A co-amorphous form of erlotinib and its preparation method and application

Abstract

The present invention belongs to the field of pharmaceutical chemical technology and specifically relates to a co-amorphous form of erlotinib, its preparation method, and application. The co-amorphous form of erlotinib is prepared from raw materials containing erlotinib hydrochloride and an excipient, wherein the molar ratio of the erlotinib hydrochloride to the excipient is 1:0.5-5, and the excipient is gallic acid or L-tryptophan. The product prepared by the present invention is a co-amorphous form containing erlotinib, thereby improving the solubility and dissolution rate of erlotinib, thereby achieving the purpose of improving its bioavailability.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical industry, and in particular to an erlotinib co-amorphous compound and a preparation method and application thereof. Background Art

[0002] Lung cancer is the most common malignant tumor in the world. Its subtypes include small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Clinically, NSCLC is the most common, accounting for approximately 85% of lung cancer patients. Currently, clinical treatments for lung cancer include medication, radiotherapy, and surgery, with surgery being the only cure. However, due to the lack of early diagnosis methods, most patients are already in the advanced stages of the disease by the time they are diagnosed, missing the opportunity for surgical treatment. Conventional first-line platinum-based chemotherapy regimens, among others, are unsatisfactory and poorly tolerated. The efficacy of other therapeutic agents has already reached a plateau, and increasing their dosage will only exacerbate their side effects.

[0003] Erlotinib Hydrochloride Tablets (ERL), shown in Formula 1, with CAS number 183319-69-9, is the first clinically available tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) gene and an FDA-approved drug for the treatment of non-small cell lung cancer (NSCLC). Studies have shown that for advanced NSCLC with EGFR mutations, erlotinib hydrochloride alone has an efficacy of 15-90%, demonstrating excellent anti-tumor activity. Due to its low water solubility and high permeability, erlotinib hydrochloride is classified as BCS Class II in the Biopharmaceutics Classification System. For BCS Class II drugs, dissolution of the active ingredient is the rate-limiting step in the absorption of the drug in the human body.

[0004]

[0005] Co-amorphous solid dispersions are single-phase amorphous solid dispersion drug delivery systems composed of two or more small molecule components. The components are typically connected by non-covalent bonds such as hydrogen bonds and π-π stacking, or by a lack of interaction. Although co-amorphous solid dispersions are conventionally classified as solid dispersions, significant differences exist between the two. Compared to traditional macromolecular solid dispersions, which suffer from poor physical stability due to the large amount of carrier material used and hygroscopicity, and amorphous drugs, which are prone to recrystallization due to their high thermodynamic energy state, co-amorphous drugs, by selecting small molecule excipients or synergistic drugs as ligands, significantly improve the solubility and dissolution of poorly soluble drugs while maintaining good stability, becoming a hot topic in pharmaceutical research in recent years. However, research on ERL co-amorphous dosage forms has yet to be reported. Summary of the Invention

[0006] The present invention addresses the lack of research on ERL co-amorphous dosage forms in the prior art and proposes an erlotinib co-amorphous material, its preparation method, and application. The erlotinib co-amorphous material is prepared by using erlotinib hydrochloride and an excipient containing specific components as raw materials, and controlling the dosage ratio of the erlotinib hydrochloride to the excipient to obtain a co-amorphous material containing erlotinib, thereby improving the solubility and dissolution rate of erlotinib and thereby enhancing its bioavailability.

[0007] In order to achieve the above-mentioned object, the first aspect of the present invention provides a co-amorphous form of erlotinib, which is prepared from raw materials containing erlotinib hydrochloride and an excipient, wherein the molar ratio of the erlotinib hydrochloride to the excipient is 1:0.5-5, and the excipient is gallic acid or L-tryptophan.

[0008] Preferably, when the excipient is gallic acid, the molar ratio of the erlotinib hydrochloride to the gallic acid is 1:0.5-2. More preferably, the glass transition temperature of the erlotinib co-amorphous compound is 60-70°C. Further preferably, the infrared absorption spectrum of the erlotinib co-amorphous compound is between 3272-3495 cm -1 、1683cm -1 、1629cm -1 、1540cm -1 、1514cm -1 、1164cm -1 、1026cm -1 and 866cm -1 More preferably, the equilibrium solubility of the erlotinib co-amorphous compound at a pH value of 1.5 to 3 is 800 to 2000 μg / mL.

[0009] Preferably, when the excipient is L-tryptophan, the molar ratio of erlotinib hydrochloride to L-tryptophan is 1:1 to 3. More preferably, the glass transition temperature of the erlotinib co-amorphous compound is 70 to 80°C. Further preferably, the infrared absorption spectrum of the erlotinib co-amorphous compound is at 3412 cm -1 , 3272cm -1 、1629cm -1 、1575cm -1 、1449cm -1 、1164cm -1 , 745cm -1 、581cm -1 and 424cm -1More preferably, the equilibrium solubility of the erlotinib co-amorphous compound at a pH value of 1.5 to 3 is 200 to 3000 μg / mL.

[0010] A second aspect of the present invention provides a method for preparing a co-amorphous form of erlotinib, which comprises mixing erlotinib hydrochloride, an excipient and an organic solvent, wherein the excipient is gallic acid or L-tryptophan, and then evaporating and drying the mixed product to obtain a co-amorphous form of erlotinib.

[0011] Preferably, the molar ratio of the erlotinib hydrochloride to the excipient is 1:0.5-5.

