Melagatran cream and method of preparation and use thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations and relates to a meloxicam cream as well as a preparation method and application thereof.The meloxicam cream comprises meloxicam and a transdermal accelerant, and the mass ratio of the meloxicam and the transdermal accelerant is (0.5-5):(1-8); the transdermal accelerant is selected from one or more of azone, propylene glycol, menthol and oleic acid.The application expands the dosage form selection of meloxicam, avoids the liver first-pass effect and systemic side effects of oral administration, improves the local drug concentration and treatment effect, has a high in-vitro transdermal rate, and enables the drug to effectively penetrate the skin barrier and reach an effective treatment concentration in local tissues; the application has significant treatment effects on diabetic neuropathic pain and neurodermatitis, realizes a technical breakthrough of simultaneously treating the two diseases by using a single active ingredient, and has a simple preparation process, stable and controllable quality, convenient use for patients and good compliance.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and relates to a melogabalin cream, its preparation method and application. Background Technology

[0002] Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes, with diabetic peripheral neuropathic pain (DPNP) severely impacting patients' quality of life. Mirogabalin, a gamma-aminobutyric acid (GABA) analogue, exerts its analgesic effect by selectively binding to the α2δ subunit of voltage-dependent presynaptic calcium channels, reducing the excessive release of excitatory neurotransmitters. Compared to similar drugs such as gabapentin and pregabalin, mirogabalin offers advantages such as a lower risk of central nervous system side effects and a simpler dosing regimen.

[0003] Currently, all commercially available melogabalin preparations are oral solid dosage forms, which have the following shortcomings: (1) Oral administration requires absorption through the gastrointestinal tract and the first-pass effect of the liver, thus limiting bioavailability; (2) Oral administration may cause systemic side effects such as dizziness and drowsiness; (3) Daily medication adherence needs to be improved.

[0004] Neurodermatitis is a common chronic skin disease characterized by intense itching and lichenification of the skin. Its pathogenesis involves a neuroimmune inflammatory response. Current topical treatments mainly include glucocorticoids and calcineurin inhibitors, but long-term use carries risks such as hormone dependence, skin atrophy, or local immunosuppression.

[0005] Currently, there are no reports of merogabaline being formulated as a topical cream for the simultaneous treatment of diabetic neuropathy and neurodermatitis. Summary of the Invention

[0006] The main objective of this invention is to overcome the technical defects of existing melogabalin, which is only available in oral formulations, has systemic side effects, and has limited application scope, and to provide a melogabalin cream, its preparation method, and its application.

[0007] To achieve the above objectives, the specific technical solution is as follows: The present invention provides a melogabalin cream comprising melogabalin and a transdermal penetration enhancer, wherein the mass ratio of melogabalin to the transdermal penetration enhancer is (0.5~5):(1~8). The transdermal penetration enhancer is selected from one or more of azone, propylene glycol, menthol, and oleic acid.

[0008] The merogabalin cream of this invention has a high in vitro transdermal rate, which can effectively penetrate the skin barrier and act locally on target tissues, while expanding its indications to include diabetic neuropathy and neurodermatitis.

[0009] Furthermore, the melogabalin is present in the cream at a weight percentage of 0.5% to 5%, and / or the transdermal penetration enhancer is present in the cream at a weight percentage of 1% to 8%.

[0010] The active ingredient merogabarine in the cream of this invention, within the above-mentioned concentration range, achieves its minimum effective blood concentration at 2 hours, reaches a plateau of peak blood concentration between 4 and 8 hours, and shows a decreasing trend between 8 and 12 hours, but remains above the minimum effective concentration within 12 hours. The transdermal penetration enhancer in the cream of this invention, within the above-mentioned concentration range, is within the maximum dosage range specified by the FDA for inactive ingredients. Furthermore, within the above-mentioned dosage range, the transdermal penetration enhancer exhibits optimal transdermal penetration enhancement for the active ingredient merogabarine, while simultaneously not causing skin irritation.

