A co-amorphous drug of afatinib, its preparation method and application

Abstract

This invention discloses an afatinib co-amorphous drug, its preparation method, and its application. The afatinib co-amorphous drug consists of the active ingredient afatinib and a ligand in a 1:1 molar ratio. Afatinib and the ligand form a single homogeneous amorphous structure through intermolecular interactions. The ligand is selected from any one of methyl gallate, gallic acid, saccharin, and protocatechuic acid. Characterization of the sample by X-ray powder diffraction and differential scanning calorimetry showed that afatinib and the ligand formed a homogeneous amorphous structure. Compared with afatinib raw material and physical mixtures, this invention improves the equilibrium solubility and dissolution rate of afatinib in physiological media, providing a new formulation strategy for improving the oral bioavailability of afatinib.

Description

Technical Field

[0001] This invention relates to afatinib, and more particularly to an amorphous afatinib drug with improved solubility and dissolution rate, its preparation method, and its application; belonging to the field of pharmaceutical technology. Background Technology

[0002] Afatinib is an oral, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that inhibits tumor cell proliferation, invasion, and metastasis. It is primarily used to treat locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR-sensitive mutations. Afatinib is commonly available in oral formulations, and salt-based modifications, such as afatinib maleate tablets, have been developed and marketed. However, afatinib is classified as a Class II drug in the Biopharmaceutics Classification System (BCS), characterized by high permeability but extremely poor water solubility. Its very low saturated solubility and dissolution rate severely limit its oral bioavailability, thus hindering further improvement in its clinical efficacy. Furthermore, even after salt-based modifications, insufficient in vivo solubility may still exist.

[0003] To address the aforementioned issues, existing technologies have conducted related formulation optimization research. Chinese invention patent application CN121177242A uses afatinib dimaleate with specific crystal form and particle size as raw material, combined with non-crystalline excipients, and prepares afatinib tablets through processes such as dry granulation, humidity control, moisture-proof film coating, and double-layer moisture-proof packaging, achieving a certain degree of high formulation stability and rapid dissolution. However, this technology imposes stringent requirements on the crystal purity, particle size distribution, and specific surface area of ​​the active pharmaceutical ingredient, and the preparation process involves multiple steps such as raw material pretreatment, segmented mixing, dry granulation, vacuum drying, moisture-proof coating, and special packaging. The parameters of each process step are strictly controlled, making the production process complex.

[0004] Chinese invention patent CN104892584B discloses an amorphous form of afatinib bismaleate, its preparation method, and formulation. The amorphous form of afatinib bismaleate is a novel crystalline form with good stability and solubility. The preparation method simplifies the operation steps, requires no special equipment, and has low production costs, showing potential for industrial production. However, using afatinib bismaleate as a raw material results in a salt-forming amorphous form, which is susceptible to disproportionation and phase transitions in vivo due to pH variations. Furthermore, the preparation process relies solely on solubility as the solvent selection criterion, employing an organic solvent dissolution-concentration-drying route. This results in products with large fluctuations in moisture content and excessive organic solvent residues. In addition, this amorphous form only improves solubility in organic solvents such as ethanol and ethyl acetate, without optimizing dissolution and extraction performance for the human small intestine absorption environment. This fails to meet the physiological needs of the main absorption sites in vivo, limiting its practical application effectiveness. Summary of the Invention

[0005] To address the problems of poor water solubility and low bioavailability of existing afatinib raw materials, this invention provides an afatinib co-amorphous drug and its preparation method that can significantly improve drug solubility and dissolution rate, and has a simple, green and environmentally friendly preparation process suitable for industrial production.

[0006] Another objective of this invention is to provide the application of the amorphous drug of afatinib in the preparation of oral pharmaceutical formulations that improve the oral bioavailability of afatinib, so as to solve the problems of low solubility and insufficient absorption of existing oral afatinib formulations.

