Compound lidocaine cream as well as preparation method and application thereof
By leveraging the synergistic effect of lidocaine and prilocaine, combined with a specific ratio of solubilizers and penetration enhancers, a compound lidocaine cream was prepared, solving the problems of high cost and slow onset of action of existing anesthetic drugs, and achieving faster onset, deeper anesthesia, and longer duration of action.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- BEIJING UNIS PHARMA
- Filing Date
- 2026-03-17
- Publication Date
- 2026-05-12
AI Technical Summary
Existing anesthetic drugs have high production costs, slow onset of action, and unsatisfactory percutaneous penetration effects.
The drug is administered via the synergistic effect of lidocaine and prilocaine, combined with polyoxyethylene hydrogenated castor oil and poloxamer 188 as solubilizers, and L-ethyl lactate and oleic acid as penetration enhancers. This method promotes drug penetration to subcutaneous nerve endings and forms a stable cream system.
It achieves deeper and longer-lasting anesthesia, faster onset of action, and high safety.
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Abstract
Description
Technical Field
[0001] This application relates to the technical field of pharmaceuticals, specifically to a compound lidocaine cream and its preparation method and application. Background Technology
[0002] Anesthetic drugs are an indispensable part of the medical industry. They can help patients reduce pain and discomfort during surgery and treatment, and improve the success rate and effectiveness of surgery and treatment.
[0003] The relevant anesthetic drugs are prepared by first soaking carbomer 934 in purified water for at least 10 hours; then, polyoxyethylene hydrogenated castor oil is directly added to a mixing container and stirred evenly with a low-melting-point eutectic mixture to form a water-in-oil mixture, which is then mixed with carbomer 934 to obtain an ointment. Its disadvantages are: high production cost; slow onset of action (generally exceeding 1 hour); and less than ideal transdermal penetration. Summary of the Invention
[0004] To address the aforementioned technical problems, this application provides a compound lidocaine cream, its preparation method, and its application.
[0005] In a first aspect, this application provides a compound lidocaine cream, specifically comprising the following components in parts by weight: 22-26 parts lidocaine, 22-26 parts prilocaine, 13-17 parts solubilizer, 9-11 parts carbomer, 3-5 parts sodium hydroxide, 0.02-0.06 parts penetration enhancer; the balance being water added to a total of 1000 parts; The solubilizer is composed of polyoxyethylene hydrogenated castor oil and poloxamer 188 in a weight ratio of 10-15:1-4. The penetration enhancer is composed of a mixture of L-ethyl lactate and oleic acid in a weight ratio of 1-4:0.2-1.
[0006] This application utilizes the synergistic effect of lidocaine and prilocaine, which are administered through the skin or mucous membranes to penetrate subcutaneous nerve endings, achieving numbing and analgesic effects. Compared to single-component drugs, this method has a faster onset of action, deeper anesthetic effect, and longer duration of action.
[0007] Hydrogenated castor oil and poloxamer 188 primarily function as solubilizers in compound lidocaine cream, playing the following important roles: Emulsification: As emulsifiers, they reduce the interfacial tension between oil and water, allowing the oil phase (lidocaine, prilocaine, etc.) to be uniformly dispersed in the aqueous phase, forming a stable cream system. Solubilization: They increase the solubility of poorly soluble drugs (lidocaine, prilocaine) in the aqueous phase, improving drug bioavailability. Permeation Enhancement: By altering the structure of the stratum corneum lipid bilayer, they increase skin permeability, promoting transdermal drug absorption and shortening the onset time. Stabilization: They maintain the physical stability of the cream, preventing oil-water separation and extending the product's shelf life. Wetting: They improve the spreadability and applicability of the cream, making it easier for the drug to be evenly distributed on the skin surface.
