A method for preparing a rapamycin gel

Abstract

The application discloses a preparation method of a rapamycin gel, which comprises the following steps: 1) matrix treatment: adding a gel matrix into a solvent, and then stirring to obtain a matrix dispersion; 2) raw material treatment: adding a prescription amount of rapamycin into a penetration promoter, and then stirring to obtain a rapamycin solution; 3) mixing: under the condition of a water bath at 0-15 DEG C, the rapamycin solution prepared in the step 2) is slowly added into the matrix dispersion obtained in the step 1) by vacuum pumping, then a prescription amount of a pH value regulator is added to adjust the pH value to the range of 5.0-7.0, and stirring is conducted to obtain a rapamycin gel; and 4) filling. The rapamycin gel obtained by the application has good stability and use feeling.

Description

Technical Field

[0001] The present application belongs to the technical field of pharmaceutical preparations, and in particular relates to a method for preparing rapamycin gel. Background Art

[0002] Rapamycin, also known as sirolimus, is an immunosuppressant drug commonly used to prevent rejection of organ transplants and to treat certain types of cancer. The chemical name is (1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R)-1,18-dihydroxy-12-{(1R)-2-[(1S), 3R, 4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]Hexatria Conta-16,24,26,28-tetraene-2,3,10,14,20-pentanone, CAS No.: 53123-88-9, and the chemical structure is as follows:

[0003]

[0004] Sirolimus is widely believed to be able to effectively suppress immune responses by inhibiting the activity of the mammalian target of rapamycin (mTOR). Rapamycin is a key regulator of cell division, proliferation, and survival. In addition, studies have clearly demonstrated that mTOR is persistently activated in lymphangioleiomyomatosis (LAM). Sirolimus inhibits mTOR via topical administration, which not only reduces the systemic side effects that may be associated with oral administration, but also provides a new, less invasive treatment approach. In particular, sirolimus can be used to treat skin lesions associated with tuberous sclerosis complex (TSC).

[0005] Sirolimus sugar-coated tablets developed by Japan Nobel Pharmaceutical Co., Ltd. were approved for marketing in Japan on July 4, 2004, and Sirolimus gel 0.2% was approved for marketing on March 23, 2018, under the trade name Sirolimus Gel 0.2%. Sirolimus Gel is the world's first topical therapeutic agent that can be used non-invasively to treat skin lesions associated with tuberous sclerosis complex (TSC).

[0006] According to existing literature, sirolimus has poor stability and is sensitive to light and high temperature conditions.

[0007] Patent CN113332228A discloses a sirolimus gel preparation that solves the stability problem of the sirolimus gel preparation by controlling the ethanol solubility and the pH value of the gel.

[0008] CN105663027A sirolimus external preparation, its preparation method and use, is with solid lipid as carrier, the drug is wrapped or inlaid in the lipid core to make a new generation of solid sub-micron particle drug delivery system, so that the drug stability is good.

[0009] The above patent aims to solve the stability and medicinal effect of sirolimus external preparation, but its production process is relatively complex. SUMMARY

[0010] In order to solve the problems existing in the prior art, the present application provides a preparation method of rapamycin gel, comprising the following steps:

[0011] 1) Matrix treatment: add the gel matrix into the solvent, then stir to obtain a matrix dispersion;

[0012] 2) Raw material treatment: add the prescription amount of rapamycin into the penetration enhancer, then stir to obtain a rapamycin solution;

[0013] 3) Mixing: under the condition of water bath at 0-15℃, the rapamycin solution prepared in step 2) is slowly added to the matrix dispersion obtained in step 1) by vacuum extraction, then the prescription amount of pH adjuster is added to adjust the pH value to the range of 5.0-7.0, and stirred to obtain a rapamycin gel;

[0014] 4) Filling.

[0015] Further, the temperature of step 1) matrix treatment is 20-25℃.

[0016] Further, the stirring speed in step 1) is 350-450rpm.

[0017] Further, the temperature of step 2) raw material treatment is 0-15℃.

[0018] Further, the stirring speed in step 2) is 350-450rpm.

[0019] Further, the vacuum degree of step 3) mixing is -0.06 to -0.08 MPa.

[0020] Further, the stirring speed in step 3) is 10-150rpm.

[0021] Further, the composition of the rapamycin gel comprises: rapamycin 0.1-0.5% (w / w), gel matrix 1-3% (w / w), penetration enhancer 40-60% (w / w), pH adjuster 0.1-1% (w / w) and solvent 40-60% (w / w).

[0022] Furthermore, the gel matrix is ​​carbomer, the permeation enhancer is ethanol, the pH regulator is triethanolamine, and the solvent is purified water.

[0023] In another aspect, the present invention provides a rapamycin gel prepared according to the above method.

[0024] Compared with the prior art, the preparation method of rapamycin gel of the present invention has the following advantages:

[0025] (1) The present invention adopts a simple and efficient method, making the production process easy to control and reducing production costs. The preparation process of the present invention is not only conducive to large-scale production, but also can ensure the consistency and reliability of product quality.

[0026] (2) The rapamycin gel prepared by the present invention can maintain stable efficacy during storage and is not easily affected by external factors such as light and temperature. This stability allows the gel to continue to exert its therapeutic effect during long-term use, providing patients with more reliable treatment effects.

[0027] (3) The rapamycin gel of the present invention has good rheological properties, allowing the gel to spread easily during application without causing a sticky feeling, providing patients with a more comfortable experience during use. In addition, the gel can form a protective film on the skin surface, which helps to slowly release the drug, thereby achieving a sustained therapeutic effect.

[0028] (4) The rapamycin gel obtained by the present invention exhibits excellent transdermal properties, ensuring that the drug can effectively penetrate the skin and reach the target area, and has excellent stability and reliability. It can release the drug continuously and stably, thereby ensuring that patients receive the expected therapeutic effect during use. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 It is a flow curve diagram of the viscosity and shear stress of commercially available products as a function of shear rate.

[0030] Figure 2 3 is a flow curve diagram showing the viscosity and shear stress of Example 1 as a function of shear rate.

[0031] Figure 3 3 is a flow curve diagram of viscosity and shear stress of Comparative Example 1 as a function of shear rate.

[0032] Figure 4 3 is a flow curve diagram of viscosity and shear stress of Comparative Example 2 as a function of shear rate.

[0033] Figure 53 is a flow curve diagram of viscosity and shear stress of Comparative Example 7 as a function of shear rate.

[0034] Figure 6 This is a graph showing the change in loss modulus and storage modulus of commercially available products relative to shear strain (linear viscoelastic region).

[0035] Figure 7 3 is a graph showing the change in loss modulus and storage modulus relative to shear strain in Example 1 (linear viscoelastic region).

