A self-emulsifying nano-preparation of tofacitinib and a preparation method thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a self-emulsifying nanometer preparation of tofacitinib and a preparation method thereof. The tofacitinib free base is mixed with diethylene glycol monoethyl ether, and is dissolved by heating and oscillation; then polyoxyethylene 40 hydrogenated castor oil and glyceryl monocaprylate are added, and are uniformly stirred to obtain a drug-containing SEDDS solution; the SEDDS solution is added dropwise into magnesium aluminosilicate to obtain a SEDDS solidified powder. The method significantly improves the solubility and stability of the tofacitinib free base, simplifies the production process, improves the bioavailability and safety of the drug, provides various preparation forms, and meets the medication needs of different patients.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a self-emulsifying nanoformulation of tofacitinib and its preparation method. Background Technology

[0002] Tofacitinib, developed by Pfizer, is the world's first approved oral JAK inhibitor for the treatment of autoimmune diseases. As a potent small-molecule JAK inhibitor, tofacitinib precisely blocks the intracellular JAK-STAT signaling pathway to inhibit the production of various inflammatory cytokines, achieving precise regulation of the immune system. Tofacitinib is primarily used to treat autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, and ulcerative colitis, offering advantages such as convenient oral administration, rapid onset of action, and a non-protein structure.

[0003] Tofacitinib exists in marketed formulations as tofacitinib citrate. The free base of tofacitinib has relatively low solubility in water, making it a restricted state. Converting it to citrate alters the drug's crystal lattice, significantly enhancing its hydrophilicity, as citric acid is a multi-level dissociated organic acid. This ensures rapid release and saturation in the gastrointestinal tract, guaranteeing effective absorption in the small intestine. Furthermore, the acidic environment of citrate buffers fluctuations in gastrointestinal pH, reducing inter-individual absorption variability and resulting in a smoother pharmacokinetic (PK) curve. However, tofacitinib citrate also has certain drawbacks: 1) Tofacitinib citrate exists in multiple crystal forms, and the water activity of the solvent in the salt formation process directly affects whether an amorphous or specific crystalline state is formed, thus affecting solubility and the dissolution profile of the formulation; 2) Tofacitinib contains an active chemical group, cyanoacetyl, which may be degraded by acid and alkali, so the pH environment needs to be precisely controlled in the salt formation process; 3) The stability of citric acid itself is a concern. If the temperature is too high during the drying stage, citric acid will dehydrate to form aconitic acid, itaconic acid, or citric anhydride, etc. These degradation products contain unsaturated double bonds, which may undergo Michael addition reactions with tofacitinib molecules to form addition impurities that are extremely difficult to remove.

[0004] Tofacitinib exhibits a significant pH-dependent solubility, with extremely high solubility in acidic environments and significantly reduced solubility in neutral and slightly alkaline environments. This pH dependence leads to instability in blood drug concentrations. Specifically, because tofacitinib dissolves rapidly in the stomach and slowly in the intestines, differences in gastric emptying rates can result in extremely high peak blood drug concentrations (Cmax) or prolonged absorption. If gastric emptying is rapid, a large amount of dissolved drug quickly enters the small intestine, resulting in an extremely high peak blood drug concentration; if gastric emptying is slow, drug absorption is prolonged. pH sensitivity amplifies the consequences of these physiological fluctuations. Individuals have different levels of gastric acid secretion. If a patient has hypoacidity or is taking a PPI (proton pump inhibitor, such as omeprazole), the gastric pH increases, limiting the initial solubility of tofacitinib in the stomach, leading to slower or reduced absorption. Furthermore, eating alters gastric pH and emptying time. Although the official instructions state that food intake does not significantly affect the AUC (total exposure) of tofacitinib, a high-fat diet does delay Tmax, which is essentially the result of the combined effects of pH environment and changes in gastric motility.

[0005] Some existing technologies report methods to improve the solubility of tofacitinib. For example, CN106924262A discloses a solid dispersion of amorphous tofacitinib citrate and pharmaceutical excipients, and its preparation method. This method involves adding pharmaceutical excipients such as diluents, lubricants, binders, disintegrants, surfactants, film-forming materials, coating materials, and capsule materials to amorphous tofacitinib citrate to form a solid dispersion, thereby improving the bioavailability and stability of tofacitinib. Solid dispersions primarily improve apparent solubility by converting the drug into an amorphous state. However, in the intestine, amorphous drugs are prone to recrystallization and precipitation. Furthermore, tofacitinib exhibits a significant pH dependence, further exacerbating the risk of precipitation in the intestine. This patent specifically addresses improvements to tofacitinib in its salt form. For example, patent CN113975280B discloses a pharmaceutical composition, formulation, and application containing a pharmaceutically acceptable salt of tofacitinib, which uses diethylene glycol monoethyl ether as a penetration enhancer to improve the solubility and stability of pharmaceutically acceptable salts of tofacitinib (such as tofacitinib tartrate, tofacitinib sulfate, or tofacitinib phosphate). Patent CN113975280B also addresses improvements to tofacitinib in salt form.

