Levadicaine pre-packaging application and preparation method thereof

Abstract

The invention relates to the field of medical application, in particular to a riptacaine pre-packaged application and a preparation method thereof. The lidocaine pre-packaged application is formed by packaging an application base material and anesthetic liquid together, and the anesthetic liquid is prepared from the following raw materials in parts by mass: 0.1 to 0.3 part of sodium hyaluronate, 0.1 to 0.3 part of a thickening agent, 7 to 13 parts of an alcohol penetration enhancer, 3 to 6 parts of a nonionic surfactant, 0.3 to 0.8 part of poloxamer and 1 to 3 parts of lidocaine, the anesthetic comprises the following components in parts by mass: 1-3 parts of prilocaine, 0.1-0.2 part of epsilon-polylysine, a pH regulator for regulating the pH value of the anesthetic liquid to 7.0-8.0, and the balance of water, totaling 100 parts by mass. According to the invention, by adding a small amount of epsilon-polylysine, the epsilon-polylysine not only has an antibacterial effect, but also can obviously improve the stability of the riptacaine liquid medicine, and through long-term storage and high-temperature acceleration experiments, the increase speed of related impurities is obviously slowed down, so that the reliability and safety of the pre-sealed riptacaine skin surface anesthesia application can be improved.

Description

Technical Field

[0001] This invention relates to the field of medical dressings, specifically to a pre-packaged levofloxacin dressing and its preparation method. Background Technology

[0002] The medical aesthetics industry has developed rapidly in recent years, with minimally invasive and painless procedures becoming a pressing consumer demand. Topical anesthetic dressings have emerged as a medical product to replace topical anesthetic ointments in recent years, offering advantages such as portability, rapid onset of action, good skin adhesion, and high biocompatibility. They avoid the drawbacks of topical creams or gels containing anesthetic drugs, such as slow onset of action, uneven application, and adverse reactions caused by large dosages. Furthermore, the application process only requires placing the dressing on the wound, eliminating complicated procedures and reducing workload. Therefore, topical anesthetic dressings are currently favored by the market.

[0003] Lidocaine and prilocaine are commonly used local anesthetics in clinical medicine, but their transdermal penetration is insufficient, requiring higher doses to achieve the desired level of anesthesia. Therefore, they are generally used in conjunction with penetration enhancers and thickeners. Existing skin surface anesthetic dressings containing lidocaine and prilocaine involve preparing a homogeneous emulsion containing lidocaine, prilocaine, and sodium hyaluronate, etc., and then soaking the dressing substrate, such as medical non-woven fabric, in the emulsion before encapsulation. Examples include those described in CN120549894A, CN117982466A, and CN118681051A. However, this type of anesthetic dressing requires preparation fresh for each use, which is cumbersome. Therefore, a new technology has emerged that directly encapsulates the dressing substrate and anesthetic solution together, allowing for direct use upon application. Examples include those described in CN120884566A and CN118743691A. These pre-packaged dressings typically have a shelf life of 1-2 years, thus placing high demands on the stability of the anesthetic solution. Testing revealed that even when stored in a refrigerator for extended periods, lidocaine and prilocaine, the main components of the anesthetic, can become unstable, producing impurities and posing potential risks. For skin surface anesthetic dressings classified as Class III medical devices, quality control is extremely stringent; exceeding standards can severely compromise the product's effectiveness and safety. Summary of the Invention

[0004] To address the inconvenience of existing lidocaine and prilocaine-containing surface anesthetic dressings, which require on-site immersion of the dressing substrate in the anesthetic solution, cumbersome procedures, and stringent requirements for anesthetic solution preservation, and to address the drawback of existing products where the anesthetic solution and substrate are packaged together, leading to instability of the active anesthetic components after prolonged storage, this invention proposes a pre-packaged lidocaine and prilocaine-containing surface anesthetic dressing and its preparation method. By adding a small amount of ε-polylysine, the long-term stability of the lidocaine and prilocaine solution is significantly improved. This allows the dressing product containing lidocaine and prilocaine solution to be pre-packaged with the dressing substrate, maintaining the lidocaine and prilocaine content without significant decrease over a period of up to one year, while significantly inhibiting the increase of related impurities. This provides assurance for the commercialization and clinical use of this pre-packaged lidocaine and prilocaine-containing surface anesthetic dressing.

