High-stability mometasone furoate cream and processing technology thereof

Abstract

The invention discloses high-stability mometasone furoate emulsifiable paste and a processing technology thereof, and relates to the technical field of emulsifiable paste preparations. A double-emulsification-system preparation process is adopted, the stability of the cream is remarkably improved, firstly, main drug active ingredients are prepared into submicron emulsion through dispersion and homogenization to form a first emulsification system (W / O) to play a role in primary protection, secondly, dispersion is added into a water phase to form an oil-in-water particle structure, and then the dispersion and an oil phase are emulsified to form a second emulsification system (O / W / O) to play a role in secondary protection. The mometasone furoate emulsifiable paste with high stability is prepared by adding auxiliary materials such as titanium dioxide and starch aluminum octenylsuccinate, so that the bioavailability of mometasone furoate is improved; by cooperating with excellent oxidation resistance of 4-vinyl guaiacol, gallic acid and glycyrrhizic acid, the oxidation resistance of the cream is remarkably improved, and the long-acting stability of the cream is further ensured.

Description

Technical Field

[0001] This invention relates to the field of cream formulation technology, specifically a highly stable mometasone furoate cream and its processing technology. Background Technology

[0002] Mometasone furoate is a highly effective topical corticosteroid that is easily degraded in water. Its stability can be improved through cream formulation processes. However, existing mometasone furoate cream formulations often struggle to balance physical stability and user experience. Some preparation processes add viscosity modifiers, resulting in products with slower release rates and lower irritation, but these often suffer from excessive viscosity, a sticky feel, and difficulty in spreading evenly. Other formulations improve spreadability to enhance coating uniformity, but new quality issues remain, such as hardening due to dehydration, emulsion breakdown, or drug crystallization upon prolonged storage. At low temperatures, dissolved mometasone furoate is also prone to crystallization, affecting efficacy. To achieve sufficient stability, existing technologies use stabilizers and preservatives to ensure the long-term stability of the active ingredient. This not only increases the difficulty of formulation design and process optimization but may also affect the stability of the final product due to compatibility issues between different excipients, increasing the risk of skin irritation or allergies. Therefore, this invention proposes a highly stable mometasone furoate cream and its processing technology to solve the aforementioned technical problems. Summary of the Invention

[0003] The purpose of this invention is to provide a highly stable mometasone furoate cream and its processing technology to solve the problems raised in the prior art.

[0004] To achieve the above objectives, the present invention provides the following technical solution: A processing technology for a highly stable mometasone furoate cream includes the following steps: S1: Preparation of the oil phase: The modified oily matrix and emulsifier are heated to 60~85℃ to melt and stirred evenly to obtain the oil phase; S2: Preparation of the aqueous phase: Glycerol and propylene glycol are added to deionized water and stirred until homogeneous to obtain the aqueous phase; S3: Preparation of active solution: Add mometasone furoate submicroemulsion system to aqueous phase, heat to 50~65℃, stir evenly to obtain active solution; S4: Preparation of cream: Add the active solution to the oil phase, heat to 50~60℃, then add gallic acid, titanium dioxide, aluminum starch octenyl succinate, emulsify, homogenize, and cool to obtain mometasone furoate cream.

[0005] In the above technical solution, gallic acid, as a polyphenol compound, has antioxidant properties, and mometasone furoate is more stable under acidic conditions. On the one hand, gallic acid can maintain the cream system in an acidic environment, and on the other hand, it can weaken the oxidation reaction by scavenging free radicals, protect the main drug ingredients, and reduce the impurity content. Titanium dioxide is used as a light-blocking agent, and aluminum starch octenyl succinate is used as a thickener to adjust the viscosity of the cream, making it easy to spread and ensuring that the cream has sufficient adhesion to the skin, avoiding the problems of stickiness or uneven application. It can have a synergistic effect with titanium dioxide and gallic acid to improve the stability of the product during storage.

[0006] Furthermore, the mometasone furoate cream comprises the following components by weight: 1-10 parts of mometasone furoate submicroemulsion system, 40-60 parts of modified oily matrix, 5-10 parts of emulsifier, 3-8 parts of gallic acid, 1-5 parts of glycerin, 5-15 parts of propylene glycol, 5-10 parts of deionized water, 1-4 parts of titanium dioxide, and 30-50 parts of aluminum starch octenyl succinate.