[0007] To achieve the above objectives, the present invention is specifically implemented through the following technical solutions:

[0008] An amorphous drug comprising the active pharmaceutical ingredient afatinib and a ligand; wherein the ligand is selected from any one of methyl gallate, gallic acid, saccharin, and protocatechuic acid; wherein afatinib and the ligand form a single homogeneous amorphous structure through intermolecular interactions; and wherein the molar ratio of afatinib to the ligand is 1:1.

[0009] To further achieve the purpose of this invention, preferably, the X-ray powder diffraction (PXRD) pattern of the amorphous drug does not contain sharp crystalline diffraction peaks of afatinib and its ligand raw materials, but instead presents broad and diffuse amorphous diffraction peaks.

[0010] Preferably, the co-amorphous drug has a single glass transition temperature (Tg) in differential scanning calorimetry (DSC) analysis.

[0011] More preferably, when the ligand is methyl gallate, the Tg of the co-amorphous drug is 85.93°C; when the ligand is gallic acid, the Tg of the co-amorphous drug is 130.63°C; when the ligand is saccharin, the Tg of the co-amorphous drug is 113.10°C; and when the ligand is protocatechuic acid, the Tg of the co-amorphous drug is 106.89°C.

[0012] The preparation method of the afatinib co-amorphous drug is as follows: afatinib and the ligand are mixed at a molar ratio of 1:1, placed in the ball mill jar of a planetary ball mill, and subjected to high-energy mechanical ball milling at room temperature, and the product is collected.

[0013] Preferably, the ball mill rotates at a speed of 300-500 rpm and the milling time is 150-240 minutes.

[0014] Preferably, the mass of afatinib fed in a single high-energy mechanical ball milling process is 500~2000 mg.

[0015] The application of the amorphous drug of afatinib in the preparation of oral pharmaceutical formulations that improve the oral bioavailability of afatinib.

[0016] Preferably, the oral pharmaceutical preparation is an oral solid dosage form; the oral solid dosage form is selected from tablets, capsules, granules or powders.

[0017] Preferably, the oral solid dosage form comprises the afatinib coamorphous drug and pharmaceutically acceptable excipients, wherein the excipients include one or more of fillers, disintegrants, glidants, and lubricants; the oral solid dosage form is prepared by directly compressing, encapsulating, or granulating the afatinib coamorphous drug with the excipients.

[0018] Compared with the prior art, the present invention has the following advantages and effects:

[0019] 1) The ligands used in this invention (methyl gallate, gallic acid, saccharin, protocatechuic acid) are all common small molecule compounds, which are widely available, safe, and inexpensive. They can form a stable multi-component system with afatinib without the need for harsh acid-base salt formation conditions.

[0020] 2) This invention addresses the inherent defects of poor water solubility and low bioavailability of the active pharmaceutical ingredient by forming a single homogeneous amorphous structure through co-amorphous technology, thereby destroying the crystal lattice of the drug, eliminating the lattice dissociation energy during the dissolution process, and improving solubility and dissolution rate from a thermodynamic perspective.

[0021] 3) This invention uses mechanical ball milling to prepare amorphous systems, avoiding the introduction of moisture. The process is green and environmentally friendly, the preparation method is simple, solvent-free, and does not require high temperature or high pressure. It has low energy consumption, no pollution, and good reproducibility, which is conducive to achieving rapid conversion and stable control of solid form.

[0022] 4) This invention significantly improves the poor solubility of afatinib while avoiding the potential toxicity and in vivo disproportionation risks associated with salt formation modification. Attached Figure Description

[0023] Figure 1 PXRD patterns of afatinib raw material (Comparative Example 1), amorphous afatinib (Comparative Example 2), and amorphous afatinib prepared in Examples 1-8.

[0024] Figure 2 DSC chromatograms of amorphous afatinib in Comparative Example 2 and amorphous afatinib prepared in Examples 1-4.