[0012] Preferably, when the excipient is gallic acid, the molar ratio of the erlotinib hydrochloride to the gallic acid is 1:0.5-2.

[0013] Preferably, when the excipient is L-tryptophan, the molar ratio of the erlotinib hydrochloride to the L-tryptophan is 1:1-3.

[0014] Preferably, the solid-to-liquid ratio of the erlotinib hydrochloride to the organic solvent is 1-3 mg:1 mL.

[0015] Preferably, the organic solvent is selected from one or more of methanol, ethanol and acetonitrile.

[0016] Preferably, the evaporation conditions include: a temperature of 30 to 50° C. and a vacuum degree of -0.1 to -0.09 MPa.

[0017] Preferably, the drying conditions include: a temperature of 20 to 35° C. and a drying time of 12 to 48 hours.

[0018] The third aspect of the present invention provides a co-amorphous form of erlotinib prepared by the above method.

[0019] The fourth aspect of the present invention provides the use of the above-mentioned erlotinib co-amorphous compound in the preparation of anti-tumor drugs.

[0020] Through the above technical solution, the present invention has at least the following beneficial effects:

[0021] (1) In the present invention, by using erlotinib hydrochloride and an excipient having gallic acid or L-tryptophan as raw materials and accurately controlling the ratio between the erlotinib hydrochloride and the excipient, the prepared product has the characteristics of a co-amorphous substance compared with single erlotinib hydrochloride, gallic acid and L-tryptophan. The solubility of the drug in the co-amorphous system is significantly improved, which is beneficial to the absorption of the drug in the body and increases the bioavailability of erlotinib;

[0022] (2) The product prepared by the solvent volatilization method of erlotinib hydrochloride and a specific component of the auxiliary material is a co-amorphous product, while the product obtained by simply physically mixing erlotinib hydrochloride and a specific component of the auxiliary material does not have the characteristics of a co-amorphous product. The solubility of the co-amorphous product prepared by the method of the present invention is significantly improved;

[0023] (3) The erlotinib co-amorphous compound prepared by the present invention has a shortened drug peak time Tmax and an increased peak concentration Cmax after oral administration, demonstrating that preparing erlotinib hydrochloride into a co-amorphous compound significantly improves its absorption in the body and duration of action;

[0024] (4) The anti-tumor efficacy evaluation results of the erlotinib co-amorphous compound prepared by the present invention on a liver cancer mouse model showed that the tumor inhibition rate of the erlotinib co-amorphous compound reached 41%. At the same time, the combined effect of the co-amorphous compound was evaluated by the Q value method, which showed a synergistic effect rather than a simple additive effect. The formation of the co-amorphous compound significantly improved the efficacy of erlotinib. This proves that the erlotinib co-amorphous compound prepared by the present invention is a potential new anti-cancer drug with good development prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The X-ray diffraction patterns of the products prepared in Example 1 and Comparative Example 1, as well as erlotinib hydrochloride crystals and gallic acid crystals;

[0026] Figure 2 The X-ray diffraction patterns of the products prepared in Example 2-3 and Comparative Example 2-3, as well as erlotinib hydrochloride crystals and L-tryptophan crystals;

[0027] Figure 3 The differential scanning calorimetry analysis patterns of the products prepared in Example 1 and Comparative Example 1, as well as erlotinib hydrochloride crystals and gallic acid crystals;

[0028] Figure 4 The differential scanning calorimetry analysis patterns of the products prepared in Example 2-3 and Comparative Example 2-3, as well as erlotinib hydrochloride crystals and L-tryptophan crystals;

[0029] Figure 5 The following are Fourier transform infrared spectroscopy analysis patterns of the products prepared in Example 1 and Comparative Example 1, as well as erlotinib hydrochloride crystals and gallic acid crystals;

[0030] Figure 6 The following are Fourier transform infrared spectroscopy analysis patterns of the products prepared in Example 2-3 and Comparative Example 2-3, as well as erlotinib hydrochloride crystals and L-tryptophan crystals;

[0031] Figure 7The solubility distribution of the products prepared in Example 1, Comparative Example 1, and Comparative Example 4 and the erlotinib hydrochloride crystals at pH values ​​of 1.0-7.4;

[0032] Figure 8 The solubility distribution of the products prepared in Examples 2-3, Comparative Examples 2-3 and Comparative Example 5 and erlotinib hydrochloride crystals at pH values ​​of 1.0-7.4;

[0033] Figure 9 The time-blood concentration curves of the products prepared in Example 1 and Example 3 and erlotinib hydrochloride crystals after oral administration to mice;

[0034] Figure 10 The curves of tumor area and time after treatment of liver cancer mice with erlotinib hydrochloride crystals, gallic acid crystals and a negative control group are shown in Example 1;

[0035] Figure 11 This is a comparison chart of the tumor inhibition rate (left) and Ki-67 positivity rate (right) after treating liver cancer mice with erlotinib hydrochloride crystals, gallic acid crystals and a negative control group in Example 1. DETAILED DESCRIPTION

[0036] The following describes the specific embodiments of the present invention in detail with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention and are not intended to limit the present invention.

[0037] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0038] Through a series of experiments, the researchers of the present invention discovered that gallic acid or L-tryptophan can be used as excipients in combination with erlotinib hydrochloride to prepare a co-amorphous compound containing erlotinib. Furthermore, studies have shown that gallic acid has multiple physiological activities, including antioxidant, anti-inflammatory, anti-tumor, anti-free radical, and antibacterial properties. When the concentration of gallic acid is greater than 10 μg / mL, gallic acid can promote apoptosis in lung cancer cells, and the effect of promoting apoptosis increases with increasing gallic acid concentration. Furthermore, studies have shown that L-tryptophan significantly reduces the metabolic level of tryptophan in the plasma of patients with non-small cell lung cancer.

