A transdermal gel preparation and preparation method thereof

Abstract

The present application discloses a transdermal gel preparation, which comprises, by mass percentage, 0.1% to 1% nanocrystals of levosimendan metabolites, 1% to 3% matrix material, 1% to 7% penetration enhancer, 10% to 25% solvent, and the balance is water; the matrix material is carbomer, and the penetration enhancer comprises one or more of propylene glycol, menthol or dimethyl sulfoxide. The present application adjusts the ratio between the matrix material and the penetration enhancer, and utilizes the synergistic effect between the two to achieve the sustained release effect of the drug. The nanocrystal technology controls the average particle size of the levosimendan metabolites to below 200nm, significantly improving the solubility and transdermal diffusion ability of the drug, so that the cumulative penetration rate of the transdermal gel preparation exceeds 25% within 2 hours, and the cumulative penetration rate can reach 70% to 95% within 6 hours, significantly improving the bioavailability of the drug.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and in particular to a transdermal gel preparation and a preparation method thereof. Background Art

[0002] OR-1896, a metabolite of levosimendan, is an effective drug for the treatment of heart failure. However, its traditional administration methods (such as oral administration and injection) have problems in absorption and compliance. Oral administration may irritate the gastrointestinal tract, and injection may be prone to infection and irritation to tissues.

[0003] The mechanism of action of transdermal gel preparations includes three processes: release of active drug ingredients, penetration of the skin or mucous membranes, and absorption and corresponding effects. The release of active drug ingredients refers to the process in which the active drug ingredients are released from the preparation and diffused to the surface of the skin and mucous membranes, while penetration of the skin and mucous membranes refers to the process in which the active ingredients reach the deeper dermis and subcutaneous tissue through the epidermis and focus on the site. Transdermal gel preparations can improve bioavailability and patient medication experience by optimizing drug release and absorption performance, effectively avoid infection, irritation to tissues, and reduce effects on the gastrointestinal tract. The preparation of levosimendan metabolites into transdermal gel preparations can alleviate the problems of absorption and compliance in oral and injection administration, which puts higher requirements on the transdermal properties of levosimendan metabolite transdermal gel preparations.

[0004] Therefore, developing a transdermal gel preparation of levosimendan metabolites that can improve the transdermal effect is an urgent problem to be solved by those skilled in the art. Summary of the invention

[0005] In view of this, the present application provides a transdermal gel preparation, which optimizes drug release and absorption performance, improves transdermal absorption efficiency, optimizes release rate, ensures preparation uniformity and stability, and at the same time improves bioavailability and improves patient medication experience.

[0006] The present application provides a transdermal gel preparation, which comprises, by mass percentage, 0.1% to 1% of levosimendan metabolite nanocrystals, 1% to 3% of a matrix material, 1% to 7% of a penetration enhancer, 10% to 25% of a solvent, and the balance is water; the matrix material comprises carbomer, and the penetration enhancer comprises one or more of propylene glycol, menthol or dimethyl sulfoxide.

[0007] The present application uses 0.1% to 1% levosimendan metabolite nanocrystals, 1% to 3% matrix material, 1% to 7% penetration enhancer, 10% to 25% solvent, and the balance is water as raw materials to prepare a transdermal gel preparation, which can significantly improve the transdermal absorption efficiency of the levosimendan metabolite transdermal gel preparation, optimize the release rate, and ensure the uniformity and stability of the scalp gel preparation. The transdermal gel preparation has the characteristics of high initial penetration rate (>25%) and large cumulative penetration rate within 6 hours (70% to 95%), which significantly improves the bioavailability of the drug.

