An antifungal liniment and a preparation method thereof

Abstract

The application discloses an antifungal liniment and a preparation method thereof. The antifungal liniment is composed of amorolfine hydrochloride, liquid excipients, a film forming agent and a solvent. The film forming agent is composed of quaternary ammonium base methacrylate copolymer type A and quaternary ammonium base methacrylate copolymer type B. The antifungal liniment obtained by the application has good stability and permeability.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to an antifungal liniment and a preparation method thereof. BACKGROUND

[0002] Amorolfine hydrochloride exerts its fungistatic effect by interfering with the biosynthetic pathway of fungal cell membrane lipids, specifically by reducing the content of ergosterol and leading to the accumulation of atypical lipids in the fungal cell membrane and organelles. This change causes morphological changes in the fungal cell membrane and its internal structure, thereby inhibiting fungal growth.

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

[0004] 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 eliminating hidden fungi in the deep. Therefore, its stability and permeability are crucial for treatment effectiveness. 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 amorolfine hydrochloride liniment, which uses non-water-soluble resin-acrylic resin RL100 to form a tough film on the surface of the diseased nail after solvent evaporation, encapsulate the diseased nail, and maintain the effective drug concentration of the nail bed. However, the actual permeability of the amorolfine hydrochloride liniment has not been verified.

[0006] Patent CN119587466A discloses an amorolfine hydrochloride liniment and its production process, which adds ingredients such as propylene glycol to the amorolfine hydrochloride liniment to increase the stability, solubility, and permeability of the drug. The process is relatively complex, and there is no specific effect. SUMMARY

[0007] The present application provides an antifungal liniment composed of amorolfine hydrochloride, liquid excipients, film-forming agents, and solvents, wherein the film-forming agents are composed of quaternary ammonium-based methacrylate copolymer type A and quaternary ammonium-based methacrylate copolymer type B.

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

[0009] Further, the antifungal liniment according to the weight percentage composition includes: amorolfine hydrochloride 2-10%, liquid adjuvant 5-35%, film forming agent 5-20% and the rest is solvent.

[0010] Further, the liquid adjuvant includes a plasticizer and a cosolvent.

[0011] Further, the plasticizer is selected from one or more of triacetin, 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] In another aspect, the present application provides a preparation method of the above-mentioned antifungal liniment, comprising the following steps: 1) liquid preparation; 2) filling; wherein the feeding sequence of step 1) liquid preparation is liquid adjuvant, film forming agent, amorolfine hydrochloride.

[0014] Further, the specific operation of step 1) is: take 30% to 60% of the total volume of solvent into the container, then add liquid adjuvant to the container, adjust the temperature of the mixed solution, then add the film forming agent and stir, when the material is completely dissolved, add amorolfine hydrochloride, stir again, and finally use the solvent to constant volume to the predetermined volume.

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

[0016] Further, the time for stirring again is 30-120min.

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

[0018] Excellent stability: the liniment of the present application performs well in the related substances, all test results meet the limit requirements, and in some cases it is better than the marketed product. This shows that the product of the present application has higher purity and better stability.

[0019] Stable content: the amorolfine hydrochloride liniment of the present application can reach the specified drug concentration in drug content, and has good stability, in addition, the effective component of the preparation can still maintain high stability under different storage conditions, which ensures the quality and curative effect of the drug within the shelf life.

[0020] Significant permeation effect: through strict permeation test verification, the tincture of amorolfine hydrochloride of the present application shows excellent effect in nail plate permeability, can effectively penetrate the hard nail plate, and ensure that the drug can reach the infection site to play its antibacterial effect. The permeation performance of the product of the present application is similar to that of the marketed product, ensuring effective treatment effect and safety. DETAILED DESCRIPTION

[0021] The technical solutions in the embodiments of the present application will be clearly described below in combination with the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all 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", and the like in the specification and claims of the present application are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data thus used 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 a category, and are not limited to the number of objects, for example, the first object can be one or more. In addition, "and / or" in the specification and claims indicates at least one of the connected objects, and the character " / ", generally indicates that the front and rear associated objects are in an "or" relationship.