[0006] Therefore, it is necessary to develop a new formulation to avoid the salt formation process of tofacitinib, while reducing the impact of pH dependence on drug absorption and improving the solubility and stability of the drug. Summary of the Invention

[0007] To overcome the pH dependence and salt formation defects in existing tofacitinib preparation methods, this invention provides a composition for preparing tofacitinib self-emulsifying nano-formulations, the tofacitinib self-emulsifying nano-formulations, and a method for their preparation. This invention directly improves the free base of tofacitinib by combining specific excipients (such as diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate) to prepare tofacitinib self-emulsifying nano-formulations. This improves tofacitinib solubility while reducing the number of precisely controlled salt formation steps, thus increasing overall process yield, reducing process difficulty, avoiding degradation risks during stability testing, and reducing the pH dependence of drug solubility. This reduces inter-individual absorption differences, making the drug's efficacy more stable and predictable.

[0008] One of the objectives of this invention is to provide a composition for preparing tofacitinib self-emulsifying nanoformulations.

[0009] To achieve the above objectives, the present invention adopts the following technical solution:

[0010] A composition for preparing tofacitinib self-emulsifying nanoformulations, the composition comprising tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil and glyceryl monocaprylate in a mass ratio of 0.1:1.5-3.0:3.5-5.0:2.5-4.5.

[0011] Preferably, the mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil and glyceryl monocaprylate is 0.1:1.88-2.5:3.86-4.81:3.0-4.0.

[0012] Preferably, the mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate is 0.1:2.00:4.00:4.00.

[0013] Preferably, the mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate is 0.1:2.32:4.18:3.50.

[0014] Preferably, the mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate is 0.1:1.88:4.13:4.00.

[0015] Preferably, the mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate is 0.1:2.33:4.67:3.00.

[0016] Preferably, the mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate is 0.1:2.50:4.50:3.00.

[0017] Preferably, the mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate is 0.1:2.03:4.47:3.50.

[0018] Preferably, the mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate is 0.1:2.14:3.86:4.00.

[0019] Preferably, the mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate is 0.1:2.17:4.33:3.50.

[0020] Preferably, the mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate is 0.1:2.19:4.81:3.00.

[0021] Preferably, the mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate is 1:21:42:37.

[0022] A second objective of this invention is to provide another composition for preparing tofacitinib self-emulsifying nanoformulations.

[0023] To achieve the above objectives, the present invention adopts the following technical solution:

[0024] Another composition for preparing tofacitinib self-emulsifying nanoformulations comprises tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, glyceryl monocaprylate, and magnesium aluminum silicate in a mass ratio of 0.1:1.5-3.0:3.5-5.0:2.5-4.5:5.0-10.0.

[0025] This invention uses magnesium aluminum silicate, an inorganic carrier with a large specific surface area, for physical encapsulation and adsorption to solidify SEDDS. This is beneficial for preparing more formulations while still achieving rapid release of SEDDS.

[0026] Preferably, the mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, glyceryl monocaprylate and magnesium aluminum silicate is 0.1:2.32:4.18:3.5:5.0.

[0027] Preferably, the mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, glyceryl monocaprylate and magnesium aluminum silicate is 0.1:2.0:4.0:4.0:5.0.

[0028] The third objective of this invention is to provide a self-emulsifying nanoformulation of tofacitinib.

[0029] To achieve the above objectives, the present invention adopts the following technical solution:

[0030] A self-emulsifying nanoformulation of tofacitinib, wherein the self-emulsifying nanoformulation is prepared from the aforementioned composition for preparing a self-emulsifying nanoformulation of tofacitinib or another aforementioned composition for preparing a self-emulsifying nanoformulation of tofacitinib.

[0031] Preferably, the dosage form of the self-emulsifying nano-formulation is a liquid formulation or a solid formulation.

[0032] Preferably, the liquid formulation comprises oral solutions and / or soft capsules.

[0033] Preferably, the solid dosage form includes tablets and / or capsules.

[0034] The fourth objective of this invention is to provide a method for preparing an SEDDS solution containing tofacitinib free base using the aforementioned composition for preparing tofacitinib self-emulsifying nanoformulations.

[0035] To achieve the above objectives, the present invention adopts the following technical solution:

[0036] The method for preparing a SEDDS solution containing tofacitinib free base using the aforementioned composition for preparing tofacitinib self-emulsifying nanoformulation involves mixing tofacitinib free base with diethylene glycol monoethyl ether, heating and shaking to dissolve; then adding polyoxyethylene 40 hydrogenated castor oil and glyceryl monocaprylate, stirring until homogeneous, to obtain a drug-containing SEDDS solution.

[0037] Preferably, the heating temperature is 50-60℃.

[0038] Preferably, the drug-containing SEDDS solution can automatically disperse in purified water into a uniform nano-solution with a particle size range of 10-50 nm.

[0039] The fifth objective of this invention is to provide a method for preparing SEDDS-cured powder using another composition described above for preparing tofacitinib self-emulsifying nanoparticles.