[0005] The present invention solves the above problems through the following technical solutions:

[0006] A pre-packaged lidocaine patch comprises a patch substrate and an anesthetic solution encapsulated together. The anesthetic solution includes the following ingredients: 0.1-0.3 parts by weight of sodium hyaluronate, 0.1-0.3 parts by weight of thickener, 7-13 parts by weight of alcohol-based penetration enhancer, 3-6 parts by weight of nonionic surfactant, 0.3-0.8 parts by weight of poloxamer, 1-3 parts by weight of lidocaine, 1-3 parts by weight of prilocaine, 0.1-0.2 parts by weight of ε-polylysine, a pH adjuster to adjust the pH of the anesthetic solution to 7.0-8.0, and water to a total of 100 parts by weight.

[0007] Further, the anesthetic solution comprises the following raw materials: 0.1-0.3 parts by weight of sodium hyaluronate, 0.1-0.3 parts by weight of thickener, 8-10 parts by weight of alcohol-based penetration enhancer, 4-5 parts by weight of nonionic surfactant, 0.42-0.65 parts by weight of poloxamer, 2.2-2.5 parts by weight of lidocaine, 2.2-2.5 parts by weight of prilocaine, 0.15-0.2 parts by weight of ε-polylysine, a pH adjuster to adjust the pH of the anesthetic solution to 7.4-7.8, and water to a total of 100 parts by weight.

[0008] The inventors discovered that the most common impurities in liprocaine anesthetic solution are o-toluidine, the AZ11163567 isomer, impurity B, and impurity D. Through extensive research, the inventors found that the formation of these impurities is related to the presence of sodium hyaluronate, a commonly used ingredient in liprocaine anesthetic solutions. Sodium hyaluronate plays multiple roles in anesthetic dressings. Its polymer chains interact with skin tissue, prolonging the drug's residence time at the site of action, forming a water-containing film on the skin surface, softening the stratum corneum, and facilitating drug diffusion; it also enhances the patch's contact and adhesion to the skin, providing moisturizing and bioadhesive properties. Furthermore, it promotes more effective penetration of the anesthetic drug through the stratum corneum barrier, thereby improving efficacy. Finally, sodium hyaluronate may regulate the drug release rate by forming a gel network structure, resulting in a more prolonged and stable anesthetic effect. Although the exact reason is unclear, the presence of sodium hyaluronate may accelerate the formation of related impurities in liprocaine anesthetic solutions. This may be due to sodium hyaluronate forming complexes with penetration enhancers and surfactants in the formulation, altering the drug's chemical stability and inducing isomerization or degradation. The inventors' original intention was to reduce or eliminate the use of conventional preservatives such as phenoxyethanol, methylparaben, and parabens. These preservatives are irritating when wounds are present. While searching for milder, more bio-friendly preservatives, they unexpectedly discovered that adding a small amount of ε-polylysine to an anesthetic solution containing liprocaine not only has a certain antibacterial effect but also effectively inhibits the formation of the aforementioned impurities. In an accelerated test at 50°C for 30 days, the formation of these impurities was significantly inhibited. Furthermore, the inventors have found that only ε-polylysine can achieve this effect of improving the stability of liprocaine; other amino acids, such as cysteine ​​and glycine, do not have this effect. In the preferred embodiment of this invention, sodium hyaluronate has a molecular weight of 100-170 kDa, resulting in even better stability of the solution.

[0009] Furthermore, the thickener is selected from at least one of sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carbomer, and xanthan gum.

[0010] Furthermore, the alcohol-based penetration enhancer is selected from at least one of glycerol, propylene glycol, ethylene glycol, polyethylene glycol, and polypropylene glycol.

[0011] Furthermore, the nonionic surfactant is selected from at least one of polyoxyethylene hydrogenated castor oil, Tween 60, Tween 80, and polyoxyethylene sorbitan monooleate.

[0012] Furthermore, the pH adjuster is selected from at least one of hydrochloric acid, citric acid, sodium hydroxide, and potassium hydroxide.

