A drug, application, kit and preparation method of the drug for treating EGFR mutant non-small cell lung cancer meningeal metastasis

Abstract

The application belongs to the field of biological medicine, and particularly relates to a drug for treating EGFR mutant non-small cell lung cancer meningeal metastasis, application, a medicine box and a preparation method of the drug, the drug is a lyophilized powder preparation or injection solution for subarachnoid injection of EGFR-TKIs, the amount of EGFR-TKIs in the drug is 0.01-5 mg per person, and the injection method comprises any one of lumbar puncture, injection through a catheter indwelled in the pre-bridge pool and Ommaya capsule injection. The prepared EGFR-TKIs injection solution can be directly injected into the subarachnoid space, greatly improving the drug concentration in the cerebrospinal fluid of the patient, the cerebrospinal fluid / plasma concentration ratio is increased from far less than 1 to more than 2 times, and even more than 10 times. The application can completely solve the problem of insufficient dose caused by the blood-brain barrier after oral administration of a targeted drug, and the drug has fast effect and can significantly improve the treatment effect of lung cancer meningeal metastasis.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a drug, its application, a drug box, and a method for preparing the drug for treating EGFR-mutant non-small cell lung cancer with leptomeningeal metastasis. Background Technology

[0002] The central nervous system is the most common site of metastasis in lung cancer, with an incidence of approximately 40%. In patients with EGFR (epidermal growth factor receptor)-mutant NSCLC (non-small cell lung cancer), the cumulative incidence of brain metastasis over 3 years is as high as approximately 50%. Patients with brain parenchymal metastasis are more prone to leptomeningeal metastasis. Leptomeningeal metastasis differs significantly from brain parenchymal metastasis and requires differentiated clinical management. Leptomeningeal metastasis in EGFR-mutant lung cancer is a complex and challenging clinical condition with an extremely poor prognosis.

[0003] A efficacy analysis of oral osimertinib 80 mg, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in treating NSCLC patients with leptomeningeal metastases after treatment with first- or second-generation EGFR-TKIs included 45 patients. Based on baseline EGFR mutation type detected in cerebrospinal fluid, patients with mutations of 19Del and 21L858R had intracranial progression-free survival (PFS) of 11.9 months and 2.8 months, respectively. Patients with EGFR mutations of S768I, L747P, G724S, 20ins, and A289T detected in cerebrospinal fluid experienced leptomeningeal progression in a short period. Currently, there are no targeted therapies available for patients initially treated with oral third-generation EGFR-TKIs who develop leptomeningeal metastases.

[0004] Leptomeningeal metastasis in lung cancer remains one of the most challenging complications for advanced-stage patients, and current treatments have not yielded satisfactory results. Intrathecal chemotherapy is an important palliative treatment for leptomeningeal metastases. Chemotherapy drugs available include pemetrexed, methotrexate, thiotepa, and cytarabine, with pemetrexed being recommended as the first-line drug. The recommended dose is 10–50 mg per dose, 1–2 times per week, with the specific dosage and duration determined based on the individual patient's condition.

[0005] EGFR-TKIs refer to epidermal growth factor receptor tyrosine kinase inhibitors, a class of drugs that inhibit tumor growth by suppressing the EGFR signaling pathway. Based on their characteristics, they can be divided into three generations: First-generation (such as gefitinib, erlotinib, and icotinib) bind reversibly to EGFR, showing significant early efficacy but are prone to developing resistance. Second-generation (such as afatinib and dacomitinib) bind irreversibly to EGFR via covalent bonds, showing better efficacy against rare mutations. Third-generation (such as osimertinib and vormetinib) not only inhibit common mutations but also overcome T790M resistance mutations and reduce side effects on normal tissues.

[0006] Furthermore, the first-generation EGFR-TKI zolitinib (AZD3759) oral formulation has good water solubility and can cross the blood-brain barrier 100%. The ratio of free drug concentration in brain tissue to free drug concentration in plasma can reach 2.96. It is the world's first EGFR-TKI drug specifically designed for patients with brain metastases from lung cancer. It is approved for "first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutation and central nervous system (CNS) metastases." However, the Phase III clinical trial of zolitinib (EVEREST) ​​clearly excluded patients with leptomeningeal metastases, so zolitinib is not currently approved for the indication of leptomeningeal metastases.

[0007] EGFR-TKIs typically refer to the plural form of third-generation EGFR-TKIs, including drugs such as osimertinib, vormetinib, amitinib, befotinib, riertinib, regrinib, retizinib, and lanzatinib. These drugs have demonstrated stronger resistance to drug resistance in clinical applications. For example, osimertinib has a significant inhibitory effect on the T790M mutation, making it a standard treatment option for EGFR-mutant lung cancer.

[0008] EGFR-TKIs are all administered orally, and they have a very poor ability to cross the blood-brain barrier. At conventional oral doses, their cerebrospinal fluid concentration is less than 10% of the blood concentration, and even with increased oral doses, the cerebrospinal fluid concentration still increases only slightly.

