Difalin acetate cream and preparation method thereof

Abstract

The present invention discloses a difaline acetate cream and a preparation method thereof. The cream comprises the following components in percentage by mass: 0.1% to 2% difaline acetate, 5% to 20% matrix, 15% to 45% moisturizer, 5% to 20% emulsifier, 2% to 5% preservative, 0% to 30% thickener, and 20% to 70% solvent. The auxiliary materials used in the present invention are simple and easy to obtain, and the preparation method is simple. The difaline acetate cream is used to treat moderate to severe itching associated with chronic kidney disease in adults receiving hemodialysis, has good stability, and is convenient for patients to use.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and particularly relates to a difacillin acetate cream and a preparation method thereof. Background Art

[0002] CKD-aP, also known as uremic pruritus, is a common generalized itch that affects more than 60% of CKD patients undergoing HD. Approximately 20% to 40% of patients report moderate to severe pruritus associated with CKD. Intense generalized pruritus is often distressing for patients and is associated with poor sleep quality, depression, decreased quality of life, increased risk of infection, and increased risk of death. In Canada, an estimated 70% of adult patients undergoing dialysis experience CKD-related pruritus, according to the International Observational Dialysis Outcomes and Practice Patterns Study.

[0003] Patients with moderate to severe CKD-aP who are undergoing HD express a need for treatments that relieve pruritus, reduce the number of office visits and the amount of overall medication required, improve health-related quality of life (e.g., sleep quality and reduce sleep disturbances), and reduce side effects.

[0004] Currently, Difelikefalin is a selective κ opioid receptor agonist on the market and has been approved by Health Canada for the treatment of CKD-aP in adult HD patients. It is used clinically by injection. Because injection is inconvenient for clinical patients to use, and at the same time, for CKD-aP patients, a route of administration that directly contacts the itchy skin area can be developed, which is more convenient for clinical medication. Therefore, for CKD-aP patients who are undergoing HD, in order to relieve itching and reduce the number of visits, it is urgent to develop new dosage forms for clinical medication. Summary of the invention

[0005] The purpose of the present invention is to provide a new treatment option for CKD-aP patients. A difacillin acetate cream is developed, which is uniformly mixed with a suitable matrix to prepare a semi-solid external preparation powder with a certain consistency, which has the characteristics of directly acting on the itchy part, taking effect quickly, being convenient for clinical use, and being easy to control the dosage.

[0006] The difaline acetate cream comprises the following components in percentage by mass: 0.1% to 2% of difaline acetate, 5% to 20% of a base, 15% to 45% of a moisturizer, 5% to 20% of an emulsifier, 2% to 5% of a preservative, 0% to 30% of a thickener, and 20% to 70% of a solvent.

[0007] Furthermore, the matrix is ​​selected from one or more of stearyl alcohol, polyethylene glycol 4000, and white vaseline; and the solvent is water.

[0008] Furthermore, the moisturizing agent is selected from one or more of Tween 80, propylene glycol and glycerin.

[0009] Furthermore, the emulsifier is selected from one or more of stearic acid, geranyl butyrate, glucose-δ-lactone, and sodium lauryl sulfate.

[0010] Furthermore, the preservative is benzyl alcohol and / or methylparaben.

[0011] Furthermore, the thickener is selected from one or more of glyceryl monostearate, α-cyclodextrin, sodium starch phosphate, and sodium carboxymethyl cellulose.

[0012] The preparation method of difacillin acetate cream comprises the following steps:

[0013] (1) Heat the base, emulsifier and thickener until they are melted and stir evenly to obtain system ①;

[0014] (2) heating the moisturizer, the solvent and the preservative to 70-80° C. and stirring evenly to obtain system ②;

[0015] (3) At 70-75° C., the system ① and the system ② are mixed and stirred, and then dimethoate acetate is added for homogenization. After the homogenization is completed, the mixture is transferred to a cold water bath and cooled to below 25° C. to obtain the product.

[0016] In step (1) of the above method, the melting temperature is 70-75°C.

[0017] In step (2) of the above method, the stirring conditions are: 200-350 rpm, and stirring for at least 20 minutes.

[0018] In step (3) of the above method, the homogenization conditions are: 2000-3000 r / min for 10-20 min.

