Imatinib formulation for parenteral administration

Abstract

The present application relates to a pharmaceutical composition comprising imatinib and a stabilizer, the stabilizer comprising a filler and a buffer, and the pH of the pharmaceutical composition being less than 6.0. Further, the present application relates to a ready-to-use solution for use in the treatment of stroke, traumatic brain injury or spinal cord injury, the solution being reconstituted from a lyophilized pharmaceutical composition by the addition of an aqueous diluent. Further, the present application relates to a method for preparing a pharmaceutical composition.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition of imatinib for use in parenteral administration for the treatment of stroke, traumatic brain injury or spinal cord injury, and to the preparation of such a pharmaceutical composition.

Background Art

[0002] Stroke is defined as the sudden death of local brain cells due to interruption or insufficient blood flow. According to the European Heart Disease Statistics 2012, stroke is the second most common cause of death in Europe: approximately 1.1 million people die each year. More than 1 in 7 women (15%) and 1 in 10 men (10%) die from this disease (Melanie Nichols et al, European Cardiovascular Disease Statistics, 2012 Edition, Department of Public Health, University of Oxford).

[0003] Stroke is mainly classified into one of the following two types according to its causative factors and progression: ischemic stroke, which results from occlusion or thrombosis in the blood vessels supplying the brain. This accounts for the majority of all strokes.

[0004] Hemorrhagic stroke occurs when a blood vessel ruptures. The cause of the rupture is an aneurysm or arteriovenous malformation, which may also be a congenital defect. However, the most common cause is uncontrolled high blood pressure. The following disclosure focuses on, but is not limited to, ischemic stroke, particularly acute ischemic stroke. The goal of existing treatments for ischemic stroke is to rapidly restore blood flow and prevent or at least reduce the likelihood of subsequent strokes. Currently, the only treatment for ischemic stroke approved by the FDA as a therapeutic agent is tissue plasminogen activator (tPA, ALTEPLASE®, ACTIVASE®). tPA acts by dissolving blood clots and improving blood flow to the parts of the brain where blood flow has decreased. However, tPA is known to have serious side effects such as neurotoxicity and increased vascular permeability due to changes in blood-brain barrier function. Delaying the initiation of tPA therapy has been shown to make the balance between the positive effects and side effects of tPA unfavorable for the patient. Although the exact thresholds vary, it is generally recommended to initiate tPA therapy as soon as possible after the onset of stroke, within 4 to 5 hours if possible. Even narrower treatment windows may be recommended.

[0005] Before administering tPA or other thrombolytic agents, it is necessary to determine whether the patient is suffering from acute ischemic stroke or hemorrhagic stroke. In the case of bleeding, thrombolytic therapy worsens the condition. Usually, this distinction cannot be made based on symptoms alone, so the patient is usually subjected to a CT scan or MRI scan of the head to rule out intracranial hemorrhage. Only then is thrombolytic therapy initiated. Depending on the available resources and diagnostic capabilities, the initiation of thrombolytic therapy may be delayed, or those providing care may refrain from thrombolytic therapy altogether for preventive reasons. Furthermore, for maximum effectiveness, thrombolytic therapy should be initiated within 3 hours of the onset of stroke, preferably as early as possible. Thrombolytic therapy is the treatment of choice for acute cerebral infarction within 3 to 4.5 hours after symptom onset. There are clinical trials showing that alteplase within 3 to 4.5 hours after onset is superior to placebo, and there are also registry studies supporting this.

[0006] Expert advice supports these results but has not been fully accepted. However, late thrombolytic therapy has been suggested to be associated with more severe side effects. As a result, due to diagnostic uncertainty (ischemic stroke or hemorrhagic stroke), diagnostic delay (delay in obtaining CT, lack of necessary equipment), or a combination thereof, patients may not receive the most appropriate treatment. In fact, only about 10% of patients receive thrombolytic therapy.

[0007] Other treatment methods include mechanical thrombectomy, that is, surgically removing or disintegrating blood clots, and antiplatelet therapy to prevent the formation of new blood clots. From the accumulated experience, thrombectomy has been shown to significantly increase the probability of recovery after stroke or at least reduce neurological damage. Different from thrombolytic drugs, antiplatelet agents have no effect on existing blood clots. Aspirin is the most commonly used antiplatelet drug, and it has been suggested to be effective in the early treatment of acute ischemic stroke, especially in combination with dipyridamole.

[0008] WO2007 / 124308 discloses methods and compositions for preventing or improving side effects, improving the treatment of tPA where thrombolysis is desired, or extending the treatment period by counteracting the undesirable effects of tPA using platelet-derived growth factor (PDGF) and PDGF antagonists. WO2007 / 124308 also discloses combination therapies in the treatment of ischemic stroke using tPA and PDGF antagonists. An example of a public substance that inhibits the PDGF receptor is imatinib mesylate.

[0009] WO2017 / 151043A1 describes that imatinib (GLEEVEC (registered trademark), GLIVEC (registered trademark), STI-571, tyrosine kinase inhibitor) can be used in the treatment of acute ischemic stroke, and the imatinib is administered to patients continuously for at least 3 days at a dose of 650 mg / day or more.

[0010] Traumatic brain injury (TBI) is the impairment of normal brain function due to hitting, being hit, or experiencing an impact to the head, or due to penetrating head trauma. Everyone is at risk of TBI, but children and the elderly are particularly vulnerable. Spinal cord injury (SCI) is an injury to the spinal cord. The symptoms of SCI include partial or complete loss of sensory function and motor control in the limbs and body. In severe cases, SCI can affect bladder and bowel control, breathing, heart rate, and blood pressure.

[0011] In Su et al. 2015, the effectiveness of imatinib in the treatment of TBI was investigated. Using a mouse model, the authors showed that imatinib treatment significantly reduced blood-brain barrier (BBB) dysfunction, which was associated with a significant reduction in lesion size, a decrease in brain edema, and the maintenance of cognitive function. Therefore, this data suggests the treatment of TBI with imatinib.

[0012] In Abrams et al. 2012, it was verified whether imatinib (GleevecH, Novartis) could improve the functional outcomes in experimental SCI. Rats with contusive spinal cord injury were orally administered imatinib from 30 minutes after injury for 5 days. As a result, imatinib significantly enhanced the integrity of the blood-spinal cord barrier, hindlimb motor function, sensorimotor integration, and bladder function, suppressed astrogliosis and the deposition of chondroitin sulfate proteoglycan, and enhanced tissue preservation. These improvements were associated with an improvement in vascular integrity and a reduction in inflammation. Imatinib is interesting as a candidate drug for clinical trials in SCI due to its positive effects on experimental SCI.