[0007] Furthermore, the emulsifier is any one of nonylphenol polyoxyethylene ether, octylphenol polyoxyethylene ether, fatty alcohol polyoxyethylene ether, and methyl stearate polyoxyethylene ether.

[0008] Furthermore, the modified oily matrix is ​​prepared by the following process: Step 1: Add D4 (octamethylcyclotetrasiloxane) to toluene and stir until homogeneous. Add tetramethyldisiloxane and acidic cation exchange resin. React at 60-70°C for 3-5 hours. After the reaction is complete, cool and filter to remove the acidic cation exchange resin to obtain hydrogen-containing silicone oil. Step 2: Add 4-vinylguaiacol to the hydrogen-containing silicone oil, heat to 70~90℃, add the caster catalyst and purge with nitrogen gas. After reacting for 5~6 hours, distill under reduced pressure to obtain the modified silicone oil. Step 3: Mix lanolin, modified silicone oil, octadecanol, paraffin, and white petrolatum to obtain a modified oily matrix.

[0009] Furthermore, the molar ratio of D4 to tetramethyldisiloxane is (2~5):1.

[0010] Furthermore, the amount of acidic cation exchange resin added is 2-3 wt% of the reaction system.

[0011] Furthermore, the mass ratio of hydrogen-containing silicone oil to 4-vinylguaiacol is (10~15):(2~4).

[0012] Furthermore, the amount of cassette catalyst added is 0.1~0.5 wt% of the reaction system.

[0013] Furthermore, the modified oily matrix comprises the following components by weight: 40-60 parts lanolin, 8-12 parts modified silicone oil, 1-3 parts octadecyl alcohol, 5-10 parts paraffin wax, and 9-12 parts white petrolatum.

[0014] In the above technical solution, by adding lanolin and modified silicone oil to the oily matrix, the degradation of mometasone furoate in the cream is inhibited. Lanolin, as a moisturizer and ointment matrix, can enhance the adhesion and lubricity of the matrix and prevent the cream from being too dry. Mometasone furoate has poor solubility and is prone to crystallization at low temperatures. The mometasone furoate cream of the present invention uses lanolin, modified silicone oil, octadecanol, paraffin, and white petrolatum as the oily matrix of the cream to improve solubility and optimize the spreadability and skin feel of the topical preparation. Hydrogen-containing silicone oil is prepared by using D4 as a monomer and tetramethyldisiloxane as a capping compound. Through the addition reaction of the silanium-hydrogen bonds of the hydrogen-silicon oil with vinyl groups, methoxy groups, benzene rings, and other groups are introduced into the silicone oil molecular chain to improve the stability of the oily matrix, thereby improving the stability of the cream and making it present a uniform and stable cream at both high and low temperatures without demulsification or crystallization.

[0015] Furthermore, the mometasone furoate submicroemulsion system is prepared by the following process: Step 1: Add glycyrrhizic acid to methanol and stir, then add EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), NHS (N-hydroxysuccinimide), and soybean lecithin. React at 40~60℃ for 8~10h, then distill under reduced pressure to obtain modified soybean lecithin. Step 2: Add mometasone furoate and modified soybean lecithin to dichloromethane, stir for 1-2 hours at 40-60°C, emulsify at 2500-2700 rpm for 3-5 minutes, homogenize at 13000-15000 rpm for 3-5 minutes, and distill under reduced pressure to obtain the mometasone furoate submicroemulsion system.

[0016] Furthermore, the particle size of the mometasone furoate submicroemulsion system is 0.4~0.8 μm.

[0017] Furthermore, the mass ratio of glycyrrhizic acid to methanol is (1~3):(10~20).

[0018] Furthermore, the mass ratio of glycyrrhizic acid, EDC, NHS, and soybean lecithin is (8.2~8.5):1.5:1:(7.5~7.8).

[0019] Furthermore, the mass ratio of mometasone furoate, modified soybean lecithin, and dichloromethane is 1:(10~20):(40~50).

