: lidocaine-prilocaine cocrystal, surfactant, diethylene glycol monoethyl ether, thickener, white petrolatum, and water; wherein the surfactant is sodium glycocholate and SPNA 40, and the mass ratio of sodium glycocholate to SPNA 40 is 1:2; the thickener is glyceryl mono- and distearate. The specific amounts of each component are shown in Table 2.

[0055] The lidocaine-prilocaine cocrystal is prepared as follows: lidocaine, prilocaine, 1,2-propanediol are mixed with ethanol at a mass ratio of 3:1:0.3 (the mass-volume ratio of lidocaine to ethanol is 1:2 g / mL), heated in an open container at 60 °C for 1 h, and cooled to obtain lidocaine-prilocaine cocrystal.

[0056] The preparation method of the compound lidocaine cream is as follows:

[0057] S1. Melt white petrolatum, thickener, and SPAN 40 at 70 °C and mix them evenly to obtain mixture I;

[0058] S2. Add lidocaine-prilocaine eutectic to mixture I, mix thoroughly to obtain mixture II;

[0059] S3. Dissolve sodium glycocholate and diethylene glycol monoethyl ether in water to obtain mixture III;

[0060] S4. Heat mixture III to 60 °C, add mixture II, and emulsify by shearing to obtain mixture IV;

[0061] S5. Cool the mixture IV to room temperature to obtain compound lidocaine cream.

[0062] Table 2: Specific dosage of each component in the compound lidocaine cream of Examples 6-10

[0063]

[0064] Comparative Example 1

[0065] Compound lidocaine cream comprises the following components by weight percentage: 7.5% lidocaine-prilocaine-propylene glycol mixture, 6% surfactant, 5% diethylene glycol monoethyl ether, 3% glyceryl mono- and distearate, 25% white petrolatum, and 53.5% water; wherein the surfactant is sodium glycocholate and SPNA 40, and the mass ratio of sodium glycocholate to SPNA 40 is 1:2.

[0066] The lidocaine-prilocaine-propylene glycol mixture is prepared as follows: lidocaine, prilocaine, and 1,2-propanediol are mixed evenly in a mass ratio of 3:1:0.3 to obtain the lidocaine-prilocaine-propylene glycol mixture.

[0067] The preparation method of the compound lidocaine cream is as follows:

[0068] S1. Melt white petrolatum, glyceryl monostearate and glyceryl distearate, and SPAN 40 at 70 °C and mix them evenly to obtain mixture I;

[0069] S2. Add the lidocaine-prilocaine-propylene glycol mixture to mixture I, mix thoroughly, and obtain mixture II;

[0070] S3. Dissolve sodium glycocholate and diethylene glycol monoethyl ether in water to obtain mixture III;

[0071] S4. Heat mixture III to 60 °C, add mixture II, and emulsify by shearing to obtain mixture IV;

[0072] S5. Cool the mixture IV to room temperature to obtain compound lidocaine cream.

[0073] Comparative Example 2

[0074] Compound lidocaine cream comprises the following components by weight percentage: lidocaine-prilocaine mixture 7.5%, surfactant 6%, diethylene glycol monoethyl ether 5%, glyceryl mono- and distearate 3%, white petrolatum 25%, and water 53.5%; wherein the surfactant is sodium glycocholate and SPNA 40, and the mass ratio of sodium glycocholate to SPNA 40 is 1:2.

[0075] The lidocaine-prilocaine mixture is prepared as follows: lidocaine and prilocaine are mixed with ethanol at a mass ratio of 3:1 (the mass-volume ratio of lidocaine to ethanol is 1:2 g / mL), heated in an open container at 60°C for 1 h, and then cooled to obtain the lidocaine-prilocaine mixture.

[0076] The preparation method of the compound lidocaine cream is as follows:

[0077] S1. Melt white petrolatum, glyceryl monostearate and glyceryl distearate, and SPAN 40 at 70 °C and mix them evenly to obtain mixture I;

[0078] S2. Add the lidocaine-prilocaine mixture to mixture I, mix thoroughly, and obtain mixture II;

[0079] S3. Dissolve sodium glycocholate and diethylene glycol monoethyl ether in water to obtain mixture III;

[0080] S4. Heat mixture III to 60 °C, add mixture II, and emulsify by shearing to obtain mixture IV;

[0081] S5. Cool the mixture IV to room temperature to obtain compound lidocaine cream.