[0008] The transdermal gel preparation provided in the present application includes nanocrystals of levosimendan metabolites. The nanocrystals of levosimendan metabolites are prepared by nanocrystal technology using levosimendan metabolites as raw materials. The average particle size of OR-1896 is controlled to be below 200nm, preferably 100nm to 200nm, by nanocrystal technology, which significantly improves the solubility and transdermal diffusion ability of the drug. In some specific implementations, the preparation method of the nanocrystals of levosimendan metabolites includes: mixing the levosimendan metabolites with a solvent, stirring to obtain a mixed solution, and homogenizing to obtain nanocrystals of levosimendan metabolites. In some specific implementations, the stirring temperature is 35°C to 45°C, preferably 38°C to 42°C; the concentration of the levosimendan metabolites in the mixed solution is 3% to 8%, preferably 5% to 7%. In some specific implementations, the number of times of the homogenization treatment is 8 to 15 times, preferably 10 to 12 times; the pressure of the homogenization treatment is 500 bar to 800 bar, preferably 600 bar to 700 bar. In some specific implementations, the levosimendan metabolite nanocrystals include but are not limited to OR-1896 nanocrystals, and the present application has no special requirements for the selection of levosimendan metabolite nanocrystals. Using nanocrystal technology, the particle size of levosimendan metabolites is reduced to less than 200 nm, significantly improving the solubility and stability of the drug.

[0009] In some specific implementations, the mass percentage of the levosimendan metabolite nanocrystals is 0.1% to 1%, and can be 0.1%, 0.2%, 0.5%, 0.8%, 1%, and preferably 0.5% to 1%.

[0010] The transdermal gel preparation provided by the present application includes a matrix material. In some specific implementations, the matrix material includes but is not limited to carbomer, and the present application has no special requirements for the selection of the matrix material. Carbomer is selected as the gel matrix of the gel preparation to provide excellent adhesion and mechanical strength.

[0011] In some specific implementations, the mass percentage of the matrix material is 1% to 3%, which can be 1%, 1.2%, 1.4%, 1.5%, 1.8%, 2%, 2.2%, 2.4%, 2.5%, 2.8%, 3%, preferably 2% to 2.8%.

[0012] The transdermal gel preparation provided by the present application includes a penetration enhancer, which includes but is not limited to one or more of propylene glycol, menthol or dimethyl sulfoxide. The present application has no special requirements for the selection of the penetration enhancer. By adjusting the ratio of the matrix material and the penetration enhancer and the synergistic effect between the two, the rapid release or sustained release control of the drug is achieved to achieve the effect of optimizing the release rate.

[0013] In some specific implementations, the mass percentage of the penetration enhancer is 1% to 7%, which can be 1%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, preferably 3% to 5%.

[0014] The transdermal gel preparation provided by the present application includes a solvent. In some specific implementations, the solvent includes but is not limited to ethanol and / or propylene glycol. The present application has no special requirements for the selection of the solvent. The solvent ethanol can not only serve as a solvent, but also improve the transdermal performance and has a synergistic enhancer effect.

[0015] The transdermal gel preparation provided by the present application includes water. In some specific implementations, the water includes deionized water. The water is used as a solvent to adjust the mass percentage of the entire transdermal gel preparation to 100%. The transdermal gel preparation provided by the present application has a wide range of indications, mainly for the treatment of acute heart failure, and is also suitable for other cardiovascular diseases that require rapid onset of action.

[0016] The transdermal gel preparation provided by the present application also includes a cooling agent. In some specific implementations, the cooling agent includes but is not limited to camphor and / or borneol, and the present application has no special requirements for the selection of the cooling agent.

[0017] In some specific implementations, the mass percentage of the coolant is 0.5% to 1%, and can be 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1%.

[0018] In some specific implementations, the composition includes, by mass percentage, 0.5% levosimendan metabolite nanocrystals, 2% matrix material, 5% penetration enhancer, 20% solvent, and the balance is water; or the composition includes, by mass percentage, 1% levosimendan metabolite nanocrystals, 2.8% matrix material, 5% penetration enhancer, 15% solvent, and the balance is water; or the composition includes, by mass percentage, 0.6% levosimendan metabolite nanocrystals, 1.5% matrix material, 3% penetration enhancer, 15% solvent, and the balance is water; or the composition includes, by mass percentage, 0.5% levosimendan metabolite nanocrystals, 2.2% matrix material, 4% penetration enhancer, 18% solvent, and the balance is water.