[0025] Figure 3The equilibrium solubility comparison chart shows the afatinib raw material of Comparative Example 1, the amorphous afatinib of Comparative Example 2, the afatinib co-amorphous drugs prepared in Examples 1-4, and the physical mixture of Comparative Example 3.

[0026] Figure 4 In vitro dissolution curves of afatinib raw material (Comparative Example 1), amorphous afatinib (Comparative Example 2), and amorphous afatinib prepared in Examples 1-4 in phosphate buffer at pH 6.8. Detailed Implementation

[0027] To better understand this invention, the objectives, technical solutions, and effects of this invention are explained below, and further description is provided in conjunction with the accompanying drawings and specific embodiments. However, the implementation of this invention is not limited thereto. The described embodiments are some, but not all, of the embodiments of this invention. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0028] Co-amorphous systems are novel solid-state dispersion systems developed in the pharmaceutical field in recent years for poorly soluble drugs. They consist of a single-phase, homogeneous amorphous substance formed by the self-assembly of the active pharmaceutical ingredient and suitable small-molecule ligands through intermolecular interactions such as hydrogen bonding, π-π stacking, and van der Waals forces. By completely disrupting the drug crystal lattice, co-amorphous systems significantly reduce the lattice energy required for drug dissolution, placing the system in a high-energy thermodynamic state. This significantly improves the apparent solubility and dissolution driving force of the drug, allowing for better dissolution in water and enhancing oral efficacy. It can significantly improve the solubility and dissolution rate of poorly soluble drugs and also provides a new strategy for the design and development of compound drugs. Simultaneously, the uniform dispersion of ligand molecules and drug molecules at the molecular level can further inhibit drug molecule aggregation, delay crystallization and recrystallization, and maintain a higher supersaturation concentration of the drug in the gastrointestinal environment, promoting drug absorption. Therefore, developing a novel co-amorphous system for afatinib, which improves water solubility while simplifying the preparation process, is of great significance for enhancing its oral bioavailability and clinical application value.

[0029] The active pharmaceutical ingredient used in this invention is afatinib, chemically named (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide. Its molecular formula is C2 24 H 25ClFN5O3, with a molecular weight of 485.94 and CAS number 850140-72-6. It should be noted that the afatinib used in the embodiments of this invention is in free base form, and its chemical structure is as follows:

[0030]

[0031] This invention employs small molecule compounds as co-amorphous ligands. The four classes of small molecules selected include antioxidants (gallic acid, protocatechuic acid, and methyl gallate) and sweeteners (saccharin), which can form a co-amorphous system with afatinib through non-covalent interactions such as intermolecular hydrogen bonds, π-π interactions, and van der Waals forces. Compared to traditional salt-forming modification strategies, the small molecule ligands selected in this invention not only avoid potential toxicity and stringent pH compatibility conditions but also rely on uniform solid-state intermolecular interaction mechanisms, laying a solid material foundation for constructing a highly water-soluble afatinib delivery system.

[0032] Therefore, this invention provides an afatinib co-amorphous drug, comprising the active pharmaceutical ingredient afatinib and a ligand in a 1:1 molar ratio; the ligand is selected from any one of methyl gallate, gallic acid, saccharin, and protocatechuic acid; afatinib and the ligand form a single homogeneous amorphous structure through intermolecular interactions. At a 1:1 molar ratio, the major interaction sites between the drug and ligand molecules can achieve saturated pairing, forming the most stable binary system. This is beneficial for forming a single homogeneous amorphous structure.

[0033] This invention, through PXRD analysis, confirmed that the four co-amorphous drugs of this invention—afatinib-methyl gallate, afatinib-gallic acid, afatinib-saccharin, and afatinib-protocatechuic acid—all formed a single amorphous phase. In the PXRD patterns, the sharp crystal diffraction peaks of afatinib and its ligand active pharmaceutical ingredients completely disappeared, replaced by broad and diffuse amorphous diffraction peaks, indicating that the drugs and ligands achieved homogeneous mixing at the molecular level, and the crystal structure was completely destroyed.