[0020] In the above technical solution, soybean phospholipids mainly consist of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol, exhibiting amphiphilicity, emulsifying properties, and biocompatibility. However, soybean phospholipids have a low HLB (hydrophilic-lipophilic balance) value, are easily oxidized, and are temperature-sensitive. Modification with glycyrrhizic acid can improve their emulsifying properties and stability. Firstly, the carboxyl groups of glycyrrhizic acid are activated using EDC and NHS, further undergoing a condensation reaction with the amino groups in the soybean phospholipid molecular chain, thus grafting glycyrrhizic acid onto the soybean phospholipid. In the molecular chain of glycyrrhizic acid, the hydroxyl groups and glycosyl groups in the molecular structure can improve the stability and antioxidant properties of soybean phospholipids. In addition, glycyrrhizic acid can produce a synergistic anti-inflammatory effect with mometasone furoate. By preparing mometasone furoate into a submicroemulsion system and dispersing the drug in the oil phase, the pain caused by mometasone furoate precipitation can be reduced and the drug irritation can be alleviated. The drug dissolved in the submicroemulsion oil phase is released through diffusion from the oil phase and then through contact with the skin, which has a significant sustained-release effect compared to the release rate of the drug itself.

[0021] In summary, the dual-emulsion system preparation process of this invention significantly improves the stability of the cream. First, the active pharmaceutical ingredient is dispersed and homogenized to form a submicroemulsion, creating a first emulsion system (W / O) that provides initial protection. Second, the dispersion is added to the aqueous phase to form an oil-in-water microparticle structure, which is then emulsified with the oil phase to form a second emulsion system (O / W / O). Combined with excipients such as gallic acid, titanium dioxide, and aluminum starch octenyl succinate, a highly stable mometasone furoate cream is obtained, improving the bioavailability of active mometasone furoate. 4-Vinylguaiacol and glycyrrhizic acid possess excellent antioxidant properties, significantly enhancing the cream's antioxidant capacity and further ensuring its long-term stability.

[0022] All solvent residues in this application meet the limits specified in Q3C: Impurities: Residual Solvents, all quality standards comply with the provisions of the Chinese Pharmacopoeia, and all production operating procedures are in compliance with the Good Manufacturing Practices for Pharmaceuticals, ensuring the quality and safety of the pharmaceutical products.

[0023] Compared with the prior art, the beneficial effects of the present invention are: 1. By adding gallic acid, this invention maintains an acidic environment in the cream system and weakens oxidation by scavenging free radicals, thereby protecting the main drug components and reducing impurity content.

[0024] 2. This invention inhibits the degradation of mometasone furoate in creams by adding lanolin and modified silicone oil to an oily matrix. Lanolin, as a moisturizer and ointment matrix, enhances the adhesion and lubricity of the matrix, preventing the cream from being too dry. Mometasone furoate has poor solubility and is prone to crystallization at low temperatures. The modified oily matrix improves the stability of the oily matrix by introducing groups such as methoxy and benzene rings into the silicone oil molecular chain, thereby improving the stability of the cream and making it present a uniform and stable cream at both high and low temperatures without demulsification or crystallization.

[0025] 3. This invention improves the emulsifying properties and stability of soybean lecithin by modifying it with glycyrrhizic acid. The hydroxyl and glycosyl groups in the glycyrrhizic acid molecular structure can improve the stability and antioxidant properties of soybean lecithin. In addition, glycyrrhizic acid can produce a synergistic anti-inflammatory effect with mometasone furoate. By preparing mometasone furoate into a submicroemulsion system, the drug is dispersed in the oil phase, reducing the pain caused by mometasone furoate precipitation and alleviating drug irritation. The drug dissolved in the submicroemulsion oil phase is released through diffusion from the oil phase before contact with the skin, which has a significant sustained-release effect compared to the release rate of the drug itself.

[0026] 4. The dual-emulsification system preparation process of this invention significantly improves the stability of the cream. First, the active pharmaceutical ingredient is dispersed and homogenized to form a submicroemulsion, forming a first emulsion system (W / O), which provides initial protection. Second, the dispersion is added to the aqueous phase to form an oil-in-water microparticle structure, and then emulsified with the oil phase to form a second emulsion system (O / W / O). In conjunction with excipients such as gallic acid, titanium dioxide, and aluminum starch octenyl succinate, a highly stable mometasone furoate cream is obtained, which improves the bioavailability of mometasone furoate. The excellent antioxidant properties of 4-vinylguaiacol and glycyrrhizic acid enhance the antioxidant properties of the cream, further ensuring the long-term stability of the cream. Attached Figure Description