[0023] In order to develop a tincture of amorolfine hydrochloride with better permeation, so as to fully exert its antibacterial effect, the present application provides a tincture of amorolfine hydrochloride, which is composed of amorolfine hydrochloride, liquid adjuvant, film-forming agent and solvent, wherein the film-forming agent is composed of quaternary ammonium methacrylate copolymer type A and quaternary ammonium methacrylate copolymer type B.

[0024] In an embodiment of the present application, the mass ratio of the quaternary ammonium methacrylate copolymer type A and the quaternary ammonium methacrylate copolymer type B is (7-9):(1-3), for example 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 the value range are also applicable, and preferably (7:3)-(9:1).

[0025] In one embodiment of the present application, the composition of the terbinafine hydrochloride liniment by weight percentage comprises: terbinafine hydrochloride 2-10%, liquid adjuvant 5-35%, film forming agent 5-20%, and the rest is solvent. Preferably, the composition of the terbinafine hydrochloride liniment by weight percentage comprises: terbinafine hydrochloride 3-8%, liquid adjuvant 10-30%, film forming agent 3-18%, and the rest is solvent. Preferably, the composition of the terbinafine hydrochloride liniment by weight percentage comprises: terbinafine hydrochloride 5-7%, liquid adjuvant 15-25%, film forming agent 8-15%, and the rest is solvent. More preferably, the composition of the terbinafine hydrochloride liniment by weight percentage comprises: terbinafine hydrochloride 5.29-5.85%, liquid adjuvant 19.99-22.10%, film forming agent 11.42-13.13%, and the rest is solvent. Further preferably, the composition of the terbinafine hydrochloride liniment by weight percentage comprises: terbinafine hydrochloride 5.57%, liquid adjuvant 21.05%, film forming agent 12.5%, and the rest is solvent.

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

[0027] However, the inventors found in their research that the use of quaternary ammonium methacrylate copolymer type A alone cannot achieve the desired performance of the drug product. In contrast, when used in combination with quaternary ammonium methacrylate copolymer type B in a specific ratio, the terbinafine hydrochloride liniment shows excellent performance in active ingredient content, impurity control, and nail penetration. 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 segments. These hydrophobic segments may enhance the compatibility between different components, thereby improving the overall quality and efficacy of the terbinafine hydrochloride liniment. Such a combination not only improves the physicochemical properties of the drug, but also provides stable and controllable therapeutic effects.

[0028] In one embodiment of the present application, the liquid adjuvant comprises a plasticizer and a cosolvent. The plasticizer is selected from one or more of triacetin, 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 anhydrous ethanol), liquid paraffin, glycerol, or vegetable oil. The "multiple" in the present application includes two and more than two.

[0029] In another aspect, in one embodiment of the present application, the preparation method of the amorolfine hydrochloride liniment comprises the following steps: 1) liquid preparation; 2) filling; wherein the feeding sequence of step 1) is liquid adjuvant, film-forming agent, and amorolfine hydrochloride.

[0030] In one specific embodiment of the present application, the specific operation of step 1) is: take 30% to 60% of the total volume of solvent into the container, then add liquid adjuvant into the container, adjust the temperature of the mixed solution, then add the film-forming agent for stirring, after the material is completely dissolved, add amorolfine hydrochloride, stir again until the material is completely dissolved, and finally use the solvent to make the solution to the predetermined volume.

[0031] In one specific embodiment of the present application, the specific operation of step 1) is: take 30% to 60% of the total volume of anhydrous ethanol into the container, then add liquid adjuvant, i.e. glyceryl triacetate, ethyl acetate and butyl acetate, into the container, adjust the temperature of the mixed solution, then add the film-forming agent, i.e. a mixture of quaternary ammonium methacrylate copolymer type A and quaternary ammonium methacrylate copolymer type B with a specific mass ratio, for stirring until the material is completely dissolved, then add the prescribed amount of amorolfine hydrochloride, stir again until the material is completely dissolved, and finally use anhydrous ethanol to make the solution to the predetermined volume.