[0036] Figure 8 3 is a graph showing the change in loss modulus and storage modulus relative to shear strain in Comparative Example 1 (linear viscoelastic region).

[0037] Figure 9 3 is a graph showing the change in loss modulus and storage modulus relative to shear strain in Comparative Example 2 (linear viscoelastic region).

[0038] Figure 10 3 is a graph showing the change in loss modulus and storage modulus relative to shear strain for Comparative Example 7 (linear viscoelastic region).

[0039] Figure 11 This is a graph showing the shear strain versus time variation (creep characteristics) of a commercially available product.

[0040] Figure 12 This is a graph showing shear strain variation with time in Example 1 (creep characteristics).

[0041] Figure 13 This is a graph showing shear strain variation with time for Comparative Example 1 (creep characteristics).

[0042] Figure 14 This is a graph showing shear strain variation with time for Comparative Example 2 (creep characteristics).

[0043] Figure 15 This is a graph showing shear strain variation with time for Comparative Example 7 (creep characteristics).

[0044] Figure 16 It is the way of placing the drug in the in vitro transdermal test, where T is the homemade preparation and R is the reference preparation (commercially available product). DETAILED DESCRIPTION

[0045] The following will be combined with the accompanying drawings in the embodiments of the present application to clearly describe the technical solutions in the embodiments of the present application. Obviously, the embodiments described are part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field are within the scope of protection of this application.

[0046] The terms "first", "second", and the like in the description and in the claims of the present application are used for distinguishing between similar objects and are not necessarily used to describe a particular sequential or chronological order. It is to be understood that the use of such terms as "first", "second", and the like, if they are used in the present application, are used to distinguish one object from another in a particular aspect and are not necessarily used to describe a particular sequential or chronological order among others. It is to be understood that such terms as "first", "second", and the like, if they are used in the present application, are used to distinguish one object from another in a particular aspect and are not necessarily used to describe a particular sequential or chronological order among others. It is to be understood that the terms "first", "second", and the like, if they are used in the present application, are used to distinguish one object from another in a particular aspect and are not necessarily used to limit the number of objects. For example, a first object can be one or more, and so on. In addition, "and / or" in the description and in the claims of the present application means at least one of the connected objects, and the character " / " generally means a "or" relationship between the front and rear associated objects.

[0047] The present inventors have found that, in the process of preparing rapamycin gel (hereinafter referred to as "sirolimus gel"), the accurate control of the feeding sequence and temperature has a crucial influence on the stability, rheological properties and absorption performance of the final product. The entire process includes the following main steps:

[0048] 1) Matrix treatment: the gel matrix is added to the solvent, and then stirred to obtain a matrix dispersion;

[0049] In an embodiment of the present application, the temperature of the matrix treatment is controlled by water bath, and the water bath temperature is 20-25°C, for example, 20°C, 21°C, 22°C, 23°C, 24°C or 25°C, but not limited to the listed values, and other values not listed in this range are also applicable.

[0050] In an embodiment of the present application, the gel matrix is added to the solvent, and then stirred, and the stirring speed is controlled, preferably the stirring speed is 350-450 rpm, for example, 350 rpm, 360 rpm, 370 rpm, 380 rpm, 390 rpm, 400 rpm, 410 rpm, 420 rpm, 430 rpm, 440 rpm or 450 rpm, but not limited to the listed values, and other values not listed in this range are also applicable. The stirring mode can be mechanical stirring, magnetic stirring, ultrasonic stirring, rotary stirring and the like common modes.

[0051] 2) Raw material treatment: the prescribed amount of sirolimus is added to the penetration enhancer, and then stirred to obtain a sirolimus solution;

[0052] In an embodiment of the present application, the temperature of the raw material treatment is controlled by water bath, and the water bath temperature is 0-15°C, preferably 2-8°C, for example, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C or 8°C, but not limited to the listed values, and other values not listed in this range are also applicable.

[0053] In one embodiment of the present invention, sirolimus is added to the permeation enhancer and then stirred. The stirring speed is controlled, preferably 350 to 450 rpm, for example, 350 rpm, 360 rpm, 370 rpm, 380 rpm, 390 rpm, 400 rpm, 410 rpm, 420 rpm, 430 rpm, 440 rpm or 450 rpm, but is not limited to the listed values. Other values ​​not listed within the numerical range are also applicable. The stirring method can be common methods such as mechanical stirring, magnetic stirring, ultrasonic stirring, and rotary stirring.

[0054] 3) Mixing: Slowly adding the sirolimus solution prepared in step 2) to the matrix dispersion obtained in step 1) in a water bath at 0-15° C. by vacuuming, then adding a prescribed amount of a pH adjuster to adjust the pH to within the range of 5.0-7.0, and stirring to obtain a sirolimus gel;

[0055] In one embodiment of the present invention, the mixing temperature is controlled by a water bath, and the water bath temperature is 0-15°C, preferably 2-8°C, for example 2°C, 3°C, 4°C, 5°C, 6°C, 7°C or 8°C, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0056] In one embodiment of the present invention, the vacuum degree is -0.06 to -0.08 MPa, such as -0.06 MPa, -0.07 MPa or -0.08 MPa, but is not limited to the listed values. Other values ​​not listed within the numerical range are also applicable.

[0057] In one embodiment of the present invention, the stirring speed of the mixing in step 3) is 10 to 150 rpm, for example, 10 rpm, 20 rpm, 30 rpm, 40 rpm, 50 rpm, 60 rpm, 70 rpm, 80 rpm, 90 rpm, 100 rpm, 110 rpm, 120 rpm, 4130 rpm, 140 rpm or 150 rpm, but is not limited to the listed values. Other values ​​not listed within the numerical range are also applicable. The stirring method can be common methods such as mechanical stirring, magnetic stirring, ultrasonic stirring, and rotary stirring.

[0058] In one embodiment of the present invention, the pH value adjusted in step 3) is in the range of 5.0 to 7.0, preferably 5.0 to 6.0, such as 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 or 6.0, but is not limited to the listed values. Other values ​​not listed in the numerical range are also applicable.

[0059] In one embodiment of the present invention, the composition of sirolimus gel comprises: 0.1-0.5% (w / w) sirolimus, 1-3% (w / w) gel matrix, 40-60% (w / w) permeation enhancer, 0.1-1% (w / w) pH adjuster and 40-60% (w / w) solvent;

[0060] In one embodiment of the present invention, the gel matrix is ​​carbomer, the permeation enhancer is ethanol, the pH adjuster is triethanolamine, and the solvent is purified water. The present invention does not limit the source and type of the raw materials and auxiliary materials. The ethanol can be in common concentrations, for example, anhydrous ethanol, 20% ethanol in water, 30% ethanol in water, 40% ethanol in water, 50% ethanol in water, 60% ethanol in water, 70% ethanol in water, or 95% ethanol in water. However, the concentrations listed are not limiting, and other commonly used concentrations are also applicable.

