Pharmaceutical composition for treating inflammatory dermatosis and preparation method thereof

Abstract

The invention relates to a pharmaceutical composition for treating inflammatory dermatosis and a preparation method thereof, and the preparation method comprises the following steps: 1) mixing oleyl alcohol, medium chain triglyceride, propylene glycol, hexadecanol and octadecanol, and heating to 65-75 DEG C to form an oil phase; adding pimerolimus and glyceryl monostearate and glyceryl distearate, and stirring to obtain an oil phase; 2) adding anhydrous citric acid, sodium hydroxide and benzyl alcohol into water, and heating to 65-75 DEG C for dissolving; adding cetostearyl sodium sulfate, and stirring to obtain a water phase; 3) pouring the oil phase into the water phase, maintaining the emulsification temperature at 65-75 DEG C, homogenizing and stirring to form an emulsion; and 4) filling and packaging. Wherein the mixed solution is subjected to homogenization treatment at the speed of 3000rpm for 10 minutes, homogenization is stopped, stirring is continued for 5 minutes at the speed of 25rpm, and the mixed solution is subjected to homogenization treatment at the speed of 3000rpm for 10 minutes again. The ratio of the humectant to the thickening agent in the pharmaceutical composition is creatively adjusted, so that the treatment efficiency of the ointment is greatly improved, and the user experience in the application process of the ointment is also remarkably improved.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical technology and relates to a pharmaceutical composition for treating inflammatory skin diseases and its preparation method, specifically to a pimecrolimus cream and its preparation method. Background Technology

[0002] Pimecrolimus, also known as pimecrolimus, has the chemical name (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E)-2-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]-1-methylvinyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxo-4-azatricyclo[22.3.1.04.9]octadec-18-ene-2,3,10,16-tetraone. It is a lipophilic, anti-inflammatory ascomycin macrolactam derivative. It can selectively inhibit the production and release of pro-inflammatory cytokines, exhibiting strong anti-inflammatory activity comparable to that of potent corticosteroids, but without side effects such as skin atrophy.

[0003] Currently, problems such as uneven mixing and bubble formation often occur during the production of pimecrolimus cream, leading to inconsistent ointment content and affecting product quality. To address this, homogenization is often added during emulsification. Specifically, homogenization is a crucial step in cream preparation, directly impacting the particle size distribution and uniformity of the cream. Existing homogenization techniques often employ single-pass homogenization with insufficiently precise control of conditions, resulting in a wide particle size distribution and limited transdermal absorption. For example, patent document (CN117398336A) discloses a pimecrolimus ointment and its preparation method, specifically involving homogenization during emulsification; however, the resulting cream exhibits poor transdermal absorption and antibacterial properties. Furthermore, the emulsifier ratio is also a significant factor affecting cream quality. Emulsifiers not only contribute to a stable cream system but also influence drug release and transdermal absorption to some extent. However, existing emulsifier ratios often fail to adequately consider their impact on cream performance, leading to inconsistent cream quality. Summary of the Invention

[0004] The inventors, through extensive experimentation, discovered that emulsifiers play a crucial role in cream preparation. They can reduce the surface tension between the oil and aqueous phases, allowing them to mix stably to form a cream. The ratio and amount of emulsifier directly affect the stability, viscosity, and appearance of the cream. Insufficient emulsifier or improper ratio can lead to cream separation, poor stability, and consequently, impaired transdermal absorption. Furthermore, the stability of the cream is essential for maintaining the antibacterial effect of its active ingredients (such as pimecrolimus). Unstable creams may cause the active ingredients to become ineffective or degraded, thereby reducing their antibacterial properties. This invention is based on the above findings. Specifically:

[0005] This invention relates to a method for preparing pimecrolimus cream, the method comprising the following steps:

[0006] 1) Oil phase preparation:

[0007] Oily components such as oleyl alcohol, medium-chain triglycerides, propylene glycol, cetyl alcohol, and octadecanol are mixed and heated to 65-75°C to form an oil phase.

[0008] The pimecrolimus active pharmaceutical ingredient was added to the oil phase and stirred until dissolved. Then, glyceryl monostearate and glyceryl distearate were added and stirred to obtain the oil phase.

[0009] 2) Aqueous phase preparation:

[0010] Add the prescribed amounts of anhydrous citric acid, sodium hydroxide, and benzyl alcohol to a measured volume of water, and heat to 65–75°C to dissolve. Add sodium hexadecyl sulfate, stir, and obtain the aqueous phase.