[0019] The present application also provides a method for preparing the above transdermal gel preparation, comprising:

[0020] Mixing the matrix material, the penetration enhancer and water, and stirring to obtain a gel matrix;

[0021] The gel matrix and the levosimendan metabolite nanocrystals are mixed and subjected to ultrasonic treatment to obtain a transdermal gel preparation.

[0022] The present application first dissolves the levosimendan metabolite in a solvent, stirs until uniform, and homogenizes in a high-pressure homogenizer to obtain levosimendan metabolite nanocrystals. In some specific implementations, the concentration of the levosimendan metabolite in the mixed solution is 3% to 8%, preferably 5% to 7%. In some specific implementations, the number of homogenization treatments is 8 to 15 times, preferably 10 to 12 times; the pressure of the homogenization treatment is 500 bar to 800 bar, preferably 600 bar to 700 bar.

[0023] The application then mixes the host material with water to obtain a solution. In some specific implementations, the mixing is carried out in a high-speed agitator, and the speed of the high-speed agitator is 500rpm to 900rpm, preferably 600rpm to 800rpm. In some specific implementations, the time of the stirring is 20min to 40min, preferably 25min to 30min.

[0024] The present application then adjusts the pH of the solution to obtain a mixture. In some specific implementations, the pH of the mixture is 5.5 to 6.5. In some specific implementations, 1M triethanolamine is used to adjust the pH.

[0025] The present application then adds a penetration enhancer to the mixture and stirs it to obtain a gel matrix. In some specific implementations, the stirring time is 20 min to 40 min, preferably 25 min to 30 min.

[0026] The present application then mixes the prepared OR-1896 nanocrystals with the gel matrix and performs ultrasonic treatment to ensure uniform distribution to obtain a transdermal gel preparation. In some specific implementations, the ultrasonic treatment time is 8 min to 15 min, preferably 9 min to 12 min.

[0027] The preparation method includes high-pressure homogenization preparation of nanocrystals and uniform mixing of a gel matrix, thereby ensuring the uniformity, stability and transdermal absorption performance of the preparation, and is suitable for the treatment of cardiovascular diseases such as heart failure.

[0028] The transdermal gel preparation described in the present application includes nanocrystals of levosimendan metabolites, matrix materials, penetration enhancers and solvents. The sustained release effect of the drug is achieved by adjusting the ratio between the matrix material and the penetration enhancer. The solvent ethanol serves as both a solvent and a synergistic enhancer. The present application utilizes the synergistic effect between the two to achieve the sustained release effect of the drug, and at the same time adjusts the ratio between the matrix material and the penetration enhancer. The nanocrystal technology controls the average particle size of the levosimendan metabolite to below 200nm, significantly improving the solubility and transdermal diffusion ability of the drug, so that the cumulative penetration of the transdermal gel preparation exceeds 30μg / cm within 2 hours. 2 The cumulative penetration can reach 70μg / cm in 6 hours. 2 Up to 95 μg / cm 2 , significantly improving the bioavailability of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The drug release curve of the transdermal gel preparation provided in Example 1 of the present application;

[0030] Figure 2 The drug release curve of the transdermal gel preparation provided in Example 2 of the present application;

[0031] Figure 3 The drug release curve of the transdermal gel preparation provided in Example 3 of the present application;

[0032] Figure 4 The drug release curve of the transdermal gel preparation provided in Example 4 of the present application;

[0033] Figure 5 The drug release curve of the transdermal gel preparation provided in Example 5 of the present application;

[0034] Figure 6 The drug release curve of the transdermal gel preparation provided in Comparative Example 1 of the present application;

[0035] Figure 7 The drug release curve of the transdermal gel preparation provided in Comparative Example 2 of the present application;