[0034] The co-amorphous forms possess a single glass transition temperature (Tg). DSC analysis confirmed that all four afatinib co-amorphous drugs of this invention possess a single Tg, further demonstrating the formation of a single homogeneous system. For example, the Tg of the afatinib-methyl gallate co-amorphous system is 85.93℃; the Tg of the afatinib-gallic acid co-amorphous system is 130.63℃; the Tg of the afatinib-saccharin co-amorphous system is 113.10℃; and the Tg of the afatinib-protocatechuic acid co-amorphous system is 106.89℃.

[0035] This invention tested the equilibrium solubility of afatinib co-amorphous drugs. The test results showed that, compared to afatinib crystals (approximately 0.06 mg / mL) and their physical mixtures, the co-amorphous system of this invention significantly improved the equilibrium solubility. Specifically, the equilibrium solubility of the afatinib-methyl gallate co-amorphous system reached approximately 0.42 mg / mL; the equilibrium solubility of the afatinib-gallic acid co-amorphous system reached approximately 3.34 mg / mL; the equilibrium solubility of the afatinib-saccharin co-amorphous system reached approximately 4.21 mg / mL; and the equilibrium solubility of the afatinib-protocatechuic acid co-amorphous system was the highest, reaching approximately 7.41 mg / mL.

[0036] This invention tested the in vitro dissolution performance of afatinib co-amorphous drug. In phosphate buffer at pH 6.8, crystalline afatinib dissolves slowly (approximately 0.09 mg / mL), while the co-amorphous system of this invention achieves a high drug concentration in the initial stage (0-20 minutes). The highest concentration in the afatinib-protocatechuic acid co-amorphous system reaches approximately 0.46 mg / mL, significantly improving the drug dissolution rate.

[0037] This invention employs mechanical ball milling to prepare amorphous systems, which features a green and environmentally friendly process, simple operation, and good reproducibility, facilitating rapid conversion and stable control of solid-state forms. The preferred process parameters for mechanical ball milling are: a milling speed of 300-500 rpm and a milling time of 150-240 minutes. More preferably, the milling speed is 400 rpm and the milling time is 180 minutes.

[0038] Example 1

[0039] Preparation of the afatinib-methyl gallate co-amorphous drug. The active ingredient afatinib and the ligand methyl gallate were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the ball mill jar of a planetary ball mill and ground at room temperature. The milling speed was set to 400 rpm, and the milling time was 180 minutes. After milling, the powder sample was collected to obtain the afatinib-methyl gallate co-amorphous drug. The obtained sample was passed through a 100-mesh sieve (150 µm) and stored in a desiccator at room temperature for later use.

[0040] Example 2

[0041] Preparation of the afatinib-gallic acid co-amorphous drug. The active ingredient afatinib and the ligand gallic acid were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the ball mill jar of a planetary ball mill and ground at room temperature. The milling speed was set to 400 rpm, and the milling time was 180 minutes. After milling, the powder sample was collected to obtain the afatinib-gallic acid co-amorphous drug. The obtained sample was passed through a 100-mesh sieve (150 µm) and stored in a desiccator at room temperature for later use.

[0042] Example 3

[0043] Preparation of afatinib-saccharin co-amorphous drug. The active ingredient afatinib and the ligand saccharin were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the grinding jar of a planetary ball mill and ground at room temperature. The milling speed was set to 400 rpm, and the milling time was 180 minutes. After milling, the powder sample was collected to obtain the afatinib-saccharin co-amorphous drug. The obtained sample was passed through a 100-mesh sieve (150 µm) and stored in a desiccator at room temperature for later use.

[0044] Example 4

[0045] Preparation of afatinib-protocatechuic acid co-amorphous drug. The active ingredient afatinib and the ligand protocatechuic acid were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the ball mill jar of a planetary ball mill and ground at room temperature. The milling speed was set to 400 rpm, and the milling time was 180 minutes. After milling, the powder sample was collected to obtain the afatinib-protocatechuic acid co-amorphous drug. The obtained sample was passed through a 100-mesh sieve (150 µm) and stored in a desiccator at room temperature for later use.

