Methods of treating ischemic stroke at risk for cerebral or cerebellar edema

Abstract

To provide the treatment of ischemic stroke at risk of brain swelling using SUR1-TRPM4 channel inhibitors in combination with mechanical thrombectomy.SOLUTION: In some embodiments, the methods include treating patients suffering from a large hemispheric infarction. In certain embodiments, the patients have a lesion volume of less than 140 cm3 or less than 125 cm3 as measured by MRI DWI or CTP. The patient may have suffered a wake-up stroke. Some embodiments involve treating patients who also undergo decompressive therapy.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 637,163, filed April 22, 2024, U.S. Provisional Patent Application No. 63 / 642,492, filed May 3, 2024, and U.S. Provisional Patent Application No. 63 / 644,658, filed May 9, 2024, the disclosures of which are incorporated herein by reference in their entireties. [Background technology]

[0002] background After extensive ischemic stroke, subject may suffer from space-occupying cerebral edema (swelling).Life-threatening cerebral swelling occurs in up to 8% of all hospitalized patients with ischemic stroke, and up to 15% of all patients with middle cerebral artery stroke.This kind of cerebral swelling (also known as edema) usually shows itself a few days after stroke, and generally reaches its peak on the second or third day.

[0003] Brain swelling can increase intracranial pressure, preventing blood from flowing to the brain and thereby depriving the brain of oxygen. Brain swelling can also block the brain's exit pathways, preventing fluid from leaving the brain. Furthermore, as intracranial pressure rises within the skull, previously healthy brain tissue can be destroyed, causing transtentorial or uncal herniation. Swelling in or around the brain can also cause morbidity and brain death, as well as secondary neurological disorders and death of the subject.

[0004] Brain swelling can be associated with two distinct molecular and physiological processes: cellular swelling of neurons and astrocytes, and transcapillary influx of ions and fluids into the injury site. Cellular swelling of neurons and astrocytes occurs as a result of ionic gradient changes between the cell and the extracellular space. One ion channel associated with cell swelling is the NC CA-ATPThe SUR1-TRPM4 channel (also known as the SUR1-TRPM4 channel) is a nonselective Ca channel that is activated when intracellular ATP is depleted in neuronal cells. 2+ Activated ATP-sensitive cation channels. CA-ATP The channel is thought to be composed of regulatory subunits, including a pore subunit related to sulfonylurea-type receptor 1 (SUR1) and transient receptor potential cation channel subfamily M member 4 (TRPM4).

[0005] Minimizing the degree of cerebral swelling is a major concern for physicians when treating subjects suffering from conditions or diseases in which cerebral edema can occur. However, treating cerebral edema is particularly challenging due to the prolonged duration associated with swelling, the brain's overall function, and the brain's placement within the skull. A wake-up stroke is an ischemic stroke associated with neurological symptoms only upon awakening. Thus, a patient's last-known-well time corresponds to the onset of sleep the night before presentation. Given the uncertainty of the time at which a stroke occurs, these patients are often ineligible for certain interventions, such as tPA and other thrombolytic agents, which have a narrow window in which they can be used without excessive harm. Thus, there is a pressing need for treatments applicable to the sleep-onset stroke population. Furthermore, the use of mechanical thrombectomy in patients with large-vessel occlusion has been low, in part due to concerns that rapid perfusion of such a large area could cause hemorrhage or other adverse effects. Therefore, it would be an advancement in the art to provide a treatment that reduces the degree of cerebral edema. Summary of the Invention [Means for solving the problem]

[0006] Abstract The present invention relates to the treatment of ischemic stroke patients at risk of brain swelling, using SUR1-TRPM4 channel inhibitors in combination with mechanical thrombectomy.In some embodiments, the method comprises treating patients suffering from extensive hemispheric infarction.In certain embodiments, patients are more than 140cm as measured by MRI DWI or CTP. 3 Less than or equal to 125cm 3 The patient may have suffered a sleep-onset stroke. Some embodiments include treating the patient with reduced pressure therapy. Embodiments of the present invention include methods of improving outcomes in patients diagnosed with ischemic stroke using a SUR1-TRPM4 channel inhibitor in combination with mechanical thrombectomy. 3 Less than or equal to 125cm 3 Less than and 50cm 3 The lesion volume may be larger than the normal volume. The lesion volume may be measured by diffusion-weighted imaging (DWI) or computed tomography perfusion (CTP) imaging. An embodiment of the present invention comprises administering a therapeutically effective amount of a SUR1-TRPM4 channel inhibitor to the patient. The SUR1-TRPM4 inhibitor may be administered by at least one continuous infusion resulting in a cumulative treatment time of at least 72 hours. The SUR1-TRPM4 channel inhibitor may be glibenclamide. The treatment may be initiated within 10 hours of the first stroke symptoms.

[0007] In some embodiments, the minimum lesion volume is 85 cm 3 In others, the maximum lesion volume may be 180 cm 3 In some embodiments, the maximum lesion volume is 125 cm 3The patient may be between 18 and 70 years old at the start of treatment. The patient may have undergone thrombectomy prior to treatment, and treatment may begin before or while the patient is undergoing thrombectomy. The patient may have undergone decompressive craniectomy before, during, or after treatment. In other embodiments, the patient has experienced a sleep-onset stroke. In certain aspects involving a sleep-onset stroke, the treatment begins within 10 hours of the midpoint between sleep onset (or last known to be normal) and awakening.

[0008] Other embodiments may involve administering one or more continuous infusions over at least 72 hours, 96 hours, at least 120 hours, or 168 hours. A bolus injection may be administered before any first continuous infusion. Certain embodiments may involve two or more continuous infusion doses, where the first continuous infusion dose is higher than the second continuous infusion dose. Some embodiments contemplate bolus dose administration and two or more continuous infusion doses, where the first continuous infusion dose is higher than the second continuous infusion dose.

[0009] Exemplary SUR1-TRPM4 channel inhibitors include glibenclamide (also known as glyburide), 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, gliquidone, LY397364, LY389382, gliclazide, glimepiride, metabolites that interact with SUR1, and combinations thereof.

[0010] In one aspect, the disclosure includes a method comprising administering a formulation comprising glyburide or a pharmaceutically acceptable salt thereof; a buffering agent; a base; and a sugar alcohol, wherein the formulation has a pH outside the buffering capacity of the buffering agent. In some aspects, the formulation does not contain cyclodextrin. In one aspect, the formulation has a pH outside the buffering capacity of the buffering agent, and the buffering agent has a pKa of 7.7 to 9.2.

[0011] In one aspect, the disclosure includes a method of administering an infusion solution comprising 500 ml saline solution, 3-5 mg glyburide, 100-140 mg mannitol, 10-12 mg Tris, and a pH of 7.8-9.

[0012] In one aspect, the disclosure encompasses a method of administering a solution comprising 10-30 ml WFI, 3-5 mg glyburide, 100-140 mg mannitol, 10-12 mg Tris, and a pH of 9-11 (e.g., 9.4-10).