[0032] The "total volume" in the present application refers to the total volume of the amorolfine hydrochloride liniment. For example, if the single dose is 2.5 milliliters, then the total volume corresponding to 200 dose units is 500 milliliters. As for the amount of solvent added to the container first, the present application does not make strict limitations, as long as it is ensured that the amount of solvent used is sufficient to completely dissolve the subsequent added raw and auxiliary materials.

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

[0034] In one embodiment of the present application, the temperature of the mixed solution is 30±10℃, for example, 20℃, 25℃, 30℃, 35℃ or 40℃, but is not limited to the listed values, and other unlisted values within this range are also applicable.

[0035] In one embodiment of the present application, the time for the two stirring is 30-120 min, for example, 30 min, 60 min, 90 min or 120 min, but not limited to the listed values, other unlisted values within the range of the values are also applicable.

[0036] The multiple stirring times mentioned in the present application can be the same or different, as long as the material is completely dissolved.

[0037] The embodiments of the present application and the comparisons are specifically listed as follows, but the present application 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 (the mass ratio of Type A and Type B is 9:1) is as follows:

[0043]

[0044] The preparation process is as follows:

[0045] 1) Liquid preparation: Take 30%-60% of the total volume of anhydrous ethanol and add it to the container, then add the prescription amount of liquid auxiliary materials, i.e., glyceryl triacetate, ethyl acetate and butyl acetate, to the container in sequence, and stir for 2 minutes to ensure uniform mixing. Adjust the temperature of the solution in the container to 30±10℃, then add the prescription amount of film-forming agent, and stir for 30-120 min until completely dissolved. Then, add the prescription amount of amorolfine hydrochloride, and stir again for 30-120 min. Finally, use anhydrous ethanol to make 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 sodium-calcium glass bottles.

[0047] Example 2

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

[0049]

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

[0051] Example 3

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

[0053]

[0054] The formulation process is the same as in Example 1.

[0055] Comparative Example 1

[0056] The mass ratio of film-forming agent type A to type B in the formulation was adjusted to 6:4.

[0057]

[0058] The formulation process is the same as in Example 1.

[0059] Comparative Example 2

[0060] The film-forming agent in the adjusted formulation is now only type A.

[0061]

[0062]

[0063] The formulation process is the same as in Example 1.

[0064] Comparative Example 3

[0065] The formulation composition is the same as in Example 1, except that the order of adding the ingredients in the preparation process is adjusted to film-forming agent, liquid excipient, and raw material (amorolfen hydrochloride). The specific formulation process is as follows:

[0066] 1) Solution preparation: Add 30% to 60% of the total volume of anhydrous ethanol to a container, adjust the temperature of the solution in the container to 30±10℃, add the prescribed amount of film-forming agent to the container, stir for 30 to 120 minutes until completely dissolved, then add the prescribed amount of liquid excipients, namely triacetin, ethyl acetate and butyl acetate, and stir for 2 minutes to mix evenly, then add the prescribed amount of amorolfine hydrochloride, and stir again for 30 to 120 minutes, finally, use anhydrous ethanol to make up the volume to the predetermined volume (drug density: 0.870 g / ml).

[0067] 2) Filling: Fill the liquid medicine into brown sodium calcium glass bottles.

[0068] Comparative Example 4

[0069] The formulation composition is the same as in Example 1, except that the order of adding the ingredients in the preparation process is adjusted to liquid excipients, raw material (amorolfen hydrochloride), and film-forming agent. The specific formulation process is as follows:

[0070] 1) Liquid preparation: Take 30% to 60% of the total volume of anhydrous ethanol into the container, then add the prescription amount of liquid adjuvant, i.e. glyceryl triacetate, ethyl acetate and butyl acetate into the container in turn, stir for 2 min to mix evenly, adjust the temperature of the solution in the container to 30±10℃, then add the prescription amount of amorolfine hydrochloride, and stir for 30 to 120 min, then add the prescription amount of film-forming agent, stir for 30 to 120 min until completely dissolved, finally, use anhydrous ethanol to make the solution to 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, and the feeding sequence of the liquid preparation in the preparation process is adjusted to raw material (amorolfine hydrochloride), liquid adjuvant, film-forming agent. The specific preparation process is as follows:

[0074] 1) Liquid preparation: Take 30% to 60% of the total volume of anhydrous ethanol into the container, then add the prescription amount of liquid adjuvant, i.e. glyceryl triacetate, ethyl acetate and butyl acetate into the container in turn, stir for 2 min to mix evenly, adjust the temperature of the solution in the container to 30±10℃, then add the prescription amount of film-forming agent, stir for 30 to 120 min until completely dissolved, finally, use anhydrous ethanol to make the solution to 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, and the film-forming agent is only type A. The specific prescription composition is as follows:

[0078]

[0079] Meanwhile, the feeding sequence of the liquid preparation in the preparation process is adjusted to raw material (amorolfine hydrochloride), film-forming agent, liquid adjuvant. The specific preparation process is as follows:

[0080] 1) Liquid preparation: Take 30% to 60% of the total volume of anhydrous ethanol and add it to the container. Add the prescribed amount of amorolfine hydrochloride to the container, stir for 30 to 120 minutes, adjust the temperature of the solution in the container to 30 ± 10°C, then add the prescribed amount of film-forming agent, stir for 30 to 120 minutes until completely dissolved, then add the prescribed amount of liquid adjuvant, i.e. glyceryl triacetate, ethyl acetate and butyl acetate, stir for 2 minutes and mix evenly. Finally, use anhydrous ethanol to make up the solution to the predetermined volume (the density of the drug solution is 0.870 g / ml).

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

[0082] Effect verification:

[0083] The content, related substances and permeability of the amorolfine hydrochloride liniment obtained in Examples 1 to 3 and Comparative Examples 1 to 6 and the commercially available product (Amorolfine Hydrochloride Liniment, Roemer, batch number: 1212416) were determined.

[0084] The detection method of the content is determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Volume IV General Rules 0512). The chromatographic conditions are as follows: octadecylsilane bonded silica gel as the filler, mobile phase: 0.02 mol / L potassium phosphate dibasic solution (pH value adjusted 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. The test method is to accurately measure the test sample solution and the control sample solution, and then inject them into the liquid chromatograph, respectively, and record the chromatogram.

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

[0086]

[0087] Note: The data under investigation may be elevated because the product has more volatile adjuvants in the prescription

[0088] From the content detection results of the active ingredients of the amorolfine hydrochloride liniment from different batches, it can be seen that the content of Examples 1 to 3 and the commercially available product is 95.0% to 105.0% of the labeled amount, and the content does not fluctuate greatly after 10 days and 30 days under high temperature (40°C, 60°C) and light, and the stability is good.

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

[0090] Different feeding sequences also had an important impact on the stability of the amorolfine hydrochloride liniment. If a feeding sequence different from the examples was used, the content of the active ingredient in the amorolfine hydrochloride liniment obtained was unstable. In particular, when the raw materials, liquid excipients, and then the film-forming agent were added in sequence (Comparative Example 5) or the raw materials were added first, followed by the film-forming agent and then the liquid excipients (Comparative Example 6), the content of amorolfine even decreased to below the minimum limit of 95%. The amorolfine hydrochloride liniment obtained according to the sequence of film-forming agent, liquid excipient, and then raw material (Comparative Example 3) and liquid excipient, raw material, and then film-forming agent (Comparative Example 4) had active ingredient contents that met the limit requirements, but the content decreased significantly after 30 days of light exposure, indicating poor stability of the content. This indicates that the correct feeding sequence is crucial to ensuring the stability and effectiveness of the active ingredient in the amorolfine hydrochloride liniment.

[0091] Related substance detection method: determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General 0512). The chromatographic conditions use hexadecyl amide bonded silica gel as the filler; acetonitrile-phosphate buffer (take dipotassium hydrogen phosphate 5.5 g, dissolve in 1000 ml of water, adjust the pH value to 6.0 with phosphoric acid)-methanol as the mobile phase A, acetonitrile-phosphate buffer-methanol as the mobile phase B, gradient elution 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 each solution and inject it into the liquid chromatograph, and record the chromatogram.