[0011] Furthermore, the transdermal penetration enhancer is composed of azone and propylene glycol, wherein the mass ratio of azone to propylene glycol is 1:2 to 5; preferably, the weight percentage of azone in the cream is 1% to 3%, and the weight percentage of propylene glycol in the cream is 2% to 6%.

[0012] This invention uses azone and propylene glycol in a certain mass ratio as a transdermal penetration enhancer. The two have a synergistic transdermal effect, which can further improve the skin penetration rate of melogabalin. Compared with a single transdermal penetration enhancer, it has a better transdermal effect and can better meet the efficacy requirements of drug administration.

[0013] Furthermore, the melogabalin is melogabalin benzylsulfonic acid.

[0014] Furthermore, the melogabalin cream, by weight, comprises the following components: Merogabalin 0.5 to 5 parts, transdermal penetration enhancer 1 to 8 parts, oil phase matrix 10 to 35 parts, emulsifier 2 to 10 parts, moisturizer 5 to 20 parts, preservative 0.1 to 0.5 parts.

[0015] Furthermore, the melogabalin cream satisfies at least one of the following (A) to (D): (A) The oil phase matrix is ​​selected from one or more of stearic acid, glyceryl monostearate, white petrolatum, liquid paraffin, cetyl alcohol, and octadecanol; (B) The emulsifier is selected from one or more of sodium dodecyl sulfate, polysorbate-80, poloxamer, and triethanolamine; (C) The moisturizer is selected from one or more of glycerin, propylene glycol, and sorbitol; (D) The preservative is selected from one or more of ethylparaben, propylparaben, and phenoxyethanol.

[0016] Preferably, the oil phase matrix is ​​a mixture of stearic acid, glyceryl monostearate, white petrolatum, and liquid paraffin.

[0017] The ointment obtained by this invention, which is a mixture of stearic acid, glyceryl monostearate, white petrolatum, and liquid paraffin, has better performance. It results in an ointment with moderate viscosity, yield stress, and linear viscoelastic region, providing a better feel on the skin. It is less prone to flowing when not in use, making it easy to store, and easy to apply with good spreadability.

[0018] Preferably, the emulsifier is composed of triethanolamine and sodium dodecyl sulfate.

[0019] This invention uses a combination of triethanolamine and sodium dodecyl sulfate as emulsifiers, which has a significant advantage in emulsifying creams compared to using either one alone. This results in creams with smaller droplet sizes, moderate viscosity, and improved skin feel and spreadability.

[0020] In one specific embodiment of the present invention, a melogabalin cream comprises, by weight percentage, the following components: Merogabalin benzenesulfonic acid 1%~3%; stearic acid 8%~15%; glyceryl monostearate 3%~8%; white petrolatum 3%~8%; liquid paraffin 2%~6%; triethanolamine 0.5%~2%; sodium dodecyl sulfate 0.5%~1.5%; azone 1%~3%; propylene glycol 2%~6%; glycerin 5%~15%; ethylparaben 0.1%~0.3%; water balance.

[0021] This invention utilizes a cream formulated with these ingredients, where the various components work synergistically to enhance the transdermal absorption efficiency of merogabalin. This allows the drug to effectively penetrate the skin barrier and achieve a therapeutic concentration in the local tissue. Furthermore, the cream has a uniform and fine texture, consistent particle size distribution, and excellent stability, making it suitable for long-term storage.

[0022] The present invention also provides a method for preparing the above-mentioned melogabalin cream, comprising the following steps: (1) Preparation of oil phase: Heat the oil phase matrix to 70~85℃, stir until completely melted, add melogabalin and transdermal accelerator, stir evenly to obtain oil phase; (2) Preparation of aqueous phase: Mix water, humectant, emulsifier and preservative, heat to 70~85℃, stir to completely dissolve, and obtain aqueous phase; (3) Emulsification: Under stirring conditions, the aqueous phase is slowly added to the oil phase, the temperature is maintained at 70~85℃, and the mixture is stirred and emulsified for 10~30 minutes; (4) Cooling: Stop heating and continue stirring to cool to room temperature.