[0036] Figure 8 The drug release curve of the transdermal gel preparation provided in Comparative Example 3 of the present application;

[0037] Fig. 9 This is a drug release curve diagram of the transdermal gel preparation provided in Comparative Example 4 of the present application. DETAILED DESCRIPTION

[0038] It should be understood that the expression "one or more of..." includes each of the items recited after the expression individually and in various different combinations of two or more of the recited items, unless otherwise understood from the context and usage. The expression "and / or" in combination with three or more recited items should be understood to have the same meaning, unless otherwise understood from the context.

[0039] The use of the terms "comprising", "having" or "containing", including their grammatical synonyms, should generally be understood as open and non-restrictive, for example not excluding other unrecited elements or steps, unless otherwise specifically stated or otherwise understood from the context.

[0040] It should be understood that the order of steps or the order in which certain actions are performed is not important as long as the application is still operable. In addition, two or more steps or actions can be performed simultaneously.

[0041] The use of any and all examples or exemplary language, such as "for example" or "including", herein is intended only to better illustrate the present application and does not limit the scope of the present application unless the claims are set forth. No language in this specification should be construed as indicating that any non-claimed element is essential to the practice of the present application.

[0042] In addition, the numerical ranges and parameters used to define the present application are approximate values, and the relevant values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Therefore, unless otherwise expressly stated, it should be understood that all ranges, quantities, values ​​and percentages used in this disclosure are modified by "about". Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range.

[0043] The present application provides a transdermal gel preparation, which comprises, by mass percentage, 0.1% to 1% of levosimendan metabolite nanocrystals, 1% to 3% of a matrix material, 1% to 7% of a penetration enhancer, 10% to 25% of a solvent, and the balance is water; the matrix material comprises carbomer, and the penetration enhancer comprises one or more of propylene glycol, menthol or dimethyl sulfoxide.

[0044] The transdermal gel preparation includes nanocrystals of levosimendan metabolites, a matrix material, a penetration enhancer and a solvent. The sustained release effect of the drug is achieved by adjusting the ratio between the matrix material and the penetration enhancer. The solvent ethanol serves as both a solvent and a synergistic enhancer. The present application utilizes the synergistic effect between the two to achieve the sustained release effect of the drug, and at the same time adjusts the ratio between the matrix material and the penetration enhancer. The nanocrystal technology controls the average particle size of the levosimendan metabolite to below 200 nm, significantly improving the solubility and transdermal diffusion ability of the drug, so that the cumulative penetration amount of the transdermal gel preparation exceeds 30 μg / cm within 2 hours. 2 The cumulative penetration can reach 70μg / cm in 6 hours. 2 Up to 95 μg / cm 2 , significantly improving the bioavailability of the drug.

[0045] The present application is further described below in conjunction with the following embodiments. The protection scope of the present application is not limited by the following embodiments.

[0046] Example 1

[0047] The present embodiment provides a transdermal gel preparation, comprising:

[0048] OR-1896 nanocrystals (average particle size 100nm to 200nm): 0.5g;

[0049] Matrix material: Carbomer 2g;

[0050] Penetration enhancer: propylene glycol 5g;

[0051] Solvent: ethanol 20g;

[0052] Deionized water to 100 g.

[0053] The preparation method comprises:

[0054] OR-1896 was dissolved in ethanol to prepare a 5% stock solution, and stirred at 40°C to ensure complete dissolution, thereby obtaining an ethanol solution of OR-1896.

[0055] The ethanol solution of OR-1896 was processed by a high pressure homogenizer for 10 cycles, with the pressure set to 800 bar each time, to obtain an OR-1896 nanocrystal solution. The average particle size of the solution was controlled to be less than 200 nm (verified by dynamic light scattering).