[0013] To date, imatinib is only available as a pharmaceutical form for oral administration. However, WO2017 / 151043A1 also suggests other administration forms, namely intravenous administration. Therefore, the object of the present invention is to provide a formulation of imatinib for parenteral administration. SUMMARY OF THE INVENTION

[0014] The inventors of the present invention have identified a formulation of imatinib that exhibits high solubility and excellent chemical and physical stability over the shelf life of the product and is suitable for parenteral administration. Thus, in a first aspect, the present invention provides a pharmaceutical composition comprising imatinib and a stabilizer, wherein the stabilizer comprises a filler and a buffer, and the pH of the pharmaceutical composition is less than 6.0.

[0015] The pharmaceutical composition according to the first aspect is preferably stored in lyophilized form and reconstituted into a solution that is ready for immediate use for the treatment of stroke. Thus, in a second aspect, the present invention relates to a ready-for-use solution for use in the treatment of stroke, which is reconstituted from the lyophilized pharmaceutical composition according to the first aspect by the addition of an aqueous diluent.

[0016] Furthermore, the present invention provides a method for preparing a pharmaceutical composition according to the first aspect, comprising the following steps: i) Supplying a first portion of the solvent, particularly 40% to 90% by volume, to a first container; ii) Adding a buffer and a filler to the first portion of the solvent and mixing to form an intermediate solution; iii) Adding imatinib to the first container and mixing the imatinib with the intermediate solution to obtain a homogeneous imatinib suspension; iv) Adding a second portion of the solvent, particularly 10% to 50% by volume, to a second container; v) Adding an antioxidant to the second portion of the solvent in the second container, mixing, and heating the mixture to obtain an antioxidant solution; vi) Adding the antioxidant solution to the imatinib suspension and optionally further adding the solvent and mixing to form a pharmaceutical composition; and vii) Optionally adjusting the pH. Detailed Description of the Invention

[0017] The present invention provides a novel formulation of imatinib for parenteral administration. In the pharmaceutical composition, imatinib is very stable and can be easily transferred to the lyophilized state. When the pharmaceutical composition is in liquid form, it substantially does not contain visible fine particles. Furthermore, the components of the formulation are well tolerated by the human body when administered parenterally.

[0018] Thus, in a first aspect, the present invention provides a pharmaceutical composition comprising imatinib and a stabilizer, wherein the stabilizer comprises a filler and a buffer, and the pH of the pharmaceutical composition is less than 6.0.

[0019] The chemical name of imatinib mesylate is 4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide methanesulfonate. CAS number: 220127-57-1.

[0020] It is white or almost white, slightly brownish or yellowish, or brownish-yellow powder. The molecular formula is C29H31N7O·CH4O3S, and the molecular weight is 589.70 g / mol. The molecular weight of imatinib is 493.603 g / mol.

[0021] The structural formula is as follows:

Chemical formula

[0022] The filler provides the structure of the lyophilized product without directly interacting with the pharmaceutical, and enhances the stability during long-term storage. Furthermore, the filler can impart additional useful properties such as adjusting the collapse temperature or providing protection against freeze-thaw. Non-limiting examples of fillers include mannitol, sorbitol, sucrose, trehalose, and amino acids such as glycine, histidine, and arginine.

[0023] The filler is crystalline (e.g., glycine, mannitol, or sodium chloride) or amorphous (e.g., dextran, or hydroxyethyl starch), and is generally used in an amount of 0.5% to 10% in the formulation.

[0024] As shown in the examples, sugar mannitol forms the basis of a formulation that confers long-term stability to imatinib. According to one embodiment, the filler is selected from sugar mannitol, sorbitol, sucrose, and trehalose. According to one embodiment, the filler is mannitol.

[0025] Mannitol is also known as D-mannitol. Mannitol is a hexavalent alcohol related to mannose and is an isomer of sorbitol. The CAS registration number is 69-65-8 and the molecular weight is 182.17. Mannitol is widely used in pharmaceutical formulations. Mannitol is generally inert and rapidly rehydrates once lyophilized.

[0026] The buffer used in the present invention is preferably a non-toxic, inert, and physiologically harmless substance. The buffer is added to the liquid formulation to adjust and / or stabilize its pH value. Suitable buffers are well-known in the art and can be found in the literature. Preferred pharmaceutically acceptable buffers include, but are not limited to, histidine buffer, citrate buffer, succinate buffer, acetate buffer, and phosphate buffer. According to one embodiment, the buffer is potassium dihydrogen phosphate.

[0027] According to one embodiment, the pharmaceutical composition further comprises an antioxidant. The antioxidant is used to prevent / minimize the oxidation reaction of the active ingredient or excipient over the shelf life of the product. Typical antioxidants are selected from L-methionine, sodium metabisulfite, ascorbic acid, acetylcysteine, sulfites (bisulfites, metabisulfites), monothioglycerol, citric acid, or mixtures thereof. As shown in the examples, the use of L-methionine protects imatinib from oxidative stress. According to one embodiment, the antioxidant is L-methionine. According to another embodiment, the pharmaceutical composition does not contain an antioxidant.

[0028] According to one embodiment, the composition is liquid and contains a solvent. The term "solvent" as used in the present invention refers to a liquid or a mixture of liquids suitable for administration to a subject as part of a pharmaceutical composition or formulation. The solvent may be selected, for example, from water, dioxolane, dimethylacetamide, butylene glycol, polyethylene glycol, glycerin, and ethanol. In one embodiment, the solvent is water. In one embodiment, the solvent is water for injection. According to one embodiment, the solvent comprises a combination of water and one or more water-miscible solvents selected from dioxolane, dimethylacetamide, butylene glycol, polyethylene glycol, glycerin, ethanol, etc., or a combination thereof. In another embodiment, the solvent is a combination of water and one additional pharmaceutically acceptable water-miscible solvent. In another embodiment, the solvent is a combination of water and ethanol.

[0029] Examples show that the solubility of imatinib decreases when the pH exceeds 6.0. Therefore, the pH should be 6.0 or less. Preferably, the pH ranges from 4.0 to 6.0. More preferably, the pH ranges from 5.0 to 6.0.