[0011] 3) Emulsification:

[0012] Ensure that the oil phase and water phase are at the same temperature. Pour the preheated oil phase into the water phase while continuously stirring. Use a fine-flow funnel or dripping device to control the flow rate and maintain the emulsification temperature at 65-75°C. Perform homogenization and stirring until an emulsion is formed.

[0013] 4) Filling and Packaging:

[0014] The prepared emulsion is filled into aluminum pharmaceutical ointment tubes, cooled to room temperature, and then sealed to complete the ointment encapsulation process.

[0015] In one specific implementation, in step 3), the homogenization process is performed two or more times.

[0016] As a specific implementation, the homogenization and stirring processes are as follows: the mixture is homogenized at a speed of 3000-5000 rpm for 10-15 minutes, then the homogenization is stopped, and stirring is continued at 20-30 rpm for 5-10 minutes. The mixture is then homogenized again at a speed of 3000-5000 rpm for 5-10 minutes.

[0017] As a specific implementation, the homogenization and stirring processes are as follows: the mixture is homogenized at 3000 rpm for 10 minutes, then homogenization is stopped, stirring is continued at 25 rpm for 5 minutes, and then the mixture is homogenized again at 3000 rpm for 10 minutes.

[0018] As a specific implementation method, the amounts of each component, by weight percentage, are as follows:

[0019] Element Target prescription dosage % pimecrolimus 0.1～0.5 Oil alcohol 8.0～10.0 cetyl alcohol 4.0～5.0 Stearyl alcohol 4.0～5.0 Glyceryl monostearate and glyceryl distearate 2.2～5.0 Sodium hexadecyl sulfate 1.0～1.2 medium-chain triglycerides 15.0～18.0 Propylene glycol 5.0～6.0 Anhydrous citric acid 0.04～0.06 Sodium hydroxide 0.01～0.02 benzyl alcohol 1.0～1.2 Purified water Add to 100

[0020] In one specific embodiment, the weight ratio of the glyceryl monostearate and glyceryl distearate to the sodium cetearyl sulfate is (2.2–5.0):1.

[0021] In one specific embodiment, the weight ratio of the mono- and di-stearyl glycerides to the sodium cetearyl sulfate is (2.5–4):1.

[0022] The present invention also relates to a pimecrolimus cream, which is prepared by the preparation method according to any one of claims 1 to 7.

[0023] Invention Effects

[0024] This invention, through rigorous scientific experimental design and optimization, innovatively adjusts the ratio of humectant to thickener in compound nystatin ointment. This key breakthrough not only greatly enhances the therapeutic efficacy of the ointment but also significantly improves the user experience during its application, specifically in the following aspects:

[0025] Enhance skin permeability:

[0026] This invention, by precisely controlling the ratio of these two components, effectively reduces the surface tension of the ointment, allowing active ingredients such as nystatin to more easily penetrate the stratum corneum and reach the lesion site. This improvement not only accelerates the onset of drug action but also increases treatment efficiency, reduces drug waste, and ensures more comprehensive antibacterial coverage.

[0027] Enhances antibacterial efficacy:

[0028] The optimized moisturizing formula helps maintain a suitable humidity environment for the ointment, which is conducive to the preservation and release of antibacterial ingredients such as nystatin, thereby enhancing its ability to fight against skin pathogens such as fungi and bacteria. At the same time, the appropriate addition of thickeners ensures the evenness of the ointment application and also forms a protective barrier, slowing down further damage to the skin by pathogens and further consolidating the antibacterial effect.

[0029] Improve user experience:

[0030] Another significant advantage of this invention is the marked improvement in the comfort of using the ointment. The appropriate ratio of humectant to thickener makes the ointment texture finer and easier to apply, reducing greasiness and discomfort, and improving patient acceptance and compliance. Furthermore, this ratio helps maintain the stability of the ointment, extends its shelf life, and reduces the risk of reduced efficacy due to drug deterioration.