[0009] For initial treatment of EGFR-mutant meningeal metastases, oral third-generation EGFR-TKIs are recommended. For meningeal metastases that develop after treatment resistance, cerebrospinal fluid gene testing is strongly recommended to help clarify the resistance mechanism. For patients with a clear resistance mechanism, intrathecal chemotherapy combined with individualized therapy is recommended; for those with an unclear resistance mechanism, intrathecal chemotherapy combined with other systemic therapies or clinical trials are suggested. For patients with unclear EGFR mutation resistance mechanisms, pulsed oral administration or increased doses of EGFR-TKIs may also be considered. For EGFR-mutant-positive meningeal metastases, a targeted therapy combined with anti-angiogenic therapy (using specific anti-angiogenic chemotherapeutic agents) may be considered. Local radiotherapy is possible for nodular meningeal lesions; whole-brain / whole-spinal cord radiotherapy should be approached with caution.

[0010] In other words, existing technologies primarily employ injectable chemotherapy drugs and oral targeted therapies (EGFR-TKIs) for treating EGFR-mutant non-small cell lung cancer with leptomeningeal metastases. However, these drugs and their combinations have not yielded satisfactory therapeutic effects. Therefore, there is a need in the art for a novel drug for treating EGFR-mutant non-small cell lung cancer with leptomeningeal metastases. Summary of the Invention

[0011] This invention first provides a drug for treating EGFR-mutant non-small cell lung cancer with leptomeningeal metastasis. The drug is a lyophilized powder or injection of EGFR-TKIs for subarachnoid injection. EGFR is epidermal growth factor receptor, and EGFR-TKIs are epidermal growth factor receptor tyrosine kinase inhibitors. The amount of EGFR-TKIs in the drug per dose is 0.01~5mg. The injection method of the drug includes any one of lumbar puncture, indwelling catheter injection in the prepontine cistern, and injection into the Ommaya capsule.

[0012] In one specific embodiment, the EGFR-TKIs are selected from one or more of osimertinib, ametinib, vormetinib, befotinib, riertinib, reertinib, retizinib, and lanzatinib; the drug further contains citrate or citrate, or the drug further contains mannitol and citrate or citrate, or the drug further contains hydroxypropyl β-cyclodextrin, mannitol, and citrate or citrate; the amount of EGFR-TKIs per person is 0.15~1.2 mg.

[0013] The present invention also provides the use of EGFR-TKIs in the preparation of a drug for treating EGFR-mutant non-small cell lung cancer with leptomeningeal metastasis, wherein the drug is a subarachnoid injection solution or a lyophilized powder preparation for injection of EGFR-TKIs, and the amount of EGFR-TKIs in each dose of the drug is 0.01~5mg.

[0014] In one specific embodiment, the EGFR-TKIs are selected from one or more of osimertinib, ametinib, vormetinib, befotinib, riertinib, reertinib, retizinib, and lanzatinib; the drug further contains citrate or citrate, or the drug further contains mannitol and citrate or citrate, or the drug further contains hydroxypropyl β-cyclodextrin, mannitol, and citrate or citrate; the amount of EGFR-TKIs per person per dose is 0.05~2 mg.

[0015] In one specific embodiment, the amount of EGFR-TKIs in the drug per person is 0.1~1.5 mg.

[0016] In one specific embodiment, the amount of EGFR-TKIs in the drug per person is 0.15~1.2 mg, and the drug is used in combination with oral EGFR-TKIs preparations.

[0017] In a specific embodiment of the present invention, the amount of EGFR-TKIs in the drug per person is 0.3~1mg.

[0018] In one specific embodiment, the drug is used to increase the ratio of osimertinib or vormetinib concentration in the cerebrospinal fluid to the plasma concentration of osimertinib or vormetinib in patients with EGFR-mutant non-small cell lung cancer leptomeningeal metastases.

[0019] The present invention also provides a medicine box comprising one or more unit dosage forms of the drug as described above, and a packaging insert indicating that the drug is used to delay or treat leptomeningeal metastases of EGFR-mutant non-small cell lung cancer.

[0020] This invention also provides a method for preparing a drug, wherein the drug is a lyophilized powder formulation of EGFR-TKIs for subarachnoid injection as described above; the method for preparing the drug includes the following steps: Step A, under a light-protected environment, dissolving EGFR-TKIs and mannitol in water for injection, optionally using hydroxypropyl β-cyclodextrin to aid in the dissolution of EGFR-TKIs, adjusting the pH value with citrate or citrate buffer, and adding water for injection to bring the volume to a final level; Step B, filtering using a filter membrane to remove impurities and bacteria; Step C, using a fully automated filling machine to rapidly fill the filtrate. Step D: Quickly fill multiple brown vials; Step E: Partially stopper the brown vials using a fully automatic stoppering machine; Step F: Freeze-dry the drug in a lyophilization chamber and then fill with nitrogen; Step G: Fully stopper the vials using a fully automatic stoppering machine in the lyophilization chamber, pressing the partially stopped rubber stopper into the vials to completely seal the drug; Step G: Use a capping machine to tightly press the aluminum-plastic cap onto the vials to obtain the lyophilized powder preparation for injection; The EGFR-TKIs content in the injection solution obtained after dissolving the lyophilized powder preparation for injection with water for injection is 0.001~0.5%.

[0021] In one specific embodiment, the lyophilized powder preparation for injection, after being dissolved in water for injection, contains 0.01-0.1% EGFR-TKIs, 4-6% mannitol, and 0-3% hydroxypropyl β-cyclodextrin in the resulting injection solution, and the pH value of the injection solution is 5-7.

[0022] In this embodiment of the invention, the content of EGFR-TKIs in the injection solution obtained after dissolving the lyophilized powder preparation in water for injection is 0.015%~0.05%.