[0056] Carbomer was added to deionized water and stirred at 800 rpm for 30 minutes using a high-speed stirrer to form a transparent and uniform gel matrix. The pH was adjusted to 5.5 with 1 M triethanolamine, and a penetration enhancer was gradually added. Stirring was continued for 20 minutes to ensure uniform dispersion to obtain a gel matrix.

[0057] The OR-1896 nanocrystal solution was slowly added to the gel matrix and treated with an ultrasonic disperser for 10 minutes to ensure uniform distribution of the drug. Ethanol was added and stirred continuously until uniform, and deionized water was added to obtain a transdermal gel preparation.

[0058] Example 2

[0059] This embodiment provides a transdermal gel preparation, comprising:

[0060] OR-1896 nanocrystals (average particle size 100nm to 200nm): 1g;

[0061] Matrix material: Carbomer 2.8g;

[0062] Penetration enhancer: propylene glycol 5g;

[0063] Solvent: ethanol 15g;

[0064] Deionized water to 100 g.

[0065] The preparation method comprises:

[0066] OR-1896 was dissolved in ethanol to prepare a 5% stock solution, and stirred at 40°C to ensure complete dissolution, thereby obtaining an ethanol solution of OR-1896.

[0067] The ethanol solution of OR-1896 was processed by a high pressure homogenizer for 10 cycles, with the pressure set to 800 bar each time, to obtain an OR-1896 nanocrystal solution. The average particle size of the solution was controlled to be less than 200 nm (verified by dynamic light scattering).

[0068] Carbomer was added to deionized water and stirred at 800 rpm for 30 minutes using a high-speed stirrer to form a transparent and uniform gel matrix. The pH was adjusted to 5.5 with 1 M triethanolamine, and a penetration enhancer was gradually added. Stirring was continued for 20 minutes to ensure uniform dispersion to obtain a gel matrix.

[0069] The OR-1896 nanocrystal solution was slowly added to the gel matrix and treated with an ultrasonic disperser for 10 minutes to ensure uniform distribution of the drug. Ethanol was added and stirred continuously until uniform, and deionized water was added to obtain a transdermal gel preparation.

[0070] Example 3

[0071] This embodiment provides a transdermal gel preparation, comprising:

[0072] OR-1896 nanocrystals (average particle size 100nm to 200nm): 0.6g;

[0073] Matrix material: Carbomer 1.5g;

[0074] Penetration enhancer: dimethyl sulfoxide 3g;

[0075] Solvent: ethanol 15g;

[0076] Deionized water to 100 g.

[0077] The preparation method is the same as that in Example 1.

[0078] Example 4

[0079] This embodiment provides a transdermal gel preparation, comprising:

[0080] OR-1896 nanocrystals (average particle size 100nm to 200nm): 0.5g;

[0081] Matrix material: Carbomer 2.2g;

[0082] Penetration enhancers: propylene glycol 3g, menthol 1g;

[0083] Solvent: ethanol 18g;

[0084] Deionized water to 100 g.

[0085] The preparation method is the same as that in Example 1.

[0086] Example 5

[0087] This embodiment provides a transdermal gel preparation, comprising:

[0088] OR-1896 nanocrystals (average particle size 100nm to 200nm): 0.5g;

[0089] Matrix material: Carbomer 1.9 g;

[0090] Penetration enhancer: menthol 1g;

[0091] Coolant: camphor 0.5g;

[0092] Solvent: ethanol 15g;

[0093] Deionized water to 100 g.

[0094] The preparation method comprises:

[0095] OR-1896 was dissolved in ethanol to prepare a 5% stock solution, and stirred at 40°C to ensure complete dissolution, thereby obtaining an ethanol solution of OR-1896.

[0096] The ethanol solution of OR-1896 was processed by a high pressure homogenizer for 10 cycles, with the pressure set to 800 bar each time, to obtain an OR-1896 nanocrystal solution. The average particle size of the solution was controlled to be less than 200 nm (verified by dynamic light scattering).

