Antifungal liniment and preparation method thereof

Abstract

The invention discloses an antifungal liniment and a preparation method thereof.The antifungal liniment is composed of amorolfine hydrochloride, a liquid auxiliary material, a film-forming agent and a solvent, the film-forming agent is composed of a quaternary ammonium methacrylate copolymer type A and a quaternary ammonium methacrylate copolymer type B, and the solvent is composed of a quaternary ammonium methacrylate copolymer type A and a quaternary ammonium methacrylate copolymer type B; the antifungal liniment obtained by the invention has good stability and nail penetration.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical preparations, and particularly relates to an antifungal liniment and a preparation method thereof. Background Art

[0002] Amorolfine hydrochloride exerts its antibacterial effect by interfering with the biosynthesis pathway of fungal cell membrane lipids, specifically by reducing the content of ergosterol and causing the accumulation of atypical lipids in the fungal cell membrane and organelles. These changes lead to morphological alterations in the fungal cell membrane and its internal structure, thereby inhibiting fungal growth.

[0003] As a topical antifungal drug, amorolfine hydrochloride is widely used in the treatment of onychomycosis caused by dermatophytes, yeasts, etc., and helps prevent the occurrence of onychomycosis. Amorolfine hydrochloride is usually prepared in the form of a liniment, which contains special components that can form a bright and waterproof protective film on the nail surface. This film not only prevents water from entering, avoiding further fungal infections, but also ensures the stable release of the active ingredients of the drug and their penetration into the nail plate. This protective film generally lasts for about a week, enabling the drug to act effectively on the deep layer of the nail for a long time and helping to eradicate fungi in difficult-to-reach areas.

[0004] When using amorolfine hydrochloride in the form of a liniment, the drug can gradually penetrate and diffuse through the nail plate to the nail bed, effectively clearing fungi hidden deep inside. Therefore, its stability and transungual permeability are crucial for the treatment effect. In addition, this administration method not only improves the convenience of use for patients but also reduces the risk of systemic side effects, providing an efficient and safe option for the treatment of onychomycosis.

[0005] Patent CN105106179A discloses a preparation method of an amorolfine hydrochloride liniment. This method uses a water-insoluble resin - acrylic resin RL100, which, after the solvent volatilizes, forms a tough film on the diseased nail surface to encapsulate the diseased nail and maintain the effective drug concentration in the nail bed. However, this patent does not verify the actual transungual permeability of the amorolfine hydrochloride liniment.

[0006] Patent CN119587466A discloses an amorolfine hydrochloride liniment and its production process, which involves adding ingredients such as propylene glycol to the amorolfine hydrochloride liniment to increase the stability, solubility, and permeability of the drug. This method has a relatively complex process and no specific effects. Summary of the Invention

[0007] In view of the deficiencies of the prior art, this application provides an antifungal liniment, which is composed of amorolfine hydrochloride, liquid excipients, film-forming agents, and solvents. Among them, the film-forming agent is composed of quaternary ammonium methacrylate copolymer type A and quaternary ammonium methacrylate copolymer type B.

[0008] Further, the mass ratio of the quaternary ammonium group methacrylate copolymer type A to the quaternary ammonium group methacrylate copolymer type B is (7-9):(1-3).

[0009] Further, the antifungal liniment comprises, by weight percentage: amorolfine hydrochloride 2-10%, liquid auxiliary materials 5-35%, film-forming agent 5-20%, and the balance being solvent.

[0010] Further, the liquid auxiliary materials include a plasticizer and a cosolvent.

[0011] Further, the plasticizer is selected from one or more of glyceryl triacetate, triacetate or phthalate, and the cosolvent is selected from one or more of methyl acetate, ethyl acetate or butyl acetate.

[0012] Further, the solvent is selected from one or more of water, ethanol, liquid paraffin, glycerol or vegetable oil.

[0013] On the other hand, the present invention provides a preparation method of the above-mentioned antifungal liniment, comprising the following steps: 1) preparing a solution; 2) filling; wherein, the feeding sequence of step 1) preparing a solution is liquid auxiliary materials, film-forming agent, amorolfine hydrochloride.