[0046] Example 5

[0047] Preparation of the afatinib-methyl gallate co-amorphous drug. The active ingredient afatinib and the ligand methyl gallate were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the ball mill jar of a planetary ball mill and ground at room temperature. The milling speed was set to 300 rpm, and the milling time was 240 minutes. After milling, the powder sample was collected to obtain the afatinib-methyl gallate co-amorphous drug. The obtained sample was passed through a 100-mesh sieve (150 µm) and stored in a desiccator at room temperature for later use.

[0048] Example 6

[0049] Preparation of the afatinib-gallic acid co-amorphous drug: The active ingredient afatinib and the ligand gallic acid were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the ball mill jar of a planetary ball mill and ground at room temperature at 500 rpm for 150 minutes. After milling, the powder sample was collected to obtain the afatinib-gallic acid co-amorphous drug.

[0050] Example 7

[0051] Preparation of afatinib-saccharin co-amorphous drug. The active ingredient afatinib and the ligand saccharin were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the grinding jar of a planetary ball mill and ground at room temperature at 400 rpm for 240 minutes. After grinding, the powder sample was collected to obtain the afatinib-saccharin co-amorphous drug.

[0052] Example 8

[0053] Preparation of the afatinib-protocatechuic acid co-amorphous drug: The active ingredient afatinib and the ligand protocatechuic acid were weighed and mixed at a molar ratio of 1:1. The mixture was placed in the ball mill jar of a planetary ball mill and ground at room temperature at 500 rpm for 180 minutes. After milling, the powder sample was collected to obtain the afatinib-protocatechuic acid co-amorphous drug.

[0054] Comparative Example 1

[0055] Afatinib API: Commercially available afatinib API is used directly, which is in a stable crystalline form.

[0056] Comparative Example 2

[0057] Amorphous afatinib: Afatinib raw material was weighed, without the addition of any ligands, and placed in a ball mill jar. It was then ground under the same conditions as described in Example 1 (400 rpm, 180 minutes) to prepare amorphous afatinib.

[0058] Comparative Example 3

[0059] Physical mixtures (PM): Afatinib, methyl gallate, gallic acid, saccharin, and protocatechuic acid were weighed separately and placed in a mortar at a molar ratio of 1:1. They were then gently ground for 5 minutes to perform simple physical mixing, resulting in afatinib-methyl gallate physical mixture, afatinib-gallic acid physical mixture, afatinib-saccharin physical mixture, and afatinib-protocatechuic acid physical mixture.

[0060] The performance characterization and test results are as follows:

[0061] PXRD analysis: The samples were characterized using X-ray powder diffraction. For example... Figure 1 As shown, the afatinib active pharmaceutical ingredient in Comparative Example 1 exhibited sharp characteristic crystallization diffraction peaks. The four afatinib co-amorphous drugs prepared in Examples 1-4, as well as the amorphous afatinib in Comparative Example 2, did not show sharp diffraction peaks in their spectra, but instead exhibited typical broad, diffuse peaks. This indicates that through mechanical ball milling, afatinib and its ligands were completely converted into an amorphous state, forming a single homogeneous amorphous system. Examples 5-8 adjusted the ball milling speed and time for afatinib and the co-formed products. PXRD characterization results showed that the co-amorphous samples prepared at different speeds and times all exhibited diffuse peaks predominantly, with no obvious crystal characteristic peaks, indicating that within the ratio and process parameters defined in this invention, afatinib and the co-formed products can form a co-amorphous system. This result further demonstrates that the method of this invention has good repeatability and process applicability.