[0013] In one aspect, the disclosure includes a method of making and administering a glyburide formulation having less than 1% weight loss of glyburide concentration (w / v) due to adsorption to a polymeric container over the course of an infusion period, comprising combining glyburide with a buffering agent having a pKa of 7.7-9.2, a sugar alcohol, and a base having a pKb of 0.1-1.5, in a molar ratio between the base and the glyburide of 5.0-6.7:1.

[0014] In some aspects, the present disclosure encompasses reconstitution of a formulation of the present disclosure in a suitable diluent (e.g., saline or water for injection (WFI)) such that the reconstituted formulation has a concentration of the buffering agent of 4-60 mM, 5-50 mM, 6-40 mM, 7-30 mM, 8-25 mM, 9-23 mM, 10-21 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, or 20 mM.

[0015] In some aspects, the present disclosure includes diluting a formulation of the present disclosure in a saline solution, wherein the formulation has a pH of 7.8-9.

[0016] In some aspects, the disclosure includes diluting the formulation in saline solution, wherein the formulation has a pH that does not fluctuate by more than 0.2 pH units during an infusion period of at least 24 hours.

[0017] In some aspects, the disclosure encompasses formulations and methods that have storage stability properties such as having high storage stability, e.g., less than 0.2% decomposition products upon storage for 6 months at 25°C / 60% RH, less than 0.4% decomposition products upon storage for 6 months at 40°C / 75% RH, and / or less than 1.0% decomposition products upon storage for 7 days at 70°C / 75% RH.

[0018] In some aspects, the disclosure includes a method for increasing the solubility of a glyburide formulation in a saline infusion solution, the method comprising combining glyburide or a pharmaceutically acceptable salt thereof with a buffering agent; a base; and a sugar alcohol, wherein the formulation has a pH outside the buffering capacity of the buffering agent at 4°C, 20°C, or 25°C to form a solubilized glyburide formulation having a glyburide solubility of 15 μg / ml in the saline infusion solution, wherein the glyburide formulation in the saline infusion solution has a pH of 7.8 to 9.

[0019] In some aspects, the disclosure includes a method for minimizing the volume of saline infusion solution required to infuse a glyburide formulation into a human over a 24-hour period, the method comprising: The method includes combining glyburide or a pharmaceutically acceptable salt thereof with a buffering agent; a base; and a sugar alcohol, wherein the formulation has a pH outside the buffering capacity of the buffering agent, wherein the glyburide formulation in the saline infusion solution has a pH of 7.8 to 9, and wherein the volume of the saline infusion solution used to inject 3 to 5 mg of glyburide or a pharmaceutically acceptable salt thereof into the human is approximately 500 ml.

[0020] In some aspects, the disclosure includes a method of increasing the storage stability of a glyburide formulation, the method comprising combining glyburide or a pharmaceutically acceptable salt thereof with a buffering agent; a base; and a sugar alcohol, wherein the formulation has a pH outside the buffering capacity of the buffering agent to form a stabilized glibenclamide formulation, wherein the stabilized glibenclamide formulation has less than 0.2% degradants after storage for at least 6 months at 25°C / 60% RH and upon storage for 6 months at 25°C / 60% RH.

[0021] The disclosure of US 2022 / 0280537 is incorporated by reference herein in its entirety for all purposes. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 shows the clinical effects of administering glyburide in combination with mechanical thrombectomy in human subjects. DETAILED DESCRIPTION OF THE INVENTION

[0023] Detailed Description The present invention is based on several surprising observations. One such observation is that when patients diagnosed with ischemic stroke involving large vessel occlusion are treated with a SUR1-TRPM4 inhibitor, the drug effect decreases as a function of lesion volume (the effect is greater than approximately 140 cm). 3The idea is that the patient's overall health is reduced to zero at the end of the study period. To observe this effect, an outcome in which the patient remains alive but bedridden, incontinent, and completely dependent on care is considered an undesirable outcome, and the data must be analyzed as such. This concept comes from the development of a class of drugs called lazaroids, whose outcomes, while life-saving, leave the patient in such a debilitated state that they are considered a "fate worse than death." Thus, on the modified Rankin Scale (the primary functional assessment in stroke research), a score of 5 (severe disability) is considered a poor outcome, along with death. In this way, any effect that "simply" represents lifesaving is not considered, ensuring that any drug effect provides a truly meaningful benefit to the patient. Analyses that include a reduction in death (mRS 6) with a concomitant increase in severe disability (mRS 5) distort this reality and are not acceptable to the FDA or other regulatory authorities. This is because it only saves lives, does not provide meaningful quality of life, and places a heavy emotional and financial burden on the patient's family.

[0024] Another observation is that SUR1-TRPM4 inhibitors can improve outcomes in patients with large-vessel occlusion who undergo mechanical thrombectomy to remove blood clots. Until recently, such patients were excluded from mechanical thrombectomy due to the fear that rapid reperfusion of such a large area would cause bleeding or other adverse effects. When thrombectomy began to be used successfully in these patients, it was not entirely clear whether these patients would benefit or be harmed by further treatment with SUR1-TRPM4 inhibitors, as they were still at risk of developing edema. Surprisingly, the combination of mechanical thrombectomy and SUR1-TRPM4 inhibitors provides very good results.

[0025] Before particular embodiments of the present invention are disclosed and described, it is to be understood that this invention is not limited to the particular process and materials disclosed herein, as such may vary to some extent. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the present invention is defined only by the appended claims and equivalents thereof.

[0026] In one embodiment, a method for improving outcomes in a subject after ischemic stroke is provided. The stroke can be a large stroke, which involves occlusion of large vessels in the cerebrum or cerebellum. Such patients can be at risk of developing cerebral or cerebellar edema. In the case of a cerebral stroke, it can involve infarction of one or more (usually proximal) segments of the internal carotid artery (ICA) and / or middle cerebral artery (MCA). In the case of a cerebellar stroke, it can involve infarction of the posterior inferior cerebellar artery (PICA) or superior cerebellar artery (SCA). The stroke can be a large hemispheric infarction (LHI) or a large cerebellar infarction (LCI). The stroke can be at least moderately severe according to the NIH Stroke Scale (NIHSS).

[0027] The extensive strokes contemplated for treatment are associated with extensive ischemic lesions that may occupy at least about one-third of either the MCA or cerebellar region in the cases of LHI and LCI, respectively. 3 or 60cm 3 It is variously defined as having a minimum lesion volume greater than 70-80 cm 3 It is defined as the smallest lesion volume.

[0028] Magnetic Resonance Imaging Diffusion Weighted Imaging ("MRI DWI" or simply "DWI" or "MRI") is considered the "gold standard" in assessing lesion size. 82 cm by MRI DWI with 98% specificity for predicting late neurological deterioration. 3 A threshold lesion size of 70–80 cm was associated with cerebral edema in LHI. 3 This is in good agreement with thresholds more easily identified by other groups. Computed tomography perfusion (CTP) can similarly be used to accurately identify lesion volume.