[0027] Figure 1 This is a microscopic characterization diagram of the active pharmaceutical ingredient in Example 1; Figure 2 This is a microscopic characterization diagram of aluminum starch octenyl succinate from Example 1; Figure 3 This is a microscopic characterization diagram of titanium dioxide from Example 1; Figure 4 The image shows the microscopic characterization of mometasone furoate cream from Example 1. Figure 5 This is a microscopic characterization diagram of mometasone furoate cream, Comparative Example 1. Detailed Implementation

[0028] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0029] In the following specific embodiments, unless otherwise specified, the number of “parts” refers to parts by mass; Acidic cation exchange resin, model: NKC-9; Castel catalyst, platinum-diethylenetetramethyldisiloxane, CAS: 68478-92-2; Titanium dioxide, model NT-50; Nonylphenol polyoxyethylene ether, model NP-10; Octenyl succinate aluminum starch, brand name HF PHARMA; Paraffin wax, pharmaceutical grade; Lanolin, pharmaceutical grade; White petroleum jelly, model number MERKUR 110.

[0030] Example 1: A processing technology for a highly stable mometasone furoate cream includes the following steps: S1: Preparation of the oil phase: The modified oily matrix and nonylphenol polyoxyethylene ether are heated to 60°C to melt and stirred evenly to obtain the oil phase; S2: Preparation of the aqueous phase: Glycerol and propylene glycol are added to deionized water and stirred until homogeneous to obtain the aqueous phase; S3: Preparation of active solution: Add mometasone furoate submicroemulsion system to aqueous phase, heat to 50℃, stir evenly to obtain active solution; S4: Preparation of cream: Add the active solution to the oil phase, heat to 50°C, then add gallic acid, titanium dioxide, aluminum starch octenyl succinate, emulsify, homogenize, and cool to obtain mometasone furoate cream. Mometasone furoate cream comprises the following components: 1 part mometasone furoate submicroemulsion system, 40 parts modified oily matrix, 5 parts nonylphenol polyoxyethylene ether, 3 parts gallic acid, 1 part glycerin, 15 parts propylene glycol, 10 parts deionized water, 4 parts titanium dioxide, and 30 parts octenyl succinate aluminum starch. The modified oily matrix is ​​prepared by the following process: Step 1: Add D4 (octamethylcyclotetrasiloxane) to toluene and stir until homogeneous. Add tetramethyldisiloxane and acidic cation exchange resin. React at 60°C for 3 hours. After the reaction is complete, cool and filter to remove the acidic cation exchange resin to obtain hydrogen-containing silicone oil. The molar ratio of D4 to tetramethyldisiloxane is 2:1; the amount of acidic cation exchange resin added is 2 wt% of the reaction system. Step 2: Add 4-vinylguaiacol to the hydrogen-containing silicone oil, heat to 70°C, add the caster catalyst and purge with nitrogen. After reacting for 5 hours, distill under reduced pressure to obtain modified silicone oil; the mass ratio of hydrogen-containing silicone oil to 4-vinylguaiacol is 10:2; the amount of caster catalyst added is 0.1 wt% of the reaction system. Step 3: Mix lanolin, modified silicone oil, octadecanol, paraffin wax, and white petrolatum to obtain a modified oily matrix; The improved oily matrix comprises the following components: 40 parts lanolin, 8 parts modified silicone oil, 1 part octadecanol, 5 parts paraffin wax, and 12 parts white petrolatum. The mometasone furoate submicroemulsion system was prepared by the following process: Step 1: Add glycyrrhizic acid to methanol and stir. Add EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), NHS (N-hydroxysuccinimide), and soybean lecithin. React at 40°C for 8 hours. Distill under reduced pressure to obtain modified soybean lecithin. The mass ratio of glycyrrhizic acid to methanol is 1:10. The mass ratio of glycyrrhizic acid, EDC, NHS, and soybean lecithin is 8.2:1.5:1:7.5. Step 2: Add mometasone furoate and modified soybean lecithin to dichloromethane, stir for 1 hour at 40°C, emulsify at 2500 rpm for 3 minutes, homogenize at 13000 rpm for 3 minutes, and distill under reduced pressure to obtain a mometasone furoate submicroemulsion system; the average particle size of the mometasone furoate submicroemulsion system is 0.45 μm; the mass ratio of mometasone furoate, modified soybean lecithin, and dichloromethane is 1:10:40.