[0030] According to one embodiment, imatinib is present in the form of imatinib mesylate. According to one embodiment of the pharmaceutical composition, the concentration of imatinib ranges from 80 mg / ml to 200 mg / ml. The concentration may be, for example, 80 mg / ml, 90 mg / ml, 100 mg / ml, 110 mg / ml, 120 mg / ml, 130 mg / ml, 140 mg / ml, 150 mg / ml, 160 mg / ml, 170 mg / ml, 180 mg / ml, 190 mg / ml, or 200 mg / ml. According to one embodiment, the concentration of imatinib ranges from 100 mg / ml to 180 mg / ml. According to one embodiment, the concentration of imatinib is within the range of 110 mg / ml to 150 mg / ml. According to one embodiment, the concentration of imatinib is within the range of 120 mg / ml to 140 mg / ml.

[0031] The inventors of the present invention defined the optimal composition of the formulation. According to one embodiment, in the pharmaceutical composition, the mass ratio of the filler to imatinib ranges from 1:4 to 1:30. If the filler is less than the ratio of 1:30, it may not exhibit structuring and stabilizing properties. If the filler is more than the ratio of 1:4, it may negatively affect the viscosity of the product. According to one embodiment, in the pharmaceutical composition, the mass ratio of the filler to imatinib ranges from 1:8 to 1:24, and according to one embodiment, the mass ratio of the filler to imatinib ranges from 1:12 to 1:20. According to one embodiment, the mass ratio of the filler to imatinib ranges from 1:14 to 1:18.

[0032] Therefore, the concentration of the filler should range from 2 mg / ml to 20 mg / ml. In one embodiment, the concentration of the filler ranges from 3 mg / ml to 14 mg / ml. In one embodiment, the concentration of the filler ranges from 5 mg / ml to 11 mg / ml. In one embodiment, the concentration of the filler ranges from 7 mg / ml to 9 mg / ml.

[0033] According to one embodiment of the pharmaceutical composition, the mass ratio of the antioxidant to imatinib ranges from 1:2 to 1:25. According to one embodiment, the mass ratio of the antioxidant to imatinib ranges from 1:4 to 1:20. If the concentration of the antioxidant is less than 1:25, it is considered that imatinib cannot be sufficiently protected from oxidation. Even if the concentration of the antioxidant exceeds 1:2, the protective effect against oxidative stress does not further improve. According to one embodiment, the mass ratio of the antioxidant to imatinib ranges from 1:8 to 1:16. According to one embodiment, the mass ratio of the antioxidant to imatinib ranges from 1:9 to 1:13.

[0034] Therefore, the concentration of the antioxidant should range from 4 mg / ml to 24 mg / ml. In one embodiment, the concentration of the antioxidant ranges from 6 mg / ml to 20 mg / ml. In one embodiment, the concentration of the antioxidant ranges from 8 mg / ml to 16 mg / ml. In one embodiment, the concentration of the antioxidant ranges from 11 mg / ml to 14 mg / ml.

[0035] According to one embodiment of the pharmaceutical composition, the mass ratio of the buffer to imatinib is in the range of 1:3 to 1:25. According to one embodiment, the mass ratio of the buffer to imatinib is in the range of 1:5 to 1:20. When the concentration of the buffer is less than 1:25, the solution cannot be sufficiently buffered. Even if the concentration of the buffer exceeds 1:2, the buffering capacity will not be further improved. According to one embodiment, the mass ratio of the buffer to imatinib is in the range of 1:9 to 1:17. According to one embodiment, the mass ratio of the buffer to imatinib is in the range of 1:11 to 1:15.

[0036] Therefore, the concentration of the buffer should be in the range of 2 mg / ml to 20 mg / ml. In one embodiment, the concentration of the buffer is in the range of 4 mg / ml to 16 mg / ml. In one embodiment, the concentration of the buffer is in the range of 6 mg / ml to 14 mg / ml. In one embodiment, the concentration of the buffer is in the range of 8 mg / ml to 11 mg / ml.

[0037] According to one embodiment, the composition contains a total amount in the range of 0.5 to 10 ml. According to one embodiment, the composition contains a total amount in the range of 1 to 8 ml. According to one embodiment, the composition contains a total amount in the range of 1 to 5 ml. According to one embodiment, the composition contains a total amount in the range of 2 to 4 ml. According to one embodiment, the composition contains a total amount in the range of about 3 ml.

[0038] According to one embodiment, the pharmaceutical composition contains imatinib at a concentration of 133.3 mg / ml, L-methionine at a concentration of 12.5 mg / ml, mannitol at a concentration of 8.3 mg / ml, and potassium dihydrogen phosphate at a concentration of 9.6 mg / ml. Preferably, in this embodiment, the composition contains a total amount of 3 ml, and the solvent is water, particularly water for injection.

[0039] The pharmaceutical composition according to the present invention has high purity and high stability. As shown in the examples, there are few impurities.

[0040] A common impurity present in the manufactured imatinib mesylate is impurity F, which is also identified as 4-methyl-N3-[4-(pyridin-3-yl)-pyrimidin-2-yl]-1,3-benzenediamine (CAS number: 152460-10-1).

[0041] Another common impurity present in the manufactured imatinib mesylate is impurity C, which is also identified as N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-4-(1-piperazinylmethyl)-benzamide (CAS-number: 404844-02-6).

[0042] Another common impurity present in the manufactured imatinib mesylate is impurity J, which is also identified as -methyl-4-(4-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl-carbamoyl)benzyl)piperazine-1-oxide (CAS-number: 571186-91-9).

[0043] Another common impurity present in the manufactured imatinib mesylate is imatinib-N-oxide, which is also identified as N-[4-methyl-3-[[4-(1-oxidopyridin-1-ium-3-yl)pyrimidin-2-yl]amino]phenyl]-4-[(4-methylpiperazin-1-yl)methyl]benzamide (CAS number: 571186-92-0)

[0044] Another common impurity present in the manufactured imatinib mesylate is imatinib di-N-oxide, which is impurity 21 or 4-[(4-methyl-1,4-dioxide-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide (CAS-number: 571186-93-1 ) and is also identified as

[0045] The concentrations of impurity F, impurity C, impurity J, imatinib - N - oxide, and imatinib di - N - oxide are measured, in particular, by liquid chromatography with mass spectrometry as defined in the European Pharmacopoeia "Imatinib mesylate".

[0046] In particular, the concentration of impurity F is less than 40 ppm. According to one embodiment, the concentration of impurity F is less than 20 ppm. In one embodiment, the concentration of impurity F is less than 10 ppm. In one embodiment, the concentration of impurity F is less than 5 ppm.

[0047] Furthermore, the concentration of impurity J in the pharmaceutical composition is less than 0.5% based on the concentration of imatinib. According to one embodiment, the concentration of impurity J is less than 0.2% based on the concentration of imatinib. In one embodiment, the concentration of impurity J is less than 0.1% based on the concentration of imatinib.