[0061] Sirolimus is relatively unstable and prone to degradation at high temperatures, so strict temperature control during the preparation process is crucial. This effectively prevents degradation of the active ingredient and ensures drug stability and efficacy.

[0062] Through experimental research, the inventors of this application discovered that temperature control is essential throughout the preparation of sirolimus gel. In particular, the dissolution and mixing temperatures must be kept within a certain range, as these temperatures may affect the matrix and the stability of the active ingredient. Furthermore, these temperatures must be kept within a certain range, as these temperatures may affect the gel's content of relevant substances, flow properties, and transdermal absorption. While conventional preparation methods typically operate at room temperature, this is not sufficient to completely avoid these issues.

[0063] Preparing sirolimus gel at generally mild temperatures, such as around 10-15°C, ensures that the content of related substances and stability of sirolimus gel meet the required limits. However, even under these conditions, its rheological properties and transdermal absorption still lag behind those of commercially available products. Therefore, only by precisely controlling the dissolution and mixing temperatures during sirolimus gel preparation within a certain appropriate range can the quality of the final product be effectively improved in terms of related substance content, rheological properties, and transdermal absorption.

[0064] While the specific reasons aren't fully understood, the inventors have discovered that the order in which the materials are added significantly impacts the quality of the final sirolimus gel. Comparing different addition sequences, the inventors found that a specific order of raw material and excipient addition is crucial for achieving a gel with excellent physical and chemical properties, such as appropriate viscosity and uniform texture. An inappropriate order of addition can lead to uneven drug distribution or affect excipient interactions, thereby compromising the overall performance of the product. Furthermore, the order of addition also significantly impacts the stability of the final product; a suitable order helps maintain drug activity and product durability.

[0065] The following are specific examples of the present invention and comparative examples, but the present invention is not limited to the following examples.

[0066] Table 1 Instruments used in Examples and Comparative Examples

[0067] name model factory Fluke mixing reaction Fisco-1S Shanghai Fluke Technology Development Co., Ltd. blender D2004W Shanghai Sile Instrument Co., Ltd. pH meter PB-10 Sartorius Scientific Instruments (Beijing) Co., Ltd. Rheometer MCR92 Anton Paar GmbH Rotational viscometer DVNXRVTJG AMETEKBrookfieldInc

[0068] Example 1

[0069] The prescription composition is as follows:

[0070] Table 2

[0071]

[0072] Preparation process:

[0073] 1) In a 25°C water bath, add the prescribed amount of purified water to a stirring tank at 400 rpm. Slowly add the prescribed amount of carbomer until fully hydrated to obtain a carbomer dispersion. Cool the carbomer dispersion to 2-8°C in a 5°C water bath and set aside.

[0074] 2) Add the prescribed amount of sirolimus to the prescribed amount of ethanol in a 5° C. water bath with a stirring speed of 400 rpm until the sirolimus is completely dissolved to obtain a sirolimus ethanol solution.

[0075] 3) In a water bath at 5°C, slowly add the sirolimus ethanol solution prepared in step 2) to the carbomer dispersion obtained in step 1). Set the stirring speed to 100 rpm and continue stirring for 10 minutes. While stirring, use a reaction jacket mixing device to maintain the vacuum degree at -0.06 to -0.08 MPa. Subsequently, slowly add the prescribed amount of triethanolamine and continue stirring at 100 rpm for 5 minutes to adjust the pH value to between 5.0 and 7.0. Afterwards, reduce the stirring speed to 20 rpm while maintaining the vacuum degree at -0.06 to -0.08 MPa for 10 minutes to thoroughly remove any bubbles that may be generated and ensure that the final gel is bubble-free.

[0076] 4) Aluminum tube filling.

[0077] Example 2

[0078] Adjust the water bath temperature from 25°C in step 1) to 20°C, and adjust the water bath temperature from 5°C in step 2) to 2°C. The specific operations are as follows:

[0079] 1) In a 20°C water bath, add the prescribed amount of purified water to a stirring tank at 400 rpm. Slowly add the prescribed amount of carbomer until fully hydrated to obtain a carbomer dispersion. Cool the carbomer dispersion to 2-8°C in a 5°C water bath and set aside.

[0080] 2) Add the prescribed amount of sirolimus to the prescribed amount of ethanol in a 2° C. water bath with a stirring speed of 400 rpm until the sirolimus is completely dissolved to obtain a sirolimus ethanol solution.

[0081] The formulation and other process steps and conditions are the same as those in Example 1.

[0082] Example 3

[0083] Adjust the water bath temperature from 5°C to 8°C in step 2) as follows:

[0084] 2) Add the prescribed amount of sirolimus to the prescribed amount of ethanol in a water bath at 8° C., set the stirring speed to 400 rpm, and stir until the sirolimus is completely dissolved to obtain a sirolimus ethanol solution.

[0085] The formulation and other process steps and conditions are the same as those in Example 1.

[0086] Example 4

[0087] Adjust the water bath temperature from 5°C to 2°C in step 3) as follows:

[0088] 3) In a water bath at 2°C, slowly add the sirolimus ethanol solution prepared in step 2) to the carbomer dispersion obtained in step 1). Set the stirring speed to 100 rpm and continue stirring for 10 minutes. While stirring, use a reaction jacket mixing device to maintain the vacuum degree at -0.06 to -0.08 MPa. Subsequently, slowly add the prescribed amount of triethanolamine and continue stirring at 100 rpm for 5 minutes to adjust the pH value to between 5.0 and 7.0. Afterwards, reduce the stirring speed to 20 rpm while maintaining the vacuum degree at -0.06 to -0.08 MPa for 10 minutes to thoroughly remove any bubbles that may be generated and ensure that the final gel is bubble-free.

[0089] The formulation and other process steps and conditions are the same as those in Example 1.

[0090] Example 5

[0091] Adjust the water bath temperature from 5°C to 8°C in step 3) as follows:

[0092] 3) In a water bath at 8°C, slowly add the sirolimus ethanol solution prepared in step 2) to the carbomer dispersion obtained in step 1). Set the stirring speed to 100 rpm and continue stirring for 10 minutes. While stirring, use a reaction jacket mixing device to maintain the vacuum degree at -0.06 to -0.08 MPa. Subsequently, slowly add the prescribed amount of triethanolamine and continue stirring at 100 rpm for 5 minutes to adjust the pH value to between 5.0 and 7.0. Afterwards, reduce the stirring speed to 20 rpm while maintaining the vacuum degree at -0.06 to -0.08 MPa for 10 minutes to thoroughly remove any bubbles that may be generated and ensure that the final gel is bubble-free.