[0082] Comparative Example 3

[0083] Compound lidocaine cream comprises the following components by weight percentage: lidocaine-prilocaine cocrystal 7.5%, surfactant 6%, diethylene glycol monoethyl ether 5%, glyceryl mono- and distearate 3%, white petrolatum 25%, and water 53.5%; wherein the surfactant is sodium glycocholate.

[0084] The lidocaine-prilocaine cocrystal is prepared as follows: lidocaine, prilocaine, 1,2-propanediol are mixed with ethanol at a mass ratio of 3:1:0.3 (the mass-volume ratio of lidocaine to ethanol is 1:2 g / mL), heated in an open container at 60 °C for 1 h, and cooled to obtain lidocaine-prilocaine cocrystal.

[0085] The preparation method of the compound lidocaine cream is as follows:

[0086] S1. Melt white petrolatum, glyceryl monostearate and glyceryl distearate, and sodium glycocholate (4%) at 70 °C and mix them evenly to obtain mixture I;

[0087] S2. Add lidocaine-prilocaine eutectic to mixture I, mix thoroughly to obtain mixture II;

[0088] S3. Dissolve sodium glycocholate (2%) and diethylene glycol monoethyl ether in water to obtain mixture III;

[0089] S4. Heat mixture III to 60 °C, add mixture II, and emulsify by shearing to obtain mixture IV;

[0090] S5. Cool the mixture IV to room temperature to obtain compound lidocaine cream.

[0091] Comparative Example 4

[0092] Compound lidocaine cream comprises the following components by weight percentage: lidocaine-prilocaine cocrystal 7.5%, surfactant 6%, diethylene glycol monoethyl ether 5%, glyceryl mono- and distearate 3%, white petrolatum 25%, and water 53.5%; wherein the surfactant is SPAN 40.

[0093] The lidocaine-prilocaine cocrystal is prepared as follows: lidocaine, prilocaine, 1,2-propanediol are mixed with ethanol at a mass ratio of 3:1:0.3 (the mass-volume ratio of lidocaine to ethanol is 1:2 g / mL), heated in an open container at 60 °C for 1 h, and cooled to obtain lidocaine-prilocaine cocrystal.

[0094] The preparation method of the compound lidocaine cream is as follows:

[0095] S1. Melt white petrolatum, glyceryl monostearate and glyceryl distearate, and SPAN 40 (4%) at 70 °C and mix them evenly to obtain mixture I;

[0096] S2. Add lidocaine-prilocaine eutectic to mixture I, mix thoroughly to obtain mixture II;

[0097] S3. Dissolve SPAN 40 (2%) and diethylene glycol monoethyl ether in water to obtain mixture III;

[0098] S4. Heat mixture III to 60 °C, add mixture II, and emulsify by shearing to obtain mixture IV;

[0099] S5. Cool the mixture IV to room temperature to obtain compound lidocaine cream.

[0100] 1. In vitro transdermal test

[0101] The compound lidocaine creams prepared in Examples 1-14 and Comparative Examples 1-4 were subjected to in vitro transdermal tests to compare the transdermal penetration and retention of the drug in skin tissue.

[0102] In vitro transdermal assays were conducted using a modified Franz vertical diffusion cell. A stir bar was placed in the receiving cell, and pretreated pigskin (back) was placed between the supply and receiving chambers, with the dermis facing the receiving solution and secured with clamps. Approximately 1.5 g of sample was evenly spread on the epidermis. The diffusion cell was placed in a water bath at 32 ℃ ± 0.5 ℃, with a stirring speed of 600 r / min. The receiving solution was completely removed at 30, 45, and 60 min, and fresh blank receiving solution was added. The obtained samples were centrifuged, and the supernatant was used to determine the concentration using HPLC. The subcutaneous permeation and interdermal retention rates were calculated. The results are shown in Table 3.