[0031] Promotes skin repair:

[0032] In addition to its direct antibacterial effects, the optimized moisturizing formula also has certain skin nourishing and repairing functions. It can replenish the moisture and lipids lost by the skin due to illness, promote the restoration of the skin barrier function, reduce adverse reactions such as dryness and peeling during treatment, and accelerate the skin's recovery process. Detailed Implementation

[0033] The technical solutions in the embodiments of this application will be clearly described below with reference to the examples. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0034] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0035] Example 1

[0036] formula

[0037]

[0038]

[0039] Preparation process

[0040] 1) Oil phase preparation:

[0041] Mix the prescribed amount of oily components such as oleyl alcohol, medium-chain triglycerides, propylene glycol, cetyl alcohol, and octadecanol, and heat to 65-75°C to ensure that all components dissolve and form an oil phase.

[0042] The pimecrolimus active pharmaceutical ingredient was added to the oil phase and stirred until dissolved. Then, glyceryl monostearate and glyceryl distearate were added and stirred to obtain the oil phase.

[0043] 2) Aqueous phase preparation:

[0044] Add the prescribed amounts of anhydrous citric acid, sodium hydroxide, and benzyl alcohol to a measured volume of water, and heat to 65–75°C to dissolve. Add sodium cetyl sulfate, stir, and obtain the aqueous phase.

[0045] 3) Emulsification:

[0046] Ensure the oil and water phases are at the same temperature. Slowly pour the preheated oil phase into the water phase while continuously stirring, using a fine-flow funnel or dripping device to control the flow rate. Maintain the emulsification temperature at 70°C to reduce the viscosity of the emulsion and increase its dispersibility. Adjust the stirring speed to 25 rpm to ensure thorough mixing of the oil and water phases. Start the homogenizer and homogenize the mixture at 3000 rpm for 10 minutes. Then stop homogenizing and continue stirring at 25 rpm for 5 minutes. Start the homogenizer again and homogenize the mixture at 3000 rpm for 10 minutes until an emulsion is formed.

[0047] 4) Filling and Packaging:

[0048] The prepared emulsion is filled into aluminum pharmaceutical ointment tubes and cooled to room temperature. The tubes are then sealed to complete the ointment encapsulation process.

[0049] Example 2

[0050] formula

[0051]

[0052] Preparation process

[0053] 1) Oil phase preparation:

[0054] Mix the prescribed amount of oily components such as oleyl alcohol, medium-chain triglycerides, propylene glycol, cetyl alcohol, and octadecanol, and heat to 65-75°C to ensure that all components dissolve and form an oil phase.

[0055] The pimecrolimus active pharmaceutical ingredient was added to the oil phase and stirred until dissolved. Then, glyceryl monostearate and glyceryl distearate were added and stirred to obtain the oil phase.

[0056] 2) Aqueous phase preparation:

[0057] Add the prescribed amounts of anhydrous citric acid, sodium hydroxide, and benzyl alcohol to a measured volume of water, and heat to 65–75°C to dissolve. Add sodium cetyl sulfate, stir, and obtain the aqueous phase.

[0058] 3) Emulsification:

[0059] Ensure the oil and water phases are at the same temperature. Slowly pour the preheated oil phase into the water phase while continuously stirring, using a fine-flow funnel or dripping device to control the flow rate. Maintain the emulsification temperature at 70°C to reduce the viscosity of the emulsion and increase its dispersibility. Adjust the stirring speed to 25 rpm to ensure thorough mixing of the oil and water phases. Start the homogenizer and homogenize the mixture at 3000 rpm for 10 minutes. Then stop homogenizing and continue stirring at 25 rpm for 5 minutes. Start the homogenizer again and homogenize the mixture at 3000 rpm for 10 minutes until an emulsion is formed.

[0060] 4) Filling and Packaging:

[0061] The prepared emulsion is filled into aluminum pharmaceutical ointment tubes and cooled to room temperature. The tubes are then sealed to complete the ointment encapsulation process.

[0062] Example 3

[0063] formula

[0064]

[0065] Preparation process

[0066] 1) Oil phase preparation:

[0067] Mix the prescribed amount of oily components such as oleyl alcohol, medium-chain triglycerides, propylene glycol, cetyl alcohol, and octadecanol, and heat to 65-75°C to ensure that all components dissolve and form an oil phase.

[0068] The pimecrolimus active pharmaceutical ingredient was added to the oil phase and stirred until dissolved. Then, glyceryl monostearate and glyceryl distearate were added and stirred to obtain the oil phase.

[0069] 2) Aqueous phase preparation:

[0070] Add the prescribed amounts of anhydrous citric acid, sodium hydroxide, and benzyl alcohol to a measured volume of water, and heat to 65–75°C to dissolve. Add sodium cetyl sulfate, stir, and obtain the aqueous phase.