[0023] The preparation method of the present invention is simple and controllable, with mild temperature conditions in each step, and does not require special or complex equipment, making it suitable for large-scale industrial production.

[0024] Furthermore, in step (3), the stirring speed is 5000~15000 rpm, and the emulsification time is 5~15 minutes.

[0025] The present invention further provides the use of the above-mentioned melogabalin cream in the preparation of a medicament for treating diabetic neuralgia and / or neurodermatitis.

[0026] The cream of this invention has significant therapeutic effects on diabetic neuralgia and neurodermatitis, achieving a technological breakthrough in treating two diseases simultaneously with a single active ingredient.

[0027] Compared with the prior art, the present invention has the following significant advantages: This invention is the first to prepare meregabrine as a topical cream, which expands the dosage form options for meregabrine, avoids the first-pass effect of the liver and systemic side effects of oral administration, and improves local drug concentration and therapeutic effect.

[0028] The merogabalin cream prepared by this invention has a high in vitro transdermal rate, and the drug can effectively penetrate the skin barrier to achieve an effective therapeutic concentration in local tissues.

[0029] The cream of this invention has significant therapeutic effects on diabetic neuralgia and neurodermatitis, achieving a technological breakthrough in treating two diseases simultaneously with a single active ingredient.

[0030] The ointment preparation process of this invention is simple, the quality is stable and controllable, it is convenient for patients to use, and the compliance is good. Attached Figure Description

[0031] To more clearly illustrate the technical solutions in this invention or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0032] Figure 1 This is a graph showing the average in vitro transdermal-cumulative permeation rate of merogabalone cream in Examples 1-5 and Comparative Example 1 of this invention. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Obviously, the described embodiments are only some embodiments of this invention, not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0034] The terms "preferred," "further preferred," and "more preferred" used in this invention, followed by technical features, constitute preferred embodiments of the invention in a specific aspect, but should not be construed as limiting the scope of protection. When the preferred definitions at each level are combined in a progressive relationship, the degree of preference increases progressively.

[0035] In this invention, the technical features described in an open-ended manner include both closed-ended technical solutions composed of the listed features and open-ended technical solutions that include the listed features.

[0036] In this invention, numerical ranges are involved. Unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0037] The technical solution of the present invention will be described in detail below through embodiments and comparative examples. It should be noted that the following embodiments are only used to help understand the technical solution of the present invention and do not constitute any limitation on the scope of protection of the present invention.

[0038] Unless otherwise specified, specific techniques or conditions in the embodiments of this invention shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Devices, instruments, reagents, etc., whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels. All raw materials used in this invention are readily available in the domestic market.

[0039] Example 1 This embodiment provides a melogabalin cream and its preparation method. The melogabalin cream, by mass percentage, consists of the following components: Merogabalin benzenesulfonic acid 2.0%; stearic acid 12%; glyceryl monostearate 5%; white petrolatum 5%; liquid paraffin 4%; triethanolamine 1%; sodium dodecyl sulfate 1%; azone 2%; propylene glycol 5%; glycerin 10%; ethylparaben 0.2%; water balance.

[0040] The present invention also provides a method for preparing the above-mentioned melogabalin cream, comprising the following steps: (1) Preparation of oil phase: Stearic acid, glyceryl monostearate, white petrolatum and liquid paraffin are placed in a water bath and heated to 80°C. Stir until completely melted, add melogabalin benzenesulfonic acid and azone, stir evenly to obtain oil phase; (2) Preparation of aqueous phase: Water, glycerol, triethanolamine, sodium dodecyl sulfate and ethylparaben are mixed, heated to 80°C and stirred until completely dissolved to obtain aqueous phase; (3) Emulsification: Under stirring conditions, the aqueous phase is slowly added to the oil phase, the temperature is kept at 80℃, and a high-speed shear emulsifier is used to emulsify at 10000rpm for 10 minutes; (4) Cooling: Stop heating, continue stirring and cool to room temperature to obtain melogabalin cream.