[0093] The formulation and other process steps and conditions are the same as those in Example 1.

[0094] Comparative Example 1

[0095] The order of adding materials was adjusted to ethanol + API + water + carbomer + triethanolamine. The prescription composition was the same as that in Example 1. The specific operation was as follows:

[0096] 1) Add the prescribed amount of sirolimus to the prescribed amount of ethanol in a 5° C. water bath, set the stirring speed to 400 rpm, and stir until the sirolimus is completely dissolved to obtain a sirolimus ethanol solution.

[0097] 2) Add the prescribed amount of purified water and the prescribed amount of carbomer to the sirolimus ethanol solution obtained in step 1) in a 5° C. water bath, set the stirring speed to 400 rpm, and stir until the solution is completely hydrated.

[0098] 3) In a 5°C water bath, using a mixing reactor, maintain a vacuum of -0.06 to -0.08 MPa. Slowly add the prescribed amount of triethanolamine to the reaction system while stirring at 100 rpm for 5 minutes to adjust the pH to between 5.0 and 7.0. Then, reduce the stirring speed to 20 rpm while maintaining a vacuum of -0.06 to -0.08 MPa for 10 minutes to completely remove any bubbles and ensure a bubble-free final gel.

[0099] 4) Aluminum tube filling.

[0100] Comparative Example 2

[0101] The order of adding materials was adjusted to water + carbomer + triethanolamine + (ethanol + API). The prescription composition was the same as that in Example 1. The specific operation was as follows:

[0102] 1) In a 25°C water bath, add the prescribed amount of purified water to a stirred tank at 400 rpm. Slowly add the prescribed amount of carbomer until fully hydrated to obtain a carbomer dispersion. Subsequently, slowly add the prescribed amount of triethanolamine and continue stirring at 100 rpm for 5 minutes to adjust the pH to between 5.0 and 7.0. Cool the carbomer dispersion to 2-8°C in a 5°C water bath and set aside.

[0103] 2) Add the prescribed amount of sirolimus to the prescribed amount of ethanol in a 5° C. water bath with a stirring speed of 400 rpm until the sirolimus is completely dissolved to obtain a sirolimus ethanol solution.

[0104] 3) In a 5°C water bath, slowly add the sirolimus ethanol solution prepared in step 2) to the carbomer dispersion obtained in step 1). Set the stirring speed to 100 rpm and continue stirring for 10 minutes. While stirring, use a reaction jacket mixing device to maintain a vacuum of -0.06 to -0.08 MPa. Then, reduce the stirring speed to 20 rpm while maintaining the vacuum at -0.06 to -0.08 MPa for 10 minutes to completely remove any bubbles that may have formed and ensure that the final gel is bubble-free.

[0105] 4) Aluminum tube filling.

[0106] Comparative Example 3

[0107] Adjust the water bath temperature from 5°C in step 2) to 0°C. The specific operation is as follows:

[0108] 2) Add the prescribed amount of sirolimus to the prescribed amount of ethanol in a water bath at 0° C., set the stirring speed to 400 rpm, and stir until the sirolimus is completely dissolved to obtain a sirolimus ethanol solution.

[0109] The formulation and other process steps and conditions are the same as those in Example 1.

[0110] Comparative Example 4

[0111] Adjust the water bath temperature from 5°C to 15°C in step 2) as follows:

[0112] 2) Add the prescribed amount of sirolimus to the prescribed amount of ethanol in a water bath at 15° C., set the stirring speed to 400 rpm, and stir until the sirolimus is completely dissolved to obtain a sirolimus ethanol solution.

[0113] The formulation and other process steps and conditions are the same as those in Example 1.

[0114] Comparative Example 5

[0115] Adjust the water bath temperature in step 3) from 5°C to 0°C, and the specific operation is as follows:

[0116] 3) Under the condition of water bath at 0°C, the sirolimus ethanol solution prepared in step 2) is slowly added into the carbomer dispersion solution obtained in step 1). The stirring speed is set to 100 rpm, and stirring is continued for 10 minutes. At the same time, the reaction jacket mixing device is used to maintain the vacuum degree at -0.06 to -0.08 MPa, and then the prescribed amount of triethanolamine is slowly added, and the stirring speed is continued at 100 rpm for 5 minutes to adjust the pH value to 5.0 to 7.0. After that, the stirring speed is reduced to 20 rpm, and the vacuum degree is maintained at -0.06 to -0.08 MPa for 10 minutes to completely remove the possible bubbles and ensure that the final gel has no bubbles.

[0117] The prescription composition and other process steps, conditions are the same as in Example 1.

[0118] Comparative Example 6

[0119] Adjust the water bath temperature in step 3) from 5°C to 15°C, and the specific operation is as follows:

[0120] 3) Under the condition of water bath at 15°C, the sirolimus ethanol solution prepared in step 2) is slowly added into the carbomer dispersion solution obtained in step 1). The stirring speed is set to 100 rpm, and stirring is continued for 10 minutes. At the same time, the reaction jacket mixing device is used to maintain the vacuum degree at -0.06 to -0.08 MPa, and then the prescribed amount of triethanolamine is slowly added, and the stirring speed is continued at 100 rpm for 5 minutes to adjust the pH value to 5.0 to 7.0. After that, the stirring speed is reduced to 20 rpm, and the vacuum degree is maintained at -0.06 to -0.08 MPa for 10 minutes to completely remove the possible bubbles and ensure that the final gel has no bubbles.

[0121] The prescription composition and other process steps, conditions are the same as in Example 1.

[0122] Comparative Example 7

[0123] Adjust the water bath temperature in step 2) from 5°C to 15°C, and the water bath temperature in step 3) from 5°C to 15°C, and the specific operation is as follows:

[0124] 2) Under the condition of water bath at 15°C, the prescribed amount of sirolimus is added into the prescribed amount of ethanol, and the stirring speed is set to 400 rpm until the sirolimus is completely dissolved to obtain a sirolimus ethanol solution.

[0125] 3) The sirolimus ethanol solution prepared in step 2) was slowly added to the carbomer dispersion obtained in step 1) under the condition of a water bath at 15°C. The stirring speed was set to 100 rpm and stirring was continued for 10 minutes. While stirring, the vacuum degree was maintained at -0.06 to -0.08 MPa using a reaction jacket mixing device, and then the prescribed amount of triethanolamine was slowly added and stirring was continued at 100 rpm for 5 minutes to adjust the pH to 5.0 to 7.0. Thereafter, the stirring speed was reduced to 20 rpm while maintaining the vacuum degree at -0.06 to -0.08 MPa for 10 minutes to completely remove any air bubbles that might have been generated, thereby ensuring that the final gel was free of air bubbles.