[0097] Carbomer was added to deionized water and stirred at 800 rpm for 30 minutes using a high-speed stirrer to form a transparent and uniform gel matrix. The pH was adjusted to 5.5-6.5 using 1 M triethanolamine to obtain a gel matrix.

[0098] The OR-1896 nanocrystal solution was slowly added to the gel matrix and treated with an ultrasonic disperser for 10 minutes to ensure uniform distribution of the drug. Ethanol was added and stirred continuously until uniform, and a coolant and deionized water were added to obtain a transdermal gel preparation.

[0099] Comparative Example 1

[0100] This comparative example provides a transdermal gel preparation, which is different from Example 1 only in that the average particle size of the OR-1896 micron particles is 15-20 μm.

[0101] The preparation method is the same as that in Example 1.

[0102] Comparative Example 2

[0103] This comparative example provides a transdermal gel preparation, which is different from Example 1 only in that carbomer is replaced with hydroxyethyl cellulose.

[0104] The preparation method is the same as that in Example 1.

[0105] Comparative Example 3

[0106] This comparative example provides a transdermal gel preparation, comprising:

[0107] OR-1896 nanocrystals (average particle size 100nm to 200nm): 0.05g;

[0108] Matrix material: Carbomer 2g;

[0109] Penetration enhancer: propylene glycol 3g;

[0110] Solvent: ethanol 15g;

[0111] Deionized water to 100 g.

[0112] The preparation method comprises:

[0113] OR-1896 was dissolved in ethanol to prepare a 5% stock solution, and stirred at 40°C to ensure complete dissolution, thereby obtaining an ethanol solution of OR-1896.

[0114] The ethanol solution of OR-1896 was processed by a high pressure homogenizer for 10 cycles, with the pressure set to 800 bar each time, to obtain an OR-1896 nanocrystal solution. The average particle size of the solution was controlled to be less than 200 nm (verified by dynamic light scattering).

[0115] Carbomer was added to deionized water and stirred at 800 rpm for 30 minutes using a high-speed stirrer to form a transparent and uniform gel matrix. The pH was adjusted to 5.5 with 1 M triethanolamine, and a penetration enhancer was gradually added. Stirring was continued for 20 minutes to ensure uniform dispersion to obtain a gel matrix.

[0116] The OR-1896 nanocrystal solution was slowly added to the gel matrix and treated with an ultrasonic disperser for 10 minutes to ensure uniform distribution of the drug. Ethanol was added and stirred continuously until uniform, and deionized water was added to obtain a transdermal gel preparation.

[0117] Comparative Example 4

[0118] The difference between this comparative example and Example 1 is that carbomer is replaced with polycarbophil.

[0119] The preparation method is the same as that in Example 1.

[0120] The transdermal gel preparations provided in Examples 1 to 5 and Comparative Examples 1 to 4 were tested using the following test methods:

[0121] In vitro permeation test:

[0122] Experimental setup: Franz diffusion cell;

[0123] Transdermal barrier: pig skin;

[0124] Experimental steps: The transdermal barrier was fixed in a diffusion cell. A certain amount of gel preparation was added to the donor chamber. 0.5% SDS, phosphate buffered saline (PBS, pH 7.4) was added to the receptor chamber and stirred at 37°C. Samples were taken at different time points (0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours) and the concentration of OR-1896 in the receptor fluid was detected by high performance liquid chromatography (HPLC).

[0125] Result analysis: Calculate the cumulative transdermal amount and transdermal rate to obtain the drug release curve. The drug release curve of the transdermal gel preparation provided in Example 1 is as follows: Figure 1 As shown, the drug release curve of the transdermal gel preparation provided in Example 2 is as follows Figure 2 As shown, the drug release curve of the transdermal gel preparation provided in Example 3 is as follows Figure 3 As shown, the drug release curve of the transdermal gel preparation provided in Example 4 is as follows Figure 4 As shown, the drug release curve of the transdermal gel preparation provided in Example 5 is as follows Figure 5As shown, the drug release curve of the transdermal gel preparation provided in Comparative Example 1 is as follows Figure 6 As shown, the drug release curve of the transdermal gel preparation provided in Comparative Example 2 is as follows Figure 7 As shown, the drug release curve of the transdermal gel preparation provided in Comparative Example 3 is as follows Figure 8 As shown, the drug release curve of the transdermal gel preparation provided in Comparative Example 4 is as follows Fig. 9 shown.