[0014] Further, the specific operation of step 1) is: adding 30% to 60% of the total volume of the solvent into a container, then adding the liquid auxiliary materials into the container, adjusting the temperature of the mixed solution, subsequently, adding the film-forming agent and stirring, when the materials are completely dissolved, adding amorolfine hydrochloride, stirring again, and finally, using the solvent to make the solution up to a predetermined volume.

[0015] Further, the temperature of the mixed solution is 30±10°C.

[0016] Further, the time of the second stirring is 30-120 min.

[0017] Compared with the prior art, the antifungal liniment of the present invention (hereinafter referred to as "amorolfine hydrochloride liniment") has the following remarkable technical effects:

[0018] Excellent stability: The liniment of the present invention shows good performance in terms of related substances, and all test results meet the limit requirements, and in some cases are better than commercially available products. This indicates that the product of the present invention has higher purity and better stability.

[0019] Stable content: The amorolfine hydrochloride liniment of the present invention can reach the specified drug concentration in terms of drug content, and has good stability. In addition, under different storage conditions, the active ingredient of this preparation can still maintain high stability, ensuring the quality and efficacy of the drug within the shelf life.

[0020] Significant nail penetration effect: Verified through strict nail penetration tests, the amorolfine hydrochloride liniment of the present invention shows excellent performance in terms of nail plate permeability, being able to effectively penetrate the hard nail plate to ensure that the drug can reach the infected site and exert its antibacterial effect. The nail penetration performance of the product of the present invention is similar to that of commercially available products, ensuring effective treatment effects and safety. Detailed implementation manners

[0021] The technical solutions in the embodiments of the present application will be clearly described below in conjunction with the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art belong to the scope of protection of the present application.

[0022] The terms "first", "second", etc. in the specification and claims of the present application are used to distinguish similar objects, rather than to describe a specific order or sequence. It should be understood that such used data can be interchanged under appropriate circumstances so that the embodiments of the present application can be implemented in an order other than those described herein, and the objects distinguished by "first", "second", etc. are generally of the same category, and do not limit the number of objects. For example, the first object can be one or multiple. In addition, "and / or" in the specification and claims means at least one of the connected objects, and the character " / " generally indicates an "or" relationship between the associated objects before and after.

[0023] In order to develop an amorolfine hydrochloride liniment with better nail penetration to fully exert its antibacterial effect, the present invention has conducted in-depth research on the composition and preparation process of the existing amorolfine hydrochloride liniment, and provides an amorolfine hydrochloride liniment, which is composed of amorolfine hydrochloride, liquid excipients, film-forming agents and solvents. Among them, the film-forming agent is composed of quaternary ammonium methacrylate copolymer type A and quaternary ammonium methacrylate copolymer type B.

[0024] In one implementation manner of the present invention, the mass ratio of the quaternary ammonium methacrylate copolymer type A to the quaternary ammonium methacrylate copolymer type B is (7-9):(1-3), such as 7:1, 7:2, 7:3, 8:1, 8:2, 8:3, 9:1, 9:2 or 9:3, but not limited to the listed values. Other unlisted values within this numerical range are also applicable, and preferably (7:3)-(9:1).

[0025] In an embodiment of the present invention, the amorolfine hydrochloride liniment comprises the following components by weight percentage: 2-10% of amorolfine hydrochloride, 5-35% of liquid excipients, 5-20% of film-forming agent, and the balance being solvent. Preferably, the amorolfine hydrochloride liniment comprises the following components by weight percentage: 3-8% of amorolfine hydrochloride, 10-30% of liquid excipients, 3-18% of film-forming agent, and the balance being solvent. More preferably, the amorolfine hydrochloride liniment comprises the following components by weight percentage: 5-7% of amorolfine hydrochloride, 15-25% of liquid excipients, 8-15% of film-forming agent, and the balance being solvent. Even more preferably, the amorolfine hydrochloride liniment comprises the following components by weight percentage: 5.29-5.85% of amorolfine hydrochloride, 19.99-22.10% of liquid excipients, 11.42-13.13% of film-forming agent, and the balance being solvent. Further preferably, the amorolfine hydrochloride liniment comprises the following components by weight percentage: 5.57% of amorolfine hydrochloride, 21.05% of liquid excipients, 12.5% of film-forming agent, and the balance being solvent.