[0023] The present invention has at least the following beneficial effects: The EGFR-TKIs injection prepared by the present invention can be directly injected into the subarachnoid space, which greatly increases the drug concentration in the patient's cerebrospinal fluid. The cerebrospinal fluid / plasma concentration ratio is increased from much less than 1 to more than 2 times, and even more than 10 times. The present invention can completely solve the problem of insufficient dosage caused by the blood-brain barrier after oral targeted drugs. The drug described in the present invention has a fast onset of action and can significantly improve the treatment effect of lung cancer dural metastasis. Attached Figure Description

[0024] The accompanying drawings, which form part of this application, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0025] Figure 1 This is a schematic diagram of the pipe placement in the forecourt of the present invention.

[0026] Figure 2 This is an X-ray view of the lumbar puncture site where a catheter is placed in the prepontine cistern of the patient in Embodiment 2 of the present invention.

[0027] Figure 3 This is an X-ray image of the prepontine cistern region where a catheter was placed in the patient in Embodiment 2 of the present invention.

[0028] Figure 4 This is a schematic diagram of Ommaya sac placement in this invention.

[0029] Figure 5 This is an X-ray image of the prepontine cistern site where a catheter was placed in the patient in Embodiment 4 of the present invention.

[0030] In the image: 1. Lumbar puncture area; 2. Prepontine cistern; 3. Catheter; 4. Osimertinib injection; 5. Catheter containing guidewire; 6. Lumbar puncture needle. Detailed Implementation

[0031] The embodiments of the present invention will be described in detail below. The specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0032] In addition to lumbar puncture (i.e., intubation), the injection methods of this invention also include, for example... Figures 1-4 The images show indwelling catheter injection in the prepontine cistern and Ommaya capsule injection. Intrathecal injection, or intrathecal injection, refers to a medical method where medication is directly injected into the cerebrospinal fluid in the subarachnoid space via lumbar puncture, bypassing the blood-brain barrier for highly effective treatment of central nervous system diseases. The prepontine cistern catheter injection technique involves inserting a catheter into the subarachnoid space via lumbar puncture, with the tip reaching the prepontine cistern and the end connected to a port implanted subcutaneously in the abdomen, facilitating repeated punctures for intrathecal drug administration. The Ommaya capsule is a fluid-retaining device implanted under the scalp and connected to the lateral ventricle. It is primarily used for intrathecal drug injection or cerebrospinal fluid drainage. It consists of a puncturable reservoir and a catheter. The reservoir, located under the scalp, is soft to the touch, allowing doctors to inject medication directly into it via puncture. This avoids repeated lumbar punctures or ventricular punctures, reducing trauma and infection risks, making it suitable for patients requiring long-term intrathecal treatment. Medication injected into the Ommaya capsule first enters the ventricle and then circulates naturally throughout the subarachnoid space. Therefore, the lumbar puncture, anterior pontomy cistern catheter injection, and Ommaya sac injection in this invention are collectively referred to as subarachnoid injection.

[0033] The subarachnoid injection drug provided by this invention is completely different from drugs used for injection via intramuscular, intravenous, arterial, subcutaneous, intradermal, intra-articular, intraosseous, intravitreal, and intracardiac methods.

[0034] Osimertinib is a selective EGFR T790M mutant inhibitor, and its clinical dosage form is 80 mg tablets orally daily. The inventors found through research that there is currently no targeted drug injection solution for lung cancer leptomeningeal metastases in the existing technology. The EGFR-TKI injection solution designed and formulated in this invention can be directly injected into the subarachnoid space, rapidly increasing the drug concentration in the cerebrospinal fluid (CSF). It has a rapid onset of action, with a CSF / plasma concentration ratio far greater than 1, reaching more than 10 times the normal level. This solves the problem of insufficient EGFR-TKI dosage in CSF caused by the blood-brain barrier, greatly improving the treatment efficacy for lung cancer leptomeningeal metastases.

[0035] Example 1

[0036] 1. Pharmaceutical formulation and preparation methods

[0037] The formulation of this invention is a lyophilized powder injection of EGFR-TKIs. Its core active ingredient is EGFR-TKIs, such as the commercially available active pharmaceutical ingredient osimertinib mesylate, with a purity ≥99%. The active pharmaceutical ingredient (API) is the active substance that constitutes the therapeutic effect of the drug. It is only after being mixed and processed with pharmaceutical excipients that it can be made into a finished drug that patients can safely and conveniently use. The excipients in this embodiment include: 1. Mannitol, content 5-6%, mainly acting as a stabilizer; 2. Citrate buffer, mainly acting to adjust pH and maintain the solubility of the API in water; 3. Water for injection, mainly acting as a solvent.