[0029] Surprisingly, the treatment effect of the SUR1-TRPM4 drug, glyburide (also known as glibenclamide), was approximately 140 cm as measured using the modified Rankin Scale (mRS). 3 It decreases to "no effect" level at approximately 125cm 3 and below, and the treatment effect in the LHI population was greater for lesion volumes The smaller In this case, mRS scores of 5 and 6 were combined for analysis, meaning that severe disability is not considered a good outcome and therefore does not provide statistical power to show that the drug works. Therefore, ideally treatable LHI patients would have a 50cm 3 ~60cm 3 with a minimum lesion volume of 70cm 3 The therapeutic effect of the SUR1-TRPM4 agent, glyburide, in combination with mechanical thrombectomy can be as low as 180 cm 3 It has also been surprisingly discovered that the level of beneficial effects extends up to 180 cm. 3 LHI patients with lesion volumes up to 1000 mg / kg can be treated according to the methods of the present disclosure to obtain beneficial effects.

[0030] Stroke patients are routinely evaluated using non-contrast computed tomography (NCCT) and can be assigned an Alberta Stroke Program Early CT (ASPECTS) score. This score is a 10-point quantitative topographic CT scan score used to systematically examine brain CT scans to identify early signs of ischemia; a score of 1 is given for normal areas and 0 for areas showing signs of ischemia. The lower the score, the more advanced the ischemic changes (i.e., the worse the stroke is considered to be). ASPECTS is determined from evaluation of two standardized regions of the MCA territory: the basal ganglia level and the supraganglionic level. Involvement of more than one-third of the MCA territory on CT indicates early ischemic involvement of the insular cortex in addition to two or more different lobes of the cerebral hemispheres and the basal ganglia.

[0031] Patients undergoing treatment with a SUR1-TRPM4 inhibitor according to the methods of the present disclosure are selected for thrombectomy. Patients are generally "selected for thrombectomy" using one or more imaging modalities. Non-contrast CT is almost always used because it can identify hemorrhage and can be used to generate an ASPECTS score. Hemorrhage or an ASPECTS score of ≦2 generally excludes a patient from being selected for thrombectomy. Additionally, some form of angiography, CT angiography or MR angiography, may typically be employed to confirm that the patient has a blockage that can be removed using thrombectomy. Patients who have recanalized, either spontaneously or using thrombolytic agents such as tPA, are not selected for thrombectomy. Occlusion of a large vessel, such as one of the proximal branches of the ICA or MCA, and / or large lesions (≧70 cm) are not considered. 3While the presence of a sigma-inducing or sigma-inducing ASPECTS ≤ 5 previously excluded thrombectomy, this is no longer the case, and although these patients are increasingly being selected for thrombectomy, other factors, such as time since stroke onset and other risk factors, are becoming more important. It is increasingly important for such patients to be selected for thrombectomy as soon as possible after the onset of stroke. Patients may also undergo CT perfusion or MRI as part of the selection process, resulting in quantitative lesion volume measurement. The precise method a physician uses to select patients for thrombectomy depends on medical judgment based on the patient's specific presentation, including all risk factors and whether the patient is likely to benefit from thrombectomy. This is routinely performed and well within the skill of those skilled in the art of stroke treatment. According to the present invention, any patient selected for thrombectomy must actually undergo thrombectomy. In other words, this aspect of the present invention contemplates that patients undergo both thrombectomy and treatment with a SUR1-TRPM4 inhibitor, but these two interventions may be performed sequentially or simultaneously in either order.

[0032] Treatment of patients selected for thrombectomy with a SUR1-TRPM4 inhibitor can begin before, during, or after thrombectomy. If treatment begins after thrombectomy, the patient may undergo a non-contrast CT scan to confirm the absence of bleeding before treatment begins. The patient may also undergo CT perfusion or MRI after thrombectomy to determine lesion volume before treatment.

[0033] Patients selected for thrombectomy are typically 180 cm 3 and a maximum ischemic lesion volume of 170, 160, 150, 140, 130, 125, or 120 cm at the start of treatment with a SUR1-TRPM4 inhibitor. 3The lesion volume may have a maximum lesion volume of 1000 sq m (1000 sq ft). The lesion volume is best confirmed using CTP or MRI. The lesion volume may be confirmed before or after thrombectomy. Before thrombectomy, the physician should have a reasonable expectation that the maximum lesion volume will not be exceeded during the thrombectomy procedure. Therefore, the maximum lesion volume determined before thrombectomy should generally be smaller than the maximum value, taking into account the expansion of the lesion over the time it takes to perform thrombectomy. Thus, the maximum lesion volume determined before thrombectomy may be 10%, 20%, 30%, or even 40% smaller than the maximum lesion volume determined after thrombectomy, depending on how quickly the procedure can be performed.

[0034] Treatment of patients experiencing a "sleep-onset" stroke is specifically contemplated. A sleep-onset stroke occurs when the patient is asleep without stroke symptoms, but awakens with symptoms. Because the stroke is likely to have occurred when the patient awakens, any time limits for treatment may be measured from the time of awakening or some early point between the time of going to sleep and the time of awakening.

[0035] The method includes administering one or more continuous infusions of a SUR1-TRPM4 channel inhibitor to a subject undergoing mechanical thrombectomy. The infusion can continue cumulatively for at least about 72 hours after the start of the continuous infusion. It has been found that administering the SUR1-TRPM4 channel inhibitor can reduce the incidence of late neurological deterioration or death, thereby improving outcome as measured by conventional scales used to evaluate stroke.

[0036] Patients with ischemic stroke are those who have a National Institutes of Health Stroke Scale (NIHSS) score of at least 10; Alberta Stroke Program Early CT Score (ASPECTS) of 7 or less; ASPECTS of 4 or less; MRI DWI lesion volume 70cm 3 MRI DWI lesion volume 82cm 3 Super; 50cm 3 Ultra-CT perfusion core; 70cm 3 Subjects may be considered for treatment if they exhibit at least one factor selected from the group consisting of: a CT perfusion core exceeding 10; inadequate collateral circulation as determined by CT angiography (or other means); a CT scan showing hypodensity covering at least 33% of the middle cerebral artery territory; and / or a CT scan showing hypodensity covering at least 50% of the middle cerebral artery territory. In some embodiments, the subject is first assessed to have an NIHSS score of 10 or greater, and then evaluated by one of the other methods outlined above. In some embodiments, the subject is first assessed to have an NIHSS score of 10-20, and then evaluated by one of the other methods outlined above.

[0037] In some embodiments, the subject is treated if the ASPECTS score is ≦5, ≦4, ≦3, or ≦2. In some embodiments, the subject has an MRI DWI lesion volume of 82 cm 3 If it exceeds this limit, treatment will be given.