[0039] A first aspect of the present invention provides an erlotinib co-amorphous compound, which is prepared from raw materials containing erlotinib hydrochloride and an excipient. The molar ratio of the erlotinib hydrochloride to the excipient is 1:0.5 to 5, for example, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5, and the excipient is gallic acid or L-tryptophan.

[0040] In the co-amorphous material of the present invention, in a specific embodiment, the erlotinib co-amorphous material prepared by the present invention uses Cu-Kα radiation, and the X-ray powder diffraction pattern shows no sharp crystal diffraction peaks.

[0041] In the co-amorphous material of the present invention, the amount of erlotinib hydrochloride and the excipient should be controlled within an appropriate range so that the prepared product forms a co-amorphous material and has high equilibrium solubility and anti-tumor effect. In a preferred embodiment, the molar ratio of the amount of erlotinib hydrochloride to the excipient is 1:0.5-3, for example, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3. In a more preferred embodiment, the molar ratio of the amount of erlotinib hydrochloride to the excipient is 1:1-2.

[0042] In the co-amorphous material of the present invention, the type of the excipient and the ratio of the erlotinib hydrochloride to the excipient will affect the properties of the prepared co-amorphous material through synergistic effects. In a preferred embodiment, when the excipient is gallic acid, the molar ratio of the amount of erlotinib hydrochloride to the gallic acid should be controlled at 1:0.5 to 2, for example, 1:0.5, 1:1, 1:1.5 or 1:2, so that the glass transition temperature of the prepared erlotinib co-amorphous material is 60 to 70°C, for example, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66.9°C, 68°C, 69°C or 70°C. At the same time, the infrared absorption spectrum of the prepared erlotinib co-amorphous material measured by KBr tablet is 3272-3495cm -1 、1683cm -1 、1629cm -1 、1540cm -1 、1514cm -1 、1164cm -1 、1026cm -1 and 866cm -1In a more preferred embodiment, when the excipient is gallic acid, the equilibrium solubility of the erlotinib co-amorphous form at a pH of 1.5 to 3 is 800 to 2000 μg / mL, for example, 800 μg / mL, 900 μg / mL, 1000 μg / mL, 1100 μg / mL, 1200 μg / mL, 1300 μg / mL, 1400 μg / mL, 1500 μg / mL, 1600 μg / mL, 1700 μg / mL, 1840 μg / mL, 1900 μg / mL or 2000 μg / mL.

[0043] In the co-amorphous material of the present invention, in a preferred embodiment, when the excipient is L-tryptophan, the molar ratio of the amount of erlotinib hydrochloride to the L-tryptophan should be controlled at 1:1 to 3, for example, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3, so that the glass transition temperature of the prepared erlotinib co-amorphous material is 70 to 80°C, for example, 70°C, 71°C, 72°C, 73°C, 73.9°C, 75°C, 76°C, 76.8°C, 78°C, 79°C or 80°C, and at the same time, the infrared absorption spectrum of the prepared erlotinib co-amorphous material measured by KBr tablet is 3412cm -1 , 3272cm -1 、1629cm -1 、1575cm -1 、1449cm -1 、1164cm -1 , 745cm -1 、581cm -1 and 424cm -1 In a more preferred embodiment, when the excipient is L-tryptophan, the equilibrium solubility of the erlotinib co-amorphous form at a pH of 1.5 to 3 is 200 to 3000 μg / mL, for example, 200 μg / mL, 250 μg / mL, 500 μg / mL, 1000 μg / mL, 1500 μg / mL, 2000 μg / mL, 2500 μg / mL, 2750 μg / mL or 3000 μg / mL.

[0044] In a specific embodiment, the erlotinib co-amorphous material is prepared from raw materials containing erlotinib hydrochloride and an auxiliary material, wherein the auxiliary material is gallic acid, and the molar ratio of the amount of erlotinib hydrochloride to the gallic acid is 1:0.5-2, so that the glass transition temperature of the prepared co-amorphous material is 60-70°C, and its infrared absorption spectrum is 3272-3495cm -1 、1683cm -1 、1629cm -1 、1540cm-1 、1514cm -1 、1164cm -1 、1026cm -1 and 866cm -1 There is an absorption peak at , and the equilibrium solubility of the erlotinib co-amorphous compound is 800-2000 μg / mL at a pH value of 1.5-3.

[0045] In another specific embodiment, the erlotinib co-amorphous material is prepared from raw materials containing erlotinib hydrochloride and an auxiliary material, wherein the auxiliary material is L-tryptophan, and the molar ratio of the amount of erlotinib hydrochloride to the L-tryptophan is 1:1-3, so that the glass transition temperature of the prepared co-amorphous material is 70-80°C, and its infrared absorption spectrum is 3412cm -1 , 3272cm -1 、1629cm -1 、1575cm -1 、1449cm -1 、1164cm -1 , 745cm -1 、581cm -1 and 424cm -1 There is an absorption peak at , and the equilibrium solubility of the erlotinib co-amorphous substance is 200-3000 μg / mL at a pH value of 1.5-3.

[0046] A second aspect of the present invention provides a method for preparing a co-amorphous form of erlotinib, which comprises mixing erlotinib hydrochloride, an excipient and an organic solvent, wherein the excipient is gallic acid or L-tryptophan, and then evaporating and drying the mixed product to obtain a co-amorphous form of erlotinib.