[0094] Limit Impurity peaks in the chromatogram of the test solution, in addition to the blank adjuvant peak with retention time less than 3 minutes, impurity A and impurity B shall not be greater than the main peak area of the control solution (0.2%); in addition to impurity A and impurity B, the sum of the peak areas of other impurities shall not be greater than the main peak area of the control solution (0.2%), the total impurity peak area shall not be greater than 3 times the main peak area of the control solution (0.6%), and the chromatographic peak less than the sensitivity solution main peak area is ignored (0.05%).

[0095] Note: Impurities A and B are the main research impurities, and other impurities are only studied but not included in the related substance quality standard.

[0096] Impurity information is as follows:

[0097]

[0098]

[0099]

[0100] The related substance detection results are as follows:

[0101]

[0102] From the related substance detection results of different batches of amorolfine hydrochloride liniment, it can be seen that the commercially available Lamisil does not detect the main research impurities A and B, but the content of impurity D is 0.225%, which is significantly higher than the limit value 0.2%, and the total impurity content is also high, which is 0.454%.

[0103] The related substances of the amorolfine hydrochloride liniment obtained in Examples 1-3 are less in type and lower in content, and the liniment has good stability and is better than the commercially available product.

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

[0105] Therefore, it can be seen that appropriate selection of the proportion of film-forming agents and following the correct feeding sequence are crucial for controlling the content of related substances in the amorolfine hydrochloride liniment. This not only helps to improve the stability and safety of the product, but also ensures that it meets the quality standards.

[0106] Permeation test operation method:

[0107] The general penetration experiment uses human nail plate and animal nail plate, among which the human nail plate material is not easy to obtain and the shape is not convenient to process, the animal nail plate has pig hoof nail and cow hoof nail, etc., but the cow hoof nail is the most common and easy to obtain and process, the swelling capacity of the cow hoof nail is strong, the permeability is generally better, at the same time, the in vitro penetration experiment in the "Preparation of Amorolfine Hydrochloride Liniment" of Hubei University of Chinese Medicine also uses the cow hoof nail, so the cow hoof nail is selected as the experimental material.

[0108] Experimental method (also refer to "Preparation of Amorolfine Hydrochloride Liniment" of Hubei University of Chinese Medicine): The sample is subjected to the penetration experiment by using a transdermal test machine, the sampling time points are 1, 3, 5, 7 and 9 hours, the amount of drug is 10 ul, the rotation speed is 800 rpm, the receiving medium is physiological saline. The nail plate at the drug administration site is cut (cut into pieces) and placed in a 20 ml sample bottle, 20 ml of medium is added, the liniment is dissolved by shaking, vortexed for 20 min, filtered, and the filtrate is obtained; after pretreatment, the sample is analyzed by high performance liquid chromatography.

[0109] Penetration test results:

[0110] Sample 9 h cumulative release (%) Residual amount (%) Retained amount (%) Total amount (%) Commercial product - L'Oreal 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) 9-hour cumulative release amount (%): refers to the cumulative amount of drug released from the preparation and penetrating through the nail plate within 9 hours. This value reflects the ability of the drug to penetrate the nail and reach the target site. Due to the special drug delivery system of Amorolfine Hydrochloride Liniment, 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 more effectively. Considering that the nail is relatively thick, the amount of drug penetrating the nail plate is relatively small, so as long as a certain cumulative release amount is reached, it can effectively play a role. In the penetration test of the present application, the 9-hour cumulative release amount of different batches of products is not much different, and has stable penetration performance.

[0112] (2) Residual amount (%): indicates the amount of drug remaining on the surface of the nail plate after a certain period of time (such as after 9 hours of experiment). Understanding the amount of drug remaining on the surface of the nail plate helps to evaluate the efficiency of drug release. And because the residual amount in this product is relatively high, therefore, the closer the residual amount is to the standard of the marketed product, the better it can ensure the effectiveness and stability of Amorolfine Hydrochloride Liniment.

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

[0114] (4) Total amount (%): This is the total recovery rate. In theory, the sum of the cumulative release amount, the residual amount, and the retention amount should equal 100%, which represents the distribution of the drug in the entire system, including the part that has penetrated the nail, the part that remains in the preparation, and the part that is retained in the nail plate. However, in actual situations, due to 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 at the same time, it also indicates that the stability of the product in each part is better.