[0038] The production process of osimertinib mesylate lyophilized powder injection is as follows: Step 1, processing of raw materials, excipients and packaging materials: 1. Weigh 5g of osimertinib mesylate raw material in a light-proof environment and place it in a sealed light-proof container for later use; 2. Weigh 500g of mannitol for injection and place it in a sealed container for later use; 3. Place freshly prepared water for injection in a container for later use; 4. Wash the 5ml brown vial, siliconize it (to protect the surface of the vial, making the vial wall smooth and facilitating drug extraction), and sterilize it by dry heat in a tunnel oven at 300℃ for 5min; 5. Clean and siliconize the bromobutyl rubber stopper, sterilize it by moist heat at 121℃ for 30min, and dry it for later use; 6. Clean the aluminum cap for later use. Step 2, Preparation and Filling of the Solution: 1. Take approximately 9000 ml of freshly prepared water for injection, add 5 g of osimertinib mesylate raw material and 500 g of mannitol, and stir at room temperature until completely dissolved at 1000 rpm; 2. Adjust the pH to 5.0-7.0 with citrate buffer; 3. Add water for injection to a final volume of 10000 ml; 4. Filter through a 0.45 μm filter to remove larger particles; 5. Filter through a 0.22 μm filter for sterilization; 6. Under Grade A conditions, use a fully automated filling machine to rapidly fill the filtrate into brown vials, with each vial containing 2.1 ml; 7. Partial stoppering using a fully automated stoppering machine. All the above steps are completed in a light-protected environment. Step 3, Freeze-drying: 1. Pre-freeze: Slowly lower the product from room temperature to -45 to -50 °C at a rate of 1 °C / min, and maintain this temperature for 2 hours to ensure all products are frozen. 2. First drying: Turn on the vacuum pump to achieve a vacuum of 50-100 mTorr in the freeze-drying chamber, slowly raise the temperature to -20℃, and maintain this temperature for 24 hours. 3. Second drying: While maintaining a high vacuum, raise the plate temperature to 25℃ at a rate of 0.1-0.2℃, and maintain this temperature for 6 hours. Fourth step, full stoppering and capping: 1. Nitrogen purging: Before the second drying is complete, slowly purge the freeze-drying chamber with sterile, high-purity nitrogen to break the vacuum environment and fill the vials with high-purity nitrogen. 2. Full stoppering: Use the fully automatic stoppering machine in the freeze-drying chamber to press the partially capped stopper into the vial, ensuring a complete seal. 3. Capping: Use a capping machine to tightly press the aluminum-plastic cap onto the vial. 4. Finished product processing: 100% manual or fully automatic light inspection to ensure the product has a normal appearance and good sealing. 5. Packaging and storage: Qualified products are packaged in opaque outer boxes.

[0039] Key quality control parameters include: the specification of osimertinib mesylate is 1 mg / vial. In this embodiment, the concentration of osimertinib mesylate is 0.05% (5g of osimertinib mesylate raw material is diluted to 10000ml, i.e., 10000g, therefore its concentration is 0.05%), and the volume of the drug solution after dispensing is 2.1ml, which is then prepared into a lyophilized powder. Before injecting the drug in the vial into the patient, the lyophilized powder is dissolved in 2ml of water for injection. 2ml of drug solution contains 2g, i.e., 2000mg, and the concentration of osimertinib mesylate is 0.05%, i.e., the amount of osimertinib mesylate in each vial is 1mg. The mannitol content in the drug in this vial is 5%.

[0040] After reconstitution, the acidity of the drug is 5.0-7.0, and the osmotic pressure is 280-320 mOsm / L. Sterility testing meets the requirements of the 2025 edition of the Chinese Pharmacopoeia. Bacterial endotoxin content is ≤0.20 EU / mg. Storage conditions: Store in a cool, dark place in a tightly closed container.

[0041] 2. Clinical administration methods

[0042] The administration routes of this invention are anterior cistern catheter injection, Ommaya bag injection, or lumbar puncture injection. The specific steps for anterior cistern catheter injection are as follows: First, the patient is placed in a lateral / supine position, and a subcutaneous infusion port is inserted and secured using a butterfly needle; Second, the connector is connected, and 5 ml of cerebrospinal fluid is aspirated using a 10 ml syringe to confirm catheter patency and absence of obstruction; Third, 2 ml of the preparation of this invention is slowly injected at a rate of 2 ml / min; Fourth, after injection, the catheter is sealed with 5 mg dexamethasone + 2 ml of normal saline, and the patient's vital signs are observed for 5 minutes. The specific steps for Ommaya sac injection are as follows: First, the patient is placed in a sitting / supine position, and a 10ml syringe tube with a 0.6×25 TW LB needle is inserted into the subcutaneous reservoir and fixed. Second, 5ml of cerebrospinal fluid is aspirated to confirm that the catheter is patent and unobstructed. Third, 2ml of the preparation of this invention is slowly injected at a rate of 2ml / min. Fourth, after the injection, the catheter is sealed with 5mg dexamethasone + 2ml of normal saline, and the patient's vital signs are observed for 5 minutes. The specific steps for lumbar puncture injection are as follows: First, the patient is placed in a lateral decubitus position, and after disinfection and local anesthesia, a routine lumbar puncture is performed between the L3 and L4 spinous processes, and the lumbar puncture needle is inserted into the subarachnoid space. Second, 5ml of cerebrospinal fluid is slowly drained and then paused. Third, 2ml of the preparation of this invention is slowly injected into the subarachnoid space at a rate of 2ml / min. Fourth, after the injection, 5mg dexamethasone + 1ml of normal saline is injected into the subarachnoid space, and the patient's vital signs are observed for 5 minutes.

[0043] The dosage and course of treatment are set as follows: the single dose is 1 mg / time; the dosing frequency is 3 times a week; the course of treatment is set as 3 consecutive weeks as one course of treatment, which can be repeated as needed until the patient's condition progresses or cannot be tolerated.

[0044] The adverse reaction management plan includes: common adverse reactions are mild dizziness and headache, and the corresponding management measures are to give non-steroidal anti-inflammatory drugs such as celecoxib for symptomatic treatment when headache occurs.

[0045] Example 2

[0046] This example is a clinical application example of the drug prepared in Example 1.