[0040] To achieve the above objectives, the present invention adopts the following technical solution:

[0041] The method for preparing SEDDS-cured powder using another composition described above for preparing tofacitinib self-emulsifying nanoformulations includes the following steps:

[0042] (1) Prepare SEDDS solution containing tofacitinib free base using the aforementioned method;

[0043] (2) The SEDDS solution obtained in step (1) is added dropwise to magnesium aluminum silicate to obtain SEDDS cured powder.

[0044] Preferably, the SEDDS solution obtained in step (1) is heated to 50-60°C and then added dropwise to magnesium aluminum silicate, stirred and mixed to obtain SEDDS cured powder.

[0045] Preferably, during step (2), the mixture is continuously stirred, and after the addition is complete, it is further sheared and stirred to obtain SEDDS cured powder.

[0046] Preferably, the SEDDS cured powder can be automatically dispersed in purified water into a nano solution with uniform particle size, ranging from 10 to 50 nm.

[0047] Preferably, in step (2), the mass ratio of the SEDDS solution to the magnesium aluminum silicate is 1:0.5-10, more preferably 1:1-2.

[0048] The sixth objective of this invention is to provide the application of diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate in the preparation of a reagent for improving the free alkali solubility of tofacitinib.

[0049] Preferably, the mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate is 0.1:1.5-3.0:3.5-5.0:2.5-4.5, more preferably 0.1:1.88-2.5:3.86-4.81:3.0-4.0.

[0050] The beneficial effects of this invention are as follows:

[0051] 1. The advantage of SEDDS (Self-Emulsified Epoxy Desserts) lies in the fact that the drug is pre-dissolved in lipids and spontaneously forms nano-sized droplets under peristalsis after entering the gastrointestinal tract. This invention prepares a tofacitinib self-emulsifying nano-formulation using a combination of specific excipients (such as diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate), significantly improving the solubility of the tofacitinib free base, enabling rapid release and absorption in the gastrointestinal tract, thereby increasing drug bioavailability and enhancing therapeutic efficacy. Furthermore, this invention has found that formulating tofacitinib into SEDDS has pH-independent characteristics, ensuring stable absorption of the formulation throughout the gastrointestinal tract and reducing individual absorption variability.

[0052] 2. Particle size analysis results show that the SEDDS solution containing tofacitinib free base prepared in this invention can be automatically dispersed into a uniform nano-solution in purified water, with a particle size range of 10-50 nm.

[0053] 3. Dissolution test results show that the drug-containing SEDDS solution and SEDDS powder prepared in this invention have excellent dissolution performance in different dissolution media (0.1N hydrochloric acid, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and water), ensuring effective drug release.

[0054] 4. In the prior art, tofacitinib is usually in the form of citrate, while the present invention avoids the salt formation process through SEDDS technology, which simplifies the production process and reduces production costs.

[0055] 5. This invention provides multiple administration methods to meet the medication needs of different patients. The drug-containing SEDDS solution provided by this invention can be further formulated into liquid preparations such as soft capsules and oral solutions; the solidified SEDDS powder can be further formulated into solid oral preparations such as hard capsules and tablets, improving the convenience of medication for patients.

[0056] 6. This invention uses magnesium aluminum silicate, an inorganic carrier with a large specific surface area, for physical encapsulation and adsorption to achieve the solidification of SEDDS. This is beneficial for preparing more formulations while still achieving rapid release of SEDDS. Attached Figure Description

[0057] Figure 1 The particle size distribution diagram is shown for the drug-containing SEDDS solution prepared in Example 4.

[0058] Figure 2 The particle size distribution diagram is shown for the drug-containing SEDDS solution prepared in Example 5.

[0059] Figure 3 The particle size distribution diagram is shown for the SEDDS cured powder prepared in Example 6.

[0060] Figure 4 The ZETA potential detection results are for the drug-containing SEDDS solution prepared in Example 7.

[0061] Figure 5 The image shows the DSC curve of the SEDDS solution in Example 8.

[0062] Figure 6 The image shows the DSC curve of the blank magnesium aluminum silicate in Example 8.

[0063] Figure 7 The image shows the DSC curve of the SEDDS cured powder in Example 8.

[0064] Figure 8 The image shows the X-ray diffraction analysis results of the SEDDS cured powder in Example 9.

[0065] Figure 9 This is a scanning electron microscope image (10,000x) of magnesium aluminum silicate blank in Example 10.

[0066] Figure 10 This is a scanning electron microscope image (50,000x magnification) of magnesium aluminum silicate blank in Example 10.

[0067] Figure 11 This is a scanning electron microscope image (10,000x magnification) of the SEDDS cured powder in Example 10.

[0068] Figure 12 This is a scanning electron microscope image (50,000x magnification) of the SEDDS cured powder in Example 10.

[0069] Figure 13 The chromatogram is of the SEDDS cured powder prepared in Example 11. Detailed Implementation

[0070] The technical solution of the present invention will be described more clearly and completely below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the protection scope of the present invention.

[0071] To enhance understanding of the present invention, certain key technical and scientific terms will be clearly defined below. Unless otherwise specified herein, all other technical and scientific terms shall follow their generally accepted and understood meanings within the art to which this invention pertains. It should be noted that the terminology used herein is intended to describe specific embodiments and not to be construed as limiting.