[0048] According to one embodiment, the concentration of imatinib N - oxide in the pharmaceutical composition is less than 0.5% based on the concentration of imatinib. According to one embodiment, the concentration of imatinib N - oxide is less than 0.2% based on the concentration of imatinib. According to one embodiment, the concentration of imatinib N - oxide is less than 0.1% based on the concentration of imatinib.

[0049] According to one embodiment, the concentration of imatinib di - N - oxide in the pharmaceutical composition is less than 0.5% based on the concentration of imatinib. According to one embodiment, the concentration of imatinib di - N - oxide is less than 0.2% based on the concentration of imatinib. According to one embodiment, the concentration of imatinib di - N - oxide is less than 0.1% based on the concentration of imatinib.

[0050] Furthermore, the concentration of a single unspecified impurity in the pharmaceutical composition is less than 0.2% based on the concentration of imatinib. In one embodiment, the concentration of any single unspecified impurity is less than 0.1% based on the concentration of imatinib.

[0051] Therefore, the total concentration of impurities in the medicine is less than 2.0% based on the concentration of imatinib. In one embodiment, the total concentration of impurities in the medicine is less than 1.0% based on the concentration of imatinib. In one embodiment, the total concentration of impurities in the medicine is less than 0.5% based on the concentration of imatinib. In one embodiment, the total concentration of impurities in the medicine is less than 0.2% based on the concentration of imatinib.

[0052] The stability indicators are the generation of impurities over time, such as impurity F, impurity J, impurity C, imatinib di-N-oxide, imatinib N-oxide, etc. According to one embodiment, the concentration of impurity F, impurity J, impurity C, imatinib di-N-oxide or imatinib N-oxide, any unspecified impurity and / or the total of impurities is still as defined above when measured after storage at 25 °C for 24 hours.

[0053] According to one embodiment, the pharmaceutical composition is lyophilized. The terms "lyophilize", "lyophilizing" and "lyophilized" as used in the present invention refer to the lyophilization process of freezing an imatinib preparation and sublimating and removing it under vacuum if water and other solvents are present while remaining in the frozen state. The term "lyophilized product" as used in the present invention refers to the powder obtained by lyophilization.

[0054] The lyophilized powder may be divided into small portions, for example, in individual vials. Each portion of the lyophilized powder may have a total mass of imatinib in the range of 200 mg to 1000 mg. The total mass of imatinib in each portion may be 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg. The total mass of imatinib in each portion may be in the range of 300 mg to 500 mg, preferably in the range of 350 mg to 450 mg, more preferably about 400 mg. Alternatively, the total mass of imatinib in each portion may be in the range of 700 mg to 900 mg, preferably in the range of 750 mg to 850 mg, more preferably in the range of about 800 mg.

[0055] With the formulation according to the present invention, the pharmaceutical composition forms a well-formed lyophilized cake. Further, by lyophilization, the pharmaceutical composition becomes even more stable. Therefore, impurity F, impurity J, impurity C, imatinib di-N-oxide, imatinib N-oxide, any unspecified impurity and / or the total of impurities is less than the threshold value defined above when measured after storage at a temperature of about 25 °C and / or a relative humidity of about 60% for at least 2 months, preferably at least 4 months, more preferably at least 6 months. The concentration of impurity J, impurity F, impurity J, impurity C, imatinib di-N-oxide, imatinib N-oxide, any unspecified impurity and / or the total of impurities is also less than the threshold value defined above even after storage at a temperature of about 40 °C and / or a relative humidity of about 75% for at least 2 months, preferably at least 4 months, more preferably at least 6 months.

[0056] The lyophilized cake has a pale yellow color. The lyophilized cake maintains the appearance of a colored cake or powder that is pale yellow or yellowish-brown or greenish-yellow for at least 2 months, preferably at least 4 months, more preferably at least 6 months under storage conditions of a temperature of about 25 °C and / or a relative humidity of about 60%. The lyophilized cake also maintains this appearance for at least 2 months, preferably at least 4 months, more preferably at least 6 months under storage conditions of a temperature of about 40 °C and / or a relative humidity of about 75%.

[0057] According to one embodiment, the pH after reconstitution of the lyophilized cake is in the range of 5.0 to 7.0. The pH after reconstitution of the lyophilized cake is maintained even after storage at a temperature of about 25 °C and / or a relative humidity of about 60% for at least 2 months, preferably at least 4 months, more preferably at least 6 months. The pH is also maintained even after storage at a temperature of about 40 °C and / or a relative humidity of about 75% for at least 2 months, preferably at least 4 months, more preferably at least 6 months.

[0058] According to one embodiment, the reconstitution time of the lyophilized cake is less than 5 minutes, preferably less than 3 minutes, more preferably less than 2 minutes. The freshly manufactured lyophilized cake most preferably has a reconstitution time of less than 1 minute. After storage for at least 2 months, preferably at least 4 months, more preferably at least 6 months, at a temperature of about 25°C and / or a relative humidity of about 60%, the reconstitution time of the lyophilized cake is less than 5 minutes, preferably less than 3 minutes, more preferably less than 2 minutes.

[0059] The formulations of the present invention are particularly useful for the treatment of stroke, particularly hemorrhagic stroke or ischemic stroke, spinal cord injury (SCI), and traumatic brain injury (TBC).

[0060] According to one embodiment, the pharmaceutical composition is for use in the treatment of stroke, spinal cord injury (SCI), and traumatic brain injury (TBC). According to one embodiment, the treatment comprises parenteral administration of an immediately usable composition based on the pharmaceutical composition, and the parenteral administration is preferably intravenous administration.

[0061] Immediately usable solution In a second aspect, the present invention relates to an immediately usable solution for use in the treatment of stroke, reconstituted from a lyophilized pharmaceutical composition according to the first aspect and comprising an aqueous diluent.

[0062] According to one embodiment, the immediately usable solution pharmaceutical is for use in the treatment of stroke, particularly hemorrhagic stroke or ischemic stroke, spinal cord injury (SCI), and traumatic brain injury (TBI).

[0063] To prepare a concentrate of the immediately usable solution, the lyophilized composition may be reconstituted with, for example, water for injection.

[0064] According to one embodiment, the volume of the reconstituted concentrate is 0.5 to 3 times the volume of the solvent of the pharmaceutical composition. According to one embodiment, the volume of the reconstituted concentrated solution is 1 to 2.5 times the volume of the solvent of the pharmaceutical composition. According to one embodiment, the volume of the reconstituted concentrated solution is 1.2 to 2 times the volume of the solvent of the pharmaceutical composition. According to one embodiment, the volume of the reconstituted concentrated solution is about 1.6 times the volume of the solvent of the pharmaceutical composition.