[0038] In particular, patients suffering from extensive cerebral hemispheric infarction are particularly at risk for brain swelling and can be treated according to the present invention. These subjects typically have a middle cerebral artery territory stroke and have an MRI DWI or CT perfusion score of at least about 70 cm. 3 , at least about 80 cm 3, or an ASPECTS score of ≦5, ≦4, ≦3, or ≦2. In the methods contemplated herein for treating a subject with LHI, the subject is preferably ≦about 75 years of age, most preferably ≦about 70 years of age. It is also preferred that the subject has an NIHSS score ≧10 and that the drug is administered ≦10 hours, most preferably within ≦9 hours, from the index stroke or time last known well. In some embodiments, the subject has an NIHSS score of 10-20. These methods produce improvement in one or more clinically relevant endpoints on the modified Rankin scale (as a full ordinal scale and / or dichotomized), but collapse mRS 5 and 6 to avoid the aforementioned lazaroid problem. These improvements appear at one or more time points, including about 90 days, about 180 days / 6 months, and about 12 months after stroke.

[0039] In connection with the method for treating extensive stroke, a method for testing a drug for treating extensive stroke is also contemplated. According to these methods, patients aged 18 or older are radiologically selected and enrolled as described above. The subject preferably has an NIHSS score of ≥ 10, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or any score between 10 and 20, for example, ≥ 10 and ≤ 16, ≤ 17, ≤ 18, ≤ 19, ≤ 20, and is treated with a SUR1-TRPM4 channel inhibitor or a matching placebo (starting within ≤ about 10 hours, more preferably ≤ 9 hours, of the stroke (or last non-event time), and treatment continues for up to about 72 hours). These methods collapse mRS 5 and 6 to yield improvements in drug versus placebo groups for one or more clinically relevant endpoints, including survival / mortality, modified Rankin scale (as a completely ordinal scale and / or dichotomous), and these assessments are performed at one or more time points, including about 90 days, about 180 days / 6 months, and about 12 months after stroke.

[0040] In assessing outcomes, the mRS is preferably an ordinal scale (e.g., Mann The results are analyzed using the Whitney test (and similar tests), ordinal logistic regression under the assumption of proportional odds, and an analysis that preserves sliding dichotomy. Success is defined in terms of a two-sided p-value of <0.05, or an odds ratio whose 90% confidence interval does not cross 1. The odds ratio so calculated should preferably be >1 to favor the drug, generally >1.1, and more preferably >1.2, and most preferably >1.3.

[0041] SUR1-TRPM4 channel inhibitors SUR1-TRPM4 channel inhibitors can include any active agent that is effective for inhibiting SUR1-TRPM4, and some examples can include glyburide (also known as glibenclamide), 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, gliquidone, LY397364, LY389382, gliclazide, or glimepiride, metabolites that interact with SUR1, pharmaceutically acceptable salts thereof, or combinations thereof.Some compounds that act on non-selective channels that can be associated with SUR include, for example, pincolant, flufenamic acid, mefenamic acid, niflumic acid, rimonabant, and SKF 9635. In one embodiment, the SUR1-TRMP4 channel inhibitor is glyburide or a pharmaceutically acceptable salt thereof. In another embodiment, the SUR1-TRMP4 channel inhibitor is tolbutamide or a pharmaceutically acceptable salt thereof. In yet another embodiment, the SUR1-TRMP4 channel inhibitor is gliclazide or a pharmaceutically acceptable salt thereof.

[0042] Dosage and Administration The SUR1-TRPM4 channel inhibitor can be administered as a bolus injection, continuous infusion, or a combination thereof. In some cases, the administration can include multiple bolus injections or multiple continuous infusions. In other embodiments, the administration can include one or more continuous infusions after a bolus injection. For example, a bolus injection can be given, followed by a first continuous infusion, followed by a second continuous infusion at a slower infusion rate than the first infusion. In another embodiment, a bolus injection is followed by a continuous infusion. In another embodiment, a first continuous infusion is followed by a bolus injection, then a second continuous infusion. In yet another embodiment, a first continuous infusion is followed by a second continuous infusion and a third continuous infusion.

[0043] The administration provided herein can occur over an extended period of time. The administration can occur over a period of ≥12 hours, ≥24 hours, ≥48 hours, ≥72 hours, ≥76 hours, ≥80 hours, ≥84 hours, ≥88 hours, ≥92 hours, ≥96 hours, ≥100 hours, ≥104 hours, ≥108 hours, ≥112 hours, ≥116 hours, ≥120 hours, ≥124 hours, ≥128 hours, ≥132 hours, ≥136 hours, ≥140 hours, ≥144 hours, ≥148 hours, ≥152 hours, ≥156 hours, ≥160 hours, ≥164 hours, ≥168 hours, or ≥172 hours. In one embodiment, the administration comprises one or more continuous infusions over a cumulative period of at least 72 hours. In another embodiment, the administration comprises one or more continuous infusions over a cumulative period of at least 96 hours. In yet another embodiment, the administration comprises one or more continuous infusions over a period of at least 120 hours. In alternative examples, the administration of the one or more continuous infusions can occur over a period of ≦72 hours, ≦48 hours, or ≦24 hours.

[0044] The exact dosage will vary based on the underlying condition, the degree of swelling, the subject's weight, and / or the SUR1-TRMP4 channel inhibitor being administered. It is recognized that the bolus injection is administered at about 100 μg to about 200 μg. In one embodiment, the bolus injection is about 110 μg to about 140 μg, or about 125 μg. In another embodiment, the bolus injection is about 140 μg to about 160 μg, or about 150 μg. In yet another embodiment, the bolus injection is about 160 μg to about 190 μg, or about 175 μg. It is recognized that the continuous infusion is administered at an infusion rate of about 100 μg / hour to about 300 μg / hour. In one embodiment, the infusion rate is about 110 μg / hour to about 140 μg / hour, or about 125 μg / hour. In another embodiment, the infusion rate is about 140 μg / hour to about 160 μg / hour, or about 150 μg / hour. In yet another embodiment, the infusion rate is about 160 μg / hour to about 190 μg / hour, or about 175 μg / hour. In a further embodiment, the infusion rate is about 190 μg / hour to about 225 μg / hour, or about 200 μg / hour. Further embodiments include infusion rates of about 225 μg / hour to about 300 μg / hour, or about 250 μg / hour.

[0045] In some aspects, the disclosure includes any of the following exemplary items: 1. A method for improving outcomes in a patient diagnosed with ischemic stroke, wherein the patient has experienced a sleep-onset stroke, the method comprising administering to the patient a SUR1-TRPM4 channel inhibitor.

[0046] 2. The method of item 1, wherein the patient is 18 to 70 years old at the start of treatment.

[0047] 3. The method of item 1 or item 2, wherein the patient has undergone mechanical thrombectomy prior to the administering step.

[0048] 4. The method of item 3, wherein the administering step begins before or during the mechanical thrombectomy.

[0049] 5. The method of any one of items 1-4, wherein treatment begins within 9 hours of the midpoint between sleep onset (or last known normal time) and wake-up time.