[0062] DSC analysis: The thermal properties of the samples were tested using a differential scanning calorimeter. For example... Figure 2 As shown, the four co-amorphous drugs prepared in Examples 1-4 exhibit a single Tg, indicating that afatinib and its ligands form a monophasic co-amorphous system. Combined with... Figure 2 As shown, the specific measured Tg values ​​are as follows:

[0063] Example 1 (afatinib-methyl gallate): glass transition occurred at 85.93°C;

[0064] Example 2 (afatinib-gallic acid): glass transition occurred at 130.63°C;

[0065] Example 3 (afatinib-saccharin): Glass transition occurred at 113.10°C;

[0066] Example 4 (afatinib-protocatechuic acid): glass transition occurred at 106.89 °C;

[0067] Comparative Example 2 (amorphous afatinib): underwent a glass transition at 90.01 °C.

[0068] Equilibrium solubility test: The equilibrium solubility in pH 6.8 phosphate buffer at 37°C was determined after 24 hours. For example... Figure 3 As shown, the co-amorphous drug of the present invention significantly improves the equilibrium solubility of afatinib, and its solubilizing effect is significantly better than that of afatinib raw material in Comparative Example 1, amorphous afatinib in Comparative Example 2, and the physical mixture in Comparative Example 3. Specific measurement results are as follows:

[0069] Comparative Example 1 (Afatinib API): Solubility is approximately 0.06 mg / mL;

[0070] Comparative Example 2 (amorphous afatinib): solubility approximately 0.21 mg / mL;

[0071] Example 1 (Afatinib-methyl gallate co-amorphous drug): Solubility was approximately 0.43 mg / mL (approximately 7.2 times higher than that of afatinib raw material in Comparative Example 1);

[0072] Example 2 (Afatinib-gallic acid co-amorphous drug): Solubility was approximately 3.34 mg / mL (approximately 55.7 times higher than that of the afatinib raw material in Comparative Example 1);

[0073] Example 3 (Afatinib-saccharin co-amorphous drug): Solubility was approximately 4.21 mg / mL (approximately 70.2 times higher than that of the afatinib raw material in Comparative Example 1);

[0074] Example 4 (Afatinib-Protocatechuic Acid Co-amorphous Drug): Solubility was approximately 7.41 mg / mL (approximately 123.5 times higher than that of the afatinib raw material in Comparative Example 1).

[0075] The physical mixtures of Comparative Example 3 had the following solubilities: afatinib-methyl gallate physical mixture: approximately 0.30 mg / mL; afatinib-gallic acid physical mixture: approximately 2.75 mg / mL; afatinib-saccharin physical mixture: approximately 3.37 mg / mL; and afatinib-protocatechuic acid physical mixture: approximately 6.82 mg / mL.

[0076] As can be seen from the above data, the equilibrium solubility of afatinib raw material, amorphous afatinib, and the four physical mixtures is lower than that of the co-amorphous system. However, the solubility of the co-amorphous system in Examples 1 to 4 shows a significant leap, which fully demonstrates that the solubilizing effect of the present invention does not stem from simple physical solubilization by the ligand, but rather from the complete disruption of the drug lattice and the formation of a high-energy amorphous structure in the system of the present invention.

[0077] As shown by the data above, the co-amorphous systems prepared in Examples 1-4 all exhibit significantly higher equilibrium solubility than afatinib raw material and its amorphous form. This indicates that the formation of the co-amorphous phase disrupts the original ordered crystal lattice structure of afatinib, weakens intermolecular forces, and lowers the solubility barrier, thereby achieving a significant increase in solubility. Furthermore, the solubility of the co-amorphous systems is also significantly higher than that of the corresponding physical mixtures, indicating that the solubilizing effect of this invention does not originate from simple physical solubilization or the superposition of effects of ligands, but rather from fundamentally improving solubility at the phase level by forming a uniform high-energy amorphous structure, thus achieving a significantly enhanced solubilizing effect.