[0065] This concentrate may be diluted with an aqueous diluent to form imatinib at a predetermined concentration. As an example, to prepare a ready-to-use infusion, the concentrated solution may be withdrawn from the vial using, for example, a plastic syringe and transferred to an infusion container containing the diluent.

[0066] According to one embodiment, the aqueous diluent is selected from 0.9% saline, 0.45% saline, Ringer's lactate, and Ringer's acetate.

[0067] 200 mL of 0.9% sodium chloride solution for infusion (providing an imatinib 2.0 mg / mL dilution).

[0068] According to one embodiment, the volume of the reconstituted solution is diluted by a factor in the range of 5 to 100, preferably in the range of 10, more preferably in the range of 20 to 60, and most preferably in the range of 30 to 50. For example, a 5 ml volume of the reconstituted concentrated solution is diluted to a final volume of 200 ml with an aqueous diluent.

[0069] According to one embodiment of the ready-to-use solution, the concentration of imatinib ranges from 0.1 mg / ml to 10 mg / ml. The concentration may be, for example, 0.1 mg / ml, 0.2 mg / ml, 0.5 mg / ml, 0.8 mg / ml, 1.0 mg / ml, 1.2 mg / ml, 1.5 mg / ml, 1.8 mg / ml, 2.0 mg / ml, 2.2 mg / ml, 2.5 mg / ml, 2.8 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4.0 mg / ml, 4.5 mg / ml, 5.0 mg / ml, 5.5 mg / ml, 6.0 mg / ml, 6.5 mg / ml, 7.0 mg / ml, 7.5 mg / ml, 8.0 mg / ml, 8.5 mg / ml, 9.0 mg / ml, 9.5 mg / ml, 10.0 mg / ml. According to one embodiment, the concentration of imatinib ranges from 0.5 mg / ml to 6.0 mg / ml. According to one embodiment, the concentration of imatinib is within the range of 1.0 mg / ml to 3.0 mg / ml. According to one embodiment, the concentration of imatinib is about 2.0 mg / ml.

[0070] According to one embodiment, the pH of the ready-to-use solution ranges from 5.0 to 7.0.

[0071] According to one embodiment, the treatment includes parenteral administration of a ready-to-use composition based on the pharmaceutical composition, and the parenteral administration is preferably intravenous administration.

[0072] The ready-to-use solution facilitates the safe and effective administration of imatinib to the patient. The ready-to-use solution does not contain particles and does not form gels or suspensions. The ready-to-use solution is clear and preferably an aqueous solution.

[0073] A clear solution is defined as a visually clear solution that essentially does not contain visually observable fine particles. Generally, when particulate matter is observed, the formulation is not suitable for intravenous administration and should not be used because there is a possibility of blood vessel occlusion. Therefore, considering the qualitative nature of visual inspection, usually, when no visually observable particulate matter is observed, the term "essentially free of visually observable particulate matter" is applied.

[0074] According to one embodiment, the ready-to-use solution is administered to a patient at a dosage of at least 400 mg / day of imatinib. According to one embodiment, the ready-to-use solution is administered to a patient at a dosage of at least 500 mg / day of imatinib. According to one embodiment, the ready-to-use solution is administered to a patient at a dosage of at least 600 mg / day of imatinib. According to one embodiment, the ready-to-use solution is administered to a patient at a dosage of at least 700 mg / day of imatinib. According to one embodiment, the ready-to-use solution is administered to a patient at a dosage of at least 800 mg / day of imatinib. According to one embodiment, the ready-to-use solution is administered twice a day. According to one embodiment, in the treatment of stroke, the ready-to-use solution is administered for at least 4 days. According to one embodiment, in the treatment of stroke, the ready-to-use solution is administered for at least 5 days. According to one embodiment, in the treatment of stroke, the ready-to-use solution is administered for at least 6 days.

[0075] According to one embodiment, in the treatment of TBI or SCI, the ready-to-use solution is administered for at least 10 days. According to one embodiment, in the treatment of TBI or SCI, the ready-to-use solution is administered for at least 10 days. According to one embodiment, in the treatment of TBI or SCI, the ready-to-use solution is administered for at least 12 days. According to one embodiment, in the treatment of TBI or SCI, the ready-to-use solution is administered for at least 14 days.

[0076] In yet another embodiment, the ready-to-use solution is administered to a patient before, simultaneously with, or after thrombectomy. The term "thrombectomy" is used in the present invention to define the surgical and / or mechanical removal or disruption of a thrombus. In the United States, three classes of mechanical thrombectomy devices have received FDA approval: coil retrievers, aspiration devices, and stent retrievers. Other devices and methods currently under development are also included in the definition of thrombectomy used in the present invention.

[0077] According to yet another embodiment, the ready-to-use solution is administered to the patient before, simultaneously with, or after thrombolysis. The term "thrombolysis" is used in the present invention to define any pharmacological disruption of a thrombus. The drug currently most commonly used in thrombolytic therapy is tissue plasminogen activator (tPA), although alternative drugs that achieve the same effect also exist.

[0078] Thrombolysis may be via a vein (IV) or an injection of a thrombolytic drug via a long catheter that delivers the drug directly to the occlusion site. Administering a thrombolytic drug to a patient within 12 hours after the onset of a stroke significantly improves the likelihood of survival and recovery from acute ischemic stroke. Ideally, thrombolytic therapy should be performed within 30 minutes of arrival at the hospital.

[0079] Most preferably, the ready-to-use solution is administered to the patient as soon as possible, even before it is determined whether the patient has suffered an acute ischemic stroke or a hemorrhagic stroke.

[0080] Both thrombectomy and thrombolysis are emergency procedures and should be performed as soon as possible. For practical reasons, thrombolytic therapy is usually initiated before performing thrombectomy, although the steps of the methods disclosed in the present invention need not be performed in the exact order disclosed, unless explicitly stated.

[0081] According to a preferred embodiment that can be freely combined with the above, the imatinib is administered to a patient who has undergone, is undergoing, or has previously undergone thrombectomy and thrombolysis. More preferably, imatinib is administered to the patient as early as possible even before it is determined whether the patient has developed acute ischemic stroke or hemorrhagic stroke. The advantage of this is that the prognosis of the patient is improved by administering imatinib. Furthermore, if the patient arrives at the hospital late, the accurate diagnosis is delayed, or for example, the access to CT or MRI equipment is delayed, resulting in a delay in determining that the patient has developed ischemic stroke rather than hemorrhagic stroke, it is possible to start thrombolytic therapy later even outside the recommended time.