[0026] Quaternary ammonium methacrylate copolymer type A is widely used as a granulation binder, film coating agent in pharmaceutical manufacturing, and as a carrier material for sustained-release preparations. Especially in the application of amorolfine hydrochloride liniment, it acts as a film-forming agent, forming a tough protective film on the surface of the infected nail through the solvent, thereby sealing the diseased nail and maintaining the effective drug concentration inside the nail bed.

[0027] However, the inventors found in the research that using quaternary ammonium methacrylate copolymer type A alone cannot achieve ideal drug product performance. In contrast, when used in combination with a specific proportion of quaternary ammonium methacrylate copolymer type B, the amorolfine hydrochloride liniment shows excellent performance in terms of active ingredient content, impurity control, and the effect of penetrating the nail. Although the exact mechanism of action remains to be further studied and clarified, it is speculated that the possible reason is that quaternary ammonium methacrylate copolymer type B contains more hydrophobic chain segments. These hydrophobic chain segments may enhance the compatibility between different components, thereby improving the overall quality and efficacy of the amorolfine hydrochloride liniment. Such a combination not only improves the physicochemical properties of the drug but also provides a stable and controllable therapeutic effect.

[0028] In an embodiment of the present invention, the liquid excipients include plasticizers and cosolvents. The plasticizer is selected from one or more of glyceryl triacetate, triacetate, or phthalate, and the cosolvent is selected from one or more of methyl acetate, ethyl acetate, or butyl acetate. The solvent is selected from one or more of water, ethanol (including absolute ethanol), liquid paraffin, glycerol, or vegetable oil. As used herein, "a plurality" includes two or more.

[0029] On the other hand, in an embodiment of the present invention, the preparation method of amorolfine hydrochloride liniment comprises the following steps: 1) preparing a solution; 2) filling. Among them, the feeding sequence in step 1) of preparing the solution is liquid excipients, film-forming agent, and amorolfine hydrochloride.

[0030] In a specific embodiment of the present invention, the specific operation of step 1) is as follows: Take 30% to 60% of the total volume of the solvent and add it to a container, then add liquid excipients to the container, adjust the temperature of the mixed solution, and then add the film-forming agent and stir. When the materials are completely dissolved, add amorolfine hydrochloride, and stir again until the materials are dissolved. Finally, use the solvent to make up the volume of the solution to the predetermined volume.

[0031] In a specific embodiment of the present invention, the specific operation of step 1) is as follows: Take 30% to 60% of the total volume of anhydrous ethanol and add it to a container, then add liquid excipients, namely triacetin, ethyl acetate, and butyl acetate, to the container, adjust the temperature of the mixed solution, and then add a mixture of type A quaternary ammonium methacrylate copolymer and type B quaternary ammonium methacrylate copolymer with a specific mass ratio as the film-forming agent. After stirring until the materials are completely dissolved, add the prescribed amount of amorolfine hydrochloride, and stir again until the materials are completely dissolved. Finally, use anhydrous ethanol to make up the volume of the solution to the predetermined volume.

[0032] The "total volume" mentioned in the present invention refers to the total volume of amorolfine hydrochloride liniment. For example, if the single dose is 2.5 ml, the total volume corresponding to 200 dose units is 500 ml. Regarding the amount of the solvent initially added to the container, the present application does not impose strict restrictions, as long as it is ensured that the amount of the solvent used is sufficient to completely dissolve the subsequent added raw and auxiliary materials.

[0033] The inventors found through research that the feeding sequence of liquid excipients, film-forming agent, and raw materials has a significant impact on the quality of amorolfine hydrochloride liniment. Experiments show that only by adding liquid excipients first, then the film-forming agent, and finally the raw materials can the best product quality be ensured. Although the specific reason is not yet fully clear, it is speculated that this specific sequence helps to ensure good compatibility between components and uniform distribution of the active ingredient, forming a stable and tough protective film covering the infected nail, thereby improving the drug efficacy and the patient's use experience. The correct feeding sequence is the key to manufacturing high-quality amorolfine hydrochloride liniment.

[0034] In an embodiment of the present invention, the temperature of the mixed solution is 30 ± 10°C, such as 20°C, 25°C, 30°C, 35°C, or 40°C, but is not limited to the listed values, and other unlisted values within this numerical range are also applicable.

[0035] In one embodiment of the present invention, the time for the two stirrings is 30 to 120 minutes, such as 30 minutes, 60 minutes, 90 minutes or 120 minutes, but is not limited to the listed values, and other unlisted values within this numerical range are equally applicable.