[0008] The penetration enhancer, composed of L-ethyl lactate and oleic acid, enables the drug to rapidly cross the stratum corneum barrier, quickly reaching an effective concentration at the nerve endings in the skin. Increased intradermal retention leads to a rapid rise in local concentration, shortening the onset time of anesthesia. Furthermore, L-ethyl lactate and oleic acid have good biocompatibility; their combination exerts a penetration-enhancing effect even at low concentrations, with minimal skin irritation. Compared to chemically synthesized penetration enhancers, it offers higher safety.
[0009] Preferably, the compound lidocaine cream specifically comprises the following components in parts by weight: 23-25 parts lidocaine, 23-25 parts prilocaine, 14-16 parts solubilizer, 9.5-10.5 parts carbomer, 3.5-4.5 parts sodium hydroxide, 0.03-0.05 parts penetration enhancer; the balance is water added to a total of 1000 parts.
[0010] Preferably, the compound lidocaine cream specifically comprises the following components in parts by weight: 24 parts lidocaine, 24 parts prilocaine, 15 parts solubilizer, 10 parts carbomer, 4 parts sodium hydroxide, 0.04 parts penetration enhancer; the balance is water added to 1000 parts.
[0011] Preferably, the solubilizer is composed of a mixture of polyoxyethylene hydrogenated castor oil and poloxamer 188 in a weight ratio of 12-13:2-3.
[0012] In one specific implementation, the weight ratio of the polyoxyethylene hydrogenated castor oil and poloxamer 188 can be 12:2, 12.5:2, 13:2, 12:2.5, 12.5:2.5, 13:2.5, 12:3, 12.5:3, or 13:3.
[0013] Experimental analysis shows that using the above-mentioned weight ratio of polyoxyethylene hydrogenated castor oil and poloxamer 188 as a solubilizer can further improve the efficacy of compound lidocaine cream.
[0014] Preferably, the polyoxyethylene hydrogenated castor oil is selected from polyoxyethylene hydrogenated castor oil PEG-40 or polyoxyethylene hydrogenated castor oil PEG-60.
[0015] Preferably, the penetration enhancer is composed of a mixture of L-ethyl lactate and oleic acid in a weight ratio of 2-3:0.5-0.7.
[0016] In one specific implementation, the weight ratio of L-ethyl lactate to oleic acid in the penetration enhancer can be 2:0.5, 2.5:0.5, 3:0.5, 2:0.6, 2.5:0.6, 3:0.6, 2:0.7, 2.5:0.7, or 3:0.7.
[0017] Experimental analysis shows that the use of L-ethyl lactate and oleic acid in the above weight ratio as penetration enhancers in this application can further improve the efficacy of compound lidocaine cream.
[0018] Secondly, this application also provides a method for preparing the compound lidocaine cream, specifically including the following steps in sequence: (1) Under stirring conditions, add carbomer to 250-350 parts by weight of water, stir and soak to obtain carbomer gel; (2) Under stirring conditions, lidocaine and prilocaine are mixed evenly and stirred evenly at room temperature. The mixture is then nano-sized by high-pressure homogenization to obtain a eutectic material. (3) Mix the solubilizer and the penetration enhancer and stir at 55-60°C until completely melted; then add the mixture to the eutectic and stir evenly to form a water-in-oil mixture. (4) Mix the carbomer gel with the oil phase mixture and stir to form an oil-in-water mixture; add sodium hydroxide solution to the oil-in-water mixture and stir until homogeneous; (5) Add the remaining water to the mixing container to the formula amount, stir evenly to form a cream; homogenize to stabilize the cream, and you will get the product.
[0019] Carbomer is obtained by crosslinking acrylic acid monomers with propylene sucrose or propylene pentaerythritol. When carbomer is dispersed in water, the repulsive effect between negative charges generated by carboxyl ionization causes the coiled polymer to unwind and expand in volume. In specific embodiments, carbomer needs to be added to water under stirring conditions to wet it and prevent dust from flying, and water is added gradually to make it swell. In this application, carbomer powder is sprinkled into the vortex formed by stirring in batches under high-speed stirring at 20-70 Hz, and stirring is continued until it is completely dispersed in the solvent.