[0126] Depend on Figures 1 to 9 It can be seen that the transdermal gel preparation provided by the embodiment has a high cumulative permeation rate within 2 hours (>25%) and a large cumulative permeation rate within 6 hours (70% to 95%), which effectively increases the blood drug concentration, while the cumulative permeation amount of Comparative Example 1, Comparative Example 3 and Comparative Example 4 within 2 hours is only 24%, and the cumulative permeation amount of Comparative Example 2 within 6 hours is only 65%, which is far lower than the permeation amount that can be achieved by the embodiment.

[0127] The above is only a preferred specific implementation manner of the present application, but the protection scope of the present application is not limited thereto. Any technician familiar with the technical field can make equivalent substitutions or changes within the technical scope disclosed in the present application according to the technical solution and application concept of the present application, which should be covered by the protection scope of the present application.

Claims

1. A transdermal gel preparation, characterized in that: The composition comprises, by mass percentage, 0.1% to 1% levosimendan metabolite nanocrystals, 1% to 3% matrix material, 1% to 7% penetration enhancer, 10% to 25% solvent, and the balance is water; the matrix material is carbomer, and the penetration enhancer comprises one or more of propylene glycol, menthol or dimethyl sulfoxide.

2. The transdermal gel preparation according to claim 1, characterized in that The average particle size of the levosimendan metabolite nanocrystals is 100nm to 200nm.

3. The transdermal gel preparation according to claim 1, characterized in that The transdermal gel preparation further comprises 0.5% to 1% of a coolant by mass percentage, and the coolant comprises camphor and / or borneol.

4. The transdermal gel preparation according to claim 1, characterized in that The solvent includes ethanol and / or propylene glycol.

5. The transdermal gel preparation according to claim 1, characterized in that The composition comprises, by weight percentage, 0.5% levosimendan metabolite nanocrystals, 2% matrix material, 5% penetration enhancer, 20% solvent, and the balance is water; Or the composition includes, by weight percentage: 1% levosimendan metabolite nanocrystals, 2.8% matrix material, 5% penetration enhancer, 15% solvent, and the balance water; Or the composition comprises, by weight percentage, 0.6% levosimendan metabolite nanocrystals, 1.5% matrix material, 3% penetration enhancer, 15% solvent, and the balance water; Or the composition includes, by weight percentage, 0.5% levosimendan metabolite nanocrystals, 2.2% matrix material, 4% penetration enhancer, 18% solvent, and the balance is water.

6. A method for preparing a transdermal gel preparation according to any one of claims 1 to 5, characterized in that: include: Mixing the matrix material, water and the penetration enhancer, and stirring to obtain a gel matrix; The gel matrix and the levosimendan metabolite nanocrystals are mixed and subjected to ultrasonic treatment to obtain a transdermal gel preparation.

7. The preparation method according to claim 6, characterized in that: The preparation method of the levosimendan metabolite nanocrystal comprises: mixing the levosimendan metabolite with a solvent, stirring to obtain a mixed solution, and homogenizing to obtain the levosimendan metabolite nanocrystal.

8. The preparation method according to claim 7, characterized in that: The number of times of the homogenization treatment is 8 to 15 times; the pressure of the homogenization treatment is 500 bar to 800 bar.

9. The preparation method according to claim 7, characterized in that: The stirring temperature is 35°C to 45°C.

10. The preparation method according to claim 7, characterized in that: The concentration of levosimendan metabolites in the mixed solution is 3% to 8%.

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