[0041] Example 2 This embodiment provides a melogabalin cream and its preparation method. The melogabalin cream, by mass percentage, consists of the following components: Merogabalin benzenesulfonic acid 1.0%; stearic acid 10%; glyceryl monostearate 4%; white petrolatum 4%; liquid paraffin 3%; triethanolamine 0.8%; sodium dodecyl sulfate 0.8%; azone 1.5%; propylene glycol 8%; glycerin 8%; ethylparaben 0.15%; water balance.

[0042] The present invention also provides a method for preparing the above-mentioned melogabalin cream, which is the same as in Example 1, and will not be repeated here.

[0043] Example 3 This embodiment provides a melogabalin cream and its preparation method. The melogabalin cream, by mass percentage, consists of the following components: Merogabalin benzyl sulfonate 3.0%, stearic acid 14%, glyceryl monostearate 6%, white petrolatum 6%, liquid paraffin 5%, triethanolamine 1.5%, sodium lauryl sulfate 1.2%, azone 2.5%, propylene glycol 6%, glycerin 12%, ethylparaben 0.25%, water balance.

[0044] The present invention also provides a method for preparing the above-mentioned melogabalin cream, which is the same as in Example 1, and will not be repeated here.

[0045] Example 4 This embodiment provides a melogabalin cream and its preparation method. Compared with Example 1, the only difference is that the composition of the transdermal penetration enhancer in the melogabalin cream is different. The transdermal penetration enhancer in this embodiment contains only 7.0% propylene glycol and does not contain azone.

[0046] Example 5 This embodiment provides a melogabalin cream and its preparation method. Compared with Example 1, the only difference is that the composition of the transdermal penetration enhancer in the melogabalin cream is different. The transdermal penetration enhancer in this embodiment contains only 7.0% azone and does not contain propylene glycol.

[0047] Example 6 This embodiment provides a melogabalin cream and its preparation method. Compared with Example 1, the only difference is that the composition of the oil phase matrix in the melogabalin cream is different. The oil phase matrix of this embodiment does not include glyceryl monostearate, but is composed of 14% stearic acid, 8% white petrolatum and 4% liquid paraffin.

[0048] Example 7 This embodiment provides a melogabalin cream and its preparation method. Compared with Example 1, the only difference is that the composition of the oil phase matrix in the melogabalin cream is different. The oil phase matrix of this embodiment does not include stearic acid and is composed of 9% glyceryl monostearate, 10% white petrolatum and 7% liquid paraffin.

[0049] Example 8 This embodiment provides a melogabalin cream and its preparation method. Compared with Example 1, the only difference is that the composition of the oil phase matrix in the melogabalin cream is different. The oil phase matrix in this embodiment does not include white petrolatum and is composed of 13% stearic acid, 7% glyceryl monostearate and 6% liquid paraffin.

[0050] Example 9 This embodiment provides a melogabalin cream and its preparation method. Compared with Example 1, the only difference is that the composition of the emulsifier in the melogabalin cream is different. The emulsifier in this embodiment does not include triethanolamine and only contains 2% sodium dodecyl sulfate.

[0051] Example 10 This embodiment provides a melogabalin cream and its preparation method. Compared with Example 1, the only difference is that the composition of the emulsifier in the melogabalin cream is different. The emulsifier in this embodiment does not include sodium dodecyl sulfate and only contains 2% triethanolamine.

[0052] Comparative Example 1 This comparative example provides a melogabalin cream and its preparation method. The only difference from Example 1 is that the composition of the transdermal penetration enhancer in the melogabalin cream is different. No transdermal penetration enhancer is added in this example.

[0053] Comparative Example 2 This comparative example provides a meregabrine cream and its preparation method. The only difference from Example 1 is that the mass ratio of meregabrine to the transdermal penetration enhancer is 1:0.5.

[0054] Comparative Example 3 This comparative example provides a melogabalin cream and its preparation method. The only difference from Example 1 is that the transdermal penetration enhancer used is sodium lauryl sulfate, and the dosage is 7%.

[0055] Comparative Example 4 This comparative example provides a melogabalin cream and its preparation method. The only difference from Example 1 is that the oil phase matrix used is beeswax, paraffin, hydrogenated vegetable oil, and lanolin, with the dosages of the ingredients being 5%, 3%, 11%, and 7%, respectively.