[0082] According to another embodiment, the thrombolysis preferably includes the administration of tissue plasminogen activator (tPA) selected from alteplase (ACTIVASE®), reteplase (RETEVASE®, RAPILYSIN®), and tenecteplase (TNKase®). Although the present disclosure focuses on the above tPA drugs, other drugs that are currently under development and under approval applications may also be useful in combination therapy.

[0083] According to an embodiment that can be freely combined with the above embodiments, the imatinib is administered to the patient at an initial dose of 1000 mg / day or more on the first day, and then at a dose interval of 650 mg / day to 1000 mg / day on subsequent days. The initial dose should be higher than the subsequent doses, but currently, it is considered that imatinib should not be administered at a dose higher than 1600 mg / day as the initial dose.

[0084] Furthermore, it is considered that imatinib should not be administered continuously at a dose exceeding 1200 mg / day. Also in this case, the accurate dose can be adjusted by the treating physician according to the severity of the condition, the age and gender of the patient, the weight of the patient, and other characteristics.

[0085] Furthermore, at least a part of the initial dosage of imatinib is administered intravenously in the form of a ready-to-use solution, but subsequent continuous administration may also be oral administration.

[0086] Manufacturing method In a third aspect, the present invention provides a method for preparing a pharmaceutical composition according to the first aspect, comprising the following steps: i) Supplying a first portion of the solvent to a first container; ii) Adding a buffering agent and a filling agent to the first portion of the solvent and mixing to form an intermediate solution; iii) Adding imatinib to the first container and mixing the imatinib with the intermediate solution to obtain a uniform imatinib suspension; iv) Supplying a second portion of the solvent to a second container; v) Adding an antioxidant to the second portion of the solvent in the second container, mixing, and heating to obtain an antioxidant solution; vi) Adding the antioxidant solution to the imatinib suspension, optionally further adding solvent, and mixing to form a pharmaceutical composition; and vii) Optionally adjusting the pH.

[0087] As shown in the examples, NaOH has a negative effect on the solubility of imatinib. Therefore, during the preparation method, preferably no NaOH is added to the solution. Furthermore, in the intermediate composition containing imatinib, the pH is maintained in the range of 5.0 to 6.0. As shown in the examples, the solubility of imatinib decreases when the pH is high.

[0088] At the end of the operation, if the pH is outside the range of 5.0 to 6.0, it is adjusted to a value within the range of 5.0 to 6.0.

[0089] The first portion of the solvent in step ii) may be 40% to 90% by volume. The second portion of the solvent in step iv) may be 10% to 60% by volume.

[0090] According to one embodiment, the mixture in step v) is heated to a temperature in the range of 15 to 50 °C during mixing. In one embodiment, the temperature is in the range of 24 to 34 °C during mixing. In one embodiment, the temperature is in the range of 28 to 30 °C during mixing.

[0091] According to one embodiment, the antioxidant is L-methionine, the filler is mannitol, the buffer is potassium dihydrogen phosphate, and / or the solvent is WFI.

[0092] According to one embodiment, the mixing in steps ii) and v) is performed by stirring at a speed in the range of 150 to 350 rpm. According to one embodiment, it is performed at a speed in the range of 200 rpm to 300 rpm. According to one embodiment, it is performed at a speed in the range of 225 to 275 rpm.

Examples

[0093] Example 1 - Manufacture Manufacturing route

[0094]

Table 1

[0095] Description of the manufacturing process: The manufacture of 400 mg imatinib powder includes the following manufacturing steps: · Weighing of components; · Preparation of intermediate products; · Sterile filtration of intermediate products; · Aseptic filling into vials and semi-capping of vials; · Freeze-drying; · Capping of vials under reduced pressure nitrogen atmosphere; · Sealing of vials with flip-off caps.

[0096] Weighing of components: All starting materials were weighed before solution preparation.

[0097] Preparation of pharmaceutical composition: The required amount of WFI was put into the reactor. The pre-weighed amounts of mannitol and potassium dihydrogen phosphate were transferred to the reactor, and subsequently, the L-methionine premixed solution and the remaining required amount of WFI were transferred to the API to make it 100%.

[0098] Sterile filtration of the pharmaceutical composition: The prepared solution was sequentially filtered through two filters (one sterile filter and one polysulfide filter). Both filters of the filtration system were sterilized before use.

[0099] Aseptic filling into vials and semi-stoppering of vials: Filling into vials and semi-stoppering with rubber stoppers were carried out by an automatic device. The filling device automatically re-calibrates the filling volume and rejects vials with incorrect filling weights, vials with incorrect or missing stopper positions as necessary.

[0100] Lyophilization: Lyophilization was carried out according to each program: · Minimum freezing set temperature: Less than -35°C. · Primary drying set temperature: In the range of -10°C to -30°C, vacuum less than 0.3 mbar. · Secondary drying set temperature: In the range of 20°C to 40°C, vacuum less than 0.3 mbar. · The total time of the lyophilization process was in the range of 100 hours to 150 hours. After the lyophilization process was completed, the vacuum was relieved with sterile filtered nitrogen (low oxygen). Complete stoppering was carried out inside the lyophilizer.

[0101] Sealing of vials with flip-off caps: Sealing was carried out with an automatic sealing device using aluminum flip-off caps.