[0071] 3) Emulsification:

[0072] Ensure the oil and water phases are at the same temperature. Slowly pour the preheated oil phase into the water phase while continuously stirring, using a fine-flow funnel or dripping device to control the flow rate. Maintain the emulsification temperature at 70°C to reduce the viscosity of the emulsion and increase its dispersibility. Adjust the stirring speed to 25 rpm to ensure thorough mixing of the oil and water phases. Start the homogenizer and homogenize the mixture at 3000 rpm for 10 minutes. Then stop homogenizing and continue stirring at 25 rpm for 5 minutes. Start the homogenizer again and homogenize the mixture at 3000 rpm for 10 minutes until an emulsion is formed.

[0073] 4) Filling and Packaging:

[0074] The prepared emulsion is filled into aluminum pharmaceutical ointment tubes and cooled to room temperature. The tubes are then sealed to complete the ointment encapsulation process.

[0075] Example 4

[0076] formula

[0077]

[0078] Preparation process

[0079] 1) Oil phase preparation:

[0080] Mix the prescribed amount of oily components such as oleyl alcohol, medium-chain triglycerides, propylene glycol, cetyl alcohol, and octadecanol, and heat to 65-75°C to ensure that all components dissolve and form an oil phase.

[0081] The pimecrolimus active pharmaceutical ingredient was added to the oil phase and stirred until dissolved. Then, glyceryl monostearate and glyceryl distearate were added and stirred to obtain the oil phase.

[0082] 2) Aqueous phase preparation:

[0083] Add the prescribed amounts of anhydrous citric acid, sodium hydroxide, and benzyl alcohol to a measured volume of water, and heat to 65–75°C to dissolve. Add sodium cetyl sulfate, stir, and obtain the aqueous phase.

[0084] 3) Emulsification:

[0085] Ensure the oil and water phases are at the same temperature. Slowly pour the preheated oil phase into the water phase while continuously stirring, using a fine-flow funnel or dripping device to control the flow rate. Maintain the emulsification temperature at 70°C to reduce the viscosity of the emulsion and increase its dispersibility. Adjust the stirring speed to 25 rpm to ensure thorough mixing of the oil and water phases. Start the homogenizer and homogenize the mixture at 5000 rpm for 15 minutes. Then stop homogenizing and continue stirring at 25 rpm for 5 minutes. Start the homogenizer again and homogenize the mixture at 5000 rpm for 5 minutes until an emulsion is formed.

[0086] 4) Filling and Packaging:

[0087] The prepared emulsion is filled into aluminum pharmaceutical ointment tubes and cooled to room temperature. The tubes are then sealed to complete the ointment encapsulation process.

[0088] Example 5

[0089] formula

[0090]

[0091]

[0092] Preparation process

[0093] 1) Oil phase preparation:

[0094] Mix the prescribed amount of oily components such as oleyl alcohol, medium-chain triglycerides, propylene glycol, cetyl alcohol, and octadecanol, and heat to 65-75°C to ensure that all components dissolve and form an oil phase.

[0095] The pimecrolimus active pharmaceutical ingredient was added to the oil phase and stirred until dissolved. Then, glyceryl monostearate and glyceryl distearate were added and stirred to obtain the oil phase.

[0096] 2) Aqueous phase preparation:

[0097] Add the prescribed amounts of anhydrous citric acid, sodium hydroxide, and benzyl alcohol to a measured volume of water, and heat to 65–75°C to dissolve. Add sodium cetyl sulfate, stir, and obtain the aqueous phase.

[0098] 3) Emulsification:

[0099] Ensure the oil and water phases are at the same temperature. Slowly pour the preheated oil phase into the water phase while continuously stirring, using a fine-flow funnel or dripping device to control the flow rate. Maintain the emulsification temperature at 70°C to reduce the viscosity of the emulsion and increase its dispersibility. Adjust the stirring speed to 25 rpm to ensure thorough mixing of the oil and water phases. Start the homogenizer and homogenize the mixture at 4000 rpm for 10 minutes. Then stop homogenizing and continue stirring at 30 rpm for 10 minutes. Start the homogenizer again and homogenize the mixture at 4000 rpm for 10 minutes until an emulsion is formed.

[0100] 4) Filling and Packaging:

[0101] The prepared emulsion is filled into aluminum pharmaceutical ointment tubes and cooled to room temperature. The tubes are then sealed to complete the ointment encapsulation process.