[0031] Example 2: A processing technology for a highly stable mometasone furoate cream includes the following steps: S1: Preparation of the oil phase: The modified oily matrix and nonylphenol polyoxyethylene ether are heated to 70°C to melt and stirred evenly to obtain the oil phase; S2: Preparation of the aqueous phase: Glycerol and propylene glycol are added to deionized water and stirred until homogeneous to obtain the aqueous phase; S3: Preparation of active solution: Add mometasone furoate submicroemulsion system to aqueous phase, heat to 60℃, stir evenly to obtain active solution; S4: Preparation of cream: Add the active solution to the oil phase, heat to 55°C, then add gallic acid, titanium dioxide, aluminum starch octenyl succinate, emulsify, homogenize, and cool to obtain mometasone furoate cream. Mometasone furoate cream comprises the following components: 5 parts mometasone furoate submicroemulsion system, 50 parts modified oily matrix, 8 parts nonylphenol polyoxyethylene ether, 5 parts gallic acid, 3 parts glycerin, 10 parts propylene glycol, 8 parts deionized water, 3 parts titanium dioxide, and 40 parts octenyl succinate aluminum starch. The modified oily matrix is ​​prepared by the following process: Step 1: Add D4 to toluene and stir until homogeneous. Add tetramethyldisiloxane and acidic cation exchange resin. React at 65°C for 4 hours. After the reaction is complete, cool and filter to remove the acidic cation exchange resin to obtain hydrogen-containing silicone oil. The molar ratio of D4 to tetramethyldisiloxane is 3:1. The amount of acidic cation exchange resin added is 2.5 wt% of the reaction system. Step 2: Add 4-vinylguaiacol to the hydrogen-containing silicone oil, heat to 90℃, add the caster catalyst and purge with nitrogen. After reacting for 6 hours, distill under reduced pressure to obtain the modified silicone oil; the mass ratio of hydrogen-containing silicone oil to 4-vinylguaiacol is 15:4; the amount of caster catalyst added is 0.5 wt% of the reaction system. Step 3: Mix lanolin, modified silicone oil, octadecanol, paraffin wax, and white petrolatum to obtain a modified oily matrix; The improved oily matrix comprises the following components by weight: 60 parts lanolin, 12 parts modified silicone oil, 3 parts octadecanol, 10 parts paraffin wax, and 12 parts white petrolatum; The mometasone furoate submicroemulsion system was prepared by the following process: Step 1: Add glycyrrhizic acid to methanol and stir, then add EDC, NHS, and soybean lecithin. React at 60℃ for 10 hours, then distill under reduced pressure to obtain modified soybean lecithin. The mass ratio of glycyrrhizic acid to methanol is 3:20; the mass ratio of glycyrrhizic acid, EDC, NHS, and soybean lecithin is 8.5:1.5:1:7.8. Step 2: Add mometasone furoate and modified soybean lecithin to dichloromethane, stir at 60°C for 2 hours, emulsify at 2700 rpm for 5 minutes, homogenize at 15000 rpm for 5 minutes, and distill under reduced pressure to obtain a mometasone furoate submicroemulsion system; the average particle size of the mometasone furoate submicroemulsion system is 0.75 μm; the mass ratio of mometasone furoate, modified soybean lecithin, and dichloromethane is 1:20:50.