[0019] The medication principle of the difalan acetate cream of the present invention is that the difalan acetate cream is directly applied to the itchy parts of CKD-aP patients. The active pharmaceutical ingredient difalan acetate can directly bind to the skin kappa-opioid receptors to exert its effect. On the other hand, difalan acetate can penetrate into the capillaries in the dermis, enter the blood circulation to participate in the body circulation, and bind to the kappa-opioid receptors to exert its effect. Due to partial loss in the percutaneous penetration process, the amount of difalan acetate used in the cream is larger than that of the injection.

[0020] Beneficial effects of the present invention: The cream prepared by the present invention can be directly applied to the itchy part of CKD-aP patients to quickly relieve itching and reduce the number of visits to the doctor. Combined with the high efficiency and safety characteristics of difacillin acetate itself, the developed difacillin acetate cream fills the market gap, facilitates the use of drugs by patients, and has broad market prospects. DETAILED DESCRIPTION

[0021] The present invention is further described below in conjunction with specific examples, but the present invention is not limited to the following examples. The methods described are conventional methods unless otherwise specified. The raw materials described can be obtained from public commercial channels unless otherwise specified. Example 1

[0022] A difacillin acetate cream, comprising the following substances in percentage by weight:

[0023]

[0024] The preparation method is as follows:

[0025] (1) Heat monostearate, α-cyclodextrin, stearic acid and white vaseline to 72°C to melt, and stir evenly to obtain system ①;

[0026] (2) Heat Tween 80, water and benzyl alcohol to 75°C and stir evenly to obtain system ②;

[0027] (3) At 72°C, add system ② into system ① and stir at 300 rpm for 40 min. Add dimethoate acetate and start homogenizing stirring (2000 r / min). Homogenize for 15 min. Transfer to a cold water bath and cool to below 25°C. Dispense. Example 2

[0028] A difacillin acetate cream, comprising the following substances in percentage by weight:

[0029]

[0030] The preparation method is as follows:

[0031] (1) Heat sodium starch phosphate, sodium carboxymethyl cellulose, stearic acid and white vaseline to 70°C to melt, and stir evenly to obtain system ①;

[0032] (2) Heat Tween 80, water and benzyl alcohol to 70°C and stir evenly to obtain system ②;

[0033] (3) At 70°C, add system ② into system ①, start stirring at 200 rpm, stir for 30 min, add dimethoate acetate, start homogenizing stirring (2500 r / min), homogenize for 15 min, transfer to a cold water bath, cool to below 25°C, and package. Example 3

[0034] A difacillin acetate cream, comprising the following substances in percentage by weight:

[0035]

[0036] The preparation method is as follows:

[0037] (1) Heat sodium carboxymethyl cellulose, geranyl butyrate, glucose delta-lactone and stearyl alcohol to 75°C to melt, and stir evenly to obtain system ①;

[0038] (2) Heat propylene glycol, water and benzyl alcohol to 80°C and stir evenly to obtain system ②;

[0039] (3) At 75°C, add system ② into system ① and stir at 350 rpm for 30 min. Add dimethoate acetate and start homogenizing (3000 r / min). Homogenize for 15 min. Transfer to a cold water bath and cool to below 25°C. Dispense. Example 4

[0040] A difacillin acetate cream, comprising the following substances in percentage by weight:

[0041]

[0042] The preparation method is as follows:

[0043] (1) Heat glyceryl monostearate, stearic acid and polyethylene glycol 4000 to 73°C to melt, and stir evenly to obtain system ①;

[0044] (2) Heat glycerin, water and methylparaben to 76°C and stir evenly to obtain system ②;

[0045] (3) At 73°C, add system ② into system ①, start stirring at 280 rpm, stir for 50 min, add difalanyl acetate, start homogenizing stirring (2300 r / min), homogenize for 20 min, transfer to a cold water bath, cool to below 25°C, and package. Comparative Example 1

[0046] A difacillin acetate cream, comprising the following substances in percentage by weight:

[0047]

[0048] The preparation method is as follows:

[0049] (1) Heat monostearate, stearic acid and white vaseline to 72°C to melt, and stir evenly to obtain system ①;

[0050] (2) Heat Tween 80, water and benzyl alcohol to 75°C and stir evenly to obtain system ②;

[0051] (3) At 72°C, add system ② into system ① and stir at 300 rpm for 40 min. Add dimethoate acetate and start homogenizing stirring (2000 r / min). Homogenize for 15 min. Transfer to a cold water bath and cool to below 25°C. Dispense. Comparative Example 2