[0013] The dressing substrate is a medical-grade cotton or linen fabric or nonwoven fabric, preferably a cotton nonwoven fabric; furthermore, the basis weight of the dressing substrate is 30-50 g / m². 2 Fabrics within the aforementioned weight range are soft, conform well, and have a certain capacity to hold the anesthetic solution. Furthermore, the size of the dressing substrate is 20-25 cm × 20-25 cm, and the mass ratio of the dressing substrate to the anesthetic solution is 1:10-20, preferably 1:14-17.

[0014] Furthermore, the molecular weight of ε-polylysine is 3000-5000, preferably 3600-4500. ε-polylysine with a molecular weight within the above range exhibits better antibacterial properties.

[0015] Optionally, the solution may also include some common excipients, such as stabilizers (ascorbic acid, α-tocopherol).

[0016] There are no specific limits on the amount of dressing substrate and anesthetic solution used, but generally the amount of anesthetic solution used should exceed the saturation absorption capacity of the dressing substrate by more than 20%, such as 30-40%.

[0017] The present invention also provides a method for preparing a skin surface anesthetic dressing containing lidocaine and prilocaine, comprising the following steps:

[0018] (S1) Sodium hyaluronate is dissolved in water to form aqueous phase 1; thickener is dissolved in water to form aqueous phase 2;

[0019] (S2) Add nonionic surfactant, lidocaine, prilocaine, alcohol penetration enhancer, poloxamer, and ε-polylysine to water, stir and mix evenly at 40-60℃, and cool to obtain emulsion.

[0020] (S3) Mix aqueous phase 1, aqueous phase 2, and emulsion evenly, add pH adjuster to adjust pH to 7.0-8.0, and obtain anesthetic solution;

[0021] (S4) The anesthetic liquid is absorbed by the dressing substrate, packaged and sealed to obtain the product skin surface anesthetic dressing.

[0022] Sodium hyaluronate and carbomer interact with each other and are not suitable to be dissolved together in water. Therefore, in the process of this invention, sodium hyaluronate and carbomer are prepared as aqueous phase 1 and aqueous phase 2, respectively.

[0023] The skin surface anesthetic dressing of the present invention has a simple preparation process and can be used directly after opening, which has great convenience for clinical use.

[0024] Compared with the prior art, the present invention achieves the following beneficial effects:

[0025] I. This invention, by adding a small amount of ε-polylysine, not only has antibacterial effects but also significantly improves the stability of leprosylate solution. After long-term storage and high-temperature accelerated experiments, the rate of increase of related impurities is significantly slowed down, which can improve the reliability and safety of pre-sealed leprosylate skin surface anesthesia patch.

[0026] Second, the preparation process of this invention is simple and easy to industrialize. In the pre-packaged skin surface anesthetic patch, the substrate has already absorbed the anesthetic solution and can be used directly after removal. Attached Figure Description

[0027] Figure 1 This is the chromatogram of the anesthetic solution at 0d in Example 1.

[0028] Figure 2 This is the chromatogram of the anesthetic solution from Example 1 after being aged at 50°C for 30 days.

[0029] Figure 3 This is the chromatogram of the anesthetic solution in Comparative Example 1 after being aged at 50°C for 30 days. Detailed Implementation

[0030] The following examples will further explain and illustrate the technical solution of the present invention.

[0031] The dressing substrate is made of cotton non-woven fabric, designed to conform to the shape of a human face. It measures 21.8 cm × 23.4 cm, with cutouts for the eyes and mouth. The eyes measure 51 mm × 20.5 mm, and the mouth measures 56 mm × 17 mm. The weight is 40 g / m². 2 Each piece of nonwoven fabric weighs approximately 1.5g and has a saturated adsorption capacity of 18.1g.

[0032] ε-Polylysine 1 was purchased from Maclean's reagent, with a molecular weight of 3600; ε-Polylysine 2 was purchased from Maclean's reagent, with a molecular weight of 4500.

[0033] Example 1

[0034] The modified formulation and dosage of the anesthetic solution are shown in Table 1 below.