[0032] Example 3: A processing technology for a highly stable mometasone furoate cream includes the following steps: S1: Preparation of the oil phase: The modified oily matrix and nonylphenol polyoxyethylene ether are heated to 85°C to melt and stirred evenly to obtain the oil phase; S2: Preparation of the aqueous phase: Glycerol and propylene glycol are added to deionized water and stirred until homogeneous to obtain the aqueous phase; S3: Preparation of active solution: Add mometasone furoate submicroemulsion system to aqueous phase, heat to 65℃, stir evenly to obtain active solution; S4: Preparation of cream: Add the active solution to the oil phase, heat to 60°C, then add gallic acid, titanium dioxide, aluminum starch octenyl succinate, emulsify, homogenize, and cool to obtain mometasone furoate cream. Mometasone furoate cream comprises the following components: 10 parts mometasone furoate submicroemulsion system, 60 parts modified oily matrix, 10 parts nonylphenol polyoxyethylene ether, 8 parts gallic acid, 5 parts glycerin, 15 parts propylene glycol, 10 parts deionized water, 4 parts titanium dioxide, and 50 parts octenyl succinate aluminum starch. The modified oily matrix is ​​prepared by the following process: Step 1: Add D4 to toluene and stir until homogeneous. Add tetramethyldisiloxane and acidic cation exchange resin. React at 70°C for 5 hours. After the reaction is complete, cool and filter to remove the acidic cation exchange resin to obtain hydrogen-containing silicone oil. The molar ratio of D4 to tetramethyldisiloxane is 5:1. The amount of acidic cation exchange resin added is 3 wt% of the reaction system. Step 2: Add 4-vinylguaiacol to the hydrogen-containing silicone oil, heat to 90°C, add the caster catalyst and purge with nitrogen. After reacting for 6 hours, distill under reduced pressure to obtain the modified silicone oil. The mass ratio of hydrogen-containing silicone oil to 4-vinylguaiacol is 15:4; the amount of caster catalyst added is 0.5 wt% of the reaction system. Step 3: Mix lanolin, modified silicone oil, octadecanol, paraffin wax, and white petrolatum to obtain a modified oily matrix; The improved oily matrix comprises the following components by weight: 60 parts lanolin, 12 parts modified silicone oil, 3 parts octadecanol, 10 parts paraffin wax, and 12 parts white petrolatum; The mometasone furoate submicroemulsion system was prepared by the following process: Step 1: Add glycyrrhizic acid to methanol and stir, then add EDC, NHS, and soybean lecithin. React at 60℃ for 10 hours, then distill under reduced pressure to obtain modified soybean lecithin. The mass ratio of glycyrrhizic acid to methanol is 3:20; the mass ratio of glycyrrhizic acid, EDC, NHS, and soybean lecithin is 8.5:1.5:1:7.8. Step 2: Add mometasone furoate and modified soybean lecithin to dichloromethane, stir at 60°C for 2 hours, emulsify at 2700 rpm for 5 minutes, homogenize at 15000 rpm for 5 minutes, and distill under reduced pressure to obtain a mometasone furoate submicroemulsion system; the average particle size of the mometasone furoate submicroemulsion system is 0.8 μm; the mass ratio of mometasone furoate, modified soybean lecithin, and dichloromethane is 1:20:50.

[0033] Comparative Example 1: This comparative example provides a processing technology for a highly stable mometasone furoate cream. The mometasone furoate cream comprises the following components by weight: 10 parts mometasone furoate, 40 parts modified oily matrix, 5 parts nonylphenol polyoxyethylene ether, 3 parts gallic acid, 1 part glycerin, 5 parts propylene glycol, 5 parts deionized water, 1 part titanium dioxide, and 30 parts aluminum starch octenyl succinate. The remaining formulation and processing technology are the same as in Example 1.

[0034] Comparative Example 2: This comparative example provides a processing technology for a highly stable mometasone furoate cream, which comprises the following components by weight: 1 part mometasone furoate submicroemulsion system, 40 parts oily matrix, 5 parts nonylphenol polyoxyethylene ether, 3 parts gallic acid, 1 part glycerin, 5 parts propylene glycol, 5 parts deionized water, 1 part titanium dioxide, and 30 parts octenyl succinate aluminum starch. The oily matrix comprises the following components by weight: 40 parts lanolin, 8 parts dimethicone, 1 part octadecanol, 5 parts paraffin wax, and 9 parts white petrolatum; the remaining formulation and processing technology are the same as in Example 1.

[0035] Comparative Example 3: This comparative example provides a processing technology for a highly stable mometasone furoate cream. The mometasone furoate cream comprises the following components by weight: 1 part mometasone furoate, 40 parts modified oily matrix, 5 parts nonylphenol polyoxyethylene ether, 3 parts gallic acid, 1 part glycerin, 5 parts propylene glycol, 5 parts deionized water, 1 part titanium dioxide, and 30 parts aluminum starch octenyl succinate. The remaining formulation and processing technology are the same as in Example 1.