[0052] A difacillin acetate cream, comprising the following substances in percentage by weight:

[0053]

[0054] The preparation method is as follows:

[0055] (1) Heat α-cyclodextrin, stearic acid and white vaseline to 72°C to melt, and stir evenly to obtain system ①;

[0056] (2) Heat Tween 80, water and benzyl alcohol to 75°C and stir evenly to obtain system ②;

[0057] (3) At 72°C, add system ② into system ① and stir at 300 rpm for 40 min. Add dimethoate acetate and start homogenizing stirring (2000 r / min). Homogenize for 15 min. Transfer to a cold water bath and cool to below 25°C. Dispense. Comparative Example 3

[0058] A difacillin acetate cream, comprising the following substances in percentage by weight:

[0059]

[0060] The preparation method is as follows:

[0061] (1) Heat sodium starch phosphate, stearic acid and white vaseline to 70°C to melt, and stir evenly to obtain system ①;

[0062] (2) Heat Tween 80, water and benzyl alcohol to 70°C and stir evenly to obtain system ②;

[0063] (3) At 70°C, add system ② into system ①, start stirring at 200 rpm, stir for 30 min, add dimethoate acetate, start homogenizing stirring (2500 r / min), homogenize for 15 min, transfer to a cold water bath, cool to below 25°C, and package. Comparative Example 4

[0064] A difacillin acetate cream, comprising the following substances in percentage by weight:

[0065]

[0066] The preparation method is as follows:

[0067] (1) Heat sodium carboxymethyl cellulose, stearic acid and white vaseline to 70°C to melt and stir evenly to obtain system ①;

[0068] (2) Heat Tween 80, water and benzyl alcohol to 70°C and stir evenly to obtain system ②;

[0069] (3) At 70°C, add system ② into system ①, start stirring at 200 rpm, stir for 30 min, add dimethoate acetate, start homogenizing stirring (2500 r / min), homogenize for 15 min, transfer to a cold water bath, cool to below 25°C, and package. Comparative Example 5

[0070] A difacillin acetate cream, comprising the following substances in percentage by weight:

[0071]

[0072] The preparation method is as follows:

[0073] (1) Heat sodium carboxymethyl cellulose, geranyl butyrate and stearyl alcohol to 75°C to melt, and stir evenly to obtain system ①;

[0074] (2) Heat propylene glycol, water and benzyl alcohol to 80°C and stir evenly to obtain system ②;

[0075] (3) At 75°C, add system ② into system ① and stir at 350 rpm for 30 min. Add dimethoate acetate and start homogenizing (3000 r / min). Homogenize for 15 min. Transfer to a cold water bath and cool to below 25°C. Dispense. Comparative Example 6

[0076] A difacillin acetate cream, comprising the following substances in percentage by weight:

[0077]

[0078] The preparation method is as follows:

[0079] (1) Heat sodium carboxymethyl cellulose, glucose delta-lactone and stearyl alcohol to 75°C to melt, and stir evenly to obtain system ①;

[0080] (2) Heat propylene glycol, water and benzyl alcohol to 80°C and stir evenly to obtain system ②;

[0081] (3) At 75°C, add system ② into system ① and stir at 350 rpm for 30 min. Add dimethoate acetate and start homogenizing (3000 r / min). Homogenize for 15 min. Transfer to a cold water bath and cool to below 25°C. Dispense.

[0082] Experimental Example 1:

[0083] Observe the appearance by visual inspection; take an appropriate amount of cream and put it in a dish, place it in bright light for observation, and observe that the cream should be a white cream. At the same time, measure the viscosity, spreadability, coating properties, and greasy feel. The results are shown in Table 1.

[0084] Table 1

[0085]

[0086] Experimental Example 2:

[0087] Using Examples 1-3 and Comparative Examples 1-6 as experimental objects, the stability of difacillin acetate cream was investigated (under 25°C conditions, 6 months), and the related indicators were investigated: total impurities%, content% (the content of difacillin acetate relative to the initial feed). The experimental results were statistically analyzed using SPSS 24.0 software, and the quantitative data results were expressed as `x±(mean±standard deviation). The Kolmogorov-Smirnov test method was used for data normality test. For data that conformed to the normal distribution, the mean difference between the two groups was compared using a t-test, and P<0.05 was considered statistically significant. The measurement results are shown in Table 2-4:

[0088] Table 2

[0089]

[0090] Table 3

[0091]

[0092] Table 4

[0093]

[0094] It can be seen from the data in the table that the quality stability of difacillin acetate in the formulations of Examples 1-3 at 25° C. is good within 6 months.