[0102] Example 2 - Technology transfer from laboratory scale to production The process for preparing imatinib 133.33 mg / mL solution for scale-up and batch production is outlined below: · 900 mL of WFI (about 50% of the total WFI requirement) was transferred to a 3.5 L bottle. · 590 mL of WFI (about 30% of the total WFI requirement) and pre-weighed L-methionine were transferred to a 1 L bottle. The suspension was mixed at a stirring speed of 250 rpm (using a PTFE crescent stirrer blade) and heated at a temperature of 30 °C for 26 minutes (the heater set temperature was 50 °C) (L-methionine dissolved after 14 minutes). Then, the solution was removed from the heater plate. · Mannitol and potassium dihydrogen phosphate were transferred to a 3.5 L bottle together with 900 mL of WFI. The suspension was stirred at a stirring speed of 250 rpm (using a PTFE crescent stirrer blade) for 4 minutes (mannitol and potassium dihydrogen phosphate dissolved after 3 minutes). · The API was transferred to a 3.5 L bottle together with the mannitol and potassium dihydrogen phosphate solution. The suspension was stirred at a stirring speed of 300 rpm (using a PTFE crescent stirrer blade) for 9 minutes to obtain a uniform suspension. · The L-methionine solution and the remaining WFI required to make 100% were transferred to the 3.5 L bottle containing the suspension. The suspension was further stirred at a stirring speed of 300 rpm (using a PTFE crescent stirrer blade) for 13 minutes (the API dissolved 9 minutes after further stirring). The temperature of the suspension 3 minutes after mixing was 24.8 °C. The pH of the solution was 5.3. · A sample of the imatinib 133.33 mg / mL solution was collected and tested according to the quality specifications. · Before filtering the imatinib 133.33 mg / mL solution, the 1st Millipore Millipak 100 filter unit of the filtration SUS was wetted with cooled WFI, filtered at a filtration rate of 0.5 L / min for NLT 5 minutes, and its integrity was tested. · To test the performance of the filtration system and sterilize the intermediate product, the imatinib 133.33 mg / mL solution was filtered through a filtration SUS (a combination of one sterile grade filter and one 0.22 μm membrane polysulfide filter arranged in sequence) at a speed of 150 rpm using a peristaltic pump. Meanwhile, the filter flush volume before filtering the imatinib 133.33 mg / mL solution was confirmed. · Automatic filling of the intermediate product was performed. · The filled half-stoppered vials were inserted into a lyophilizer. Lyophilization of imatinib 133.33 mg / mL was carried out. · After completion of the lyophilization process, the nitrogen atmospheric pressure was slightly reduced, and vacuum relief with nitrogen and low oxygen was performed until it reached 880 mbar (instead of 800 ± 50 mbar because the wire-drawing process was controlled manually, not automatically), and the vials were stoppered under this pressure (set hydraulic shelf extrusion pressure - 45 bar). The hydrophobic filter Sartofluor GA, Cat. No. 5182507T1 GA (0.2 μm) was used as the sterile gas filter. After completion of the stoppering, the pressure inside the lyophilizer was raised to 990 mbar. · For 456 imatinib 400 mg powder vials, the vials were sealed with 20 mm flip-off caps. · Samples of imatinib 400 mg powder were collected; analysis was performed according to the quality specifications.

[0103] Example 3 - Development of imatinib 400 mg powder formulation Various intermediate product formulations of imatinib 400 mg powder and various preparation procedures were investigated. The initial requirements for the imatinib 400 mg powder formulation were as follows: The vial should contain imatinib mesylate, mannitol, sodium hydroxide (NaOH), and potassium dihydrogen phosphate (KH2PO4), and the pH after reconstituting the bulk product with 5 mL of WFI should be within the range of 5.5 to 7.0.

[0104] The formulation and preparation procedures of the intermediate product are described in Table 1 below:

[0105]

Table 2

[0106] Based on the formulation development results, the following conclusions were drawn: 1. When added to a solution containing NaOH during the preparation of the intermediate product, the API does not dissolve, or when NaOH is added to a solution containing the API, an emulsion is formed. Therefore, NaOH should not be formulated in the preparation. In either case, a homogeneous solution is not easily formed, which is unacceptable.

[0107] 2. The pH of the pharmaceutical composition without NaOH was in the range of 5.43 - 5.72, and the pH could not be increased using a base. Since the pH of a 1% (m / V) imatinib mesylate aqueous solution is in the range of 5.4 - 5.5, it was predicted that the pH of the solution after adding the API would not change significantly within a wide range. Therefore, the pH of the pharmaceutical composition is expected to be highly reproducible even for different API batches.

[0108] 3. The pH of the reconstituted bulk product was lower than the expected range of 5.5 - 7.0, that is, in the range of 5.2 - 5.3 respectively.

[0109] 4. To significantly reduce the time of the primary drying stage in the freeze-drying process, a formulation of imatinib 133.33 mg / mL solution as an intermediate product is used with a target filling volume of 3.0 mL.

[0110]

Table 3

[0111] Example 4 - Influence of Antioxidants on Stability To evaluate the oxidative degradation process of imatinib, the necessity of antioxidants in the formulation, and identify potential degradation impurities, oxidation tests were carried out using Composition I with and without antioxidants, and with intentionally added oxidant (hydrogen peroxide) to promote oxidative degradation. The samples were stored at 25 ± 2°C and relative humidity 60 ± 2%. The measurement results of the impurities in the samples are summarized in Table 3 for the case without hydrogen peroxide and in Table 4 for the case with hydrogen peroxide.

[0112]

Table 4

[0113] As shown in Table 3, in the case without hydrogen peroxide that promotes oxidative decomposition, the concentration of impurities remains below the detection limit.

[0114]

Table 5

[0115] As shown in the table, under severe conditions using hydrogen peroxide that promotes oxidative decomposition, when no antioxidant is used, the concentration of impurity J increases little by little and reaches a total of 0.4%. The concentration of impurity J is below the detection limit in the presence of L-methionine. Furthermore, the concentrations of other impurities remain below the detection limit regardless of the presence or absence of 0.1% H2O2.

[0116] Example 4 - Long-term storage stability To evaluate the long-term storage stability of the lyophilized pharmaceutical composition, a sample of lyophilized composition I was stored at a relative humidity of 75 ± 5% and 40 ± 2°C. At the start, and after 2 months, 4 months, and 6 months, the appearance was evaluated, and the reconstitution time, pH, and the concentrations of impurity J, imatinib N-oxide, imatinib di-N-oxide, and impurity C were measured. The measurement results of the impurities in the sample are summarized in Table 5.

[0117]

Table 6

[0118] As shown in the table, all impurities and the total of impurities remained below 0.1% of the detection limit with respect to the concentration of imatinib, and thus were significantly below the required values. Even the total of impurities remained below the detection limit at all time points. In all samples, the appearance of the lyophilized product was a pale yellow cake. Thus, the appearance did not change over time and met the required values at all time points. At any time point, the pH after reconstitution was maintained at pH 5.3 and thus was within the required range. The reconstitution time increased with the storage time from 56 seconds at the start of storage to 96 seconds after 6 months of storage, but was far less than the acceptance criterion of 5 minutes.

[0119] Example 5 - Presence of Impurity J According to information from the European Pharmacopoeia monograph, it is known that imatinib 400 mg powder may contain genotoxic impurity F. Further tests (exposing imatinib to specific stress conditions) were carried out to confirm the expected content of genotoxic impurity F in imatinib 400 mg powder and to justify its absence in the quality specifications.

[0120] The influence of temperature and atmosphere on the imatinib bulk product as a liquid dosage form with respect to the stability of impurity F.