[0036] Comparative Example 4: This comparative example provides a processing technology for a highly stable mometasone furoate cream, which comprises the following components by weight: 1 part mometasone furoate, 40 parts oily matrix, 5 parts nonylphenol polyoxyethylene ether, 3 parts gallic acid, 1 part glycerin, 5 parts propylene glycol, 5 parts deionized water, 1 part titanium dioxide, and 30 parts aluminum starch octenyl succinate. The oily matrix comprises the following components by weight: 40 parts lanolin, 8 parts dimethicone, 1 part octadecanol, 5 parts paraffin wax, and 9 parts white petrolatum; the remaining formulation and processing technology are the same as in Example 1.

[0037] experiment: Mometasone furoate creams obtained in Examples 1-3 and Comparative Examples 1-4 were prepared into samples, and their drug quality and stability were tested. The test results were recorded. Drug testing: The samples were tested and the data were recorded in accordance with the testing standards and methods of the Chinese Pharmacopoeia. The testing process complied with the Good Manufacturing Practice for Pharmaceuticals. Stability testing: In accordance with the guidelines for stability testing in the Chinese Pharmacopoeia and the technical guidelines for stability research of chemical drugs, stability tests were conducted under high temperature, high humidity, and low temperature conditions, and the data were recorded.

[0038] Table 1. Detection data of mometasone furoate cream formulation. Table 2. Detection data of mometasone furoate cream formulation. Table 3. Stability testing of mometasone furoate cream formulation Based on the data in the table above, the following conclusions can be clearly drawn: The results of the tests conducted in Examples 1-3 and Comparative Examples 1-4 show that: As can be seen from the microscopic characterization diagram, the cream in Example 1 has a uniform and delicate structure, and the drug is well dispersed. Figure 4 In contrast, Comparative Example 1 showed obvious particle aggregation or crystallization. Figure 5 ).

[0039] Depend on Figure 1 , Figure 2 , Figure 3 , Figure 4 It can be seen that the mometasone furoate raw material (API) of this product is in the form of block or short rod-shaped crystals, the aluminum starch octenyl succinate appears as a four-lobed shape under polarized light, and the titanium dioxide is a black granule that does not emit light under polarized light. Therefore, the raw materials and excipients suspended in this product can be clearly distinguished.

[0040] Depend on Figure 5 It can be seen that in Comparative Example 1, mometasone furoate was added in excess, and the microscopic characterization showed that it was in the form of blocky or short rod-shaped crystals. This indicates that if the API is not dissolved, blocky or short rod-shaped crystals can be clearly observed, which proves that the raw material of this product exists in dissolved form.

[0041] Compared with the comparative examples, the pH values ​​of Examples 1-3 were maintained in the acidic range of 4.8-4.9, with moderate viscosity and yield stress, uniform D50 and D90 particle sizes, relatively uniform dispersion, stable flow curve parameters and creep parameters, and a storage modulus (G') higher than the loss modulus (G"), indicating that the preparation process and formulation of mometasone furoate cream of the present invention help maintain the stability of mometasone furoate, with good spreadability and adhesion, solid elasticity, which is beneficial for storage and application, good recovery performance, and long-term stability under high temperature, high humidity, and low temperature storage; the T / R confidence interval of the in vitro release rate is moderate, indicating uniform and sustained drug release and high bioavailability.

[0042] Compared with Example 1, Comparative Example 1 had an excess of active pharmaceutical ingredient; Comparative Example 2 used conventional components in its oily matrix; Comparative Example 3 did not prepare the mometasone furoate active pharmaceutical ingredient into a submicroemulsion system; Comparative Example 4 did not prepare the mometasone furoate active pharmaceutical ingredient into a submicroemulsion system, and its oily matrix used conventional components. Under conditions of 40°C and RH 90%, the total impurity content of the examples increased slowly, while the total impurities of Comparative Examples 1-4 increased significantly, confirming that the improved oily matrix and submicroemulsion system improved drug solubility and prevented low-temperature instability. Antioxidant components such as 4-vinylguaiacol and glycyrrhizic acid can effectively inhibit the degradation of the active pharmaceutical ingredient. This demonstrates the technical advantage of the present invention in that the dual emulsification process synergistically improves the components and enhances the stability of mometasone furoate cream.