[0072] Self-emulsifying drug delivery systems (SEDDS) are solid or liquid formulations composed of an oil phase, nonionic surfactants, and co-surfactants. Their key characteristic is the ability to spontaneously emulsify in the gastrointestinal tract or under suitable ambient temperature and gentle stirring conditions to form an emulsion with a particle size of approximately 100–500 nm. Existing research indicates that SEDDS can significantly increase the solubility and dispersion of poorly soluble drugs, enhance their absorption, and improve bioavailability.

[0073] Dissolution assay: An experimental method used to evaluate the rate and extent to which a drug dissolves from its formulation, helping to assess the drug's bioavailability and release characteristics. It is typically performed in media with different pH values ​​to simulate drug dissolution in the stomach and intestines.

[0074] Differential scanning calorimetry (DSC): A thermal analysis technique mainly used to measure the heat absorbed or released by a substance during heating or cooling. It can be used to analyze the phase transition, purity, and thermal stability of a substance.

[0075] X-ray diffraction (XRD) analysis: This is a phase analysis method that determines the crystal structure of a substance by analyzing the diffraction pattern of X-rays. It can be used to determine whether a substance is crystalline or amorphous.

[0076] Scanning electron microscope (SEM): A microscope that uses an electron beam to scan the surface of a sample, thereby obtaining information about the surface morphology. It can be used to observe the surface structure, morphological features, and pore filling of materials.

[0077] Example 1

[0078] Weigh 0.1 g of tofacitinib free base, add 0.8-8.1 g of diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add 0.8-8.1 g of polyethylene glycol glycerol ester and 1.0-2.0 g of octanoic acid ester mono- and diglycerides, stir well to prepare the drug-containing SEDDS solution. The specific proportions of each raw material and key reagent are shown in Table 1.

[0079] Take the above-mentioned drug-containing SEDDS solution and dilute it 50, 200, and 500 times at pH 1.2 (simulated gastric juice) and pH 6.8 (simulated intestinal juice), respectively. Then, transfer the solution to a 37°C air bath shaker and vortex at 100 rpm for 6 hours, observing the results visually. The experimental results are shown in Table 1.

[0080] Table 1. Observation results of experimental phenomena with SEDDS solution

[0081]

[0082] Example 2

[0083] Weigh 0.1g of tofacitinib free base, add 0.5-4.5g of diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add 0.5-3.0g of polyoxyethylene 40 hydrogenated castor oil and 4.0-9.0g of glyceryl monocaprylate, stir well to prepare a drug-containing SEDDS solution. The specific proportions of each raw material and key reagent are shown in Table 2.

[0084] Take the above-mentioned drug-containing SEDDS solution and dilute it 50, 200, and 500 times at pH 1.2 (simulated gastric juice) and pH 6.8 (simulated intestinal juice), respectively. Then, transfer the solution to a 37°C air bath shaker and vortex at 100 rpm for 6 hours, observing the results visually. The experimental results are shown in Table 2.

[0085] Table 2. Observation results of experimental phenomena with SEDDS solution

[0086]

[0087] Example 3

[0088] Weigh 0.1g of tofacitinib free base, add 1.88-2.50g of diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add 3.86-4.81g of polyoxyethylene 40 hydrogenated castor oil and 3.0-4.0g of glyceryl monocaprylate, stir well to prepare a drug-containing SEDDS solution. The specific proportions of each raw material and key reagent are shown in Table 3.

[0089] Take the above-mentioned drug-containing SEDDS solution and dilute it 50, 200, and 500 times at pH 1.2 (simulated gastric juice) and pH 6.8 (simulated intestinal juice), respectively. Then, transfer the solution to a 37°C air bath shaker and vortex at 100 rpm for 6 hours, observing the results visually. The experimental results are shown in Table 3.

[0090] Table 3. Observation results of experimental phenomena with SEDDS solution

[0091]

[0092] Example 4

[0093] Weigh 0.1g of tofacitinib free base, add 2.50g of diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add 4.50g of polyoxyethylene 40 hydrogenated castor oil and 3.0g of glyceryl monocaprylate, stir evenly to prepare drug-containing SEDDS solution.

[0094] Take the above-mentioned drug-containing SEDDS solution, dilute it with 200X purified water, gently shake to disperse, and visually observe that it is a uniformly dispersed liquid with obvious Tyndall effect. The particle size distribution of the dispersed liquid was tested using a nanoparticle size analyzer (Anton Paar, Model: Litesizer 500). The results are as follows... Figure 1 As shown in Table 4, the SEDDS solution can be automatically dispersed in purified water into a uniform nano-solution with a particle size range of 10-50 nm. The dispersed liquid was then transferred to a 37°C air bath shaker and vortexed at 150 rpm for 5 hours; no precipitation or stratification occurred.