[0047] In the method of the present invention, the amount of erlotinib hydrochloride and the excipient should be controlled within an appropriate range so that the prepared product forms a co-amorphous substance and has high equilibrium solubility and anti-tumor effect. In a specific embodiment, the molar ratio of erlotinib hydrochloride to the excipient is 1:0.5 to 5, for example, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5.

[0048] In the method of the present invention, in a preferred embodiment, when the excipient is gallic acid, the molar ratio of the erlotinib hydrochloride to the gallic acid is 1:0.5-2, for example, 1:0.5, 1:1, 1:1.5 or 1:2.

[0049] In the method of the present invention, in a preferred embodiment, when the excipient is L-tryptophan, the molar ratio of the erlotinib hydrochloride to the L-tryptophan is 1:1 to 3, for example, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0050] In the method of the present invention, the erlotinib hydrochloride and the excipient require an appropriate amount of organic solvent for dissolution reaction to prepare an erlotinib co-amorphous compound with a high equilibrium solubility. In a specific embodiment, the solid-to-liquid ratio of the erlotinib hydrochloride to the organic solvent is 1 to 3 mg:1 mL, for example, 1 mg:1 mL, 1.34 mg:1 mL, 2 mg:1 mL, 2.5 mg:1 mL, or 3 mg:1 mL.

[0051] In the method of the present invention, in a specific embodiment, the organic solvent can be a conventional choice in the field of preparing co-amorphous materials. In a preferred embodiment, the organic solvent is selected from one or more of methanol, ethanol and acetonitrile.

[0052] In the method of the present invention, in a specific embodiment, the erlotinib hydrochloride, the excipient and the organic solvent are mixed by ultrasonic oscillation.

[0053] In the method of the present invention, in order to make the erlotinib hydrochloride and the excipients dissolve and react more thoroughly in the organic solvent, so that the prepared co-amorphous material has higher equilibrium solubility and anti-tumor effect, in a specific embodiment, the erlotinib hydrochloride and the excipients can be added to the organic solvent separately.

[0054] In the method of the present invention, in a specific embodiment, evaporation and drying are started after the mixed product becomes a clear and transparent solution.

[0055] In the method of the present invention, the temperature and vacuum degree during evaporation should be controlled within an appropriate range, so that the volatilization efficiency of the organic solvent can be improved while the co-amorphous material can be formed well. In a specific embodiment, the evaporation conditions include: a temperature of 30 to 50°C, for example, 30°C, 35°C, 40°C, 45°C or 50°C, and a vacuum degree of -0.1 to -0.09 MPa, for example, -0.1 MPa, -0.099 MPa, -0.098 MPa, -0.097 MPa, -0.096 MPa, -0.095 MPa, -0.094 MPa, -0.093 MPa, -0.092 MPa, -0.091 MPa or -0.09 MPa. In a preferred embodiment, the evaporation conditions include: a temperature of 40 to 45°C, and a vacuum degree of -0.1 to -0.09 MPa.

[0056] In the method of the present invention, after the organic solvent is completely volatilized, the residual organic solvent is effectively removed by drying. In a specific embodiment, the drying conditions include: a temperature of 20 to 35°C, for example, 20°C, 25°C, 30°C, or 35°C, and a drying time of 12 to 48 hours, for example, 12 hours, 18 hours, 24 hours, 36 hours, or 48 hours.

[0057] In the method of the present invention, in a specific embodiment, the method further comprises pulverizing the dried product. In a preferred embodiment, the dried product is pulverized to 100-300 mesh.

[0058] In the method of the present invention, in a specific embodiment, the pulverized product is placed in a dryer for use.

[0059] In a first specific embodiment, erlotinib hydrochloride, an excipient and an organic solvent are mixed, wherein the excipient is gallic acid or L-tryptophan, and the mixed product is evaporated and dried to obtain erlotinib co-amorphous.

[0060] In a second specific embodiment, erlotinib hydrochloride, an excipient and an organic solvent are mixed, wherein the excipient is gallic acid or L-tryptophan, and the molar ratio of the erlotinib hydrochloride to the excipient is 1:0.5-5. The mixed product is then evaporated and dried to obtain erlotinib co-amorphous.

[0061] In a third specific embodiment, erlotinib hydrochloride, gallic acid and an organic solvent are mixed, wherein the molar ratio of the erlotinib hydrochloride to the gallic acid is 1:0.5-2, and then the mixed product is evaporated and dried to obtain erlotinib co-amorphous.

[0062] In a fourth specific embodiment, erlotinib hydrochloride, L-tryptophan and an organic solvent are mixed, wherein the molar ratio of the erlotinib hydrochloride to the L-tryptophan is 1:1-3, and then the mixed product is evaporated and dried to obtain erlotinib co-amorphous.

[0063] In a fifth specific embodiment, erlotinib hydrochloride, gallic acid and an organic solvent are mixed, wherein the molar ratio of the erlotinib hydrochloride to the gallic acid is 1:0.5-2, and the solid-liquid ratio of the erlotinib hydrochloride to the organic solvent is 1-3 mg:1 mL, and then the mixed product is evaporated and dried to obtain erlotinib co-amorphous.

[0064] In a sixth specific embodiment, erlotinib hydrochloride, gallic acid and an organic solvent are mixed, wherein the molar ratio of the erlotinib hydrochloride to the gallic acid is 1:0.5-2, and the solid-liquid ratio of the erlotinib hydrochloride to the organic solvent is 1-3 mg:1 mL, and then the mixed product is evaporated at a temperature of 30-50°C and a vacuum degree of -0.1 to -0.09 MPa, and finally dried to obtain erlotinib co-amorphous.