[0020] Preferably, in step (2), the process parameters for the high-pressure homogenization process are as follows: first, homogenize for 15-30 minutes at a temperature of 30-40℃, a pressure of 60-80MPa, and a rotation speed of 2000-3000rpm; then, homogenize for 30-90 minutes at a temperature of 40-50℃, a pressure of 80-120MPa, and a rotation speed of 2000-3000rpm.
[0021] In a specific implementation plan, this application uses the above-mentioned high-pressure homogenization method to nano-size the active pharmaceutical ingredient mixture: the eutectic mixture formed by mixing base lidocaine and base prilocaine is nano-sized to promote drug absorption and shorten the onset time.
[0022] Preferably, in step (5), the process parameters for homogenization are: homogenization for 20-90 minutes at a temperature of 30-40℃, a pressure of 40-70 MPa, and a rotation speed of 2000-3000 rpm.
[0023] Thirdly, this application provides the use of the aforementioned compound lidocaine cream in the preparation of anesthetic drugs.
[0024] In summary, the technical solution of this application has the following effects: The compound lidocaine cream prepared in this application has good safety, and it has the effects of faster onset, deeper anesthetic effect, and longer duration.
[0025] The compound lidocaine cream provided in this application can be used for local anesthesia of the skin during needle puncture and superficial surgery. Detailed Implementation
[0026] The present application will be further described in detail below with reference to embodiments, comparative examples and performance test results. These embodiments should not be construed as limiting the scope of protection claimed in this application.
[0027] Example
[0028] Examples 1-3 Examples 1-3 provide a compound lidocaine cream and its preparation method, respectively.
[0029] The difference in the above embodiments is that the amount of each raw material component is different, as shown in Table 1.
[0030] The preparation method of the compound lidocaine cream in the above embodiments is as follows: (1) Under stirring conditions of 50 Hz, add 10 g of carbomer 934 to 300 g of purified water, stir and soak overnight to obtain carbomer gel.
[0031] (2) Under the stirring condition of 30 Hz, lidocaine and prilocaine are mixed evenly and stirred evenly at room temperature. The mixture is then nano-sized by high-pressure homogenization to obtain a low eutectic material. The process parameters of the high-pressure homogenization treatment are as follows: first, homogenize for 20 min at a temperature of 35 ℃, a pressure of 70 MPa and a rotation speed of 2500 rpm; then, homogenize for 60 min at a temperature of 45 ℃, a pressure of 100 MPa and a rotation speed of 2500 rpm.
[0032] (3) Mix the solubilizer (composed of polyoxyethylene hydrogenated castor oil PEG-60 and poloxamer 188 in a weight ratio of 13:2) and the penetration promoter (composed of L-lactic acid ethyl ester and oleic acid in a weight ratio of 2:0.7) and stir at 55°C and 50Hz until completely melted; then add the mixture to the eutectic and stir evenly to form a water-in-oil mixture.
[0033] (4) Mix the carbomer gel with the oil phase mixture and stir to form an oil-in-water mixture; add sodium hydroxide solution to the oil-in-water mixture and stir evenly; wherein, the sodium hydroxide solution is prepared by weighing 100g of purified water into a stainless steel bucket, adding 4g of weighed sodium hydroxide and stirring until dissolved.
[0034] (5) Add the remaining water to the mixing container to make up to 1000g of the formula, and stir evenly to form a cream; homogenize to stabilize the cream, and the product is obtained. The process parameters for the homogenization are: homogenize for 5min at a temperature of 35℃, a pressure of 60MPa, and a rotation speed of 2500rpm.
[0035] Table 1. Amounts of each raw material component in Examples 1-3
[0036] Examples 4-9 Examples 4-9 provide a compound lidocaine cream and its preparation method, respectively.
[0037] The specific difference between the above embodiments and Embodiment 1 is that the composition of the solubilizer or penetration enhancer is different, as shown below.
[0038] In Example 4, the solubilizer was composed of a mixture of PEG-40 hydrogenated castor oil and poloxamer 188 in a weight ratio of 13:2.