[0095] Table 4. Detection results of nanoparticle size distribution in drug-containing SEDDS solutions

[0096]

[0097] Example 5

[0098] Weigh 0.1g of tofacitinib free base, add 2.19g of diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add 4.81g of polyoxyethylene 40 hydrogenated castor oil and 3.0g of glyceryl monocaprylate, stir well to prepare drug-containing SEDDS solution.

[0099] Take the above-mentioned drug-containing SEDDS solution, dilute it with 200X purified water, gently shake to disperse, and visually observe that it is a uniformly dispersed liquid with obvious Tyndall effect. The particle size distribution of the dispersed liquid was tested using a nanoparticle size analyzer (Anton Paar, Model: Litesizer 500). The results are as follows... Figure 2 As shown in Table 5, the SEDDS solution can be automatically dispersed in purified water into a uniform nano-solution with a particle size range of 10-50 nm. The dispersed liquid was then transferred to a 37°C air bath shaker and vortexed at 150 rpm for 5 hours; no precipitation or stratification occurred.

[0100] Table 5. Detection results of nanoparticle size distribution in drug-containing SEDDS solutions

[0101]

[0102] Example 6

[0103] Weigh 0.1g of tofacitinib free base, add 2.32g of diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add 4.18g of polyoxyethylene 40 hydrogenated castor oil and 3.5g of glyceryl monocaprylate, stir well to prepare a drug-containing SEDDS solution. Then heat the SEDDS solution to 50-60℃, and slowly add it dropwise to 5.0g of magnesium aluminum silicate, stirring continuously during the dropwise addition. After the dropwise addition is complete, continue to shear and stir to mix evenly to obtain a cured SEDDS powder.

[0104] Take the above-mentioned SEDDS cured powder, dilute it with 200X purified water, and gently shake to disperse it. Visually, except for magnesium aluminum silicate at the bottom, the upper layer is a uniformly dispersed liquid with obvious Tyndall effect. Transfer the dispersed liquid to a 37℃ air bath shaker and vortex at 150 rpm for 5 hours. The upper liquid did not separate into layers. Filter the above liquid and test the particle size distribution of the upper liquid using a nanoparticle size analyzer (brand: Anton Paar, model: Litesizer 500). The results are as follows. Figure 3 As shown in Table 6, the SEDDS solidified powder can be automatically dispersed into a uniform nano solution in purified water, with a particle size range of 10-50 nm.

[0105] Table 6. Detection results of nanoparticle size distribution of drug-containing SEDDS cured powder

[0106]

[0107] Example 7

[0108] Weigh 0.1g of tofacitinib free base, add 2.00g of diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add 4.00g of polyoxyethylene 40 hydrogenated castor oil and 4.0g of glyceryl monocaprylate, stir evenly to prepare drug-containing SEDDS solution.

[0109] Take the above-mentioned drug-containing SEDDS solution and dilute it with 200X pH 6.8 phosphate buffer. Gently shake to disperse. Visually, it is a uniformly dispersed liquid with obvious Tyndall effect. The zeta potential (ξ) of the particles in the dispersed liquid was measured using a nanoparticle size analyzer (Anton Paar, Model: Litesizer 500). The results are as follows... Figure 4 As shown in Table 7, the surface of the particles in the SEDDS solution after dispersion in pH 6.8 phosphate buffer is electrically neutral.

[0110] Table 7. Detection results of ZETA potential in drug-containing SEDDS solutions

[0111]

[0112] Example 8

[0113] Weigh 0.1g of tofacitinib free base, add 2.0g of diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add 4.0g of polyoxyethylene 40 hydrogenated castor oil and 4.0g of glyceryl monocaprylate, stir well to prepare a drug-containing SEDDS solution. Then heat the SEDDS solution to 50-60℃, and slowly add it dropwise to 5.0g of magnesium aluminum silicate, stirring continuously during the dropwise addition. After the dropwise addition is complete, continue to shear and stir to mix evenly, and obtain solidified SEDDS powder.

[0114] The above-mentioned SEDDS solution, SEDDS cured powder, and blank magnesium aluminum silicate were analyzed for their thermophysical properties using a differential scanning calorimeter (brand: TA, model: DSC25). The results are as follows: Figure 5-7 As shown, there are significant differences in the DSC curves between blank magnesium aluminum silicate and SEDDS-cured powder, and significant differences in the DSC curves between the SEDDS solution and the SEDDS-cured powder. These results indicate that SEDDS solution was successfully adsorbed and loaded onto porous magnesium aluminum silicate, achieving solution curing.

[0115] Example 9

[0116] Weigh 0.1g of tofacitinib free base, add 2.0g of diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add 4.0g of polyoxyethylene 40 hydrogenated castor oil and 4.0g of glyceryl monocaprylate, stir well to prepare a drug-containing SEDDS solution. Then heat the SEDDS solution to 50-60℃, and slowly add it dropwise to 5.0g of magnesium aluminum silicate, stirring continuously during the dropwise addition. After the dropwise addition is complete, continue to shear and stir to mix evenly to obtain a cured SEDDS powder.

[0117] Take the above-mentioned SEDDS cured powder and analyze it using an X-ray diffractometer (brand: Panaco, model: X'Pert). 3 Analysis. Results are as follows: Figure 8 As shown, the SEDDS cured powder exhibits a distinct amorphous morphology, ensuring the solubility and dissolution rate of tofacitinib free alkali after SEDDS curing.