[0036] The multiple stirring times mentioned in this application can be the same or different, as long as the materials are completely dissolved.

[0037] The specific examples and comparative examples of the present invention are listed below, but the present invention is not limited to the following examples.

[0038] The sources and functions of the raw and auxiliary materials are as follows:

[0039]

[0040]

[0041] Example 1

[0042] The prescription composition (mass ratio of type A to type B is 9:1) is as follows:

[0043]

[0044] Formulation process:

[0045] 1) Solution preparation: Add 30% to 60% of the total volume of absolute ethanol to the container. Sequentially add the prescription amounts of liquid auxiliary materials, namely glycerol triacetate, ethyl acetate, and butyl acetate, to the container, and stir for 2 minutes to ensure uniform mixing. Adjust the temperature of the solution in the container to 30 ± 10 °C. Subsequently, add the prescription amount of film-forming agent and stir for 30 to 120 minutes until completely dissolved. Then, add the prescription amount of amorolfine hydrochloride and stir again for 30 to 120 minutes. Finally, use absolute ethanol to make up the volume of the solution to the predetermined volume (the density of the liquid medicine is: 0.870 g / ml).

[0046] 2) Filling: Fill the liquid medicine into brown soda-lime glass bottles.

[0047] Example 2

[0048] Adjust the mass ratio of film-forming agent type A to type B in the prescription composition to 8:2:

[0049]

[0050] The formulation process is the same as that of Example 1.

[0051] Example 3

[0052] Adjust the mass ratio of film-forming agent type A to type B in the prescription composition to 7:3:

[0053]

[0054] The preparation process is the same as that of Example 1.

[0055] Comparative Example 1

[0056] Adjust the mass ratio of film-forming agent A to film-forming agent B in the prescription composition to 6:4:

[0057]

[0058] The preparation process is the same as that of Example 1.

[0059] Comparative Example 2

[0060] The film-forming agent in the prescription composition is only type A:

[0061]

[0062]

[0063] The preparation process is the same as that of Example 1.

[0064] Comparative Example 3

[0065] The prescription composition is the same as that of Example 1. Adjust the feeding order of the liquid preparation in the preparation process to film-forming agent, liquid auxiliary materials, raw material (amorolfine hydrochloride). The specific preparation process is as follows:

[0066] 1) Liquid preparation: Add 30% - 60% of the total volume of anhydrous ethanol to a container, adjust the temperature of the solution in the container to 30 ± 10 °C, add the prescribed amount of film-forming agent to the container, stir for 30 - 120 min until completely dissolved. Then, add the prescribed amount of liquid auxiliary materials, namely glyceryl triacetate, ethyl acetate and butyl acetate, stir for 2 min to mix evenly, and then add the prescribed amount of amorolfine hydrochloride and stir again for 30 - 120 min. Finally, use anhydrous ethanol to make the solution volume up to the predetermined volume (the density of the liquid medicine is: 0.870 g / ml).

[0067] 2) Filling: Fill the liquid medicine into brown soda-lime glass bottles.

[0068] Comparative Example 4

[0069] The prescription composition is the same as that of Example 1. Adjust the feeding order of the liquid preparation in the preparation process to liquid auxiliary materials, raw material (amorolfine hydrochloride), film-forming agent. The specific preparation process is as follows:

[0070] 1) Liquid preparation: Add anhydrous ethanol accounting for 30% - 60% of the total volume into a container. Sequentially add the prescribed amounts of liquid excipients, namely triacetin, ethyl acetate, and butyl acetate, into the container and stir for 2 min to mix evenly. Adjust the temperature of the solution in the container to 30 ± 10 °C, then add the prescribed amount of amorolfine hydrochloride and stir for 30 - 120 min. After that, add the prescribed amount of film-forming agent and stir for 30 - 120 min until completely dissolved. Finally, use anhydrous ethanol to make the solution reach the predetermined volume (the density of the liquid medicine is: 0.870 g / ml).

[0071] 2) Filling: Fill the liquid medicine into brown soda-lime glass bottles.