[0039] In Example 5, the solubilizer was composed of a mixture of PEG-60 hydrogenated castor oil and poloxamer 188 in a weight ratio of 10:4.
[0040] In Example 6, the solubilizer was composed of a mixture of PEG-60 hydrogenated castor oil and poloxamer 188 in a weight ratio of 15:1.
[0041] In Example 7: the penetration enhancer is composed of L-ethyl lactate and oleic acid in a weight ratio of 3:0.5.
[0042] In Example 8: the penetration enhancer is composed of a mixture of L-ethyl lactate and oleic acid in a weight ratio of 1:1.
[0043] In Example 9: the penetration enhancer is composed of L-ethyl lactate and oleic acid in a weight ratio of 4:0.2.
[0044] All other process parameters in the above embodiments are the same as those in Embodiment 1.
[0045] Comparative Example Comparative Examples 1-4 Comparative Examples 1-4 each provide a compound lidocaine cream and its preparation method.
[0046] The difference between the above comparative examples and Example 1 is that the composition of the solubilizer or penetration enhancer is different, as shown below.
[0047] In Comparative Example 1: the solubilizer was polyoxyethylene hydrogenated castor oil PEG-60, and no penetration enhancer was added.
[0048] In Comparative Example 2, the solubilizer was composed of a mixture of PEG-60 hydrogenated castor oil and poloxamer 188 in a weight ratio of 9:2.
[0049] In Comparative Example 3: the penetration enhancer was composed of isopropyl myristate and oleic acid in a weight ratio of 4:0.2.
[0050] In Comparative Example 4, the penetration enhancer was composed of a mixture of L-ethyl lactate and oleic acid in a weight ratio of 0.7:2.
[0051] All other process parameters in the above comparative examples are the same as those in Example 1.
[0052] Performance testing (1) Safety evaluation Guinea pigs were used as experimental animals. Compound lidocaine cream was applied topically to the shaved skin on the back of white guinea pigs, and the resulting skin irritation was observed. A single administration of 0.25g was administered, covering an effective area of 1.69 cm². Visual observations were performed at 1 hour, 24 hours, and 48 hours after administration, and the average irritation score was recorded. Three administrations (one every 24 hours) were administered, with a dosage of 0.25g per administration and an effective coverage area of 1.69 cm² each time. Visual observations were performed at 1 hour, 24 hours, and 48 hours after each administration, and the average irritation score was recorded. Five mice were used in each experimental group, and five researchers provided visual observation scores for the irritation.
[0053] The scoring criteria for irritant symptoms are as follows: Erythema scoring: 0 points for no visible erythema, 1 point for barely visible erythema, 2 points for moderate erythema, 3 points for severe erythema, and 4 points for purplish-red erythema with eschar formation.
[0054] Edema scoring: 0 points for no visible edema, 1 point for barely visible edema, 2 points for clearly defined skin edema, and 4 points for edema ...
[0055] Irritation symptom score = average erythema score + average edema score. Irritation intensity assessment criteria: Score ≤ 0.5: no irritation; 0.5 < Score ≤ 2.99: mild irritation; 2.99 < Score ≤ 6.0: moderate irritation; Score ≥ 6.0: strong irritation.
[0056] Test results are shown in Table 2.
[0057] Table 2. Safety test results of compound lidocaine cream in the examples or comparative examples.
[0058] As shown in Table 2, the average reaction scores of the compound lidocaine cream prepared in this application on broken skin in guinea pigs were ≤0.5 at 1h, 24h, and 48h after a single administration, indicating no irritation to the broken skin. After three administrations, the scores were >0.5 but <2.99 at 1h and 24h, indicating mild irritation to the broken skin, but this irritation disappeared after 48h. These results demonstrate that the compound lidocaine cream prepared in this application has good safety.
[0059] (2) In vitro transdermal test Referring to the "Chinese Journal of Hospital Pharmacy", pig skin was used as the transdermal permeation material. A vertical modified Franz diffusion cell was used to determine the permeation and absorption characteristics of compound lidocaine cream. High performance liquid chromatography was used to determine the total amount of drug absorbed in the receiving solution and the amount of drug retained in the pig skin.