[0103] Table 3: Cumulative retention rates of drugs in subcutaneous, intradermal, and supradermal regions

[0104]

[0105] As can be seen from Table 3 above, the drug samples prepared in Examples 1-10 showed significantly higher intradermal drug retention, and the increased intradermal retention indicates better local efficacy. In the preparation of lidocaine-prilocaine cocrystal, the transdermal effect of the drug was better when the mass ratio of lidocaine, prilocaine, and propylene glycol was 3:1:0.3. However, comparative examples 1-2 did not prepare cocrystals, and comparative examples 3-4 used only the surfactant sodium glycocholate or SPAN 40 when preparing compound lidocaine cream, which both resulted in a significant decrease in subcutaneous penetration and intradermal retention of the drug.

[0106] 2. Drug efficacy evaluation

[0107] The efficacy of compound lidocaine creams prepared in Examples 1-10 and Comparative Examples 1-4 was tested using a guinea pig acupuncture reaction model. Acupuncture was performed on the administration site at different times after administration to observe whether the guinea pigs had a stinging reaction, so as to determine the onset time of the drug. After the drug took effect, the administration device was removed and the duration of drug efficacy was further examined. The efficacy evaluation results are shown in Table 4.

[0108] Table 4: Efficacy Evaluation Results of Compound Lidocaine Cream

[0109]

[0110] As shown in Table 4, the compound lidocaine cream of the present invention has a fast onset time and a long duration of efficacy. Compared with the lidocaine-prilocaine cream (Enna Cream) in the prior art, the drug has a faster onset time and a longer duration of efficacy. The onset time of comparative examples 1 to 4 was significantly prolonged after the formulation was changed.

[0111] In summary, this invention uses lidocaine and prilocaine as active ingredients and employs a specific method to prepare lidocaine-prilocaine cocrystals. The compound lidocaine cream prepared by emulsification of the lidocaine-prilocaine cocrystals under the synergistic effect of sodium glycocholate and SPAN40 in a specific ratio has advantages such as rapid onset of action and long duration of efficacy.

[0112] The above detailed embodiments describe the implementation of the present invention; however, the present invention is not limited to the specific details described in the above embodiments. Within the scope of the claims and technical concept of the present invention, various simple modifications and changes can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. Compound lidocaine cream, characterized in that, The product contains the following components by weight percentage: lidocaine-prilocaine cocrystal 5%~10%, surfactant 2%~8%, diethylene glycol monoethyl ether 2%~10%, thickener 3~5%, white petrolatum 15~35%, and water as needed; The surfactants are sodium glycocholate and SPNA 40.

2. The compound lidocaine cream according to claim 1, characterized in that, The compound lidocaine cream comprises the following components by weight percentage: lidocaine-prilocaine 5%, surfactant 6%, diethylene glycol monoethyl ether 5%, thickener 5%, white petrolatum 25%, and water as needed.

3. The compound lidocaine cream according to claim 1, characterized in that, The compound lidocaine cream comprises the following components by weight percentage: lidocaine-prilocaine 7.5%, surfactant 6%, diethylene glycol monoethyl ether 5%, thickener 3%, white petrolatum 25%, and water as needed.

4. The compound lidocaine cream according to claim 1, characterized in that, The compound lidocaine cream comprises the following components by weight percentage: lidocaine-prilocaine 10%, surfactant 6%, diethylene glycol monoethyl ether 5%, thickener 3%, white petrolatum 25%, and water as needed.

5. The compound lidocaine cream according to claim 1, characterized in that, The mass ratio of sodium glycocholate to SPNA 40 is 1:

2.

6. The compound lidocaine cream according to claim 1, characterized in that, The method for preparing the lidocaine-prilocaine co-crystal, The process includes the following steps: mixing lidocaine, prilocaine, propylene glycol with a solvent and then heating the mixture, followed by cooling to obtain a lidocaine-prilocaine eutectic.

7. The compound lidocaine cream according to claim 6, characterized in that, The mass ratio of docaine, prilocaine, and propylene glycol is (1~3):1:(0.1~0.5).

8. The compound lidocaine cream according to claim 1, characterized in that, The thickener is one or more of the following: glyceryl monostearate, glyceryl monostearate, beeswax, cetyl alcohol, and octadecanol.

9. The compound lidocaine cream according to claim 8, characterized in that, The thickener is glyceryl mono- and di-stearyl esters.

10. The compound lidocaine cream according to claim 1, characterized in that, The components also include dimethicone.

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