[0118] Example 10

[0119] Weigh 0.1g of tofacitinib free base, add 2.0g of diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add 4.0g of polyoxyethylene 40 hydrogenated castor oil and 4.0g of glyceryl monocaprylate, stir well to prepare a drug-containing SEDDS solution. Then heat the SEDDS solution to 50-60℃, and slowly add it dropwise to 5.0g of magnesium aluminum silicate, stirring continuously during the dropwise addition. After the dropwise addition is complete, continue to shear and stir to mix evenly, and obtain solidified SEDDS powder.

[0120] The surface morphology of the above-mentioned blank magnesium aluminum silicate and SEDDS cured powder was observed using a scanning electron microscope (brand: TESCAN, model: MIRA3XMH). The results are as follows: Figure 9-12 As shown, compared with the blank magnesium aluminum silicate particles, the SEM image of the SEDDS-containing cured powder shows that the interior of the pores of the SEDDS-containing cured powder exhibits a "full" gray scale, indicating that the SEDDS is dispersed and filled in the porous magnesium aluminum silicate pores.

[0121] Example 11

[0122] Weigh 1g of tofacitinib free base, add 21g of diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add 42g of polyoxyethylene 40 hydrogenated castor oil and 37g of glyceryl monocaprylate, stir well to prepare a drug-containing SEDDS solution. Take 10g of the above drug-containing SEDDS solution, heat to 50-60℃, and then slowly add dropwise to 10g of magnesium aluminum silicate, stirring continuously during the dropwise addition. After the dropwise addition is complete, continue to shear and stir to mix evenly to obtain the cured SEDDS powder.

[0123] Weigh 1.5 g of the cured SEDDS powder (approximately equivalent to 10 mg of tofacitinib free base), place it in a 50 ml volumetric flask, add an appropriate amount of methanol, extract by ultrasonic shaking, cool, dilute to the mark with purified water, shake well, and filter. Use octadecylsilane-bonded silica gel as the packing material; use 0.1% trifluoroacetic acid solution-acetonitrile (95:5) as mobile phase A and acetonitrile as mobile phase B, and perform linear gradient elution according to Table 8; the detection wavelength is 254 nm; the injection volume is 5 μL.

[0124] Table 8. Elution Procedure

[0125]

[0126] Experimental results are as follows Figure 13 As shown. By Figure 13 As can be seen from the chromatographic analysis, the SEDDS prepared by this invention showed that the active pharmaceutical ingredient peak was symmetrical and the retention time was stable. Integral calculations showed that the purity of the active pharmaceutical ingredient was 98.4%, and no significant new impurity peaks were observed except for one characteristic process impurity. This indicates that the formulation of this invention is chemically stable during the preparation process.

[0127] Example 12. Dissolution Experiment

[0128] 1. Dissolution determination of drug-containing SEDDS solutions

[0129] Weigh 1g of tofacitinib free base, add 21g of diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add 42g of polyoxyethylene 40 hydrogenated castor oil and 37g of glyceryl monocaprylate, stir evenly to prepare drug-containing SEDDS solution.

[0130] Weigh 1 g of the above-mentioned drug-containing SEDDS solution (approximately equivalent to 10 mg of tofacitinib free base) and determine the amount dissolved according to Method II of General Chapter 0931 in the 2025 edition of the Chinese Pharmacopoeia. Use 0.1N hydrochloric acid as the dissolution medium, with a volume of 1000 ml and a rotation speed of 75 rpm. After 5, 10, 15, 20, 30, 45, and 60 minutes, collect the dissolution solution, filter it, inject it into the liquid chromatograph, and calculate the amount dissolved by peak area using the external standard method.

[0131] Weigh 1 g of the above-mentioned drug-containing SEDDS solution (approximately equivalent to 10 mg of tofacitinib free base) and determine the amount dissolved according to Method II of General Chapter 0931 in the 2025 edition of the Chinese Pharmacopoeia. Use pH 4.5 acetate buffer as the dissolution medium, with a volume of 1000 ml and a rotation speed of 75 rpm. After 5, 10, 15, 20, 30, 45, and 60 minutes, collect the dissolution solution, filter it, inject it into the liquid chromatograph, and calculate the dissolution amount by peak area using the external standard method.

[0132] Weigh 1 g of the above-mentioned drug-containing SEDDS solution (approximately equivalent to 10 mg of tofacitinib free base) and determine the amount dissolved according to Method II of General Chapter 0931 in the 2025 edition of the Chinese Pharmacopoeia. Use pH 6.8 phosphate buffer as the dissolution medium, with a volume of 1000 ml and a rotation speed of 75 rpm. After 5, 10, 15, 20, 30, 45, and 60 minutes, collect the dissolution solution, filter it, and inject it into the liquid chromatograph. Calculate the dissolution amount based on peak area using the external standard method.