[0060] Skin was harvested from the back of pigs, subcutaneous tissue and fat were removed, and the skin was rinsed with physiological saline and wiped with alcohol. It was then stored at -20℃ for later use. An in vitro transdermal test was conducted using a modified Franz diffusion cell. The specific procedure was as follows: the excised skin was fixed between the donor and receiver cells, with the stratum corneum facing the donor cell; the drug dosage was 0.25g, the effective application area was approximately 1.69cm², and the receiver cell volume was 16mL. Phosphate buffer (pH 7.4) was used as the receiver solution. The test was conducted at a constant temperature of 32℃ with a magnetic stirring speed of 300r / min. Samples were taken at 0.5, 1, 2, 3, 4, and 5 hours, with 4mL of receiver solution taken each time, and an equal volume of receiver solution was replenished isothermally.
[0061] The concentrations of lidocaine and prilocaine in the receiving solution were determined by high-performance liquid chromatography (HPLC). Chromatographic conditions: Agilent XDB-C18 column; mobile phase: phosphate buffer-acetonitrile (60:40); detection wavelength: 220-235 nm; injection volume: 20 μL. Cumulative permeate was calculated at each time point. Analysis of variance was performed using SPSS software, with p < 0.05 considered statistically significant.
[0062] After the transdermal test, the residual cream on the skin surface was scraped off and rinsed with physiological saline. The skin was then cut into pieces and extracted with acetonitrile by ultrasonication for 40 min. The supernatant was collected after centrifugation. The amount of drug retained in the skin was calculated by HPLC.
[0063] Test results are shown in Table 3.
[0064] Table 3 Performance test results of compound lidocaine cream in the examples or comparative examples
[0065] As shown in Table 3 above, the in vitro transdermal test results indicate that the compound lidocaine cream prepared in this application has a high cumulative penetration and intradermal drug retention. A high cumulative penetration indicates strong transdermal absorption, a short time required to reach an effective therapeutic concentration, and rapid onset of action. The intradermal retention parameter reflects the distribution and accumulation of the drug in the stratum corneum, epidermis, and dermis. Lidocaine and prilocaine need to reach effective concentrations at the nerve endings in the skin to produce an anesthetic effect. A higher intradermal retention indicates slower drug release, maintaining a local effective concentration, meaning a higher concentration at the site of action results in a stronger local anesthetic effect and a longer duration of anesthetic action. In other words, the compound lidocaine cream prepared using the technical solution of this application has both rapid onset and long-lasting effect.
[0066] By comparing the test results of Example 1 and Comparative Example 1, it can be seen that the solubilizer in Comparative Example 1 is polyoxyethylene hydrogenated castor oil PEG-60, without the addition of a penetration enhancer. It is a traditional compound lidocaine cream with low cumulative penetration and intradermal drug retention.
[0067] By comparing the test results of Examples 1, 4-6, and Comparative Example 2, it can be seen that the solubilizer in Comparative Example 2, composed of a mixture of polyoxyethylene hydrogenated castor oil PEG-60 and poloxamer 188 in a weight ratio of 9:2, has a lower cumulative penetration and intradermal drug retention. In contrast, the compound lidocaine cream prepared in this application, using a solubilizer composed of a mixture of polyoxyethylene hydrogenated castor oil and poloxamer 188 in a weight ratio of 10-15:1-4, has a higher cumulative penetration and intradermal drug retention.
[0068] By comparing the test results of Examples 1, 7-9, and Comparative Examples 3-4, it can be seen that the penetration enhancer in Comparative Example 3 is composed of a mixture of isopropyl myristate and oleic acid in a weight ratio of 4:0.2. The penetration enhancer in Comparative Example 4 is composed of a mixture of ethyl L-lactic acid and oleic acid in a weight ratio of 0.7:2, resulting in lower cumulative penetration and intradermal drug retention. In contrast, the compound lidocaine cream prepared in this application using a penetration enhancer composed of a mixture of ethyl L-lactic acid and oleic acid in a weight ratio of 1-4:0.2-1 exhibits higher cumulative penetration and intradermal drug retention.