[0102] Example 6

[0103] formula

[0104]

[0105]

[0106] Preparation process

[0107] 1) Oil phase preparation:

[0108] Mix the prescribed amount of oily components such as oleyl alcohol, medium-chain triglycerides, propylene glycol, cetyl alcohol, and octadecanol, and heat to 65-75°C to ensure that all components dissolve and form an oil phase.

[0109] The pimecrolimus active pharmaceutical ingredient was added to the oil phase and stirred until dissolved. Then, glyceryl monostearate and glyceryl distearate were added and stirred to obtain the oil phase.

[0110] 2) Aqueous phase preparation:

[0111] Add the prescribed amounts of anhydrous citric acid, sodium hydroxide, and benzyl alcohol to a measured volume of water, and heat to 65–75°C to dissolve. Add sodium cetyl sulfate, stir, and obtain the aqueous phase.

[0112] 3) Emulsification:

[0113] Ensure the oil and water phases are at the same temperature. Slowly pour the preheated oil phase into the water phase while continuously stirring, using a fine-flow funnel or dripping device to control the flow rate. Maintain the emulsification temperature at 70°C to reduce the viscosity of the emulsion and increase its dispersibility. Adjust the stirring speed to 25 rpm to ensure thorough mixing of the oil and water phases. Start the homogenizer and homogenize the mixture at 4000 rpm for 10 minutes. Then stop homogenizing and continue stirring at 30 rpm for 10 minutes. Start the homogenizer again and homogenize the mixture at 4000 rpm for 10 minutes until an emulsion is formed.

[0114] 4) Filling and Packaging:

[0115] The prepared emulsion is filled into aluminum pharmaceutical ointment tubes and cooled to room temperature. The tubes are then sealed to complete the ointment encapsulation process.

[0116] Comparative Example 1

[0117] formula

[0118]

[0119] Preparation process

[0120] 1) Oil phase preparation:

[0121] Mix the prescribed amount of oily components such as oleyl alcohol, medium-chain triglycerides, propylene glycol, cetyl alcohol, and octadecanol, and heat to 65-75°C to ensure that all components dissolve and form an oil phase.

[0122] The pimecrolimus active pharmaceutical ingredient was added to the oil phase and stirred until dissolved. Then, glyceryl monostearate and glyceryl distearate were added and stirred to obtain the oil phase.

[0123] 2) Aqueous phase preparation:

[0124] Add the prescribed amounts of anhydrous citric acid, sodium hydroxide, and benzyl alcohol to a measured volume of water, and heat to 65–75°C to dissolve. Add sodium cetyl sulfate, stir, and obtain the aqueous phase.

[0125] 3) Emulsification:

[0126] Ensure the oil and water phases are at the same temperature. Slowly pour the preheated oil phase into the water phase while continuously stirring, using a fine-flow funnel or dripping device to control the flow rate. Maintain the emulsification temperature at 70°C to reduce the viscosity of the emulsion and increase its dispersibility. Adjust the stirring speed to 25 rpm to ensure thorough mixing of the oil and water phases. Start the homogenizer and homogenize the mixture at 3000 rpm for 10 minutes. Then stop homogenizing and continue stirring at 25 rpm for 5 minutes. Start the homogenizer again and homogenize the mixture at 3000 rpm for 10 minutes until an emulsion is formed.

[0127] 4) Filling and Packaging:

[0128] The prepared emulsion is filled into aluminum pharmaceutical ointment tubes and cooled to room temperature. The tubes are then sealed to complete the ointment encapsulation process.

[0129] Comparative Example 2

[0130] formula

[0131]

[0132] Preparation process

[0133] 1) Oil phase preparation:

[0134] Mix the prescribed amount of oily components such as oleyl alcohol, medium-chain triglycerides, propylene glycol, cetyl alcohol, and octadecanol, and heat to 65-75°C to ensure that all components dissolve and form an oil phase.

[0135] The pimecrolimus active pharmaceutical ingredient was added to the oil phase and stirred until dissolved. Then, glyceryl monostearate and glyceryl distearate were added and stirred to obtain the oil phase.

[0136] 2) Aqueous phase preparation:

[0137] Add the prescribed amounts of anhydrous citric acid, sodium hydroxide, and benzyl alcohol to a measured volume of water, and heat to 65–75°C to dissolve. Add sodium cetyl sulfate, stir, and obtain the aqueous phase.