[0133] Weigh 1 g of the above-mentioned drug-containing SEDDS solution (approximately equivalent to 10 mg of tofacitinib free base) and determine the amount dissolved according to Method II of General Chapter 0931 in the 2025 edition of the Chinese Pharmacopoeia. Use water as the dissolution medium, with a volume of 1000 ml and a rotation speed of 75 rpm. After 5, 10, 15, 20, 30, 45, and 60 minutes, collect the dissolution solution, filter it, inject it into the liquid chromatograph, and calculate the dissolution amount based on the peak area using the external standard method.

[0134] 2. Determination of dissolution rate of SEDDS powder

[0135] Weigh 1g of tofacitinib free base, add 21g of diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add 42g of polyoxyethylene 40 hydrogenated castor oil and 37g of glyceryl monocaprylate, stir well to prepare a drug-containing SEDDS solution. Take 10g of the above drug-containing SEDDS solution, heat to 50-60℃, and then slowly add dropwise to 20g of magnesium aluminum silicate, stirring continuously during the dropwise addition. After the dropwise addition is complete, continue to shear and stir to mix evenly to obtain the cured SEDDS powder.

[0136] Weigh 2g of the cured SEDDS powder (approximately equivalent to 10mg of tofacitinib free base) and determine its content according to Method II of General Chapter 0931 in the 2025 edition of the Chinese Pharmacopoeia. Use 0.1N hydrochloric acid as the dissolution medium, with a volume of 1000ml and a rotation speed of 75 rpm. After 5, 10, 15, 20, 30, 45, and 60 minutes, collect the dissolution solution, filter it, inject it into the liquid chromatograph, and calculate the dissolution amount based on the peak area using the external standard method.

[0137] Weigh 2g of the cured SEDDS powder (approximately equivalent to 10mg of tofacitinib free base) and determine its content according to Method II of General Chapter 0931, Chinese Pharmacopoeia 2025 Edition. Use pH 4.5 acetate buffer as the dissolution medium, with a volume of 1000ml and a rotation speed of 75 rpm. After 5, 10, 15, 20, 30, 45, and 60 minutes, collect the dissolution solution, filter it, inject it into the liquid chromatograph, and calculate the dissolution amount based on peak area using the external standard method.

[0138] Weigh 2g of the cured SEDDS powder (approximately equivalent to 10mg of tofacitinib free base) and determine its content according to Method II of General Chapter 0931, Chinese Pharmacopoeia 2025 Edition. Use pH 6.8 phosphate buffer as the dissolution medium, with a volume of 1000ml and a rotation speed of 75 rpm. After 5, 10, 15, 20, 30, 45, and 60 minutes, collect the dissolution solution, filter it, inject it into the liquid chromatograph, and calculate the dissolution amount based on peak area using the external standard method.

[0139] Weigh 2g of the cured SEDDS powder (approximately equivalent to 10mg of tofacitinib free base) and determine its content according to Method II of General Chapter 0931 in the 2025 edition of the Chinese Pharmacopoeia. Use water as the dissolution medium, with a volume of 1000ml and a rotation speed of 75 rpm. After 5, 10, 15, 20, 30, 45, and 60 minutes, collect the dissolution solution, filter it, inject it into the liquid chromatograph, and calculate the dissolution amount based on the peak area using the external standard method.

[0140] 3. Determination of the dissolution rate of tofacitinib free base

[0141] Weigh 0.1 g of tofacitinib free base and determine its concentration according to Method II of General Chapter 0931 in the 2025 edition of the Chinese Pharmacopoeia. Use 0.1 N hydrochloric acid as the dissolution medium, with a volume of 1000 ml and a rotation speed of 75 rpm. After 5, 10, 15, 20, 30, 45, and 60 minutes, collect the dissolution solution, filter it, inject it into the liquid chromatograph, and calculate the dissolution amount based on the peak area using the external standard method.

[0142] Weigh 0.1 g of tofacitinib free base and determine its concentration according to Method II, General Chapter 0931, Chinese Pharmacopoeia 2025 Edition. Use pH 4.5 acetate buffer as the dissolution medium (1000 ml) at a rotation speed of 75 rpm. After 5, 10, 15, 20, 30, 45, and 60 minutes, collect the dissolution solution, filter it, inject it into the liquid chromatograph, and calculate the dissolution amount based on peak area using the external standard method.

[0143] Weigh 0.1 g of tofacitinib free base and determine its concentration according to Method II, General Chapter 0931, Chinese Pharmacopoeia 2025 Edition. Use pH 6.8 phosphate buffer as the dissolution medium (1000 ml) at a rotation speed of 75 rpm. After 5, 10, 15, 20, 30, 45, and 60 minutes, collect the dissolution solution, filter it, inject it into the liquid chromatograph, and calculate the dissolution amount based on peak area using the external standard method.

[0144] Weigh 0.1 g of tofacitinib free base and determine its concentration according to Method II of General Chapter 0931 in the 2025 edition of the Chinese Pharmacopoeia. Use water as the dissolution medium (1000 ml) at a rotation speed of 75 rpm. After 5, 10, 15, 20, 30, 45, and 60 minutes, collect the dissolution solution, filter it, and inject it into the liquid chromatograph. Calculate the dissolution amount based on peak area using the external standard method.