[0069] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.
Claims
1. A compound lidocaine cream, characterized in that, Specifically, it includes the following components in parts by weight: lidocaine 22-26 parts, prilocaine 22-26 parts, solubilizer 13-17 parts, carbomer 9-11 parts, sodium hydroxide 3-5 parts, penetration enhancer 0.02-0.06 parts; the balance is water added to 1000 parts. The solubilizer is composed of polyoxyethylene hydrogenated castor oil and poloxamer 188 in a weight ratio of 10-15:1-4. The penetration enhancer is prepared in a weight ratio of 1-4: It consists of 0.2-1 L-ethyl lactate and oleic acid.
2. The compound lidocaine cream according to claim 1, characterized in that, Specifically, it includes the following components in parts by weight: lidocaine 23-25 parts, prilocaine 23-25 parts, solubilizer 14-16 parts, carbomer 9.5-10.5 parts, sodium hydroxide 3.5-4.5 parts, penetration enhancer 0.03-0.05 parts; the balance is water added to 1000 parts.
3. The compound lidocaine cream according to claim 1, characterized in that, Specifically, the components include the following parts by weight: 24 parts lidocaine, 24 parts prilocaine, 15 parts solubilizer, 10 parts carbomer, 4 parts sodium hydroxide, 0.04 parts penetration enhancer; the balance is water added to 1000 parts.
4. The compound lidocaine cream according to claim 1, characterized in that, The solubilizer is composed of a mixture of polyoxyethylene hydrogenated castor oil and poloxamer 188 in a weight ratio of 12-13:2-3.
5. The compound lidocaine cream according to claim 1, characterized in that, The polyoxyethylene hydrogenated castor oil is selected from polyoxyethylene hydrogenated castor oil PEG-40 or polyoxyethylene hydrogenated castor oil PEG-60.
6. The compound lidocaine cream according to claim 1, characterized in that, The penetration enhancer is composed of a mixture of L-ethyl lactate and oleic acid in a weight ratio of 2-3:0.5-0.
7.
7. A method for preparing a compound lidocaine cream as described in any one of claims 1-6, characterized in that, Specifically, the following steps are performed sequentially: (1) Under stirring conditions, add carbomer to 250-350 parts by weight of water, stir and soak to obtain carbomer gel; (2) Under stirring conditions, lidocaine and prilocaine are mixed evenly and stirred evenly at room temperature. The mixture is then nano-sized by high-pressure homogenization to obtain a eutectic material. (3) Mix the solubilizer and the penetration enhancer and stir at 55-60°C until completely melted; then add the mixture to the eutectic and stir evenly to form a water-in-oil mixture. (4) Mix the carbomer gel with the oil phase mixture and stir to form an oil-in-water mixture; add sodium hydroxide solution to the oil-in-water mixture and stir until homogeneous; (5) Add the remaining water to the mixing container to the formula amount, stir evenly to form a cream; homogenize to stabilize the cream, and you will get the product.
8. The method for preparing compound lidocaine cream according to claim 7, characterized in that, In step (2), the process parameters for the high-pressure homogenization process are as follows: first, homogenize for 15-30 minutes at a temperature of 30-40℃, a pressure of 60-80 MPa, and a rotation speed of 2000-3000 rpm; then, homogenize for 30-90 minutes at a temperature of 40-50℃, a pressure of 80-120 MPa, and a rotation speed of 2000-3000 rpm.
9. The method for preparing compound lidocaine cream according to claim 7, characterized in that, In step (5), the process parameters for homogenization are: homogenization for 20-90 minutes at a temperature of 30-40℃, a pressure of 40-70 MPa, and a rotation speed of 2000-3000 rpm.
10. The use of the compound lidocaine cream as described in any one of claims 1-6 in the preparation of anesthetic drugs.