[0138] 3) Emulsification:

[0139] Ensure the oil and water phases are at the same temperature. Slowly pour the preheated oil phase into the water phase while continuously stirring, using a fine-flow funnel or dripping device to control the flow rate. Maintain the emulsification temperature at 70°C to reduce the viscosity of the emulsion and increase its dispersibility. Adjust the stirring speed to 25 rpm to ensure thorough mixing of the oil and water phases. Start the homogenizer and homogenize the mixture at 3000 rpm for 10 minutes. Then stop homogenizing and continue stirring at 25 rpm for 5 minutes. Start the homogenizer again and homogenize the mixture at 3000 rpm for 10 minutes until an emulsion is formed.

[0140] 4) Filling and Packaging:

[0141] The prepared emulsion is filled into aluminum pharmaceutical ointment tubes and cooled to room temperature. The tubes are then sealed to complete the ointment encapsulation process.

[0142] Comparative Example 3

[0143] formula

[0144]

[0145]

[0146] Preparation process

[0147] 1) Oil phase preparation:

[0148] Mix the prescribed amount of oily components such as oleyl alcohol, medium-chain triglycerides, propylene glycol, cetyl alcohol, and octadecanol, and heat to 65-75°C to ensure that all components dissolve and form an oil phase.

[0149] The pimecrolimus active pharmaceutical ingredient was added to the oil phase and stirred until dissolved. Then, glyceryl monostearate and glyceryl distearate were added and stirred to obtain the oil phase.

[0150] 2) Aqueous phase preparation:

[0151] Add the prescribed amounts of anhydrous citric acid, sodium hydroxide, and benzyl alcohol to a measured volume of water, and heat to 65–75°C to dissolve. Add sodium cetyl sulfate, stir, and obtain the aqueous phase.

[0152] 3) Emulsification:

[0153] Ensure the oil and water phases are at the same temperature. Slowly pour the preheated oil phase into the water phase while continuously stirring, using a fine-flow funnel or dripping device to control the flow rate. Maintain the emulsification temperature at 70°C to reduce the viscosity of the emulsion and increase its dispersibility. Adjust the stirring speed to 25 rpm to ensure thorough mixing of the oil and water phases. Start the homogenizer and homogenize the mixture at 3000 rpm for 10 minutes. Then stop homogenizing and continue stirring at 25 rpm for 5 minutes until an emulsion is formed.

[0154] 4) Filling and Packaging:

[0155] The prepared emulsion is filled into aluminum pharmaceutical ointment tubes and cooled to room temperature. The tubes are then sealed to complete the ointment encapsulation process.

[0156] Comparative Example 4

[0157] formula

[0158]

[0159]

[0160] Preparation process

[0161] 1) Oil phase preparation:

[0162] Mix the prescribed amount of oily components such as oleyl alcohol, medium-chain triglycerides, propylene glycol, cetyl alcohol, and octadecanol, and heat to 65-75°C to ensure that all components dissolve and form an oil phase.

[0163] The pimecrolimus active pharmaceutical ingredient was added to the oil phase and stirred until dissolved. Then, glyceryl monostearate and glyceryl distearate were added and stirred to obtain the oil phase.

[0164] 2) Aqueous phase preparation:

[0165] Add the prescribed amounts of anhydrous citric acid, sodium hydroxide, and benzyl alcohol to a measured volume of water, and heat to 65–75°C to dissolve. Add sodium cetyl sulfate, stir, and obtain the aqueous phase.

[0166] 3) Emulsification:

[0167] Ensure the oil and water phases are at the same temperature. Slowly pour the preheated oil phase into the water phase while continuously stirring, using a fine-flow funnel or dripping device to control the flow rate. Maintain the emulsification temperature at 70°C to reduce the viscosity of the emulsion and increase its dispersibility. Adjust the stirring speed to 25 rpm to ensure thorough mixing of the oil and water phases. Stir at 40 rpm for 10 minutes, then start a homogenizer and homogenize the mixture at 5000 rpm for 15 minutes until an emulsion is formed.

[0168] 4) Filling and Packaging:

[0169] The prepared emulsion is filled into aluminum pharmaceutical ointment tubes and cooled to room temperature. The tubes are then sealed to complete the ointment encapsulation process.