[0047] Basic case information includes: Patient name: Chen Xiyang; Gender: Male; Age: 53 years old; Admission date (Xiangya Second Hospital, Central South University): May 26, 2025; Chief complaint: Headache for more than 10 days, worsening with dizziness and vomiting for 7 days; Past medical history: Lung cancer history of 4.4 years, underwent radical resection of left upper lobe lung cancer on January 7, 2021, postoperative pathology showed adenosquamous carcinoma, postoperative stage pT1bN2bM0 stage IIIA. Gene testing results: EGFR exon 21 L858R, T854A double (+); PD-L1 TPS=1%, CPS=70. Postoperatively, the patient received oral osimertinib 80mg once daily as adjuvant therapy. On May 30, 2024, a follow-up examination revealed recurrence of multiple mediastinal lymph node enlargement and multiple brain parenchymal metastases. The patient was treated with a regimen of paclitaxel liposome + carboplatin + bevacizumab + toripalimab for 4 cycles, achieving a partial response (PR). The brain parenchymal metastases disappeared. Oral osimertinib was administered for consolidation and maintenance therapy between and after chemotherapy.

[0048] The patient's diagnosis was based on the following: Imaging examination: Head MRI with diffusion impairment showed a lesion with restricted diffusion in the left frontal lobe, the nature of which was undetermined, and no diffuse enhancement of the meninges was observed. Laboratory examination: Cerebrospinal fluid cytology revealed tumor cells, and cerebrospinal fluid NGS testing showed EGFR gene detection with EGFR exon 21 L858R (+) and T854A (+). Final diagnosis: Stage IV postoperative adenosquamous carcinoma of the left lung with meningeal metastasis. After the diagnosis of meningeal metastasis, the patient received two cycles of intrathecal chemotherapy with pemetrexed (30 mg, June 5, 2025; 20 mg, June 9, 2025) via lumbar puncture, but clinical symptoms such as headache did not improve. This indicates that intrathecal chemotherapy is essentially ineffective in this patient with lung cancer and meningeal metastasis.

[0049] The pre-treatment assessment according to the protocol described in this invention includes the following aspects: Clinical symptoms: persistent headache (VAS score 10), bilateral blurred vision, where the VAS score is the Visual Analogue Scale used for pain assessment. TDM blood drug concentration monitoring: before treatment, high-performance liquid chromatography (HPLC) was used to detect osimertinib concentration in cerebrospinal fluid <5 ng / ml, plasma concentration was 130 ng / ml, and osimertinib cerebrospinal fluid / plasma concentration ratio <0.038. Performance status assessment: KPS score 60 points, the KPS score is a tool proposed in 1949 for quantitatively assessing the performance status of cancer patients. Other relevant indicators: cerebrospinal fluid pressure 400 mmH2O, protein content 698 g / L.

[0050] In this embodiment, the treatment regimen using osimertinib injection includes administration via an indwelling catheter in the prepontine cistern using the formulation of this invention, with a single dose of 1 mg (2 ml). The dosing frequency is: three consecutive injections per week (once daily), followed by a four-day rest period (during which osimertinib 80 mg orally daily is continued for maintenance). The treatment cycle is: starting from June 12, 2025, continuous treatment for 8 weeks, followed by weekly injections for consolidation and maintenance. Figure 2 and Figure 3 The X-ray showed that the patient's X-ray was taken on June 11, 2025. During clinical treatment, a catheter was placed in the prepontine cistern on that day, and medication was started the following day.

[0051] The treatment process record in this embodiment includes the following aspects. First administration: June 12, 2025. The injection process was smooth, with no immediate adverse reactions. Therapeutic drug monitoring (TDM) results after the first administration: Cerebrospinal fluid concentration peaked at 2022 ng / ml 1 hour after administration, and was 42 ng / ml at 24 hours. The peak plasma concentration was 143.7 ng / ml, and the osimertinib cerebrospinal fluid / plasma concentration ratio increased to a maximum of 14.1:1. Post-first administration assessment: The patient's headache symptoms disappeared on the second day (VAS score dropped to 0), and blurred vision and double vision disappeared. Adverse reactions: No significant adverse reactions.

[0052] The efficacy evaluation results of this embodiment include the following aspects: Improvement of clinical symptoms: headache basically disappeared, vision returned to normal, and the KPS score improved to 100 points. Changes in laboratory indicators: cerebrospinal fluid pressure decreased to 120 mmH2O, and protein content decreased to 167 g / L. After the first course of treatment, the abundance of EGFR mutation sites L858R and T854A in cerebrospinal fluid decreased from 53.0% and 53.6% to 5.1% and 6.0%, respectively. These are the test results as of July 21, 2025. During maintenance treatment, a follow-up cerebrospinal fluid NGS examination on August 29, 2025, showed that the abundance of EGFR mutation sites L858R and T854A further decreased to 3.4% and 3.6%, respectively.

[0053] Example 3

[0054] 1. Pharmaceutical formulation and preparation methods

[0055] The formulation of this invention is a lyophilized powder injection of EGFR-TKIs. Its core active ingredient is EGFR-TKI vometinib (free base), with a purity ≥99%. The excipients in this embodiment include: 1. Mannitol, content 4-5%, mainly acting as a stabilizer and osmotic pressure regulator; 2. Hydroxypropyl β-cyclodextrin, content 2%, mainly acting as a solubilizer and also working with mannitol to regulate osmotic pressure; 3. Citric acid solution, mainly acting to adjust the pH of the drug; 4. Water for injection, mainly acting as a solvent.