[0035] Table 1. Formulation of anesthetic solution in Example 1

[0036]

[0037] The preparation method for skin surface anesthetic dressing is as follows:

[0038] (S1) Dissolve 0.22g of sodium hyaluronate (molecular weight 160kDa) in water as aqueous phase 1; dissolve 0.17g of carbomer 940 in water as aqueous phase 2;

[0039] (S2) Add 5g of polyoxyethylene 40 hydrogenated castor oil, 2.5g of lidocaine, 2.5g of prilocaine, 5g of glycerin, 5g of propylene glycol, 0.5g of poloxamer, and 0.15g of ε-polylysine to water, stir and mix evenly at 50℃, and cool to obtain an emulsion.

[0040] (S3) Mix aqueous phase 1, aqueous phase 2, and emulsion evenly, and adjust the pH to 7.8 with 0.5wt% hydrochloric acid to obtain 100g of anesthetic solution;

[0041] (S4) Place the dressing substrate and 25g of anesthetic solution into aluminum foil, package and seal the bag to obtain the product skin surface anesthetic dressing.

[0042] The stability of the anesthetic solution obtained in step S3 of Example 1 was tested according to the method in the National Medical Products Administration Import Drug Registration Standard (Standard No.: JX20190207): Liprocaine Cream. The results are shown in Table 2 below. Figure 1 This is the chromatogram of the anesthetic solution at day 0 in Example 1. Figure 2 This is the chromatogram of the anesthetic solution from Example 1 after being aged at 50°C for 30 days.

[0043] Table 2 Stability Test of High Temperature Accelerated Experiment in Example 1

[0044]

[0045] The chemical structures of isomer 1 and isomer 2 of AZ11163567 are as follows:

[0046] , ;

[0047] The chemical structures of isomer 1 and isomer 2 of AZ13418980 are as follows:

[0048] , ;

[0049] The chemical structure of lidocaine impurity B is as follows: ;

[0050] The chemical structure of lidocaine impurity D is as follows: .

[0051] Example 2

[0052] Other conditions are the same as in Example 1, except that the dosage of the anesthetic solution is modified as shown in Table 3, and the results of high-temperature accelerated stability are shown in Table 4.

[0053] Table 3. Formulation of Anesthetic Solution in Example 2

[0054]

[0055] Table 4. Stability Test of High Temperature Accelerated Experiment in Example 2

[0056]

[0057] Example 3

[0058] Other conditions are the same as in Example 1, except that the dosage of the anesthetic solution is modified as shown in Table 5, and the results of high-temperature accelerated stability are shown in Table 6.

[0059] Table 5. Formulation of anesthetic solution in Example 3

[0060]

[0061] Table 6. Stability Test of High Temperature Accelerated Experiment in Example 3

[0062]

[0063] Example 4

[0064] Other conditions were the same as in Example 1, except that the molecular weight of sodium hyaluronate was 300 kDa. The results of accelerated stability at high temperature are shown in Table 7.

[0065] Table 7. Stability Test of High Temperature Accelerated Experiment in Example 4

[0066]

[0067] Comparative Example 1

[0068] The preparation method of the skin surface anesthetic dressing is basically the same as that in Example 1, except that ε-polylysine is not added in step S2. The results of high-temperature accelerated stability are shown in Table 8. Figure 3 This is the chromatogram of the anesthetic solution in Comparative Example 1 after being aged at 50°C for 30 days.

[0069] Table 8 Stability Test of High Temperature Accelerated Experiment in Comparative Example 1

[0070]

[0071] Comparative Example 2

[0072] The preparation method of the skin surface anesthetic dressing is basically the same as that in Example 1, except that in step S2, ε-polylysine is replaced with an equal mass of cysteine. The results of high-temperature accelerated stability are shown in Table 9.

[0073] Table 9 Stability Tests of High Temperature Accelerated Experiment in Comparative Example 2

[0074]

[0075] Comparative Example 3

[0076] The preparation method of the skin surface anesthetic dressing is basically the same as that in Example 1, except that in step S2, ε-polylysine is replaced with an equal mass of methylparaben. The results of high-temperature accelerated stability are shown in Table 10.

[0077] Table 10 Stability Tests of High Temperature Accelerated Experiment in Comparative Example 3

[0078]

[0079] The above accelerated stability tests at high temperatures demonstrate that the addition of a small amount of ε-polylysine to the anesthetic solution significantly improves its stability. During the accelerated stability test at 50°C for 30 days, the content of related impurities did not exceed the limits. Replacing ε-polylysine with other amino acids or conventional preservatives did not achieve the aforementioned effect of improving solution stability.