[0050] 6. The method of claim 1, wherein the treatment begins within 10 hours of the midpoint between sleep onset (or the last known normal time) and awakening.

[0051] 7. The method of any one of items 1 to 6, wherein the administering step begins within 8 hours of the first stroke symptoms.

[0052] 8. The method of any one of items 1 to 7, wherein the SUR1-TRPM4 inhibitor is administered in one or more continuous infusions for a total duration of at least 72 hours.

[0053] 9. The method of any one of items 1 to 8, wherein the patient undergoes decompressive craniectomy.

[0054] 10. The patient is 180 cm tall. 3 10. The method according to any one of items 1 to 9, wherein the lesion volume is equal to or smaller than this.

[0055] 11. The patient is 180 cm tall. 3 , 170cm 3 , 160cm 3 , 150cm 3 , 140cm 3 , 130cm 3 , 125cm 3 , 120cm 3 , 110cm 3 , 100cm 3 , 90cm 3 , or 80cm 3 10. The method according to any one of items 1 to 9, wherein the lesion volume is less than 100 μg / mL.

[0056] 12. The patient has a pelvic floor of >50cm 3 and <125cm 3 or >50cm 3 and <100cm 3 10. The method according to any one of items 1 to 9, wherein the lesion volume is

[0057] 13. The method of any one of items 1 to 12, wherein the SUR1-TRPM4 channel inhibitor comprises a member selected from the group consisting of glibenclamide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, gliquidone, LY397364, LY389382, gliclazide, glimepiride, and pharmaceutically acceptable salts thereof, metabolites thereof that interact with SUR1, and combinations thereof.

[0058] 14. The method of any one of items 1 to 13, wherein the SUR1-TRPM4 channel inhibitor is glibenclamide.

[0059] 15. A method of treating ischemic stroke in a patient who has experienced a sleep-onset stroke, said method comprising treating said patient with a therapeutically effective amount of a SUR1-TRPM4 inhibitor.

[0060] 16. The method according to item 15, wherein treatment begins before mechanical thrombectomy.

[0061] 17. The method according to item 15, wherein treatment begins during or after mechanical thrombectomy.

[0062] 18. The patient is 180 cm tall. 3 , 170cm 3 , 160cm 3 , 150cm 3 , 140cm 3 , 130cm 3 , 125cm 3 , 120cm3 , 110cm 3 , 100cm 3 , 90cm 3 , or 80cm 3 18. The method according to any one of items 15 to 17, wherein the lesion volume is less than 100 μg / mL.

[0063] 19. The method of any one of items 1 to 18, wherein the patient is selected to undergo mechanical thrombectomy using non-contrast computed tomography.

[0064] 20. The method of any one of items 1 to 18, wherein the patient is treated with tissue plasminogen activator.

[0065] 21. The method of item 20, wherein the patient has an ASPECTS score of ≦7.

[0066] 22. The method of any one of items 15 to 21, wherein the patient is selected for mechanical thrombectomy using computed tomography perfusion or magnetic resonance imaging.

[0067] 23. The method of any one of items 18 to 22, wherein the lesion volume is measured by using computed tomography perfusion or magnetic resonance imaging.

[0068] 24. The method of any one of items 17 to 23, wherein the patient undergoes non-contrast computed tomography after mechanical thrombectomy but before treatment with the SUR1-TRPM4 inhibitor begins.

[0069] 25. The method according to any one of items 17 to 23, wherein the lesion volume is determined before mechanical thrombectomy.

[0070] 26. The method according to any one of items 17 to 23, wherein the lesion volume is determined after mechanical thrombectomy.

[0071] 27. The method of any one of items 1 to 26, wherein the patient has an NIH Stroke Scale (NIHSS) score of 10 to 20.

[0072] 28. The method of any one of items 1 to 26, wherein the patient has an NIH Stroke Scale (NIHSS) score of 10 to 18.

[0073] 29. The method of any one of items 1 to 26, wherein the SUR1-TRPM4 channel inhibitor is glyburide or a pharmaceutically acceptable salt thereof in a formulation comprising a buffering agent, a base, and a sugar alcohol, wherein the formulation has a pH outside the buffering capacity of the buffering agent, and the buffering agent has a pKa of 7.7 to 9.2.

[0074] 30. The method according to any of the preceding items, wherein the pharmaceutically acceptable salt thereof is a sodium addition salt.

[0075] 31. The method according to any of the preceding items, wherein the glyburide or pharmaceutically acceptable salt thereof is about 2.7 to 3.1% (w / w) of the formulation.

[0076] 32. The method according to any of the preceding items, wherein the sugar alcohol is about 84-90% w / w of the formulation.

[0077] 33. The method according to any of the preceding items, comprising the sugar alcohol and the glyburide or pharmaceutically acceptable salt thereof in a weight ratio of 28 to 35:1.

[0078] 34. The method of any of the preceding items, wherein upon storage for 12 months at 25°C / 60% relative humidity (RH), the formulation has a pH that is within about 0.2 pH units of the formulation before storage, or upon storage for 6 months at 40°C / 75% RH, the formulation has a pH that is within about 0.2 pH units of the formulation before storage, or upon storage for 4 weeks at 70°C / 75% RH, the formulation has a pH that is within about 0.2 pH units of the formulation before storage.

[0079] 35. The method according to any one of the preceding items, wherein the buffering agent is a buffer solution having a pH of 7.8 to 9.

[0080] 36. The method of any of the preceding items, wherein the formulation comprises the base and the glyburide or a pharmaceutically acceptable salt thereof in a ratio such that the formulation has a pH of 10.1 to 10.9 when reconstituted in water for injection (WFI).

[0081] 37. The method according to any of the preceding items, wherein the formulation comprises the sugar alcohol and the glyburide or a pharmaceutically acceptable salt thereof in a weight ratio of 27 to 40:1.

[0082] 38. The method according to any of the preceding items, wherein the formulation comprises the sugar alcohol and the buffering agent in a weight ratio of 8 to 12:1.

[0083] 39. The method according to any one of the preceding items, wherein the formulation contains 26 to 34 mg / ml of the sugar alcohol.

[0084] 40. The method according to any of the preceding items, wherein the base and the glyburide or pharmaceutically acceptable salt thereof have a molar ratio of 5.4 to 6.3:1 in the formulation.

[0085] 41. The method according to any of the preceding items, wherein the formulation contains about 8 to 12% (w / w) of the buffering agent.

[0086] 42. The method of any preceding item, wherein the formulation does not contain cyclodextrin.

[0087] 43. The above formulation is a) glyburide or a pharmaceutically acceptable salt thereof; b) buffering agents; c) a base; and d) sugar alcohols, Including, wherein the formulation has a pH outside the buffering capacity of the buffering agent; wherein the formulation does not contain cyclodextrin. 30. The method according to any one of items 1 to 29.