[0065] In a seventh specific embodiment, erlotinib hydrochloride, gallic acid and an organic solvent are mixed, wherein the molar ratio of the erlotinib hydrochloride to the gallic acid is 1:0.5-2, and the solid-liquid ratio of the erlotinib hydrochloride to the organic solvent is 1-3 mg:1 mL, and then the mixed product is evaporated at a temperature of 30-50°C and a vacuum degree of -0.1 to -0.09 MPa, and the evaporated product is dried at a temperature of 20-35°C for 12 to 48 hours to obtain erlotinib co-amorphous.

[0066] In an eighth specific embodiment, erlotinib hydrochloride, L-tryptophan and an organic solvent are mixed, wherein the molar ratio of the erlotinib hydrochloride to the L-tryptophan is 1:1-3, and the solid-liquid ratio of the erlotinib hydrochloride to the organic solvent is 1-3 mg:1 mL, and then the mixed product is evaporated at a temperature of 30-50°C and a vacuum degree of -0.1 to -0.09 MPa, and finally dried to obtain erlotinib co-amorphous.

[0067] In a ninth specific embodiment, erlotinib hydrochloride, L-tryptophan and an organic solvent are mixed, wherein the molar ratio of the erlotinib hydrochloride to the L-tryptophan is 1:1-3, and the solid-liquid ratio of the erlotinib hydrochloride to the organic solvent is 1-3 mg:1 mL, and then the mixed product is evaporated at a temperature of 30-50°C and a vacuum degree of -0.1 to -0.09 MPa, and the evaporated product is dried at a temperature of 20-35°C for 12 to 48 hours to obtain erlotinib co-amorphous.

[0068] The third aspect of the present invention provides a co-amorphous form of erlotinib prepared by the above method.

[0069] The fourth aspect of the present invention provides the use of the above-mentioned erlotinib co-amorphous compound in the preparation of anti-tumor drugs.

[0070] The present invention will be described in detail below through examples, but the protection scope of the present invention is not limited thereto.

[0071] In the examples and comparative examples described in the present invention, unless otherwise specified, all reagents used are commercially available.

[0072] Example 1

[0073] (1) Weigh 53.64 mg of erlotinib hydrochloride powder and place it in a 100 mL rotary evaporator. Add 40 mL of methanol and ultrasonically vibrate for 10 minutes to completely dissolve it to obtain a clear and transparent solution. Then, add 21.27 mg of gallic acid powder to the clear and transparent solution and ultrasonically vibrate to completely dissolve it to obtain a clear and transparent solution again.

[0074] (2) The clear and transparent solution finally obtained in step (1) was placed in a water bath rotary evaporator at 45°C and a vacuum degree of -0.098 MPa to evaporate the solvent. After the solvent was completely evaporated, the obtained solid product was placed in a constant temperature and reduced pressure drying oven at 30°C and dried for 24 hours to remove the residual solvent in the obtained co-rotary evaporation product. The completely dried co-amorphous material was scraped off with a clean medicine spoon and passed through a 100 mesh sieve. The sieved solid powder was placed in a desiccator and stored for use.

[0075] Example 2

[0076] (1) Weigh 53.64 mg of erlotinib hydrochloride powder and place it in a 100 mL rotary evaporator. Add 40 mL of methanol and ultrasonically vibrate for 10 minutes to completely dissolve it to obtain a clear and transparent solution. Then, add 25.53 mg of L-tryptophan powder to the clear and transparent solution and ultrasonically vibrate to completely dissolve it to obtain a clear and transparent solution again.

[0077] (2) The clear and transparent solution finally obtained in step (1) was placed in a water bath rotary evaporator at 45°C and a vacuum degree of -0.098 MPa to evaporate the solvent. After the solvent was completely evaporated, the obtained solid product was placed in a constant temperature and reduced pressure drying oven at 30°C and dried for 24 hours to remove the residual solvent in the obtained co-rotary evaporation product. The completely dried co-amorphous material was scraped off with a clean medicine spoon and passed through a 100 mesh sieve. The sieved solid powder was placed in a desiccator and stored for use.

[0078] Example 3

[0079] (1) Weigh 53.64 mg of erlotinib hydrochloride powder and place it in a 100 mL rotary evaporator. Add 40 mL of methanol and ultrasonically vibrate for 10 minutes to completely dissolve it to obtain a clear and transparent solution. Then, add 51.06 mg of L-tryptophan powder to the clear and transparent solution and ultrasonically vibrate to completely dissolve it to obtain a clear and transparent solution again.

[0080] (2) The clear and transparent solution finally obtained in step (1) was placed in a water bath rotary evaporator at 45°C and a vacuum degree of -0.098 MPa to evaporate the solvent. After the solvent was completely evaporated, the obtained solid product was placed in a constant temperature and reduced pressure drying oven at 30°C and dried for 24 hours to remove the residual solvent in the obtained co-rotary evaporation product. The completely dried co-amorphous material was scraped off with a clean medicine spoon and passed through a 100 mesh sieve. The sieved solid powder was placed in a desiccator and stored for use.