[0056] The production process of vometinib lyophilized powder injection is as follows: Step 1, processing of raw materials and packaging materials: 1. Weigh 1.5g of vometinib free base raw material in a light-proof environment and place it in a sealed light-proof container for later use; 2. Weigh 500g of mannitol for injection and place it in a sealed container for later use; 3. Place freshly prepared water for injection in a container for later use; 4. Wash the 5ml brown vial, siliconize it (to protect the surface of the vial, making the vial wall smooth and facilitating drug extraction), and sterilize it by dry heat at 300℃ for 5min in a tunnel oven for later use; 5. Clean and siliconize the bromobutyl rubber stopper, sterilize it by moist heat at 121℃ for 30min, and dry it for later use; 6. Clean the aluminum cap for later use. The second step, preparation and filling of the drug solution: 1. Take approximately 9000 ml of freshly prepared water for injection, add 200 g of hydroxypropyl β-cyclodextrin, stir until a clear solution is formed, add 1.5 g of vormetinib (free base), and stir at room temperature until completely dissolved at 1000 rpm; 2. Add approximately 500 g of mannitol and stir thoroughly until completely dissolved; 3. Adjust the pH to 5.0-7.0 with citric acid solution; 4. Add water for injection to a total volume of 10000 ml; 5. Filter through a 0.45 μm filter membrane to remove larger particles; 6. Filter through a 0.22 μm filter membrane for sterilization; 7. Under Grade A conditions, use a fully automated filling machine to quickly fill the filtrate into brown vials, with each vial containing 2.1 ml; 8. Partially stopper the vials using a fully automated stoppering machine. All the above steps are completed in a light-protected environment. Step 3, Freeze-drying: 1. Pre-freezing: Slowly lower the product from room temperature to -45 to -50°C at a rate of 1°C / min, and maintain this temperature for 2 hours to ensure all products are frozen. 2. First drying: Turn on the vacuum pump to achieve a vacuum of 50-100 mTorr in the freeze-drying chamber, slowly raise the temperature to -20°C, and maintain this temperature for 24 hours. 3. Second drying: While maintaining a high vacuum, raise the plate temperature to 25°C at a rate of 0.1-0.2°C, and maintain this temperature for 6 hours. Step 4, Full stoppering and capping: 1. Nitrogen purging: Before the second drying is completed, slowly purge the freeze-drying chamber with sterile, high-purity nitrogen to break the vacuum environment and fill the vials with high-purity nitrogen. 2. Full stoppering: Use the fully automatic stoppering machine in the freeze-drying chamber to press the partially capped stoppers into the vials, ensuring a complete seal. 3. Capping: Use a capping machine to tightly press the aluminum-plastic caps onto the vials. 4. Finished product processing: 100% manual or fully automated light inspection to ensure normal product appearance and good sealing. 5. Packaging and storage: Qualified products are packaged in opaque outer boxes.

[0057] Key quality control parameters include: the specification of vormetinib free base is 0.3 mg / vial. In this embodiment, the concentration of vormetinib free base is 0.015% (1.5 g of vormetinib free base is diluted to 10000 ml, i.e., 10000 g, therefore its concentration is 0.015%), the volume of the drug solution after dispensing is 2.1 ml, and then it is prepared into a lyophilized powder. Before injecting the drug in the vial into the patient, the lyophilized powder is dissolved in 2 ml of water for injection. 2 ml of drug solution contains 2 g, i.e., 2000 mg, and the concentration of vormetinib free base is 0.015%, i.e., the amount of vormetinib free base in each vial is 0.3 mg. The mannitol content in the drug in this vial is 5%.

[0058] After reconstitution, the acidity of the drug is 5.0-7.0, and the osmotic pressure is 280-320 mOsm / L. Sterility testing meets the requirements of the 2025 edition of the Chinese Pharmacopoeia. Bacterial endotoxin content is ≤0.20 EU / mg. Storage conditions: Store in a cool, dark place in a tightly closed container.

[0059] Example 4

[0060] This example is a clinical application example of the drug prepared in Example 3.

[0061] Basic case information includes: Patient name: Yao Xihua; Gender: Female; Age: 69 years; Admission date (Xiangya Second Hospital, Central South University): October 21, 2025; Chief complaint: Dizziness for more than 3 months after radical resection of lung cancer with osimertinib adjuvant targeted therapy for 3 years; Past medical history: 3.8-year history of lung cancer. On January 27, 2022, she underwent robotic resection of the right lower lobectomy and lymph node dissection under general anesthesia. Postoperative pathology showed moderately to poorly differentiated adenocarcinoma. Tissue gene testing results: EGFR exon 19 Del (+), abundance 10.2%. Subsequently, on June 2, 2022, she underwent left upper lobe resection and lymph node dissection under general anesthesia with robot-assisted thoracoscopic surgery. Postoperative pathology showed moderately to poorly differentiated adenocarcinoma. No tissue gene testing was performed after this surgery. Based on the first postoperative gene testing result showing EGFR mutation, she continued oral osimertinib adjuvant therapy until June 2025. Due to dizziness for 3 months, a head MRI was performed at a local hospital on September 1, 2025, which revealed a subcortical lesion in the right frontal lobe and a diagnosis of meningeal metastasis. On September 4, 2025, the patient began taking voremerinib 80mg orally once daily. In October 2025, the patient developed neck stiffness and unsteady gait, and the voremerinib dosage was increased to 160mg orally once daily. On October 29, 2025, the patient underwent a lumbar puncture and prepontine cistern catheter placement under local anesthesia. Figure 5 This is an X-ray image of the prepontine cistern site where the catheter was placed in the patient in this embodiment.