[0056] Comparative Example 5 This comparative example provides a melogabalin cream and its preparation method. The only difference from Example 1 is that the emulsifier used is cocamidopropyl betaine, and the dosage is 2%.

[0057] In vitro transdermal tests were conducted on the merogabalone creams of Examples 1-5 and Comparative Examples 1-3 of this invention. The test method was as follows: using the Franz diffusion cell method, isolated mouse skin was used as the transdermal barrier, and PBS (pH 7.4) was used as the receiving solution. The creams prepared in Examples 1-3 and Examples 4-6 were administered, and samples were taken at different time points. The cumulative permeation amount of merogabalone in the receiving solution was determined by HPLC, and the cumulative permeation amount over 24 hours was calculated. The test results are shown in Table 1 and... Figure 1 As shown.

[0058] Table 1

[0059] As shown in Table 2, the meregabalin creams prepared in the embodiments of this invention all exhibit high in vitro transdermal permeability, with a significantly higher cumulative permeation amount over 24 hours compared to Comparative Example 1, which did not contain a transdermal permeability enhancer. Furthermore, the meregabalin creams prepared in Examples 1-3, which simultaneously added azone and propylene glycol, all showed even higher in vitro transdermal permeability, with a higher cumulative permeation amount over 24 hours than Example 4 (which only added propylene glycol without azone) and Example 5 (which only added azone without propylene glycol). Example 1 demonstrated the best transdermal permeability. This indicates that the optimal in vitro transdermal permeability of this cream is achieved when the transdermal permeability enhancer is a combination of azone and propylene glycol (with azone:propylene glycol ratio of 1:2 to 1:5).

[0060] In Comparative Example 2, the mass ratio of merogabarine to the transdermal penetration enhancer was 1:0.5, which is lower than the proportion of the transdermal penetration enhancer used in the claims of this invention. The cumulative permeation amount of Comparative Example 2 after 24 hours of in vitro transdermal penetration was only 10% of that in Example 1. In Comparative Example 3, the transdermal penetration enhancer used was sodium lauryl sulfate, and the cumulative permeation amount of the resulting cream after 24 hours of in vitro transdermal penetration was only 20% of that in Example 1.

[0061] The properties, viscosity, droplet size, and skin feel of the melogabalin creams of Example 1 and Comparative Examples 4-5 of the present invention were tested using the following methods.

[0062] Appearance: Visual inspection.

[0063] Viscosity: Based on: Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0633, Viscosity Determination Method.

[0064] Droplet size: Take an appropriate amount of sample and place it on a glass slide. Cover the sample with a coverslip to make the sample evenly dispersed. Use a polarizing microscope with a 40x objective to observe and statistically analyze the droplet size in the field of view.

[0065] Skin feel: Eight volunteers were recruited to apply the same dose (approximately 2 mg / cm²) to designated areas on their forearms and backs of hands. 2 The cream was tested under uniform environmental conditions (temperature 20-25℃, relative humidity 40%-60%) and allowed to stand for approximately 15-30 minutes to allow it to adapt. Immediate sensations, absorption process, and post-use skin feel (oilyness, moisturizing, softness, spreadability, whitening, absorption speed, film formation, and drying time, etc.) were evaluated at preset time points. The evaluation data was recorded in a questionnaire.

[0066] The test results are shown in Table 2.

[0067] Table 2

[0068] As shown in Table 2, the color of Comparative Example 4 is darker than that of Example 1, with higher viscosity, larger droplet size, and a greasy feel, making it difficult to spread. Comparative Example 5 has greater fluidity, lower viscosity, larger droplet size, and a smoother texture on the skin than Example 1. The properties, viscosity, droplet size, and skin feel of Example 1 of this invention are all superior to those of Comparative Example 4 and Comparative Example 5.

[0069] The properties, viscosity, and rheological characteristics (yield stress, linear viscoelastic region) of the melogabalin cream in Examples 1, 6-8 were tested using the following methods.