[0121] After storing the imatinib 400 mg concentrate (batch No. 530520L, produced as a liquid dosage form) under accelerated storage conditions (25 ± 2°C / 60 ± 5% RH) for 3 months, the content of genotoxic impurity F (European Pharmacopoeia) was tested. To simulate the worst manufacturing conditions, the concentrate was stored under an air atmosphere. The results are shown in the table below.

[0122] From these results, even after 3 months of storage under the condition of (40 ± 2°C / 75 ± 5% RH), the amount of impurity F remained low (3 - 5 ppm). When these results are compared with the results of impurity F of the freshly prepared imatinib 133.33 mg / mL solution (batch No. 870820L, refer to the oxidation test), it is found that the difference is only about Δ3 ppm; both results are below the method detection limit (5 ppm). From this, it can be seen that the increase in impurity F in the bulk product stored under a nitrogen and low-oxygen atmosphere is slight. Therefore, during the storage period under the intended storage conditions (25 ± 2 °C / (60 ± 5) %RH), an increase in impurity F in the 400 mg powder of imatinib exceeding the above-mentioned required limit (100 ppm) is not expected and should not be controlled.

[0123]

Table 7

[0124] Many modifications and other embodiments of the invention described herein will come to the mind of those skilled in the art to which this invention pertains, having the benefit of the teachings presented in the foregoing specification and the related drawings. Accordingly, it is to be understood that the invention is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Specific terms are used in this invention, but they are used only in a general and descriptive sense and not for purposes of limitation.

Claims

1. A pharmaceutical composition comprising imatinib and a stabilizer, wherein the stabilizer comprises a filler and a buffer, and the pH of the pharmaceutical composition is less than 6.

0.

2. The pharmaceutical composition according to claim 1, wherein the composition is liquid and contains a solvent, preferably water.

3. The pharmaceutical composition according to claim 1, wherein the buffering agent is selected from histidine buffering agent, citrate buffering agent, succinate buffering agent, acetate buffering agent and phosphate buffering agent, and preferably the buffering agent is potassium dihydrogen phosphate.

4. The pharmaceutical composition according to claim 1, wherein the filler is selected from mannitol, sorbitol, sucrose, and trehalose, and preferably the filler is mannitol.

5. The pharmaceutical composition according to claim 1, further comprising an antioxidant preferably selected from L-methionine and sodium metabisulfite.

6. The mass ratio of the filler to imatinib is in the range of 1:4 to 1:30, preferably in the range of 1:8 to 1:24, more preferably in the range of 1:12 to 1:20, and most preferably in the range of 1:14 to 1:18; The mass ratio of the antioxidant to imatinib is in the range of 1:2 to 1:25, preferably in the range of 1:4 to 1:20, more preferably in the range of 1:6 to 1:16, and most preferably in the range of 1:8 to 1:12; and / or The mass ratio of the buffer to imatinib is in the range of 1:3 to 1:25, preferably in the range of 1:5 to 1:20, more preferably in the range of 1:9 to 1:17, and most preferably in the range of 1:11 to 1:

15. The pharmaceutical composition according to claim 1 or 5.

7. The pharmaceutical composition according to claim 1, wherein the concentration of imatinib is in the range of 100 mg / ml to 160 mg / ml, preferably in the range of 110 mg / ml to 150 mg / ml, more preferably in the range of 120 mg / ml to 140 mg / ml, and preferably imatinib exists in the form of imatinib mesylate.

8. The concentration of impurity F is less than 40 ppm, preferably less than 20 ppm, more preferably less than 10 ppm, and most preferably less than 5 ppm, and preferably the concentration of impurity F is measured after storage at 25°C for 24 hours; The concentration of impurity J is less than 0.5%, preferably less than 0.2%, and more preferably less than 0.1%, based on the concentration of imatinib. The pharmaceutical composition according to claim 1.

9. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is freeze-dried, and preferably the composition contains imatinib in a dose of 200 mg to 600 mg, preferably 300 to 500 mg, more preferably 350 to 450 mg.

10. After 6 months of storage at a temperature of approximately 40°C and / or a relative humidity of approximately 75%: The concentration of impurity J, imatinib di-N-oxide, and / or imatinib N-oxide is less than 0.5%, preferably less than 0.2%, and more preferably less than 0.1%, based on the concentration of imatinib; The concentration of impurity J is less than 40 ppm, preferably less than 20 ppm, and more preferably less than 10 ppm; The concentration of any unspecified impurity is less than 0.2%, preferably less than 0.1%, relative to the concentration of imatinib; The total concentration of impurities in the pharmaceutical composition is less than 2.0%, preferably less than 1.0%, more preferably less than 0.5%, and most preferably less than 0.2%, based on the concentration of imatinib; The reconstitution time for the freeze-dried cake is less than 5 minutes, preferably less than 3 minutes, and more preferably less than 2 minutes. The pharmaceutical composition according to claim 9.

11. A ready-to-use solution for use in the treatment of stroke, spinal cord injury (SCI), and traumatic brain injury (TBI), which can be reconstituted from the frozen pharmaceutical composition of claim 10 by the addition of an aqueous diluent.

12. The ready-to-use solution according to claim 11, wherein the treatment includes parenteral administration, and the parenteral administration is preferably intravenous administration.

13. The ready-to-use solution according to claim 11 or 12, wherein the aqueous diluent is selected from 0.9% physiological saline, 0.45% physiological saline, Ringer's lactate, and Ringer's acetate.

14. A method for preparing the pharmaceutical composition according to claim 5, comprising the following steps: i) Supplying the first portion of the solvent, particularly 40% to 90% of its volume, into the first container; ii) Adding the buffer and filler to the first part of the solvent and mixing them to form an intermediate solution; iii) Add imatinib to the first container and mix the imatinib with the intermediate solution to obtain a homogeneous imatinib suspension; iv) Adding a second portion of the solvent, particularly 10% to 50% by volume, to the second container; v) Add the antioxidant to the second part of the solvent in the second container, mix, and heat the mixture to obtain an antioxidant solution; vi) Adding an antioxidant solution to an imatinib suspension, optionally adding a further solvent, and mixing to form a pharmaceutical composition; and vii) Adjusting the pH as desired.

15. The method according to claim 14, wherein the mixture of step v) is heated during mixing to a temperature in the range of 15 to 50°C, preferably 24 to 34°C, more preferably 28 to 30°C.

16. The method according to claim 14 or 15, wherein the pH of any intermediate composition containing imatinib is maintained in the range of 4.0 to 6.0.