[0072] Comparative Example 5

[0073] The prescription composition is the same as that of Example 1. Adjust the feeding order in liquid preparation during the preparation process to raw materials (amorolfine hydrochloride), liquid excipients, and film-forming agent. The specific preparation process is as follows:

[0074] 1) Liquid preparation: Add anhydrous ethanol accounting for 30% - 60% of the total volume into a container. Add the prescribed amount of amorolfine hydrochloride into the container and stir for 30 - 120 min. Then, sequentially add the prescribed amounts of liquid excipients, namely triacetin, ethyl acetate, and butyl acetate, and stir for 2 min to mix evenly. Adjust the temperature of the solution in the container to 30 ± 10 °C, then add the prescribed amount of film-forming agent and stir for 30 - 120 min until completely dissolved. Finally, use anhydrous ethanol to make the solution reach the predetermined volume (the density of the liquid medicine is: 0.870 g / ml).

[0075] 2) Filling: Fill the liquid medicine into brown soda-lime glass bottles.

[0076] Comparative Example 6

[0077] The prescription composition is the same as that of Comparative Example 2. The film-forming agent is only of Type A. The specific prescription composition is as follows:

[0078]

[0079] Meanwhile, adjust the feeding order in liquid preparation during the preparation process to raw materials (amorolfine hydrochloride), film-forming agent, and liquid excipients. The specific preparation process is as follows:

[0080] 1) Preparation of liquid: Take anhydrous ethanol accounting for 30% - 60% of the total volume and add it to a container. Add the prescribed amount of amorolfine hydrochloride to the container and stir for 30 - 120 min. Adjust the temperature of the solution in the container to 30 ± 10 °C, then add the prescribed amount of film-forming agent and stir for 30 - 120 min until completely dissolved. After that, sequentially add the prescribed amount of liquid excipients, namely glyceryl triacetate, ethyl acetate, and butyl acetate, and stir for 2 min to mix evenly. Finally, use anhydrous ethanol to make the solution up to the predetermined volume (the density of the medicinal liquid is: 0.870 g / ml).

[0081] 2) Filling: Fill the medicinal liquid into brown soda-lime glass bottles.

[0082] Effect verification:

[0083] Determine the content, related substances, and transungual permeability of the amorolfine hydrochloride liniments obtained in Examples 1 - 3, Comparative Examples 1 - 6, and the commercial product (the amorolfine hydrochloride liniment, Lorinden of Amorolfine Hydrochloride Liniment, batch number: 1212416).

[0084] Detection method for content: Determine according to the high performance liquid chromatography method (General Principles 0512, Volume IV, Chinese Pharmacopoeia 2020 Edition). Chromatographic conditions Chromatographic column: Octadecylsilane chemically bonded silica gel as the filler, Mobile phase: 0.02 mol / L dipotassium hydrogen phosphate solution (adjust the pH value to 6.0 with phosphoric acid) - methanol (30:70), Flow rate: 1.5 ml / min, Column temperature: 25 °C, Detection wavelength: 214 nm, Injection volume: 20 μl Determination method Accurately measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively, and record the chromatogram.

[0085] The detection results of the content are as follows: (Limit 95.0% - 105.0%)

[0086]

[0087] Note: The data under investigation may increase because there are many volatile excipients in the prescription of this product

[0088] It can be seen from the detection results of the active ingredient content of different batches of amorolfine hydrochloride liniments that the content of Examples 1 - 3 and the commercial product in terms of amorolfine is 95.0% - 105.0% of the labeled amount, and there is no significant fluctuation in the content after 10 days and 30 days under high temperature (40 °C, 60 °C) and light, and the stability is good.

[0089] However, when we compare products using different proportions of film-forming agents, the situation is different. In Comparative Example 1, a smaller amount of Film-Forming Agent A was used (the ratio of Film-Forming Agent A to Film-Forming Agent B was 6:4), while in Comparative Example 2, only Film-Forming Agent A was used. Although the amorolfine content in the amorolfine hydrochloride liniment prepared in both cases was also within the range of 95.0% to 105.0%, its content showed more obvious fluctuations under high temperature and light conditions. Especially after 30 days of light exposure, the amorolfine content even dropped below the specified minimum of 95%, indicating that the stability of the amorolfine hydrochloride liniment under such formulations was poor.