[0088] 44. The method according to Item 43, wherein the glyburide or pharmaceutically acceptable salt thereof is about 2.7 to 3.1% (w / w) of the formulation, and the sugar alcohol is about 84 to 90% (w / w) of the formulation.

[0089] 45. The method according to item 43, comprising the sugar alcohol and the glyburide or a pharmaceutically acceptable salt thereof in a weight ratio of 28 to 35:1.

[0090] 46. ​​Upon storage for 12 months at 25°C / 60% relative humidity (RH), the formulation has a pH that is within about 0.2 pH units of the formulation before storage, or upon storage for 6 months at 40°C / 75% RH, the formulation has a pH that is within about 0.2 pH units of the formulation before storage, or upon storage for 4 weeks at 70°C / 75% RH, the formulation has a pH that is within about 0.2 pH units of the formulation before storage. 44. The method of claim 43, having a pH that is within pH units.

[0091] 47. The method according to Item 43, wherein the buffering agent is a buffer solution having a pH of 7.8 to 9.

[0092] 48. The method according to item 43, wherein the base and the glyburide or pharmaceutically acceptable salt thereof are contained in a ratio such that the formulation has a pH of 10.1 to 10.9 when reconstituted in water for injection (WFI).

[0093] 49. The method according to Item 43, wherein the formulation comprises the sugar alcohol and the glyburide or a pharmaceutically acceptable salt thereof in a weight ratio of 27 to 40:1.

[0094] 50. The method according to Item 43, wherein the formulation comprises the sugar alcohol and the buffering agent in a weight ratio of 8 to 12:1.

[0095] 51. The method according to item 43, wherein the formulation contains 26 to 34 mg / ml of the sugar alcohol.

[0096] 52. The method according to item 43, wherein the base and the glyburide or pharmaceutically acceptable salt thereof have a molar ratio of 5.4 to 6.3:1.

[0097] 53. The method according to item 43, wherein the formulation comprises about 8 to 12% (w / w) of the buffering agent, and the buffering agent has a pKa of 7.7 to 9.2.

[0098] formulation The methods and formulations provided herein provide pharmaceutically acceptable glyburide formulations that overcome the adsorption, degradation, instability, and low solubility problems associated with prior art pharmaceutical formulations of glyburide, including concentrated solutions, diluted solutions, and lyophilized formulations.

[0099] Examples of suitable pharmaceutically acceptable diluents (e.g., solutions including WFI (water for injection) and isotonic saline) are known in the art. Pharmaceutically acceptable aqueous solutions include Ringer's solution, Hartmann's solution, 0.9% saline, 0.45% N saline, WFI (water for injection), D5W (5% dextrose in water), phosphate buffered saline (PBS), and dextrose / saline solutions (D2.5W (i.e., 2.5% dextrose in water) and 0.45% N saline).

[0100] As used herein, "Ringer's solution" refers to a pharmaceutically acceptable buffered saline solution having sodium chloride, potassium chloride, and calcium chloride salts.

[0101] As used herein, "Hartmann's solution" refers to lactated Ringer's solution. A representative Hartmann's solution contains 131 mM sodium, 5 mM potassium, 2 mM calcium, 11 mM chloride, and 29 mM lactate (0.6% sodium chloride, 0.25% sodium lactate, 0.04% potassium chloride, 0.027% calcium chloride).

[0102] As used herein, a pharmaceutically acceptable saline solution is a solution suitable for administration to a patient that contains water and sodium chloride, and may optionally contain buffers, preservatives, or other components, typically in small amounts. For example, pharmaceutically acceptable saline solutions include 0.9% saline (9 g NaCl in 100 ml distilled-filtered water, containing 150 mM sodium and 150 mM chloride) and saline solutions having 154 mM sodium and 154 mM chloride.

[0103] Generally, in this specification the term "or" includes "and / or". As used herein, a plurality of compounds, elements, or steps may be presented in a common list for convenience. However, these lists should be construed as though each member of said list is individually identified as a separate and unique member. Accordingly, the individual members of such lists should not be construed as de facto equivalents of any other members of the same list solely based on their presentation in a common group, absent indication to the contrary.

[0104] Furthermore, certain compositions, elements, excipients, ingredients, disorders, conditions, features, steps, etc. may be discussed within the context of one particular embodiment or aspect or within a separate paragraph or section of this disclosure. This is for convenience and brevity only, and it is understood that any such disclosure is equally applicable to and intended to be combined with any other embodiment or aspect found anywhere in this disclosure and claims, all of which form the specification as filed and the present invention. For example, a listing of method steps, active agents, kits, or compositions described with respect to a formulation or method of treating a particular subject is intended to directly support, and finds, embodiments related to the compositions, formulations, and methods described anywhere else in this disclosure, even if those method steps, active agents, kits, or compositions are not relisted in the context or section of that embodiment or aspect.

[0105] The present inventors have found that glyburide in conventional intravenous glyburide formulations readily and extensively binds to polymer containers (e.g., including polyvinyl chloride (PVC) and polyurethane (PUR) infusion sets). While the use of low-grade polyethylene-lined infusion sets minimizes adsorption, such specialized infusion sets are impractical for several reasons, including the difficulty of supplying such specialized infusion sets and the fact that intravenous glyburide is intended for use in emergency care settings and for indications where minimizing the time between administration and the patient's last known normal time is critical to efficacy (i.e., "time is brain"). Therefore, presenting additional complications in the handling and administration of intravenous glyburide, i.e., requiring the strict use of specialized infusion components in emergency settings, delays patient administration and adversely affects patient outcomes. Furthermore, the use of materials commonly used with prior art intravenous glyburide formulations results in the loss of significant amounts of the active pharmaceutical ingredient due to adsorption, resulting in the administration of unknown and possibly subtherapeutic doses of glyburide. Furthermore, the use of substances commonly used with prior art intravenous glyburide formulations results in instability and degradation, resulting in a drug product of unacceptable quality. Furthermore, administering unknown amounts of glyburide or attempting to increase the volume of drug administered is unsafe because administering higher doses (e.g., at rates greater than an average rate of 0.25 mg / hour (6 mg / day)) of glyburide can result in hypoglycemia. Furthermore, performing a flushing procedure that is complicated, time-consuming, inaccurate, wasteful, and potentially carries a risk of contamination is undesirable. Furthermore, the inventors have found that the glyburide in prior art intravenous glyburide formulations readily and extensively binds to all filter components (data not shown).Therefore, there is a need to provide a new intravenous glyburide formulation that allows healthcare providers to treat patients with the correct dose within the appropriate administration window (such as in the immediate aftermath of a stroke, infarction, injury, etc.) using commonly used medical supplies, avoiding binding to commonly used infusion sets and filter materials, and avoiding complexity, avoiding drug waste, and reducing the amount of infusion fluid administered to the patient.