[0081] Comparative Example 1

[0082] The method of Example 1 was followed, except that the solvent volatilization method in Example 1 was replaced with a simple physical mixing method. The specific steps are as follows:

[0083] Weigh 53.64 mg of erlotinib hydrochloride powder and place it in a dry and clean mortar. Then add 21.27 mg of gallic acid powder to the mortar and grind it thoroughly. Then pass it through a 100-mesh sieve. Place the sieved solid powder in a desiccator and store it for later use.

[0084] Comparative Example 2

[0085] The method of Example 2 was followed, except that the solvent volatilization method in Example 2 was replaced with a simple physical mixing method. The specific steps are as follows:

[0086] Weigh 53.64 mg of erlotinib hydrochloride powder and place it in a dry and clean mortar. Then add 25.53 mg of L-tryptophan powder to the mortar and grind it thoroughly. Then pass it through a 100-mesh sieve. Place the sieved solid powder in a desiccator and store it for later use.

[0087] Comparative Example 3

[0088] The method of Example 3 was followed, except that the solvent evaporation method in Example 3 was replaced by a simple physical mixing method. The specific steps are as follows:

[0089] Weigh 53.64 mg of erlotinib hydrochloride powder and place it in a dry and clean mortar. Then add 51.06 mg of L-tryptophan powder to the mortar and grind it thoroughly. Then pass it through a 100-mesh sieve. Place the sieved solid powder in a desiccator and store it for later use.

[0090] Comparative Example 4

[0091] The method of Example 1 was followed, except that gallic acid was replaced by caffeic acid.

[0092] Comparative Example 5

[0093] The method of Example 2 was followed, except that L-tryptophan was replaced by arginine.

[0094] Comparative Example 6

[0095] The method of Example 1 was followed, except that the molar ratio of erlotinib hydrochloride to the excipient was 1:0.3. The specific steps were as follows:

[0096] (1) Weigh 53.64 mg of erlotinib hydrochloride powder and place it in a 100 mL rotary evaporator. Add 40 mL of methanol and ultrasonically vibrate for 10 minutes to completely dissolve it to obtain a clear and transparent solution. Then, add 6.38 mg of gallic acid powder to the clear and transparent solution and ultrasonically vibrate to completely dissolve it to obtain a clear and transparent solution again.

[0097] (2) The clear and transparent solution obtained in step (1) was placed in a water bath rotary evaporator at 45°C and a vacuum degree of -0.098 MPa to evaporate the solvent. After the solvent was completely evaporated, the solid product was placed in a constant temperature and reduced pressure drying oven at 30°C and dried for 24 hours to remove the residual solvent in the co-evaporated product. The completely dried product was scraped off with a clean medicine spoon and passed through a 100 mesh sieve. The sieved solid powder was placed in a desiccator and stored for future use. The prepared product is not a co-amorphous substance and does not have the characteristics of a co-amorphous substance.

[0098] Comparative Example 7

[0099] The method of Example 1 was followed, except that the molar ratio of erlotinib hydrochloride to the excipient was 1:6. The specific steps were as follows:

[0100] (1) Weigh 53.64 mg of erlotinib hydrochloride powder and place it in a 100 mL rotary evaporator. Add 40 mL of methanol and ultrasonically vibrate for 10 minutes to completely dissolve it to obtain a clear and transparent solution. Then, add 127.59 mg of gallic acid powder to the clear and transparent solution and ultrasonically vibrate until it is completely dissolved to obtain a clear and transparent solution again.

[0101] (2) The clear and transparent solution obtained in step (1) was placed in a water bath rotary evaporator at 45°C and a vacuum degree of -0.098 MPa to evaporate the solvent. After the solvent was completely evaporated, the solid product was placed in a constant temperature and reduced pressure drying oven at 30°C and dried for 24 hours to remove the residual solvent in the co-evaporated product. The completely dried product was scraped off with a clean medicine spoon and passed through a 100 mesh sieve. The sieved solid powder was placed in a desiccator and stored for future use. The prepared product is not a co-amorphous substance and does not have the characteristics of a co-amorphous substance.

[0102] Test Case

[0103] (1) X-ray diffraction patterns (PXRD), differential scanning calorimetry analysis patterns, and Fourier transform infrared spectroscopy analysis patterns of the products prepared in Examples 1-3 and Comparative Examples 1-3, as well as erlotinib hydrochloride crystals, gallic acid crystals, and L-tryptophan crystals were measured.

[0104] X-ray diffraction (PXRD) patterns were obtained using a D8 Advance X-ray diffractometer. The following conditions were used: a rated output power of 3 kW, a 2θ scanning range of 5–60°, a goniometer radius ≥ 200 mm, a scanning speed of 10° / min, a step size of 0.05, and an angle reproducibility of 0.001°. The experimental data were analyzed using Origin 8.0 software (OriginLab, USA). Figure 1-2 shown.

[0105] from Figure 1 and Figure 2 It can be seen that the spectra of the co-amorphous materials prepared in Examples 1-3 do not have sharp diffraction peaks, which are completely different from the spectra of erlotinib hydrochloride crystals, gallic acid crystals, L-tryptophan crystals, and the physical mixture of the preparation raw materials. This proves that the amorphous material prepared by the present invention is a new solid form that is completely different from the monomers and their physical mixtures.

[0106] Differential Scanning Calorimetry (DSC) analysis: A TA-DSC2500 differential scanning calorimeter was used. Testing conditions: a heating rate of 10°C / min, and a drug determination range of 25-300°C. TA-Universal Analysis 2000 software (version 4.7A) was used to determine the glass transition temperature (Tg) and melting point (T) of the drug. The data were analyzed using Origin 8.0 software. The results are shown in Figure 2. Figure 3-4 shown.