[0090] Different feeding sequences also have an important impact on the stability of the amorolfine hydrochloride liniment. If a feeding sequence different from that in the examples is adopted, the content of the active ingredient in the obtained amorolfine hydrochloride liniment is unstable. Especially when adding in the order of raw materials, liquid excipients and then film-forming agents (Comparative Example 5) or in the order of raw materials first, then film-forming agents and finally liquid excipients (Comparative Example 6), the amorolfine content may even drop below the specified minimum of 95%. For the amorolfine hydrochloride liniment obtained in the order of film-forming agents, liquid excipients and then raw materials (Comparative Example 3) and in the order of liquid excipients, raw materials and then film-forming agents (Comparative Example 4), although the content of the active ingredient meets the limit requirements, after 30 days of light exposure, the content decreased significantly, and the stability of the content was poor. This indicates that the correct feeding sequence is crucial for ensuring the stability and effectiveness of the active ingredient in the amorolfine hydrochloride liniment.

[0091] Method for detecting related substances: Determined by high performance liquid chromatography (General Principles 0512, Volume IV, Chinese Pharmacopoeia 2020 Edition). The chromatographic conditions are as follows: the filler is octadecylamide-bonded silica gel; the mobile phase A is acetonitrile - phosphate buffer solution (take 5.5 g of dipotassium hydrogen phosphate, dissolve it in 1000 ml of water, adjust the pH value to 6.0 with phosphoric acid) - methanol, and the mobile phase B is acetonitrile - phosphate buffer solution - methanol. Gradient elution is carried out according to the following table; the flow rate is 1.5 ml per minute; the detection wavelength is 224 nm; the injection volume is 10 μl.

[0092] Time (min) Mobile Phase A (%) Mobile Phase B (%) 0 85 15 2 85 15 25 0 100 35 0 100 35.1 85 15 45 85 15

[0093] Determination method: Accurately measure the above-mentioned solutions respectively and inject them into the liquid chromatograph, and record the chromatogram.

[0094] In the chromatogram of the limit test sample solution, if there are impurity peaks, except for the blank excipient peaks with retention times less than 3 minutes, the areas of impurity A and impurity B shall not be greater than the area of the main peak in the control solution (0.2%); except for impurity A and impurity B, the sum of the areas of other impurity peaks shall not be greater than the area of the main peak in the control solution (0.2%), and the total area of impurity peaks shall not be greater than 3 times the area of the main peak in the control solution (0.6%). Chromatographic peaks smaller than the main peak area of the sensitivity solution shall be ignored (0.05%).

[0095] Note: Impurity A and B are the main impurities under study, and other impurities are only studied but not necessarily included in the quality standard for related substances.

[0096] The impurity information is as follows:

[0097]

[0098]

[0099]

[0100] The test results for related substances are as follows:

[0101]

[0102] From the test results for related substances of amorolfine hydrochloride liniment of different batches, it can be seen that the main impurities under study, impurity A and impurity B, were not detected in the commercially available Loceryl, but the content of impurity D was 0.225%, significantly exceeding the limit value of 0.2%. At the same time, the total impurity content was also relatively high at 0.454%.

[0103] The amorolfine hydrochloride liniments obtained in Examples 1 to 3 had fewer types of related substances and lower contents, and the liniment had good stability, which was better than that of the commercially available products.

[0104] However, when using products with different proportions of film-forming agents and different feeding sequences, the content of related substances in the products was significantly higher than that of the amorolfine hydrochloride liniment obtained in the examples, especially for impurity A and total impurities. The single impurity content of the product obtained by the method of liquid excipient, raw material and then latex film-forming agent (Comparative Example 4) was 0.48%, far exceeding the limit value of 0.2%.

[0105] Thus, it can be seen that appropriately selecting the proportion of the film-forming agent and following the correct feeding sequence are crucial for controlling the content of related substances in amorolfine hydrochloride liniment. This not only helps to improve the stability and safety of the product but also ensures its compliance with the quality standards.

[0106] Operation method for transungual test:

[0107] For the nail penetration experiment, human nail plates and animal nail plates are generally used. Among them, human nail plate materials are not easy to obtain, and their shapes are not convenient for processing. Animal nail plates include pig hoof nails and cow hoof nails, etc. Cow hoof nails are the most common, easy to obtain and process. Cow hoof nails have strong swelling ability and usually good permeability. At the same time, referring to the in vitro nail penetration research in the "Development of Amorolfine Hydrochloride Liniment" of Hubei University of Chinese Medicine, which also used cow hoof nails, so cow hoof nails are selected as the experimental materials.