[0170] Comparative Example 5

[0171] formula

[0172]

[0173] Preparation process

[0174] 1) Oil phase preparation:

[0175] Mix the prescribed amount of oily components such as oleyl alcohol, medium-chain triglycerides, propylene glycol, cetyl alcohol, and octadecanol, and heat to 65-75°C to ensure that all components dissolve and form an oil phase.

[0176] The pimecrolimus active pharmaceutical ingredient was added to the oil phase and stirred until dissolved. Then, glyceryl monostearate and glyceryl distearate were added and stirred to obtain the oil phase.

[0177] 2) Aqueous phase preparation:

[0178] Add the prescribed amounts of anhydrous citric acid, sodium hydroxide, and benzyl alcohol to a measured volume of water, and heat to 65–75°C to dissolve. Add sodium cetyl sulfate, stir, and obtain the aqueous phase.

[0179] 3) Emulsification:

[0180] Ensure the oil and water phases are at the same temperature. Slowly pour the preheated oil phase into the water phase while continuously stirring, using a fine-flow funnel or dripping device to control the flow rate. Maintain the emulsification temperature at 70°C to reduce the viscosity of the emulsion and increase its dispersibility. Adjust the stirring speed to 25 rpm to ensure thorough mixing of the oil and water phases. Start the homogenizer and homogenize the mixture at 6000 rpm for 30 minutes until an emulsion is formed.

[0181] 4) Filling and Packaging:

[0182] The prepared emulsion is filled into aluminum pharmaceutical ointment tubes and cooled to room temperature. The tubes are then sealed to complete the ointment encapsulation process.

[0183] In vitro transdermal test

[0184] In vitro transdermal tests were conducted on the ointments obtained in Examples 1-6 and Comparative Examples 1-5, as detailed below:

[0185] Healthy skin samples from Bama miniature pigs were used as the receiving fluid in in vitro transdermal experiments (Examples 1-6 and Comparative Examples 1-5). The water bath temperature in the receiving tank was 32°C, the stirring speed was 350 rpm, and the drug dosage was approximately 30 mg. The receiving fluid was collected before administration (0 h) and at 2, 4, 6, 8, 10, 12, 16, 20, and 24 h after administration. Skin samples and residual drug were collected 24 h after administration, and the results were analyzed using a validated LC-100 assay. The concentration of pimecrolimus in the above samples was detected by MS / MS (ESI+, MRM, pimecrolimus ion pair: 832.55 / 604.50, internal standard tacrolimus ion pair: 821.45 / 768.20, linear range in receiving solution: 0.300–60.0 ng / mL, linear range in skin homogenate: 100–20,000 ng / mL, linear range for residue detection: 100–20,000 ng / mL). In the comparative test between formulations A and B, six skin samples from Bama miniature pigs were taken for each test, in duplicate, resulting in 12 skin samples for each formulation for statistical analysis.

[0186] Samples of receiving fluid, skin, and residue were collected at the corresponding time points for testing. The results are summarized in Table 1 below.

[0187] Table 1

[0188]

[0189] As shown in the table above, the permeation percentage, skin absorption percentage, residue percentage, and overall recovery rate of the pimecrolimus ointments in Examples 1-6 all meet the requirements. However, as shown in Comparative Examples 1-5, the emulsifier ratio and dosage, as well as the homogenization and stirring conditions, do not meet the specific ranges, resulting in transdermal test results that completely fail to meet the standards.

[0190] Antibacterial test

[0191] Test materials

[0192] Test strains: Select common pathogenic microorganisms related to the target indication, namely Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger.

[0193] Culture medium: Nutrient agar medium or special culture medium suitable for the growth of test strains.

[0194] Incubator: A constant temperature incubator used for culturing bacteria.

[0195] Petri dishes: used for pouring culture media and streaking in plates.

[0196] Pipettes: Used for accurately measuring bacterial suspensions and creams.

[0197] Sterile swabs or inoculation loops: used for inoculating bacterial strains.

[0198] Microscope: Used to observe colony morphology.

[0199] Test methods

[0200] Inoculum preparation:

[0201] Recover the bacterial strain from the standard strain and culture it on a suitable culture medium according to standard operating procedures.

[0202] Prepare a bacterial suspension and adjust its concentration to 0.5 McFarland units, which is equivalent to approximately 1.5 × 10^8 CFU / mL.

[0203] Plate preparation:

[0204] Melt the nutrient agar medium and cool it to 45-50℃.