[0126] The prescription composition and other process steps and conditions were the same as in Example 1.

[0127] Comparative Example 8

[0128] The entire process was performed at room temperature (25°C as an example) and the prescription composition was the same as in Example 1, and the process was performed as follows:

[0129] 1) The prescribed amount of purified water was added to a stirring tank and the stirring speed was set to 400 rpm, and the prescribed amount of carbomer was slowly added until complete hydration of the carbomer was achieved, thereby obtaining a carbomer dispersion.

[0130] 2) The prescribed amount of sirolimus was added to the prescribed amount of ethanol and the stirring speed was set to 400 rpm until the sirolimus was completely dissolved, thereby obtaining a sirolimus ethanol solution.

[0131] 3) The sirolimus ethanol solution prepared in step 2) was slowly added to the carbomer dispersion obtained in step 1) under the condition of a water bath at 15°C. The stirring speed was set to 100 rpm and stirring was continued for 10 minutes. While stirring, the vacuum degree was maintained at -0.06 to -0.08 MPa using a reaction jacket mixing device, and then the prescribed amount of triethanolamine was slowly added and stirring was continued at 100 rpm for 5 minutes to adjust the pH to 5.0 to 7.0. Thereafter, the stirring speed was reduced to 20 rpm while maintaining the vacuum degree at -0.06 to -0.08 MPa for 10 minutes to completely remove any air bubbles that might have been generated, thereby ensuring that the final gel was free of air bubbles.

[0132] The stability, rheological properties and in vitro absorption of the sirolimus gels obtained in Examples 1 to 5 and Comparative Examples 1 to 8 and a commercially available sirolimus gel (trade name: Rapalimus, manufacturer: Nobelpharma Co., Ltd., batch number: BG01) were measured.

[0133] Determination of related substances :

[0134] Determine by high performance liquid chromatography (ChP 2020 Vol IV 0512).

[0135] Solvent Acetonitrile-water-glacial acetic acid (800:200:5)

[0136] Take 2.0 g of the product (about 4 mg of sirolimus) and place it in a 20 ml volumetric flask. Add solvent to dissolve sirolimus by ultrasonic, dilute to the mark with solvent, shake well, and centrifuge at 5000 rpm for 10 minutes. Take the supernatant.

[0137] Take about 10 mg of sirolimus reference substance and place it in a 50 ml volumetric flask. Dissolve and dilute to the mark with solvent, shake well, and take 1 ml accurately. Place it in a 100 ml volumetric flask and dilute to the mark with solvent, shake well.

[0138] Take appropriate amounts of impurity A, impurity B, and sirolimus reference substance, accurately weigh, dissolve and quantitatively dilute to prepare a solution containing about 2 μg of impurity A, 2 μg of impurity B, and 200 μg of sirolimus per 1 ml.

[0139] Chromatographic conditions: octadecylsilane-bonded silica gel as filler (Agilent ZORBAX SB-C18 注 4.6 mm x 250 mm, 5 μm or equivalent performance chromatographic column); 0.6% glacial acetic acid solution (take 6 ml of glacial acetic acid, add 1000 ml of water to dissolve, adjust the pH to 3.6 ± 0.05 with triethylamine)-1,4 dioxane (42:58) as mobile phase; flow rate is 1.0 ml per minute; detection wavelength is 277 nm; column temperature is 40°C; injection volume is 50 μl.

[0140] System suitability requirements: in the chromatogram of the system suitability solution, impurity A, sirolimus trans-isomer (main peak), sirolimus cis-isomer, and impurity B elute in order, the separation between sirolimus cis-isomer and impurity B should be greater than 1.5, and the theoretical plate number should not be less than 2500 calculated by the sirolimus trans-isomer peak.

[0141] Determination method: accurately measure the reference substance solution and the test sample solution, inject them into the liquid chromatograph respectively, and record the chromatogram to 2.0 times the retention time of the main component peak.

[0142] Limits: if there are impurity peaks in the chromatogram of the test sample solution, calculate by the external standard method of the main component, the sum of the peak areas of sirolimus trans-isomer and sirolimus cis-isomer, impurity A should not exceed 6.0%, impurity B should not exceed 1.0%, other single impurities should not exceed 0.2%, and the total impurities (not including impurity A) should not exceed 2.0%.

[0143] Determine the degradation products of component II by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part Four General Chapter 0512).

[0144] Precisely weigh 5.0 g of the product (about equivalent to 10 mg of sirolimus) into a 25 ml volumetric flask, add acetonitrile to dissolve sirolimus by ultrasonic, dilute to the mark with acetonitrile, shake well, centrifuge at 5000 rpm for 10 minutes, and take the supernatant.

[0145] Precisely weigh an appropriate amount of sirolimus reference substance, dissolve and quantitatively dilute with acetonitrile to prepare a solution containing about 10 μg per 1 ml.

[0146] Precisely weigh an appropriate amount of impurity C and sirolimus reference substance, dissolve and quantitatively dilute with acetonitrile to prepare a solution containing about 4 μg of impurity C and 400 μg of sirolimus per 1 ml.

[0147] Chromatographic conditions: octadecylsilane-bonded silica gel as the filler (Agilent ZORBAX SB-C18 4.6 mm x 250 mm, 5 μm or a chromatographic column with equivalent performance); 0.01% trifluoroacetic acid solution as mobile phase A and acetonitrile as mobile phase B; flow rate of 1.2 ml per minute; gradient elution according to the following Table 3; detection wavelength of 240 nm; column temperature of 35°C; injection volume of 50 μl.

[0148] Table 3

[0149]

[0150] System suitability The separation between the impurity C peak and the sirolimus peak in the chromatogram of the system suitability solution should be greater than 1.5, and the retention time of the sirolimus trans-isomer peak should be between 22 and 30 minutes; in the chromatogram of the reference solution, the theoretical plate number calculated by the sirolimus trans-isomer peak should not be less than 8000, and the signal-to-noise ratio of the sirolimus trans-isomer peak height should be greater than 50.

[0151] Determination method: precisely take the reference solution and the test solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0152] Limits: if there are impurity peaks in the chromatogram of the test solution, take the impurity peak between the relative retention time of 0.45 and 0.91 of the sirolimus trans-isomer peak as the component II degradation product peak, calculate according to the following formula, the impurity C should not be more than 1.0%, other single maximum degradation product should not be more than 0.75%, and the total degradation product should not be more than 5.0%.