[0078] In vitro dissolution test: Using phosphate buffer solution at pH 6.8 as the dissolution medium, the in vitro dissolution curve of the sample was determined. For example... Figure 4 As shown, Comparative Example 1 (afatinib API) exhibited an extremely slow dissolution rate. Samples from Examples 1-4 all showed a rapid initial dissolution rate followed by a gradual plateauing. Among them, the dissolution performance of afatinib-methyl gallate in Example 1 was slightly better than that of afatinib API; the dissolution rates of afatinib-gallic acid, afatinib-saccharin, and afatinib-protocatechuic acid in Examples 2-4 were significantly better than those of afatinib API, especially afatinib-protocatechuic acid, which showed the most outstanding performance. Its concentration rapidly increased to 0.37 mg / mL within the first 20 minutes of dissolution, and then continued to rise slowly over time, reaching 0.46 mg / mL at 300 minutes, exhibiting the fastest dissolution rate and the highest steady-state concentration.

[0079] As can be seen from the test results of Examples 1-8 and Comparative Examples 1-3, the present invention forms a single-phase homogeneous co-amorphous system through co-amorphous technology, effectively solving the problem of low solubility of afatinib raw material, and has the following characteristics:

[0080] 1) Solubility and dissolution achieve order-of-magnitude improvement

[0081] Compared to the active pharmaceutical ingredient (API), the solubility of co-amorphous drugs is significantly increased, with a solubilizing effect far exceeding that of API, pure amorphous drugs, and physical mixtures. Moreover, the in vitro dissolution rate is significantly accelerated, and the potential for rapid onset of action is stronger, fundamentally improving the absorption bottleneck of afatinib's high permeability and low solubility.

[0082] 2) Avoid the risks of in vivo instability and disproportionation associated with salt formation modification.

[0083] Existing technologies often use salt formation modification to prepare afatinib maleate, which suffers from unstable in vivo solubility, pH dependence, and potential disproportionation problems. This invention employs a combination of a free base and a safe small-molecule ligand, avoiding salt formation dependent on strong acids and bases, reducing the risk of side reactions and impurities, and avoiding in vivo phase transitions and absorption fluctuations caused by salt formation, thus better meeting drug safety requirements.

[0084] 3) Simple process and safe ligands

[0085] Compared with Chinese invention patent application CN121177242A, this invention uses mechanical ball milling, which is solvent-free, water-free, and requires no high temperature or high pressure. It has low energy consumption, no pollution, and good reproducibility, significantly outperforming existing complex tablet manufacturing processes. Moreover, the selected methyl gallate, gallic acid, saccharin, and protocatechuic acid ligands are all common small molecules with advantages such as wide availability, high safety, and low cost, making them suitable for large-scale process development.

[0086] Compared to Chinese invention patent CN104892584B, this invention features zero organic residue throughout the entire process, controllable moisture content, and is environmentally friendly. While CN104892584B is a single-component salt-forming amorphous system, this invention is a binary co-amorphous system formed by the free base of afatinib and a safe ligand. This system relies on intermolecular interactions to stabilize the structure, resulting in a higher glass transition temperature and significantly improved resistance to crystallization and crystal transformation. Furthermore, the salt-forming amorphous system is susceptible to disproportionation and phase transition due to the pH influence of the gastrointestinal tract. This invention uses the free base of afatinib, eliminating the need for strong acid-base salt formation, and is combined with a safe pharmaceutical-grade ligand, eliminating the risk of disproportionation in vivo and offering superior safety. Chinese invention patent CN104892584B only improves the solubility of afatinib bismaleate in organic solvents such as ethanol and ethyl acetate, failing to reflect the actual absorption environment in vivo. This invention, however, was evaluated in a physiological pH 6.8 medium simulating the human small intestine, achieving an order-of-magnitude improvement in solubility and dissolution rate.