[0108] Experimental method (also referring to the "Development of Amorolfine Hydrochloride Liniment" of Hubei University of Chinese Medicine): Use a transdermal tester to conduct a nail penetration experiment on the sample. The sampling time points are 1, 3, 5, 7, and 9 hours, the dosage of the drug is 10 μl, the rotation speed is 800 rpm, and the receiving medium is normal saline. Cut (cut into pieces) the nail plate at the drug administration site, place it in a 20 ml sample bottle, add 20 ml of the medium, shake to dissolve the liniment, vortex for 20 min, filter, and take the subsequent filtrate to obtain the residue extract; use a high-performance liquid detection method for sample preparation and then injection analysis.

[0109] Results of the nail penetration test:

[0110] Sample Cumulative Release Amount in 9h (%) Residual Amount (%) Retention Amount (%) Total Amount (%) Commercially Available Product - Loceryl 1.17 92.12 5.80 99.09 Example 1 0.31 94.83 5.47 100.61 Example 2 1.33 93.70 4.86 99.89 Example 3 0.39 93.89 5.65 99.93 Comparative Example 1 0.31 89.65 5.32 95.28 Comparative Example 2 0.28 101.2 3.00 104.5 Comparative Example 3 1.60 91.50 3.82 96.92 Comparative Example 4 1.31 89.9 5.47 96.68 Comparative Example 5 0.28 91.2 3.00 94.5 Comparative Example 6 1.62 91.54 3.76 96.92

[0111] (1) Cumulative release amount (%) at 9 hours: It refers to the cumulative amount of the drug released from the preparation and passing through the nail layer within 9 hours. This value reflects the ability of the drug to penetrate the nail and reach the action site. Since Amorolfine Hydrochloride Liniment has a special drug delivery system, it can form a waterproof film on the nail plate and prevent bacterial infection. This film can last for a week, which helps the drug penetrate the nail plate more effectively. Considering that the nail is relatively thick and the amount of drug penetrating through the nail plate is relatively small, as long as a certain cumulative release amount is achieved, it can effectively play its role. In the nail penetration test of the present invention, the cumulative release amounts at 9 hours of different batches of products have little difference, showing stable nail penetration performance.

[0112] (2) Residual amount (%): It represents the amount of the drug remaining on the surface of the nail plate after a certain period of time (such as after the 9-hour experiment). Understanding the amount of the drug remaining on the nail surface helps to evaluate the drug release efficiency. And since the residual amount in this product accounts for a relatively high proportion, the closer the residual amount is to the standard of the commercially available product, the more it can ensure the effectiveness and stability of Amorolfine Hydrochloride Liniment.

[0113] (3) Retention amount (%): It refers to the amount of the drug remaining in the nail plate after the experiment. The retention amount reflects the ability of the drug to continuously play its role inside the nail, which is crucial for the long-term treatment effect. Therefore, the closer the retention amount is to the level of the commercially available product, the more it can ensure that Amorolfine Hydrochloride Liniment has good sustained release performance, thus maintaining the long-term therapeutic effect.

[0114] (4) Total amount (%): That is, the overall recovery rate. In theory, the sum of the cumulative release amount, the residue amount, and the retention amount should be equal to 100%, which represents the distribution of the drug in the entire system - including the part that has penetrated the nail, the part remaining in the preparation, and the part retained on the nail plate. However, in actual situations, due to factors such as measurement errors or drug degradation, the sum of these percentages may be slightly lower or higher than 100%. Nevertheless, the closer the total amount is to 100%, the more accurate the detection method is, and it also indicates better stability of the product in various parts.

[0115] From the results of the transungual penetration tests of different batches of amorolfine hydrochloride liniment, the 9-hour cumulative release amounts of the products in each batch showed little difference. However, in terms of the residue amount and the retention amount, the amorolfine hydrochloride liniments prepared in Examples 1 to 3 showed values closer to those of the commercially available products, indicating that these batches not only had good performance in terms of stability but also ensured their effectiveness. In addition, the total amounts of these batches were close to 100%, which also reflected the stability of the product at different stages (release, residue, retention), further confirming the high quality of the product.