[0153]

[0154] In the formula: A 单个降解: Sum of peak areas of other individual major degradation products; A 总降解 : Sum of peak areas of total degradation products between 0.45 and 0.91; A 总 : Sum of all peak areas except solvent peak; 2.16: Relative response factor for impurity C.

[0155] Table 4

[0156]

[0157] The test results of relevant substances are shown in Table 5 :

[0158] Table 5

[0159]

[0160]

[0161]

[0162]

[0163] According to the data in Table 5, when the commercially available sirolimus gel was stored at 25°C for 7 days, the maximum single impurity in the related substances had reached the limit value of 0.2%, and the impurity content was still increasing thereafter. In addition, the initial content of impurity A was relatively high at 0.11%, and after being stored at 25°C for 30 days, the content had risen to 5.79%, very close to the limit value of 6.0%. It can be seen that, although the content of the related substances in the commercially available sirolimus gel was still within the acceptable limit, the overall impurity content was generally high, indicating that the stability of the sirolimus gel was poor when stored at 25°C.

[0164] As can be seen from the related substance data of Examples 1-5 and Comparative Examples 3-8, by accurately controlling the temperature of steps 2) and 3), the impurity content of the produced sirolimus gel can be significantly reduced, and the limit requirements can be ensured.

[0165] During the short-term storage (7 days, 15 days and 30 days) of the sirolimus gels obtained in Examples 1-5 at 25°C, although the content of the maximum single impurity increased, the contents of the remaining impurities met the limit requirements; and when stored at 2-8°C for 3 months, 7 months and 15 months, the contents of all related substances could be kept within the specified limits.

[0166] When the temperature in step 2) is controlled too low (e.g., 0°C, see Comparative Example 3), the sirolimus gel obtained in Comparative Example 3, when stored at 25°C, has a maximum single impurity content of 0.23% on day 15, exceeding the limit, and reaches 0.32% on day 30, significantly higher than in Example 1. Furthermore, the impurity A content is relatively high, at 0.11% on day 0, and reaches 5.14% after 15 months of storage at 2-8°C, very close to the limit of 6.0%. If the temperature is too high (e.g., 15°C, see Comparative Example 4), not only does the impurity content increase rapidly during storage at 25°C (the maximum single impurity content is 0.20% on day 15), but even at 2-8°C, the impurity A content reaches 5.4% after 15 months of storage, very close to the limit of 6.0%. This indicates that the operating temperature in step 2) has a significant impact on the stability of related substances in the final product.

[0167] Similarly, improper temperature control in step 3 (either too low or too high, as seen in Comparative Examples 5 and 6) can also result in impurity levels in the final product exceeding specified limits under various storage conditions. In Comparative Example 5, the temperature in step 3) was too low (0°C). When stored at 25°C, the sirolimus gel obtained in Comparative Example 5 had the largest single impurity reaching the limit of 0.29% on day 15 and 0.47% on day 30. The largest degradation product also reached 0.71% on day 30, very close to the limit of 0.75%. Furthermore, the impurity A content on day 0 was relatively high at 0.15%, reaching 5.31% after 15 months of storage at 2-8°C. The total impurity content reached 1.52% on day 30, very close to the limit of 2.0%. In Comparative Example 6, the temperature control in step 3) was too high (15°C). When the sirolimus gel obtained in Comparative Example 6 was stored at 25°C, the maximum single impurity content reached 0.19% on the 7th day, which was very close to the limit value. It then continued to increase rapidly, far exceeding the limit value. Moreover, when stored at 2-8°C for 3-15 months, the maximum single impurity content began to approach the limit value from the 3rd month and exceeded the limit value at the 15th month (0.21%), indicating its poor stability.

[0168] The temperature of steps 2) and 3) of Comparative Example 7 was controlled at 15°C. When the sirolimus gel obtained in Comparative Example 7 was stored at 25°C, the maximum single impurity content reached 0.19% on the 15th day, which was very close to the limit value. It reached 0.36% on the 30th day, far exceeding the limit value and that of Example 1. Moreover, when stored at 2-8°C for 3-15 months, the maximum single impurity content began to approach the limit value from the 3rd month and exceeded the limit value (0.24%) at the 15th month.

[0169] Comparative Example 8 was prepared at room temperature, and the resulting sirolimus gel had an overall high impurity content. When stored at 25°C, the maximum single impurity content reached 0.21% on day 15, exceeding the limit. It reached 0.45% on day 30, significantly higher than that of the other examples. The total impurity content (2.17%) also exceeded the limit on day 30. The other largest degradation product among the degradation products of Component II exceeded the limit after 7 days of storage at 25°C, and also exceeded the limit after 7 months of storage at 2-8°C (0.97%). This indicates that the sirolimus gel obtained at room temperature exhibits poor stability with respect to related substances.

[0170] In summary, strict control of temperature conditions during the production process is crucial to maintaining the quality stability of sirolimus gel and reducing the impurity content.

[0171] Comparative Examples 1 and 2 compare different addition sequences. Data from the relevant materials show that, under the same conditions, the sirolimus gel obtained according to the process sequence of Comparative Example 1, when stored at 25°C, had a maximum single impurity content of 0.19% on day 15, very close to the limit, and reached 0.32% on day 30. After 15 months of storage at 2-8°C (0.18%), it was also very close to the limit. The sirolimus gel obtained according to the process sequence of Comparative Example 2, when stored at 25°C, had a maximum single impurity content of 0.2% on day 15, reaching the limit, and reached 0.35% on day 30. After 7 months of storage at 2-8°C (0.18%), it was also very close to the limit, reaching the limit of 0.20% after 15 months. The overall stability of Comparative Examples 1 and 2 was worse than that of Example 1. This shows that the order of addition is equally important for maintaining the quality stability of sirolimus gel and reducing impurity content.