[0115] From the results of the in-vivo permeation test of different batches of amorolfine hydrochloride liniment, it can be seen that the cumulative release amount of 9 hours of each batch of product is not much different. However, in terms of residual amount and retention amount, the amorolfine hydrochloride liniment prepared in Examples 1 to 3 shows more similar values to the commercially available product, which indicates that these batches not only have good stability, but also ensure the effectiveness. In addition, the total amount of these batches is close to 100%, which also reflects the stability of the product at different stages (release, residual, retention), further confirming the high quality of the product.

[0116] In contrast, the products using different proportions of film-forming agents or different feeding sequences (Comparative Examples 1 to 6) show some differences in residual amount and retention amount compared with the commercially available product. This difference may have a greater impact on the stability of amorolfine, and thus affect the overall efficacy of the drug.

[0117] Therefore, selecting the appropriate proportion of film-forming agents and strictly following the correct feeding sequence is crucial to ensure the stability, effectiveness, and safety of the amorolfine hydrochloride liniment. Doing so not only optimizes the release characteristics of the drug, but also improves the therapeutic effect and ensures that patients have the best treatment experience.

[0118] The present application ensures that the content stability of the amorolfine hydrochloride liniment and its related substances meet the requirements through the synergistic effect of selecting the appropriate proportion of film-forming agents and the feeding sequence, and achieves good transdermal release performance.

[0119] Example and comparative example condition setting:

[0120] A-type : B-type Order of addition Example 1 9:1 Liquid adjuvant, film-forming agent, raw material Example 2 8:2 Liquid adjuvant, film-forming agent, raw material Example 3 7:3 Liquid adjuvant, film-forming agent, raw material Comparative Example 1 6:4 Liquid adjuvant, film-forming agent, raw material Comparative Example 2 10:0 Liquid adjuvant, film-forming agent, raw material Comparative Example 3 9:1 Film-forming agent, liquid adjuvant, raw material Comparative Example 4 9:1 Liquid adjuvant, raw material, film-forming agent Comparative Example 5 9:1 Raw material, liquid adjuvant, film-forming agent Comparative Example 6 10:0 Raw material, film-forming agent, liquid adjuvant

[0121] The above describes the embodiments of the present application, but the present application is not limited to the specific embodiments described above, which are only illustrative and not limiting. Those skilled in the art can make many forms without departing from the purpose of the present application and the scope protected by the claims under the inspiration of the present application, which are all within the protection of the present application.

Claims

1. An antifungal liniment, characterized in that, The antifungal liniment comprises, by weight percentage: 2-10% amorolfine hydrochloride, 5-35% liquid excipients, 5-20% film-forming agent, and the remainder being solvent. The film-forming agent is composed of quaternary ammonium methacrylate copolymer type A and quaternary ammonium methacrylate copolymer type B, with a mass ratio of (7-9):(1-3) between the two types. The method for preparing the antifungal liniment includes the following steps: 1) preparing the solution; 2) filling; wherein, the order of adding the ingredients in step 1) preparing the solution is liquid excipient, film-forming agent, and amorolfine hydrochloride.

2. The antifungal liniment according to claim 1, characterized in that, The liquid additives include plasticizers and cosolvents.

3. The antifungal liniment according to claim 2, characterized in that, The plasticizer is selected from one or more of triacetin, triacetate, or phthalate, and the cosolvent is selected from one or more of methyl acetate, ethyl acetate, or butyl acetate.

4. The antifungal liniment according to claim 3, characterized in that, The solvent is selected from one or more of water, ethanol, liquid paraffin, glycerin, or vegetable oil.

5. The antifungal liniment according to claim 4, characterized in that, Step 1) The specific operation is as follows: Add 30% to 60% of the total volume of solvent to the container, then add liquid excipients to the container, adjust the temperature of the mixed solution, then add film-forming agent and stir. After the material is completely dissolved, add amorolfine hydrochloride and stir again. Finally, use solvent to make up the volume of the solution to the predetermined volume.

6. The antifungal liniment according to claim 5, characterized in that, The temperature of the mixed solution is 30±10℃.

7. The antifungal liniment according to claim 6, characterized in that, The re-stirring time is 30-120 minutes.

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