[0107] from Figure 3 and Figure 4 It can be seen that the endothermic transition of erlotinib hydrochloride crystals is at 232.1°C, the endothermic transition of gallic acid crystals is at 261.9°C, the endothermic transition of L-tryptophan crystals is at 293.6°C, the endothermic transition of the product prepared by physical mixing of erlotinib hydrochloride and gallic acid is at 178.3°C, the endothermic transition of the product prepared by physical mixing of erlotinib hydrochloride and L-tryptophan is at 221°C, the endothermic transition of erlotinib hydrochloride-gallic acid (1:2) co-amorphous is at 66.9°C, the endothermic transition of erlotinib hydrochloride-L-tryptophan (1:1) co-amorphous is at 73.9°C, and the endothermic transition of erlotinib hydrochloride-L-tryptophan (1:2) co-amorphous is at 76.8°C.

[0108] Fourier transform infrared spectroscopy analysis: Fourier transform infrared spectroscopy (FTIR) was used. Detection conditions: appropriate amount of KBr pellet was used, and Fourier transform infrared spectrometer was used at 4000-400 cm -1 The infrared spectrum was recorded using OPUS software, and the experimental data were analyzed using Origin8.0 software (OriginLab, USA). Figure 5-6 shown.

[0109] from Figure 5 and Figure 6 It can be seen that the infrared absorption spectrum of erlotinib hydrochloride-gallic acid (1:2) amorphous compound is at 3272-3495 cm -1 、1683cm -1 、1629cm -1 、1540cm -1 、1514cm -1 、1164cm -1 、1026cm -1 、866cm -1 There is an absorption peak at 3412 cm; the infrared absorption spectrum of the amorphous compound of erlotinib hydrochloride and L-tryptophan (1:1, 1:2) is at 3412 cm -1 , 3272cm -1 、1629cm -1 、1575cm -1 、1449cm -1 、1164cm -1 , 745cm -1 、581cm -1 、424cm -1 There is an absorption peak at.

[0110] (2) Determine and calculate the equilibrium solubility of the products prepared in Examples 1-3 and Comparative Examples 1-5 and the erlotinib hydrochloride crystals.

[0111] Equilibrium solubility: Excessive amounts of the products prepared in Examples 1-3 and Comparative Examples 1-5 and erlotinib hydrochloride crystals were weighed, and then each was dissolved in 10 mL of buffer solution with pH values ​​of 1.0, 2.0, 3.3, 5.6, 6.8 and 7.4, respectively. The buffer solution (pH of the buffer solution was prepared with reference to the European Pharmacopoeia) was placed in a constant temperature oscillator at 25°C and vigorously shaken for 24 hours. After the solution was balanced, the sample was taken out, and the filtrate was taken out through a 0.22 μm microporous filter membrane. The concentration of erlotinib hydrochloride in each sample was determined by HPLC. Each group of experiments was repeated 3 times, and the results are shown in Tables 1-2 and Figure 7-8 shown.

[0112] Table 1

[0113]

[0114]

[0115] Table 2

[0116]

[0117] From Table 1-2 and Figure 7-8 It can be seen that the solubility of the erlotinib hydrochloride-gallic acid co-amorphous system is significantly improved, with the maximum solubility at pH 2.0, reaching 1.84 mg / mL, which is 2.6 times the solubility of erlotinib hydrochloride crystals under the same conditions, and the equilibrium solubility is 800-2000 μg / mL at pH 1.5-3; compared with erlotinib hydrochloride crystals and the product obtained by simple physical mixing method, the solubility of the erlotinib hydrochloride-L-tryptophan co-amorphous system is significantly improved at pH 2.0, reaching 2.73 mg / mL, which is nearly 3 times higher than that of erlotinib hydrochloride crystals and the product obtained by simple physical mixing method, and the equilibrium solubility is 200-3000 μg / mL at pH 1.5-3.

[0118] (3) Determine and calculate the pharmacokinetics of the products prepared in Example 1 and Example 3 and the erlotinib hydrochloride crystals.

[0119] The assay method involved weighing appropriate amounts of erlotinib hydrochloride crystals and the co-amorphous compounds prepared in Examples 1 and 3, then preparing oral suspensions containing 1.0 mg / mL of erlotinib hydrochloride or the co-amorphous compounds for pharmacokinetic studies. Eighteen male SD rats were randomly divided into three groups of six rats each. Each group received 10 mg / kg of erlotinib hydrochloride via oral gavage. Blood samples were collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0, and 24 hours after administration to measure erlotinib hydrochloride concentrations. The pharmacokinetic data were analyzed using the non-compartmental model analysis-non-vascular administration model of PKSolver pharmacokinetic and pharmacodynamic data processing software (China Pharmaceutical University). The peak time Tmax and peak concentration Cmax of the drug were recorded, and the elimination half-life t1 / 2 = 0.693 / k and the mean residence time MRT = AUMC / AUC of the drug were calculated. The results are shown in Table 2 and Figure 9 shown.

[0120] Table 2 Pharmacokinetic parameters after oral administration

[0121]

[0122] From Table 2 and Figure 9It can be seen that the time to peak plasma concentration of erlotinib hydrochloride crystals is 2.29 hours, while the time to peak plasma concentration of the co-amorphous drug in rats is less than 1 hour, which is significantly shorter than the peak time of erlotinib hydrochloride crystals. In addition, the maximum plasma concentration of the co-amorphous compound in Example 1 can reach 3.6 times that of the original drug, and the maximum plasma concentration of the co-amorphous compound in Example 3 can also reach 2.3 times that of the original drug, indicating that the co-amorphous drug has a faster effect and a higher blood concentration than the original drug. The results show that preparing erlotinib hydrochloride into a co-amorphous form significantly improves its absorption in the body and the duration of action.