[0106] In a first aspect, the present disclosure provides formulations comprising a stable therapeutic dose of glyburide having a loss of less than 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, 0.1%, 0.05%, 0.01% of the glyburide concentration (w / v) due to adsorption to polymeric containers (e.g., including polyvinyl chloride (PVC), polyurethane (PUR), polypropylene, polyamide, polystyrene, polyethylene terephthalate (PET), polycarbonate (PC), acrylonitrile butadiene (ABS), polybutadiene, polyolefin, ethylene vinyl acetate, polyether ether ketone (PEEK), and mixtures, combinations, and copolymers thereof).

[0107] In a second aspect, the present disclosure provides formulations comprising a stable therapeutic dose of glyburide having less than 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, 0.1%, 0.05%, 0.01% loss of glyburide concentration (w / v) due to adsorption to in-line filter materials.

[0108] In a third aspect, the present disclosure provides methods and formulations for controlling the pH of a glyburide solution within a desired narrow range, both before and after dilution in an infusion fluid.

[0109] In a fourth aspect, the present disclosure provides methods and formulations for minimizing or avoiding the formation of degradation products in stored glyburide solutions.

[0110] In a fifth aspect, the present disclosure provides methods and formulations for reducing the infusion rate, reducing drug wastage, and reducing salt uptake in subjects being treated with intravenous glyburide.

[0111] In a sixth aspect, the present disclosure provides methods and formulations for maintaining a sufficiently high concentration of glyburide in solution during formulation compounding that can allow filling into appropriately sized containers to achieve the above-mentioned therapeutic doses (e.g., 3-5 mg / day glyburide).

[0112] In a seventh aspect, the present disclosure provides methods and formulations for providing sufficient solubility, stability, and a desired pH upon reconstitution to achieve a desired high concentration during drug preparation.

[0113] In an eighth aspect, the present disclosure provides methods and formulations for providing sufficient solubility, stability, and a desired pH upon further dilution of a glyburide formulation reconstituted into an infusion fluid (e.g., in a saline bag at a concentration of 6-10 μg / ml) for administration over a period of 3, 4, 6, 12, 24, 30, 36, 48, 72, 96, or 120 hours.

[0114] In one aspect, the disclosed methods and formulations include formulating a glyburide formulation comprising glyburide, a buffering agent, and a base, as specified herein. In one aspect, the buffering agent has a pKa of 7.7-9.2, 7.8-9.1, 7.9-9.0, 8.0-8.9, 8.05-8.8, or 8.1-8.7, or any specific pKa within the specified range. For example, and without limiting the foregoing disclosure, the buffering agent can be Tris, lysine, arginine, ethylenediamine, imidazole, 4-(2-hydroxyethyl)morpholine, triethanolamine, glucamine, deanol (dimethylaminoethanol), phosphate, phosphate-buffered saline (PBS), or a combination thereof. In one aspect, the disclosed buffering agent has a buffering capacity in the pH range of 7-9. In one aspect, the Tris can be a combination of Tris-HCl and Tris-base. In one aspect, the lysine is lysine-HCl. In one aspect, the arginine is arginine-HCl.

[0115] In one aspect, the present disclosure provides methods and formulations comprising glyburide, a buffering agent, a base, and a sugar alcohol, wherein the formulation has a pH outside the buffering capacity of the buffering agent, and the formulation is suitable for infusion into humans over a 24-hour period or longer (including being safe and tolerable at sustained therapeutically effective doses). In one aspect, the formulation (reconstituted formulation) has a pH greater than 9.0, greater than 9.5, greater than 10.0, or greater than 10.5, e.g., 9.3-11, while the buffering agent has a buffering capacity in the pH range of 7-9.

[0116] In some embodiments, the formulation can maintain a stable pH. For example, the formulation has a pH that is within about 0.1 or about 0.2 pH units after 1, 2, or 4 weeks, or 3, 6, or 12 months of storage at or around 25°C / 60% relative humidity (RH), 40°C / 75% RH, or 70°C / 75% RH. In some embodiments, the glyburide has increased stability compared to the same formulation either lacking a buffer or having a buffer with a buffering capacity that overlaps with the pH of the formulation. In some aspects, the stability can be determined by measuring the production of degradation products. For example, the degradation products can be measured by HPLC. In some aspects, the degradation products are quantified based on relative retention time (RRT) on HPLC.

[0117] In some aspects, the buffering agent is a combination of Tris-HCl and Tris-base, hi some aspects, the weight ratio between Tris-HCl and Tris-base is 7:4, 6.7:4.5, 6.5:4.7, 6.4:4.8, 6.3:4.9, 6.2:5.0, or 6.1:5.1.

[0118] In some aspects, the lyophilized glyburide formulation contains about 5-15%, 6-14%, 7-13%, 8-12%, 9-13%, or 10-12% (w / w) of the buffering agent. In some aspects, the reconstituted glyburide formulation contains about 5-15%, 6-14%, 7-13%, 8-12%, 9-13%, or 10-12% (w / w) of the buffering agent. In some aspects, the reconstituted glyburide formulation contains about 1-100 mM, 2-80 mM, 3-70 mM, 4-60 mM, 5-50 mM, 6-40 mM, 7-30 mM, 8-25 mM, 9-23 mM, 10-21 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, or 20 mM of the buffering agent. In some aspects, the reconstituted glyburide formulation contains about 1-5 mg / ml, 1.2-4 mg / ml, 1.5-3.5 mg / ml, or 2-3 mg / ml of the buffering agent.

[0119] In some aspects, the buffering agent is a buffer solution having a pH of 7.8 to 9, 8.1 to 8.9, 8.2 to 8.8, 8.3 to 8.7, 8.4 to 8.6, or 8.5.

[0120] In some aspects, the present disclosure includes the use of a mixing device that allows for the reconstitution and transfer of a lyophilized formulation between a vial and an IV bag prior to administration. The mixing device can be a needleless device. The mixing device can be a USP <797> The mixing device may have a dual channel design that provides dedicated fluid paths for entry and exit from the IV bag. In one aspect, the present disclosure includes the use of a mixing device as described in U.S. Pat. No. 8,551,067 (Zinger), which is incorporated herein by reference in its entirety. In one aspect, the present disclosure includes the use of a mixing device as described in U.S. Pat. No. 10,688,295 (Lev), which is incorporated herein by reference in its entirety. In some aspects, the present disclosure includes the use of a mixing device such as VIAL2BAG®, VIAL2BAG ADVANCED, or the like, for reconstituting and transferring a lyophilized formulation between a vial and an IV bag prior to administration. TM and / or a MIX2VIAL® mixing device.

[0121] In a second aspect, the base is a strong base having a pKb of 0.1 to 1.5. Any pharmaceutically acceptable strong base can be used. For example, and without limiting the foregoing disclosure, the base can be NaOH, CaOH, or KOH.

[0122] In a third aspect, the formulations of the present disclosure comprise a specific weight ratio between the glyburide and the base to achieve a target pH in the formulation ranging from 9.8 to 11.2, 9.9 to 11.1, 10.0 to 11.0, 10.1 to 10.9, 10.2 to 10.8, 10.3 to 10.7, or 10.4 to 10.6.