[0070] Appearance: Visual inspection.

[0071] Viscosity: Based on: Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0633, Viscosity Determination Method.

[0072] Rheological properties: measured using a rotational rheometer (manufacturer: Netzsch, model: Kinexus Prime lab+), with a fixture rotor model PU25 L4298 SS, and a measurement temperature of 25℃.

[0073] Yield stress test method: After loading the sample, select the yield stress measurement item in the rotational rheometer operation interface, set the scan time to 90s, and the shear stress range to 0Pa-200Pa.

[0074] Linear viscoelastic region test method: After loading the sample, select the viscoelasticity measurement item in the rotational rheometer operation interface, set the number of sampling points for each order of magnitude to 10, and fix the scanning frequency to 1.592Hz; shear strain 0.1%~100%.

[0075] The test results are shown in Table 3.

[0076] Table 3

[0077] As shown in Table 3, the viscosity, yield stress, and linear viscoelastic region of Example 1 are moderate, indicating that the cream of Example 1 has a good user experience, is not easily flowable and easy to store when not in use, and is easy to apply and spread when used. Examples 6 and 7 have lower viscosity, are prone to flow and are not easy to store, and have poor spreadability during use. Example 8 has higher viscosity, is difficult to apply, and has a poor user experience. This indicates that the cream obtained with an oily matrix of stearic acid, glyceryl monostearate, white petrolatum, and liquid paraffin has better performance. When only three of these substances are present, the cream has poor viscosity and rheological properties, and an overall unpleasant user experience. Therefore, the combination of these four substances as an oily matrix has significant advantages.

[0078] The droplet size, viscosity, and rheological properties (yield stress, linear viscoelastic region) of the melogabalin cream in Examples 1, 9-10 were tested, and the test results are shown in Table 4.

[0079] Table 4

[0080] As shown in Table 4, the droplet size was smallest in Example 1, which used both triethanolamine and sodium lauryl sulfate as emulsifiers. The droplet sizes in Examples 8-1 and 8-2 were larger. Example 1 had moderate viscosity, while the cream prepared using only one emulsifier had lower viscosity, resulting in poorer skin feel and spreadability. This indicates that the combination of triethanolamine and sodium lauryl sulfate as emulsifiers performs better than using either alone, and the combination of triethanolamine and sodium lauryl sulfate as emulsifiers has a significant advantage in emulsifying this cream.

[0081] Pharmacodynamic trials I. Analgesic effect on diabetic neuralgia model rats Experimental Methods: A streptozotocin (STZ)-induced diabetic neuropathy model rat was randomly divided into a model group, a blank cream group, an Example 1 group (merogabalin cream, 2%), and a positive control group (pregabalin oral administration, 30 mg / kg). The treatment groups received the medication once daily for 14 consecutive days. The mechanical pain threshold (Von Frey method) of the rats was measured before administration, on day 7, and on day 14 after administration. The experimental results are shown in Table 5.

[0082] Table 5

[0083] Note: *P<0.05 vs. model group As shown in Table 5, the melogabalin cream of the present invention has a significant analgesic effect on diabetic neuralgia model rats, and its efficacy is comparable to that of the positive control drug pregabalin (P>0.05), and no obvious systemic side effects were observed.

[0084] II. Therapeutic effect on a mouse model of neurodermatitis Experimental Methods: A neurodermatitis model mouse induced by dinitrochlorobenzene (DNCB) was randomly divided into a model group, a blank cream group, an Example 1 group (merogabalin cream, 2%), and a positive control group (0.1% mometasone furoate cream). The treatment groups received the cream twice daily for 14 consecutive days. Skin inflammation scores (erythema, edema, lichenification, on a 0-3 scale) and the number of scratches were observed and recorded. The results are shown in Table 6.

[0085] Table 6

[0086] *P<0.05 vs model group As shown in Table 6, the merogalamine cream of this invention has a significant therapeutic effect on mice with neurodermatitis, effectively reducing skin inflammation scores and scratching behavior. Its efficacy is comparable to that of the positive control drug mometasone furoate cream.