[0172] Table 6 Flow curve determination method :

[0173] parameter Setting conditions Test Mode Rotation mode; logarithmic scan; linear coordinates rotor pp25 / S Temperature (℃) 25 Holding time (min) 1 Pre-shearing time (s) 60 shear rate 0.1-100 s -1 ]] Changes in sampling time points 10s~1s Sample gap 0.8mm Data processing model Herschel-Bulkley

[0174] Table 7 Linear viscoelastic region determination method:

[0175]

[0176]

[0177] Table 8 Creep determination method:

[0178] parameter Setting conditions rotor pp25 / S Temperature (℃) 25 Holding time (s) 60 Sample gap 0.8mm Load phase 91 data points; 0.01S-25S; time 300S; shear stress 13Pa Recovery phase 91 data points; 0.01S-25S; time 600S; shear stress 0Pa

[0179] The rheological properties test results are shown in Table 9 :

[0180] Table 9

[0181]

[0182] Figure 2 Figures 1 to 5 are flow curves of the commercial product, Example 1, Comparative Example 1, Comparative Example 2 and Comparative Example 7 measured according to the method of Table 6, using an Anton Paar rheometer to measure flow properties, embodied in the Herschel-Bulkley model (a mathematical model commonly used to describe the rheological behavior of non-Newtonian fluids). In the graph, the fluid shear stress is proportional to the shear rate, i.e. as the shear rate increases, the shear stress also increases, and the viscosity of the fluid decreases as the shear rate increases (from left to right). The parameters represent the following: Consistency index: b, also known as the consistency coefficient, b value is a measure of viscosity, but not equal to the viscosity value, and the higher the viscosity, the higher the b value;

[0183] Power law index: p, flow behavior index or non-Newtonian index, is a parameter related to temperature, the greater the deviation of p from 1, the stronger the non-Newtonian nature of the material; when p > 1, it is a generalized Bingham fluid that thickens with shear; when p < 1, it is a generalized Bingham fluid that thins with shear; when p = 1, it is an ideal Bingham fluid;

[0184] Yield stress τ0, flow occurs only when the external force exceeds this stress;

[0185] Eta represents the viscosity, which is the effective viscosity or apparent viscosity of a plastic fluid;

[0186] Figure 3 Figures 6-10 are linear viscoelastic region plots of the commercial product, Example 1, Comparative Example 1, Comparative Example 2 and Comparative Example 7 measured according to the method of Table 7, linear viscoelastic region, where the material exhibits a range of approximately linear stress-strain response, i.e. the interval where the storage modulus is much greater than the loss modulus, i.e. the linear viscoelastic region. Within this region, the behavior of the material can be described by a linear elastic model, which means that the material can completely recover to its original state without permanent deformation. As the shear strain increases, it is possible that G' and G" will intersect, which is called the "yield point", marking the beginning of the transition from solid to liquid.

[0187] Tau is the shear stress, representing the shear force per unit area;

[0188] Gamma is the shear strain, representing the degree of deformation of the material when subjected to shear stress;

[0189] Figure 4 Figures 11-15are the creep curves, also known as time-strain curves, of the commercially available product, Example 1, Comparative Example 1, Comparative Example 2 and Comparative Example 7 measured according to the creep test method of Table 8. The two curves represent the change in shear stress with time for the loading and recovery phases, respectively. Creep is a phenomenon in which a material undergoes plastic deformation over time, especially under a constant external force. Creep tests are often used to evaluate the ability of a material to resist long-term loading and to predict its long-term performance.

[0190] η0is the viscosity at zero shear rate, that is, the viscosity of the material when the shear rate is close to zero. The higher the η0, the stronger the material's ability to resist flow when under stress. During the creep process, η0reflects the amount of energy required for the material to resist deformation, directly affecting the creep rate.

[0191] Je0is the creep rate constant, which describes the speed at which the material deforms over time under constant stress. The larger the Je0, the faster the material's creep rate, or the more easily the material undergoes plastic deformation.

[0192] From Table 9 and the flow curves, linear viscoelastic region and creep data and graphs of the Examples and Comparative Examples in the Appendix Figures 1 to 15 It can be seen from Table 9 and the flow curves, linear viscoelastic region and creep data and graphs of the Examples and Comparative Examples in the Appendix

[0193] In vitro transdermal test (IVPT test)

[0194] To investigate the skin permeability of the sirolimus gels obtained in the above Examples 1-5 and Comparative Examples 1-8, a transdermal test was performed, as follows:

[0195] In-vitro transdermal method:

[0196] Method: Franz diffusion cell apparatus: Transdermal diffusion instrument (SYSTEM 9118-12) skin: pig skin receiving medium: pH 7.4 phosphate buffer (PBS) temperature: 32°C ± 1°C rotation speed: 600 revolutions per minute

[0197] Receiving liquid volume: 12 ml sample amount: 100 mg (equivalent to 0.2 mg of sirolimus)

[0198] Sampling time: 2h, 4h, 6h, 8h, 12h, 18h and 24h Sampling method: full sampling.

[0199] Detection method:

[0200] Detection method: LC-MS

[0201] HPLC chromatography conditions:

[0202] Chromatographic column: Octadecylsilane bonded silica gel as filler (Welch XB-C18, 150 mm × 4.6 mm, 5 μm or equivalent column) Mobile phase: 0.1% phosphoric acid solution-acetonitrile (50:50)

[0203] Detection wavelength: 254 nm Flow rate: 1.0 ml / min Injection room temperature: 15°C Column temperature: 30°C Injection volume: 10 μl MS conditions:

[0204] Ion source ESI+, MRM scan, sirolimus m / z 930.2→865.4, internal standard 32-desmethoxysirolimus m / z 900.2→833.9, analysis time 10.0 min

[0205] Specific operations:

[0206] Solvent A: pH 7.4 phosphate buffer (PBS) Solvent B: acetonitrile

[0207] Reference solution (high concentration): Accurately weigh an appropriate amount of sirolimus reference substance, dissolve it in solvent B, and quantitatively dilute it to a solution containing approximately 20 μg per 1 ml. (For testing residual test solution on skin)

[0208] Reference solution (low concentration): Accurately measure 1 ml of reference solution (high concentration) and place it in a 20 ml volumetric flask. Dilute to the mark with solvent B and shake well. Accurately measure 1 ml again and place it in a 100 ml volumetric flask. Dilute to the mark with solvent A and shake well. This gives 10 ng / ml. (For in vitro transdermal and intradermal retention test solutions)

[0209] In vitro transdermal test solution at each time point: 12 pig skins were taken, and homemade preparations and reference preparations were weighed alternately. Figure 16 ), place it on a pigskin with a 0.5mm thick quantitative ring, fill it with the sample and scrape the quantitative ring (containing about 100mg of this product), place the whole group (12 parts) of pigskin after drug application on the sample pool of the transdermal diffusion instrument, and start the test, and perform fixed-point sampling according to the above sampling time.

[0210] Residue on skin: After the test is completed, remove the diffusion cell and gently scrape off the residual drug on the pig skin with a clean scraper. Place the scraper and the quantitative loop in a 50ml centrifuge tube, accurately add 10ml of acetonitrile, cover and seal, sonicate for 20 minutes, filter, and take the filtrate as the test solution for residue on skin.

[0211] Intradermal retention: Cut the cleaned pigskin into small pieces and place them in a 50ml centrifuge tube. Add 10ml of acetonitrile and seal the tube. Ultrasonicate for 20min and filter. Take the filtrate as the test solution for intradermal retention.