[0062] The patient's diagnosis was based on the following: Clinical symptoms: dizziness, neck stiffness, and unsteady gait. Imaging examinations: Plain MRI of the head with contrast and diffusion imaging showed multiple abnormal enhancements of the pia mater (involving both supratentorial and infratentorial regions), indicating meningeal metastasis. Laboratory tests: One cerebrospinal fluid cytology examination did not detect tumor cells; however, an NGS test of the cerebrospinal fluid on October 31, 2025, showed EGFR exon 21 L858R (+), abundance 3.9%. Final diagnosis: Stage IV postoperative lung adenocarcinoma with meningeal metastasis.

[0063] The pre-treatment assessment according to the protocol described in this invention includes the following aspects: Clinical symptoms: dizziness, neck stiffness, unsteady gait. Performance status score: KPS score 70. Other relevant indicators: normal cerebrospinal fluid pressure, normal protein content.

[0064] In this embodiment, the treatment regimen using vortexinib injection includes administration via an indwelling catheter in the prepontine cistern using the formulation of this invention, with a single dose of 0.3 mg (2 ml). The dosing frequency is: five consecutive injections per week (once daily), followed by a two-day rest period (80 mg of vortexinib orally throughout the treatment). Treatment with vortexinib injection began on October 31, 2025.

[0065] The efficacy evaluation results of this embodiment include the following aspects. Consistent with Example 2, before the first injection of voremtinib, the voremtinib cerebrospinal fluid / plasma concentration ratio was much less than 1; however, the TDM (Therapeutic Drug Monitoring) results after the first administration showed that 15 minutes after administration, the voremtinib cerebrospinal fluid concentration was 458 ng / ml, corresponding to a plasma concentration of 218 ng / ml, and the voremtinib cerebrospinal fluid / plasma concentration ratio increased to 2.1:1. Improvement of clinical symptoms: Neck stiffness improved after 1 day of administration, and dizziness, neck stiffness, and gait instability basically disappeared after 3 days of administration, with the KPS score improving to 100 points. Adverse reactions: No significant adverse reactions.

[0066] The conclusion of this invention is that after patients were treated with the formulation of this invention, TDM monitoring confirmed that the concentrations of osimertinib and vormetinib in the cerebrospinal fluid were significantly increased and maintained at an effective therapeutic concentration for 24 hours after administration via the indwelling catheter in the prepontine cistern. Clinical symptoms and laboratory indicators were significantly improved and the condition was well tolerated.

[0067] Existing technologies include intrathecal administration of chemotherapy drugs such as pemetrexed, methotrexate, thiotepa, and cytarabine, which involves directly injecting the drug into the cerebrospinal fluid in the subarachnoid space via lumbar puncture. However, existing technologies have not utilized epidermal growth factor receptor tyrosine kinase inhibitors such as osimertinib and gefitinib for intrathecal administration. The inventors speculate that the main reasons are as follows: First, EGFR-TKIs have poor water solubility. Even though osimertinib has been formulated into more soluble forms such as osimertinib mesylate, it is only available in oral dosage forms. Second, the application of targeted drugs for lung cancer patients was previously limited, resulting in few patients with lung cancer leptomeningeal metastases. In recent years, with the widespread use of targeted drugs, the number of patients with lung cancer leptomeningeal metastases has increased. This is also one of the reasons why existing technologies have not considered formulating targeted drugs for subarachnoid injection. Third, there is a technical bias among those skilled in the art that drugs require sufficient dosage to be effective. Existing targeted drugs, osimertinib and vormetinib, are oral medications, requiring patients to take 80 mg or more daily. This implies a technical bias, as injectable EGFR-TKIs also require higher doses to be effective. However, cerebrospinal fluid (CSF) has a volume of only 150-200 ml, allowing for significant increases in CSF concentration without requiring large amounts of dissolved targeted drugs. Clinical trials on multiple lung cancer patients with leptomeningeal metastases have shown that even with generally low water solubility of targeted drugs, daily injections of EGFR-TKIs at doses of 0.01-5 mg, preferably 0.05-2 mg, more preferably 0.1-1.5 mg, and most preferably 0.15-1.2 mg, all demonstrate excellent therapeutic effects. In specific embodiments of this invention, the dosage of vormetinib and osimertinib per patient is only 0.3-1 mg. Vometinib has even worse solubility than osimertinib mesylate. It dissolves 5g of osimertinib mesylate in 10kg of water for injection, but even with the addition of the solubilizing agent hydroxypropyl β-cyclodextrin, only about 1.5g of vometinib dissolves in 10kg of water for injection. Therefore, some in the field have a technical bias that developing subarachnoid injection drugs of EGFR-TKIs such as vometinib or osimertinib is impossible. However, in reality, doses of EGFR-TKIs such as vometinib or osimertinib below 5mg are sufficient to treat patients with lung cancer leptomeningeal metastases. Even when the daily doses of vometinib and osimertinib are as low as 0.3mg and 1mg respectively, the therapeutic effect is already very significant.