[0116] In contrast, products using different proportions of film-forming agents or different feeding sequences (Comparative Examples 1 to 6) showed certain differences from the commercially available products in terms of the residue amount and the retention amount. Such differences may have a greater impact on the stable exertion of amorolfine and thus affect the overall efficacy of the drug.

[0117] Therefore, choosing an appropriate proportion of the film-forming agent and strictly following the correct feeding sequence is crucial for ensuring the stability, effectiveness, and safety of amorolfine hydrochloride liniment. Doing so can not only optimize the release characteristics of the drug but also improve the therapeutic effect and ensure that patients obtain the best treatment experience.

[0118] Through the synergistic effect of choosing an appropriate proportion of the film-forming agent and the feeding sequence, the present invention ensures that the content stability of amorolfine hydrochloride liniment and its related substances meet the requirements, and achieves good transdermal release performance.

[0119] Setting of conditions for examples and comparative examples:

[0120] Type A: Type B Feeding Order Example 1 9:1 Liquid Excipient, Film-Forming Agent, Raw Material Example 2 8:2 Liquid Excipient, Film-Forming Agent, Raw Material Example 3 7:3 Liquid Excipient, Film-Forming Agent, Raw Material Comparative Example 1 6:4 Liquid Excipient, Film-Forming Agent, Raw Material Comparative Example 2 10:0 Liquid Excipient, Film-Forming Agent, Raw Material Comparative Example 3 9:1 Film-Forming Agent, Liquid Excipient, Raw Material Comparative Example 4 9:1 Liquid Excipient, Raw Material, Film-Forming Agent Comparative Example 5 9:1 Raw Material, Liquid Excipient, Film-Forming Agent Comparative Example 6 10:0 Raw Material, Film-Forming Agent, Liquid Excipient

[0121] The above describes the embodiments of the present application, but the present application is not limited to the above specific embodiments. The above specific embodiments are merely illustrative and not restrictive. Under the inspiration of the present application, those of ordinary skill in the art can also make many forms without departing from the purpose of the present application and the scope protected by the claims, and all belong to the protection scope of the present application.

Claims

1. An antifungal liniment, characterized in that, The antifungal liniment is composed of amorolfine hydrochloride, liquid excipients, film-forming agent and solvent. Among them, the film-forming agent is composed of quaternary ammonium methacrylate copolymer type A and quaternary ammonium methacrylate copolymer type B.

2. The antifungal liniment according to claim 1, characterized in that, The mass ratio of the quaternary ammonium methacrylate copolymer type A to the quaternary ammonium methacrylate copolymer type B is (7-9):(1-3).

3. The antifungal liniment according to claim 2, characterized in that, The composition of the antifungal liniment by weight percentage includes: amorolfine hydrochloride 2-10%, liquid excipients 5-35%, film-forming agent 5-20%, and the rest is solvent.

4. The antifungal liniment according to claim 3, characterized in that, The liquid excipients include plasticizer and cosolvent.

5. The antifungal liniment according to claim 4, characterized in that, The plasticizer is selected from one or more of glyceryl triacetate, triacetate or phthalate, and the cosolvent is selected from one or more of methyl acetate, ethyl acetate or butyl acetate.

6. The antifungal liniment according to claim 5, characterized in that, The solvent is selected from one or more of water, ethanol, liquid paraffin, glycerol or vegetable oil.

7. The preparation method of the antifungal liniment according to any one of claims 1 to 6, characterized in that, It includes the following steps: 1) preparing the solution; 2) filling. Among them, the feeding order in step 1) of preparing the solution is liquid excipients, film-forming agent, amorolfine hydrochloride.

8. The preparation method of the antifungal liniment according to claim 7, characterized in that, The specific operation of step 1) is: adding 30% to 60% of the total volume of the solvent into the container, then adding liquid excipients into the container, adjusting the temperature of the mixed solution, and then adding the film-forming agent and stirring. When the materials are completely dissolved, adding amorolfine hydrochloride and stirring again. Finally, using the solvent to make the solution volume up to the predetermined volume.

9. The preparation method of the antifungal liniment according to claim 8, characterized in that, The temperature of the mixed solution is 30±10°C.

10. The preparation method of the antifungal liniment according to claim 9, wherein The time of the second stirring is 30-120 min.

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