Claims

1. A pre-packaged levofloxacin dressing, comprising a dressing substrate and an anesthetic solution encapsulated together, characterized in that, The anesthetic solution comprises the following ingredients: 0.1-0.3 parts by weight of sodium hyaluronate, 0.1-0.3 parts by weight of thickener, 7-13 parts by weight of alcohol-based penetration enhancer, 3-6 parts by weight of nonionic surfactant, 0.3-0.8 parts by weight of poloxamer, 1-3 parts by weight of lidocaine, 1-3 parts by weight of prilocaine, 0.1-0.2 parts by weight of ε-polylysine, a pH adjuster to adjust the pH of the anesthetic solution to 7.0-8.0, and water to a total of 100 parts by weight.

2. The pre-packaged dressing of lipofuscin according to claim 1, characterized in that, The anesthetic solution comprises the following ingredients: 0.1-0.3 parts by weight of sodium hyaluronate, 0.1-0.3 parts by weight of thickener, 8-10 parts by weight of alcohol-based penetration enhancer, 4-5 parts by weight of nonionic surfactant, 0.42-0.65 parts by weight of poloxamer, 2.2-2.5 parts by weight of lidocaine, 2.2-2.5 parts by weight of prilocaine, 0.15-0.2 parts by weight of ε-polylysine, pH adjuster to adjust the pH of the anesthetic solution to 7.4-7.8, and water to bring the total to 100 parts by weight.

3. The pre-packaged dressing of lipofuscin according to claim 1, characterized in that, The thickener is selected from at least one of sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carbomer, and xanthan gum.

4. The pre-packaged dressing of lipofuscin according to claim 1, characterized in that, The alcohol-based penetration enhancer is selected from at least one of glycerol, propylene glycol, ethylene glycol, polyethylene glycol, and polypropylene glycol.

5. The pre-packaged dressing of lipofuscin according to claim 1, characterized in that, The nonionic surfactant is selected from at least one of polyoxyethylene hydrogenated castor oil, Tween 60, Tween 80, and polyoxyethylene dehydrated sorbitan monooleate.

6. The pre-packaged dressing of lipofuscin according to claim 1, characterized in that, The pH adjuster is selected from at least one of hydrochloric acid, citric acid, sodium hydroxide, and potassium hydroxide; the pH adjuster adjusts the pH of the anesthetic solution to 7.5-7.

8.

7. The pre-packaged dressing of lipofuscin according to claim 1, characterized in that, The dressing substrate is a medical-grade cotton or linen fabric or nonwoven fabric, preferably a cotton nonwoven fabric; further, the basis weight of the dressing substrate is 30-50 g / m². 2 Furthermore, the size of the dressing substrate is 20-25 cm × 20-25 cm, and the mass ratio of the dressing substrate to the anesthetic solution is 1:10-20, preferably 1:14-17.

8. The pre-packaged dressing of lipofuscin according to claim 1, characterized in that, The molecular weight of ε-polylysine is 3000-5000, preferably 3600-4500.

9. The pre-packaged dressing of lipofuscin according to claim 1, characterized in that, The solution may also include common excipients, such as stabilizers (ascorbic acid, α-tocopherol).

10. A method for preparing the skin surface anesthetic dressing containing lidocaine and prilocaine according to any one of claims 1-9, characterized in that, Includes the following steps: (S1) Sodium hyaluronate is dissolved in water to form aqueous phase 1; thickener is dissolved in water to form aqueous phase 2; (S2) Add nonionic surfactant, lidocaine, prilocaine, alcohol penetration enhancer, poloxamer, and ε-polylysine to water, stir and mix evenly at 40-60℃, and cool to obtain emulsion. (S3) Mix aqueous phase 1, aqueous phase 2, and emulsion evenly, add pH adjuster to adjust pH to 7.0-8.0, and obtain anesthetic solution; (S4) The anesthetic liquid is absorbed by the dressing substrate, packaged and sealed to obtain the product skin surface anesthetic dressing.

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