[0068] Those skilled in the art will recognize that osimertinib mesylate is the clinically used form of osimertinib, and osimertinib is its active ingredient that exerts its anticancer effect. This invention first developed a subarachnoid injection solution or lyophilized powder formulation of EGFR-TKIs, and applied it to the treatment of patients with EGFR-mutant non-small cell lung cancer with leptomeningeal metastases, achieving significant therapeutic effects.

[0069] Furthermore, the inventors believe that, in the prior art, the efficacy of non-EGFR-TKI drugs prepared into subarachnoid injections for the treatment of EGFR-mutant lung cancer leptomeningeal metastases is limited. For example, Example 2 of this invention shows that the chemotherapy drug pemetrexed injection is ineffective in treating lung cancer leptomeningeal metastases.

[0070] If the drug in this invention is an EGFR-TKI injection, then EGFR-TKIs and the excipient citrate are required. If the drug in this invention is an injectable lyophilized powder, then EGFR-TKIs and the excipient citrate and mannitol are required. For some EGFR-TKIs that are more difficult to dissolve in water, hydroxypropyl β-cyclodextrin is also required to aid dissolution.

[0071] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A medicament for treating EGFR mutant non-small cell lung cancer meningeal metastasis, characterized in that, The drug is a lyophilized powder preparation or an injection solution of EGFR-TKIs for subarachnoid injection, the EGFR is an epidermal growth factor receptor, the EGFR-TKIs is an epidermal growth factor receptor tyrosine kinase inhibitor, the amount of EGFR-TKIs in the drug is 0.01-5 mg per person per time, and the injection method of the drug comprises any one of lumbar puncture, injection through a catheter indwelled in the pre-bridge pool and Ommaya capsule injection; The EGFR-TKIs is osimertinib mesylate, and the drug further comprises 5-6 wt% of mannitol, a citrate buffer and water for injection; Or the EGFR-TKIs is free base of vorsetinib, and the drug further comprises 4-5 wt% of mannitol, 2 wt% of hydroxypropyl β-cyclodextrin, a citric acid solution and water for injection.

2. The medicament according to claim 1, characterized in that, The amount of EGFR-TKIs in the drug is 0.15-1.2 mg per person per time.

3. The medicament according to claim 1, characterized in that, The specification of osimertinib mesylate in the drug is 1 mg / bottle, or the specification of free base of vorsetinib in the drug is 0.3 mg / bottle.

4. Use of EGFR-TKIs in the preparation of a medicament for treating EGFR mutant non-small cell lung cancer meningeal metastasis, characterized in that, The drug is a lyophilized powder preparation or an injection solution of EGFR-TKIs for subarachnoid injection, the amount of EGFR-TKIs in the drug is 0.01-5 mg per person per time; The EGFR-TKIs is osimertinib mesylate, and the drug further comprises 5-6 wt% of mannitol, a citrate buffer and water for injection; Or the EGFR-TKIs is free base of vorsetinib, and the drug further comprises 4-5 wt% of mannitol, 2 wt% of hydroxypropyl β-cyclodextrin, a citric acid solution and water for injection.

5. Use according to claim 4, characterized in that, The amount of EGFR-TKIs in the drug is 0.05-2 mg per person per time.

6. Use according to claim 5, characterized in that, The amount of EGFR-TKIs in the drug is 0.15-1.2 mg per person per time, and the drug is used in combination with an oral EGFR-TKIs preparation.

7. Use according to claim 4, characterized in that, The drug is used for increasing the ratio of the concentration of osimertinib or vorsetinib in cerebrospinal fluid to the concentration of osimertinib or vorsetinib in plasma of a patient with EGFR mutant non-small cell lung cancer meningeal metastasis, the specification of osimertinib mesylate in the drug is 1 mg / bottle, or the specification of free base of vorsetinib in the drug is 0.3 mg / bottle.

8. A kit comprising one or more unit dosage forms of the drug as claimed in any one of claims 1-3, and a package insert indicating that the drug is used for delaying or treating EGFR mutant non-small cell lung cancer meningeal metastasis.

9. A method of preparing a medicament, comprising combining a compound of any one of claims 1-8 with a pharmaceutically acceptable carrier. The drug is a lyophilized powder preparation of EGFR-TKIs for subarachnoid injection as claimed in any one of claims 1-3; and the preparation method of the drug comprises the following steps: Step A, dissolving EGFR-TKIs and mannitol in water for injection in a light-proof environment, optionally using hydroxypropyl β-cyclodextrin to help dissolve EGFR-TKIs, adjusting pH value with citric acid or a citrate buffer and adding water for injection to constant volume; Step B, filtering impurities and sterilizing with a filter membrane; and Step C, filling the drug into a vial. Step C, rapidly filling the filtrate into multiple brown vials using a full-automatic filling machine; Step D, semi-tamping the brown vials using a full-automatic tamping machine; Step E, nitrogen-filling after freeze-drying the drug in a freeze-drying box; Step F, full-tamping using a full-automatic tamping machine in the freeze-drying box, the semi-tamped rubber stopper is pressed into the vial to completely seal the drug; Step G, tightly pressing the aluminum plastic cover on the vial using a cover pressing machine, thus obtaining the freeze-dried powder preparation for injection; the content of EGFR-TKIs in the injection solution obtained by dissolving the freeze-dried powder preparation for injection in water for injection is 0.001-0.5%.

10. The method of claim 9, wherein the medicament is prepared by, The content of EGFR-TKIs in the injection solution obtained by dissolving the freeze-dried powder preparation for injection in water for injection is 0.01-0.1%, and the pH value of the injection solution is 5-7.

Images