[0087] This invention relates to afatinib co-amorphous drug that can be used to prepare oral pharmaceutical formulations to improve the oral bioavailability of afatinib. Oral pharmaceutical formulations refer to pharmaceutical formulations administered orally, including types such as oral solid dosage forms and oral liquid dosage forms; this invention preferably uses oral solid dosage forms. The oral solid dosage form is selected from tablets, capsules, granules, or powders. The oral solid dosage form contains afatinib co-amorphous drug and pharmaceutically acceptable excipients, including one or more of fillers, disintegrants, flow aids, and lubricants; wherein the filler can be selected from one or more of lactose, mannitol, microcrystalline cellulose, starch, or pregelatinized starch; the disintegrant can be selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, or low-substituted hydroxypropyl cellulose; the flow aid can be selected from one or more of colloidal silica or talc; and the lubricant can be selected from one or more of magnesium stearate, calcium stearate, sodium stearate fumarate, or polyethylene glycol.

[0088] The oral solid dosage form is prepared by directly compressing, encapsulating, or granulating afatinib co-amorphous drug with excipients. Compared with existing oral afatinib formulations, the oral solid dosage form of afatinib co-amorphous drug of this invention can improve the oral administration performance of afatinib by utilizing its higher solubility and dissolution rate, which helps to improve the quality stability and dosing consistency of the formulation, and solves the problems of poor water solubility and insufficient absorption of existing oral afatinib formulations.

[0089] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An amorphous drug, characterized in that, It is composed of the active ingredient afatinib and a ligand; the ligand is selected from any one of methyl gallate, gallic acid, saccharin and protocatechuic acid; the afatinib and the ligand form a single homogeneous amorphous structure through intermolecular interactions; the molar ratio of afatinib to the ligand is 1:

1.

2. The afatinib co-amorphous drug according to claim 1, characterized in that, The sharp crystalline diffraction peaks of afatinib and its ligand raw materials in the X-ray powder diffraction pattern of the amorphous drug are presented as broad and diffuse amorphous diffraction peaks.

3. The afatinib co-amorphous drug according to claim 1, characterized in that, The co-amorphous drug has a single glass transition temperature Tg in differential scanning calorimetry.

4. The afatinib co-amorphous drug according to claim 3, characterized in that, When the ligand is methyl gallate, the Tg of the co-amorphous drug is 85.93℃; when the ligand is gallic acid, the Tg of the co-amorphous drug is 130.63℃; when the ligand is saccharin, the Tg of the co-amorphous drug is 113.10℃; and when the ligand is protocatechuic acid, the Tg of the co-amorphous drug is 106.89℃.

5. The method for preparing afatinib co-amorphous drug according to any one of claims 1 to 4, characterized in that, Afatinib and the ligand were mixed at a molar ratio of 1:1 and placed in the ball mill jar of a planetary ball mill. The mixture was subjected to high-energy mechanical ball milling at room temperature, and the product was collected.

6. The method for preparing afatinib co-amorphous drug according to claim 5, characterized in that, The ball mill operates at a speed of 300-500 rpm for 150-240 minutes.

7. The method for preparing afatinib co-amorphous drug according to claim 5, characterized in that, The mass of afatinib fed in a single high-energy mechanical ball milling process is 500-2000 mg.

8. The use of the afatinib co-amorphous drug according to any one of claims 1 to 4 in the preparation of an oral pharmaceutical formulation that improves the oral bioavailability of afatinib.

9. The use of the afatinib co-amorphous drug according to claim 8 in the preparation of oral pharmaceutical formulations with improved oral bioavailability of afatinib, characterized in that, The oral pharmaceutical preparation is an oral solid dosage form; the oral solid dosage form is selected from one of tablets, capsules, granules or powders.

10. The use of the afatinib co-amorphous drug according to claim 9 in the preparation of oral pharmaceutical formulations with improved oral bioavailability of afatinib, characterized in that, The oral solid dosage form comprises the afatinib co-amorphous drug and pharmaceutically acceptable excipients; the excipients include one or more of fillers, disintegrants, glidants, and lubricants; the oral solid dosage form is prepared by directly compressing, encapsulating, or granulating the afatinib co-amorphous drug with the excipients.

Images