[0123] (4) Determination and calculation of the pharmacodynamics of Example 1, erlotinib hydrochloride crystals and gallic acid crystals.

[0124] The assay method is: the anti-tumor efficacy is evaluated using a liver cancer mouse model. 50 SPF grade, 4-5 week old C57BL / 6 mice (Liaoning, 210726221101982662) were selected for adaptive feeding. After 7 days, the cultured mice were cultured at a density of 2*10 6 Hepatocellular carcinoma cells (HEPA-1-6 cell line) were inoculated subcutaneously in mice, with 0.2 mL in each mouse. Tumor growth was then observed, and mice with failed tumor formation or deformities that affected accurate measurement were removed. The remaining mice were randomly divided into four groups of eight mice each, ensuring a consistent average tumor volume of 100 mm in each group. 3 The negative control group was given an equivalent amount of sodium carboxymethylcellulose (0.5% CMCNa) as the drug administration group. The erlotinib group (ERL) was given a dose of 40 mg / kg, the gallic acid administration group (GA) was given a dose of 80 mg / kg, and the amorphous administration group (Example 1 sample, ERL + 2GA) was given a dose of 40 mg / kg. Administration was performed by gavage daily, and tumor volume was measured every other day with a vernier caliper. The length (A) and width (B) were recorded, and tumor volume was calculated according to the formula V = A*B2 / 2. After 14 days of administration, the animals were sacrificed and samples were collected.

[0125] According to the Q value method recognized by the international pharmaceutical community, the synergistic effect of the co-amorphous compound formed by erlotinib and gallic acid was evaluated. Ea is the inhibition rate of the erlotinib group, Eb is the inhibition rate of the gallic acid group, and Eab is the inhibition rate of the co-amorphous compound group. According to Q=Eab / (Ea+Eb-EaXEb), Q≥1.15 indicates synergistic effect. The results are as follows. Figure 10 and Figure 11 shown.

[0126] from Figure 10 and Figure 11As can be seen, all three drug groups inhibited tumor growth to varying degrees, with the co-amorphous group showing significantly superior efficacy compared to the erlotinib and gallic acid groups administered alone. Post-mortem analysis revealed that erlotinib inhibited tumor volume by 15%, gallic acid inhibited tumor volume by 19%, and the co-amorphous group exhibited an inhibition rate of 41%. This finding was further confirmed by immunohistochemical analysis of Ki-67 positivity. Furthermore, the Q-value method was used to assess whether the combined effect of the co-amorphous group was synergistic or additive. A Q-value of 1.3 indicated a synergistic effect, rather than a simple additive effect, indicating that the co-amorphous group significantly enhanced the efficacy of erlotinib. These results demonstrate that the co-amorphous combination of gallic acid and erlotinib exhibits a more potent antitumor effect, making it a potential new anticancer drug.

[0127] The above are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent transformations made using the contents of the present invention specification, or any direct or indirect application in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. An erlotinib co-amorphous compound, characterized in that: The erlotinib co-amorphous compound is prepared from raw materials containing erlotinib hydrochloride and an auxiliary material, wherein the molar ratio of the erlotinib hydrochloride to the auxiliary material is 1:0.5-5, and the auxiliary material is gallic acid; The erlotinib co-amorphous material was prepared according to the following steps: mixing erlotinib hydrochloride, excipients and an organic solvent, and then evaporating and drying the mixed product to obtain an erlotinib co-amorphous substance; The evaporation conditions include: a temperature of 30-50° C. and a vacuum degree of -0.1-0.09 MPa.

2. The erlotinib co-amorphous compound according to claim 1, characterized in that: The molar ratio of the erlotinib hydrochloride to the gallic acid is 1:0.5-2.

3. The erlotinib co-amorphous compound according to claim 2, characterized in that: The infrared absorption spectrum of the erlotinib co-amorphous compound is between 3272 and 3495 cm -1 、1683cm -1 、1629cm -1 、1540cm -1 、1514cm -1 、1164cm -1 、1026cm -1 and 866cm -1 There is an absorption peak at.

4. The erlotinib co-amorphous compound according to claim 1 or 3, characterized in that: The glass transition temperature of the erlotinib co-amorphous compound is 60-70°C.

5. The erlotinib co-amorphous compound according to claim 1 or 3, characterized in that: The equilibrium solubility of the erlotinib co-amorphous compound at a pH value of 1.5-3 is 800-2000 μg / mL.

6. The erlotinib co-amorphous compound according to claim 1, characterized in that: The molar ratio of the erlotinib hydrochloride to the auxiliary material is 1:0.5-5.

7. The erlotinib co-amorphous compound according to claim 1 or 6, characterized in that: The solid-to-liquid ratio of the erlotinib hydrochloride to the organic solvent is 1-3 mg:1 mL.

8. The erlotinib co-amorphous compound according to claim 1 or 6, characterized in that: The organic solvent is selected from one or more of methanol, ethanol and acetonitrile.

9. The erlotinib co-amorphous compound according to claim 1 or 6, characterized in that: The drying conditions include: a temperature of 20-35° C. and a drying time of 12-48 hours.

10. Use of the erlotinib co-amorphous compound according to any one of claims 1 to 9 in the preparation of anti-tumor drugs.

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