[0087] Stability test Merogabalin cream prepared in Example 1 was placed under high temperature (40°C), high humidity (75%RH), and strong light (4500±500Lx) conditions for 10 days, and the changes in appearance, pH value, content, and related substances of the cream were investigated. The test results are shown in Table 7.

[0088] Table 7

[0089] As shown in Table 7, the melogabalin cream prepared in this invention showed no significant changes in appearance, pH value, content, and related substances after being placed under high temperature, high humidity, and strong light conditions for 10 days, indicating good stability.

[0090] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. A melogabalin cream, characterized in that, It includes merogabaline and a transdermal penetration enhancer, wherein the mass ratio of merogabaline to the transdermal penetration enhancer is (0.5~5):(1~8); The transdermal penetration enhancer is selected from one or more of azone, propylene glycol, menthol, and oleic acid.

2. The melogabalin cream according to claim 1, characterized in that, The melogabalin is present in the cream at a weight percentage of 0.5% to 5%, and / or the transdermal penetration enhancer is present in the cream at a weight percentage of 1% to 8%.

3. The melogabalin cream according to claim 1 or 2, characterized in that, The transdermal penetration enhancer is composed of azone and propylene glycol, wherein the mass ratio of azone to propylene glycol is 1:2 to 5; preferably, the weight percentage of azone in the cream is 1% to 3%, and the weight percentage of propylene glycol in the cream is 2% to 6%.

4. The merogabarine cream according to claim 1, characterized in that, The melogabalin mentioned is melogabalin benzylsulfonic acid.

5. The melogabalin cream according to claim 1, 2, or 4, characterized in that, Based on parts by weight, it includes the following components: Merogabalin 0.5 to 5 parts, transdermal penetration enhancer 1 to 8 parts, oil phase matrix 10 to 35 parts, emulsifier 2 to 10 parts, moisturizer 5 to 20 parts, preservative 0.1 to 0.5 parts.

6. The melogabalin cream according to claim 5, characterized in that, Satisfy at least one of the following (A) to (D): (A) The oil phase matrix is ​​selected from one or more of stearic acid, glyceryl monostearate, white petrolatum, liquid paraffin, cetyl alcohol, and octadecanol; (B) The emulsifier is selected from one or more of sodium dodecyl sulfate, polysorbate-80, poloxamer, and triethanolamine; (C) The moisturizer is selected from one or more of glycerin, propylene glycol, and sorbitol; (D) The preservative is selected from one or more of ethylparaben, propylparaben, and phenoxyethanol.

7. The melogabalin cream according to claim 6, characterized in that, It consists of the following components by weight percentage: Merogabalin benzenesulfonic acid 1%~3%; stearic acid 8%~15%; glyceryl monostearate 3%~8%; white petrolatum 3%~8%; liquid paraffin 2%~6%; triethanolamine 0.5%~2%; sodium dodecyl sulfate 0.5%~1.5%; azone 1%~3%; propylene glycol 2%~6%; glycerin 5%~15%; ethylparaben 0.1%~0.3%; water balance.

8. A method for preparing a melogabalin cream as described in any one of claims 1 to 7, characterized in that, Includes the following steps: (1) Preparation of oil phase: Heat the oil phase matrix to 70~85℃, stir until completely melted, add melogabalin and transdermal accelerator, stir evenly to obtain oil phase; (2) Preparation of aqueous phase: Mix water, humectant, emulsifier and preservative, heat to 70~85℃, stir to completely dissolve, and obtain aqueous phase; (3) Emulsification: Under stirring conditions, the aqueous phase is slowly added to the oil phase, the temperature is maintained at 70~85℃, and the mixture is stirred and emulsified for 10~30 minutes; (4) Cooling: Stop heating and continue stirring to cool to room temperature.

9. The method for preparing merogalamine cream according to claim 8, characterized in that, In step (3), the stirring speed is 5000~15000 rpm and the emulsification time is 5~15 minutes.

10. The use of merogabaline cream as described in any one of claims 1 to 7 in the preparation of a medicament for treating diabetic neuropathy and / or neurodermatitis.

Images