[0095] Experimental Example 3:

[0096] Clinical case 1-2 was followed up as follows: Taking the cream prepared in Example 1 as an example, it was applied to the cleansed affected area once a day, morning and evening;

[0097] Case 1: A 30-year-old male patient came to the hospital with the chief complaint of "local ulcers on the waist for 7 days". Dermatology examination upon admission: the local integrity of one side of the waist was damaged, the epidermis peeled off, and blisters and ulcers appeared. The itching was moderate. On the 4th day of treatment, the blisters on one side of the waist subsided, most of the ulcers gradually became smaller, the epidermis peeled off, and the itching was significantly relieved. Vital signs were stable. On the 5th day of treatment, the blisters on one side of the waist basically disappeared, there was no peeling on the surface, and the patient reported no itching. The body temperature was 36.6℃, the blood pressure was 118 / 83mmHg, and no abnormalities were found during physical examination. On the 8th day of treatment, the skin on the waist returned to normal.

[0098] Case 2: Male patient, 28 years old, came to the hospital with the chief complaint of "back erythema for 2 days". Dermatology examination upon admission: erythema appeared on the local skin of the back, with black dry scabs or visible subcutaneous fat. Severe itching. On the third day of treatment, the erythema on the back faded, the black dry scabs gradually fell off, the subcutaneous surface gradually returned to flatness, and the itching was moderate. Vital signs were stable. On the fourth day of treatment, the erythema on the back subsided, all the dry scabs fell off and became flat, the subcutaneous surface was basically flat, and the patient reported no itching. The body temperature was 36.6℃, the blood pressure was 121 / 84mmHg, and no abnormalities were found in the physical examination. On the fifth day of treatment, the skin on the back turned white and returned to normal.

[0099] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. A difacillin acetate cream, characterized in that, The following weight percentages of substances Composition: 1% difascic acid glyceryl monostearate, 2% α-cyclodextrin, 5% stearic acid, 5% white vaseline, 15% Tween 80, 67% water, 3% benzyl alcohol; the preparation method is as follows: heat monofascic acid glyceryl monostearate, α-cyclodextrin, stearic acid and white vaseline to 72°C to melt, stir evenly to obtain system ①; heat Tween 80, water and benzyl alcohol to 75°C, stir evenly to obtain system ②; under the condition of 72°C, add system ② into system ①, start stirring at 300 rpm, stir for 40 minutes, add difascic acid glyceryl monostearate, start homogenization stirring at 2000 r / min, homogenize for 15 minutes, transfer to a cold water bath to cool to below 25°C, and package; Alternatively, the following weight percentages of substances Composition: 2% difamoyl acetate, 4% sodium starch phosphate, 4% sodium carboxymethyl cellulose, 8% stearic acid, 10% white vaseline, 20% Tween 80, 48% water, 4% benzyl alcohol; the preparation method is as follows: heat sodium starch phosphate, sodium carboxymethyl cellulose, stearic acid and white vaseline to 70°C to melt, stir evenly to obtain system ①; heat Tween 80, water and benzyl alcohol to 70°C, stir evenly to obtain system ②; add system ② into system ① at 70°C, start stirring at 200 rpm, stir for 30 minutes, add difamoyl acetate, start homogenizing stirring at 2500 r / min, homogenize for 15 minutes, transfer to a cold water bath to cool to below 25°C, and package; Alternatively, the following weight percentages of substances Composition: 1% difacoum acetate, 20% sodium carboxymethyl cellulose, 7.5% geranyl butyrate, 7.5% glucose delta lactone, 6% stearyl alcohol, 35% propylene glycol, 2% benzyl alcohol, and 21% water; the preparation method is as follows: heat sodium carboxymethyl cellulose, geranyl butyrate, glucose delta lactone and stearyl alcohol to 75°C to melt, stir evenly to obtain system ①; heat propylene glycol, water and benzyl alcohol to 80°C, stir evenly to obtain system ②; at 75°C, add system ② into system ①, start stirring at 350rpm, stir for 30min, add difacoum acetate, start homogenizing stirring at 3000r / min, homogenize for 15min, transfer to a cold water bath to cool to below 25°C, and package.

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