[0145] 4. Experimental Results

[0146] The dissolution test results of the drug-containing SEDDS solution are shown in Table 9.

[0147] Table 9. Dissolution test results of drug-containing SEDDS solutions in different dissolution media at 5-60 min.

[0148]

[0149] The dissolution test results of SEDDS powder are shown in Table 10.

[0150] Table 10. Dissolution test results of SEDDS powder in different dissolution media at 5-60 min.

[0151]

[0152] The dissolution test results of tofacitinib free base are shown in Table 11.

[0153] Table 11. Dissolution test results of tofacitinib free base

[0154]

[0155] The above experimental results show that the drug-containing SEDDS solution and SEDDS powder prepared in this invention have excellent dissolution in 0.1N hydrochloric acid, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and water; while the free base of tofacitinib has good dissolution in 0.1N hydrochloric acid, but poor dissolution in pH 4.5 acetate buffer, pH 6.8 phosphate buffer and water.

[0156] Example 13. Pharmaceutical Formulation

[0157] This invention provides two forms of pharmaceutical preparations, as detailed below:

[0158] A. Formulation: Liquid preparations such as oral solutions and soft capsules.

[0159] Preparation method: Take tofacitinib free base, add diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add polyoxyethylene 40 hydrogenated castor oil and glyceryl monocaprylate to the specified volume, stir evenly to obtain a drug-containing SEDDS solution. The mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate is 0.1:1.5-3.0:3.5-5.0:2.5-4.5. Then, with the assistance of gelatin, sorbitol, coloring agents, flavoring agents, and other soft capsule shell excipients, soft capsules are prepared by pelleting process, or an oral solution is prepared by adding flavoring agents and coloring agents.

[0160] B. Formulation: Solid oral preparations such as tablets and capsules.

[0161] Preparation method: Take tofacitinib free base, add diethylene glycol monoethyl ether, heat and shake at 50-60℃ to dissolve, then add polyoxyethylene 40 hydrogenated castor oil and glyceryl monocaprylate to the specified amount, stir evenly to obtain a drug-containing SEDDS solution. Then heat the SEDDS solution to 50-60℃, and slowly add it dropwise to the stirred magnesium aluminum silicate. After the addition is complete, continue to shear and stir to mix evenly to obtain SEDDS solidified powder. Then, with the assistance of fillers, disintegrants, binders and other excipients, it can be prepared into hard capsules or tablets. The mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, glyceryl monocaprylate and magnesium aluminum silicate is 0.1:1.5-3.0:3.5-5.0:2.5-4.5:5.0-10.0.

Claims

1. A composition for preparing tofacitinib self-emulsifying nanoformulations, characterized in that, The composition comprises tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate in a mass ratio of 0.1:1.5-3.0:3.5-5.0:2.5-4.

5.

2. The composition according to claim 1, characterized in that, The mass ratio of tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, and glyceryl monocaprylate is 0.1:1.88-2.5:3.86-4.81:3.0-4.

0.

3. Another composition for preparing tofacitinib self-emulsifying nanoformulations, characterized in that, The composition comprises tofacitinib free base, diethylene glycol monoethyl ether, polyoxyethylene 40 hydrogenated castor oil, glyceryl monocaprylate and magnesium aluminum silicate, in a mass ratio of 0.1:1.5-3.0:3.5-5.0:2.5-4.5:5.0-10.

0.

4. A self-emulsifying nanoformulation of tofacitinib, characterized in that, The self-emulsifying nanoformulation is prepared from the composition according to any one of claims 1 to 2 or the composition according to claim 3.

5. The self-emulsifying nano-formulation according to claim 4, characterized in that, The dosage form of the self-emulsifying nano-formulation is a liquid or solid formulation; the liquid formulation includes oral solutions and / or soft capsules; the solid formulation includes tablets and / or capsules.

6. A method for preparing an SEDDS solution containing tofacitinib free base using the composition according to any one of claims 1 to 2, characterized in that, Tofacitinib free base was mixed with diethylene glycol monoethyl ether and heated and shaken to dissolve; then polyoxyethylene 40 hydrogenated castor oil and glyceryl monocaprylate were added and stirred evenly to obtain a drug-containing SEDDS solution.

7. The method according to claim 6, characterized in that, The heating temperature is 50-60℃.

8. A method for preparing SEDDS cured powder using the composition of claim 3, characterized in that, Includes the following steps: (1) Prepare an SEDDS solution containing tofacitinib free base using the method described in any one of claims 6 to 7; (2) The SEDDS solution obtained in step (1) is added dropwise to magnesium aluminum silicate to obtain SEDDS cured powder.

9. The method according to claim 8, characterized in that, The SEDDS solution obtained in step (1) is heated to 50-60℃ and then added dropwise to magnesium aluminum silicate. The mixture is stirred and mixed to obtain SEDDS cured powder.

10. The method according to claim 8, characterized in that, In step (2), the mass ratio of the SEDDS solution to the magnesium aluminum silicate is 1:0.5-10.

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