[0043] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

Claims

1. A processing method for a highly stable mometasone furoate cream, characterized in that: Including the following processes: S1: Preparation of the oil phase: The modified oily matrix and emulsifier are heated to melt and stirred evenly to obtain the oil phase; S2: Preparation of the aqueous phase: Glycerol and propylene glycol are added to deionized water and stirred until homogeneous to obtain the aqueous phase; S3: Preparation of active solution: Add mometasone furoate submicroemulsion system to aqueous phase, heat and stir until homogeneous to obtain active solution; S4: Preparation of cream: Add the active solution to the oil phase, then add gallic acid, titanium dioxide, aluminum starch octenyl succinate, emulsify, homogenize, and cool to obtain mometasone furoate cream.

2. The processing method of a highly stable mometasone furoate cream according to claim 1, characterized in that: The mometasone furoate cream comprises the following components by weight: 1-10 parts of mometasone furoate submicroemulsion system, 40-60 parts of modified oily matrix, 5-10 parts of emulsifier, 3-8 parts of gallic acid, 1-5 parts of glycerin, 5-15 parts of propylene glycol, 5-10 parts of deionized water, 1-4 parts of titanium dioxide, and 30-50 parts of aluminum starch octenyl succinate.

3. The processing method for a highly stable mometasone furoate cream according to claim 1, characterized in that: The modified oily matrix is ​​prepared by the following process: Step 1: Add D4 to toluene and stir well. Add tetramethyldisiloxane and acidic cation exchange resin. React at 60-70°C for 3-5 hours. After the reaction is complete, cool and filter to remove the acidic cation exchange resin to obtain hydrogen-containing silicone oil. Step 2: Add 4-vinylguaiacol to the hydrogen-containing silicone oil, heat to 70~90℃, add the caster catalyst and purge with nitrogen gas. After reacting for 5~6 hours, distill under reduced pressure to obtain the modified silicone oil. Step 3: Mix lanolin, modified silicone oil, octadecanol, paraffin, and white petrolatum to obtain a modified oily matrix.

4. The processing method of a highly stable mometasone furoate cream according to claim 1, characterized in that: The mometasone furoate submicroemulsion system was prepared by the following process: Step 1: Add glycyrrhizic acid to methanol and stir, add EDC and NHS, add soybean lecithin, heat to react, and distill under reduced pressure to obtain modified soybean lecithin; Step 2: Add mometasone furoate and modified soybean lecithin to dichloromethane, stir for 1-2 hours at 40-60℃ to emulsify, then homogenize and distill under reduced pressure to obtain mometasone furoate submicroemulsion system.

5. The processing technology of a highly stable mometasone furoate cream according to claim 1, characterized in that: The particle size of the mometasone furoate submicroemulsion system is 0.4~0.8 μm.

6. The processing method for a highly stable mometasone furoate cream according to claim 3, characterized in that: The modified oily matrix comprises the following components by weight: 40-60 parts lanolin, 8-12 parts modified silicone oil, 1-3 parts octadecanol, 5-10 parts paraffin wax, and 9-12 parts white petrolatum.

7. The processing method for a highly stable mometasone furoate cream according to claim 2, characterized in that: The emulsifier is any one of nonylphenol polyoxyethylene ether, octylphenol polyoxyethylene ether, fatty alcohol polyoxyethylene ether, and methyl stearate polyoxyethylene ether.

8. The processing method for a highly stable mometasone furoate cream according to claim 4, characterized in that: The mass ratio of glycyrrhizic acid to methanol is (1~3):(10~20); the mass ratio of glycyrrhizic acid, EDC, NHS, and soybean lecithin is (8.2~8.5):1.5:1:(7.5~7.8); the mass ratio of mometasone furoate, modified soybean lecithin, and dichloromethane is 1:(10~20):(40~50).

9. The processing method for a highly stable mometasone furoate cream according to claim 3, characterized in that: The molar ratio of D4 to tetramethyldisiloxane is (2~5):1; the amount of acidic cation exchange resin added is 2~3wt% of the reaction system; the mass ratio of hydrogen-containing silicone oil to 4-vinylguaiacol is (10~15):(2~4); and the amount of caster catalyst added is 0.1~0.5wt% of the reaction system.

10. A highly stable mometasone furoate cream, characterized in that: It is prepared by the processing technology according to any one of claims 1-9.

Images