[0212] Calculation formula

[0213] (1) The cumulative transdermal dose Q at time t is calculated using the following formula:

[0214] Q=Cn×V+∑Ci×Vi

[0215] Where Q is the cumulative transdermal dose per unit area in time t (%); V is the volume of the solution in the receiving pool; Vi is the volume of the sample; Cn is the measured concentration of the nth sample; Ci is the measured concentration of the n-1th sample;

[0216] (2) Absorption rate (J): J = (Q-Q0) / (h-h0)

[0217] (Q is the cumulative permeation per unit area at the sampling time point (μg·cm -2 ), Q0 is the cumulative permeation per unit area at the previous sampling time point (μg·cm -2 ); h is the sampling time point, h0 is the previous sampling time point)

[0218] (3) Intradermal retention: Intradermal retention = detection concentration of drug in skin homogenate × homogenate dilution volume

[0219] (4) Residue on skin: Residue on skin = detection concentration of drug in residue × pre-treatment dilution volume

[0220] Total amount of material (%) = 24h cumulative transdermal amount (%) + skin residue (%) + intradermal retention (%)

[0221] Accurately measure the above solutions, inject them into LC-MS respectively, and record the chromatogram.

[0222] The results are shown in Tables 10 and 11:

[0223] Table 10

[0224]

[0225]

[0226] Table 11

[0227] sample <![CDATA[皮内滞留量(μg / cm 2 )]]> sample <![CDATA[皮内滞留量(μg / cm 2 )]]> Commercially available products 4.12 Comparative Example 1 3.24 Example 1 4.23 Comparative Example 2 3.42 Example 2 3.93 Comparative Example 3 3.26 Example 3 4.50 Comparative Example 4 3.12 Example 4 3.88 Comparative Example 5 2.98 Example 5 3.59 Comparative Example 6 3.09 / / Comparative Example 7 4.77 / / Comparative Example 8 3.22

[0228] Comparing the 90% confidence intervals for the maximum absorption rate (Jmax) per unit area of ​​skin per unit time for the Examples and Comparative Examples in Table 10 reveals that the 90% confidence intervals for the Examples are narrower, indicating greater data consistency and reliability, closer to the experimental results of commercially available products. This demonstrates that the maximum rate of skin permeation of the sirolimus gel obtained in the Examples exhibits greater stability. Furthermore, comparing the 90% confidence intervals for the total skin permeation (Atotal) for the Examples and Comparative Examples in Table 10 shows that the Examples also exhibit narrower confidence intervals, further confirming their high consistency with the experimental results of commercially available products and greater reliability. This demonstrates that the stability of the cumulative amount of sirolimus gel permeated through the skin prepared in the Examples is also superior to that of the Comparative Examples.

[0229] Sirolimus gel is primarily used to treat facial angiofibromas in patients with tuberous sclerosis complex (TSC). It is applied topically, directly to the affected skin area, reducing the volume and amount of affected tissue, thereby improving skin appearance. Unlike transdermal preparations that exert systemic effects, drugs used to treat localized skin conditions penetrate more deeply into the stratum corneum and are retained there, exerting their antifungal effects while minimizing their entry into the dermis and systemic circulation, thereby reducing the occurrence of systemic adverse reactions.

[0230] Therefore, for topical preparations that act on the superficial layers of the skin, by measuring the drug content in the stratum corneum or dermis, i.e., the skin retention, it is possible to study the distribution of the drug in the skin and evaluate its efficacy. According to the data in Table 11, the intradermal retention of the commercially available product is 4.12 μg / cm 2 . The intradermal retention of the sirolimus gel obtained in Examples 1 to 5 is close to that of the commercially available product, showing good consistency. In contrast, the intradermal retention of the sirolimus gel obtained by adjusting the order of addition (such as Comparative Examples 1 and 2) is significantly lower than that of the commercially available product. As for the sirolimus gel obtained by adjusting the temperature conditions (such as Comparative Examples 3 to 8), its intradermal retention is significantly too low or too high compared to the commercially available product.

[0231] A rational manufacturing process is crucial for ensuring effective drug concentration in the target treatment area and minimizing potential side effects. The examples not only maintain similar skin retention to commercially available products, but also provide greater data reliability and improved stability. This is crucial for ensuring drug efficacy and safety, thereby improving patients' quality of life.

[0232] The sirolimus gel prepared by the process of the present invention has lower impurity content, excellent stability, outstanding rheological properties and transdermal absorption effect.

[0233] The embodiments of the present application are described above in conjunction with the accompanying drawings, but the present application is not limited to the above-mentioned specific implementation methods. The above-mentioned specific implementation methods are merely illustrative and not restrictive. Under the guidance of this application, ordinary technicians in this field can also make many forms without departing from the purpose of this application and the scope of protection of the claims, all of which are within the protection of this application.

Claims

1. A method for preparing rapamycin gel, characterized in that: The steps include: 1) Matrix treatment: Add the gel matrix to the solvent and stir to obtain a matrix dispersion; 2) Raw material processing: adding the prescribed amount of rapamycin to the permeation enhancer, followed by stirring to obtain a rapamycin solution; 3) Mixing: Slowly add the rapamycin solution prepared in step 2) to the matrix dispersion obtained in step 1) in a water bath at 0-15°C under vacuum, then add the prescribed amount of pH adjuster to adjust the pH to within the range of 5.0-7.0, and stir to obtain rapamycin gel; 4) Filling, The temperature of the raw material treatment in step 2) is 0-15°C. The gel matrix is ​​carbomer, the permeation enhancer is ethanol, the pH regulator is triethanolamine, and the solvent is purified water.

2. The method for preparing rapamycin gel according to claim 1, wherein: The temperature of the substrate treatment in step 1) is 20-25°C.

3. The method for preparing rapamycin gel according to claim 2, characterized in that: The stirring speed in step 1) is 350-450 rpm.

4. The method for preparing rapamycin gel according to claim 3, characterized in that: The stirring speed in step 2) is 350-450 rpm.

5. The method for preparing rapamycin gel according to claim 1, wherein The vacuum degree of mixing in step 3) is -0.06 to -0.08 MPa.

6. The method for preparing rapamycin gel according to claim 5, characterized in that: The stirring speed in step 3) is 10-150 rpm.

7. The method for preparing rapamycin gel according to claim 1, wherein The rapamycin gel comprises: rapamycin w / w 0.1-0.5%, gel matrix w / w 1-3%, permeation enhancer w / w 40-60%, pH regulator w / w 0.1-1% and solvent w / w 40-60%.

8. Rapamycin gel prepared by the method according to any one of claims 1 to 7.

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