[0205] Pour approximately 20 mL of culture base into each petri dish and allow it to solidify naturally into a plate.

[0206] The plate is ready for use after cooling to room temperature.

[0207] Cream sample preparation:

[0208] Prepare the prepared pimecrolimus cream sample.

[0209] The control group used either a blank cream or saline solution without the drug.

[0210] Plate inoculation:

[0211] Use a sterile cotton swab or inoculation loop to spread the bacterial suspension evenly on the surface of the agar plate.

[0212] Ensure the entire surface of the flat plate is evenly covered.

[0213] Cream application:

[0214] Using a sterile cotton swab or inoculation loop, apply a certain amount of cream sample (e.g., 10 μL) evenly to the surface of the plate.

[0215] The control group was treated with the same volume of blank cream or saline solution.

[0216] nourish:

[0217] Turn the plate upside down so that the cream side is facing down, and incubate it in a 37°C constant temperature incubator for 24 hours.

[0218] Observation results:

[0219] After 24 hours, remove the plate and observe and record the size of the inhibition zone.

[0220] The diameter of the inhibition zone is calculated to evaluate its antibacterial efficacy.

[0221] Data Analysis

[0222] Inhibition zone diameter measurement: The diameter of the inhibition zone is measured using specialized software.

[0223] Antibacterial efficacy assessment: The larger the inhibition zone, the stronger the antibacterial efficacy of the cream.

[0224] result

[0225] Table 2

[0226]

[0227] in conclusion:

[0228] Based on the above data, the creams of Examples 1-6 showed better antibacterial effects against Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger compared to Comparative Examples 1-5. The inhibitory zones were larger in diameter, indicating that they had stronger antibacterial efficacy.

[0229] The embodiments of this application have been described above, but this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A method for preparing a pharmaceutical composition for treating inflammatory skin diseases, characterized in that, The method includes the following steps: 1) Oil phase preparation: Oily components such as oleyl alcohol, medium-chain triglycerides, propylene glycol, cetyl alcohol, and octadecanol are mixed and heated to 65-75°C to form an oil phase. The pimecrolimus active pharmaceutical ingredient was added to the oil phase and stirred until dissolved. Then, glyceryl monostearate and glyceryl distearate were added and stirred to obtain the oil phase. 2) Aqueous phase preparation: Add the prescribed amounts of anhydrous citric acid, sodium hydroxide, and benzyl alcohol to a measured volume of water, and heat to 65–75°C to dissolve. Add sodium hexadecyl sulfate, stir, and obtain the aqueous phase. 3) Emulsification: Ensure that the oil phase and water phase are at the same temperature. Pour the preheated oil phase into the water phase while continuously stirring. Use a fine-flow funnel or dripping device to control the flow rate and maintain the emulsification temperature at 65-75°C. Perform homogenization and stirring until an emulsion is formed. 4) Filling and Packaging: The prepared emulsion is filled into aluminum pharmaceutical ointment tubes, cooled to room temperature, and then sealed to complete the ointment encapsulation process.

2. The preparation method according to claim 1, wherein, In step 3), the homogenization process is performed two or more times.

3. The preparation method according to claim 2, wherein, The homogenization and stirring processes are as follows: the mixture is homogenized at a speed of 3000-5000 rpm for 10-15 minutes, then the homogenization is stopped, and stirring is continued at 20-30 rpm for 5-10 minutes. The mixture is then homogenized again at a speed of 3000-5000 rpm for 5-10 minutes.

4. The preparation method according to claim 3, wherein, The homogenization and stirring processes are as follows: the mixture is homogenized at 3000 rpm for 10 minutes, then homogenization is stopped, stirring is continued at 25 rpm for 5 minutes, and then the mixture is homogenized again at 3000 rpm for 10 minutes.

5. The preparation method according to any one of claims 1 to 4, wherein, The amounts of each component, by weight percentage, are as follows:

6. The preparation method according to claim 5, wherein, The weight ratio of the mono- and di-stearyl glycerides to the sodium cetearyl sulfate is (2.2–5.0):

1.

7. The preparation method according to claim 6, wherein, The weight ratio of the mono- and di-stearyl glycerides to the sodium cetearyl sulfate is (2.5–4):

1.

8. A pharmaceutical composition for treating inflammatory skin diseases, characterized in that, It is prepared by the preparation method according to any one of claims 1 to 7.

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