[0123] In some aspects, the formulations of the present disclosure include a specific molar ratio between the base and the glyburide in the formulation of 5.0-6.7:1, 5.1-6.6:1, 5.2-6.5:1, 5.3-6.4:1, 5.4-6.3:1, 5.5-6.2:1, 5.6-6.1:1, 5.7-6.0:1, or 5.2:1, 5.3:1, 5.4:1, 5.5:1, or 5.6:1. The molar ratios used in accordance with the present disclosure are unexpectedly about two-fold higher than those used in prior art glyburide formulations.

[0124] In some aspects, the lyophilized glyburide formulation comprises about 2-3.5%, 2.5-3.3%, 2.7-3.1%, 2.8-2.98%, 2.9-2.97%, or 2.94-2.96% (w / w) of the glyburide.

[0125] In some aspects, the lyophilized glyburide formulation comprises about 70-93%, 75-92%, 80-91%, 84-90%, 86-89%, or 87-89% (w / w) of a sugar alcohol of the present disclosure. In some aspects, the sugar alcohol is mannitol, sorbitol, xylitol, or a combination thereof. In some aspects, the sugar alcohol is mannitol.

[0126] In some aspects, the formulations of the present disclosure include a specific weight ratio between the sugar alcohol and the glyburide in the formulation.

[0127] In some aspects, the formulations of the present disclosure include a specific weight ratio between the sugar alcohol and the buffering agent in the formulation that is 5-15:1, 6-14:1, 7-13:1, 8-12:1, 9-11:1, 9.5:1, 10:1, or 10.5:1.

[0128] In some aspects, the reconstituted glyburide formulation contains about 20-40 mg / ml, 24-36 mg / ml, 26-34 mg / ml, 38-32 mg / ml, 29 mg / ml, 30 mg / ml, or 31 mg / ml of the sugar alcohol.

[0129] In some aspects, the reconstituted glyburide formulation has a pH of about 9.3-11, 9.4-10.9, 9.5-10.8, 9.6-10.7, 9.7-10.6, 9.6-10.5, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, or 10.4. In some aspects, the reconstituted glyburide formulation has a pH of 9.5-10.0.

[0130] In some aspects, the glyburide is a free acid or a pharmaceutically acceptable salt thereof. In some aspects, the glyburide formulation comprises a sodium addition salt of glyburide. As used throughout this disclosure, the term "glyburide" may also describe salts, esters, hydrates, solvates, racemates, tautomers, stereoisomers, and / or optically active forms thereof.

[0131] In some aspects, the present disclosure includes preparing an aqueous solution of glyburide in a buffer solution of the present disclosure at a concentration described herein, adding a base of the present disclosure in a weight ratio to glyburide described herein, and lyophilizing the solution to provide a lyophilized solid composition. In some aspects, the aqueous solution may further include a sugar alcohol of the present disclosure at a concentration described herein.

[0132] In some aspects, the formulations of the present disclosure include cyclodextrin, meglumine, sugars (such as, for example, fructose, mannose, galactose, arabinose, xylose, and ribose), as well as oligosaccharides (such as disaccharides (maltose, lactose, sucrose, trehalose, and the like) and trisaccharides (such as, for example, raffinose, maltotriose, and the like)), salts, alcohols (such as, for example, ethanol), diethanolamine, Britton-Robi The composition does not contain one or more of the following: nson buffer, lactate, acetate, glutamate, glycine, citrate, succinate, surfactants, polysorbates, solubilizing polymers (e.g., polyethylene glycol), inorganic or organic acids (e.g., methanesulfonic acid, lactic acid, tartaric acid, citric acid, succinic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.), choline, n-methylglucamine, diethylamine, procaine, etc.

[0133] In some aspects, the reconstituted formulations of the present disclosure have an osmolality of between about 250 milliosmoles per liter (mOsm) and about 350 mOsm; or between about 280 mOsm and about 320 mOsm; or between about 290 mOsm and about 310 mOsm.

[0134] The present disclosure provides methods and formulations that allow for the provision of glyburide formulations with significantly higher glyburide solubility in the administration solution (i.e., approximately three-fold higher than prior art intravenous glyburide administration solutions (i.e., greater than 15 μg / ml, as opposed to less than 5.7 μg / ml in prior art intravenous glyburide administration solutions). Furthermore, even at these three-fold higher concentrations, there is no detectable loss of glyburide due to precipitation or adsorption.

[0135] In some aspects, the diluted glyburide formulation (also referred to herein as the "final dosing" formulation) according to the present disclosure has a glyburide concentration of 7.2 (±0.2) μg / mL and an injection pH of up to about 8.3 (±0.1).

[0136] In some aspects, the final dose glyburide formulation has a pH of 7.8-9.0, 7.9-9.0, 8.0-9.0, 7.8-9, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, or 8.9.

[0137] In some aspects, the final administered glyburide formulation has a buffer concentration of about 0.1-0.5 mM, about 0.15-0.4 mM, about 0.2-0.3 mM, or about 0.2 mM.

[0138] In some aspects, the diluted glyburide formulations of the present disclosure are diluted into a 500 mL IV infusion bag, thereby reducing the amount of infusion fluid administered to the subject. Given their increased solubility, stability, and minimized adsorption to medical containers, the formulations of the present disclosure allow for the use of more concentrated dosage formulations, thereby delivering a consistent therapeutic dose over the infusion period while using significantly less infusion fluid.

[0139] In some aspects, the present disclosure provides methods for reducing the volume of infusion fluid administered to the subject over an infusion period by about 25-30%, e.g., from about 2 L to 1.5 L during a 4-day infusion period or from about 1.5 L to 1.1 L during a 3-day infusion period.

[0140] In some aspects, due to the advantages of the present invention, the diluted glyburide formulation can be administered at a slower rate than prior art intravenous glyburide formulations, for example, the infusion rate can be reduced to about 80% of the infusion rate used to infuse prior art intravenous glyburide formulations (e.g., 23 ml / hour for the first 6 hours and 15.9 ml / hour thereafter, compared to 29 ml / hour for the first 6 hours and 20 ml / hour thereafter, compared to prior art intravenous glyburide formulations).

[0141] In some aspects, the present disclosure encompasses sterilizing a formulation of the present disclosure. In some aspects, the formulation may be filter sterilized. In some aspects, the formulation may be sterilized to have a bioburden of 0. In some aspects, the product of the present disclosure may be terminally sterilized. In some aspects, the product is sterilized with gamma irradiation. In some aspects, the product is sterilized by electron beam, x-ray, hydrogen peroxide, or ethylene oxide. In some aspects, the product may be a powder, solution, vial, kit, pre-filled syringe, injection device, cartridge, on-body injector, auto-injector, infusion bag, or any other container or set of containers suitable for storing, infusing, and / or injecting a product of the present disclosure. In some aspects, the product may be sterilized in a manner similar to that described above. -3 , 10 -4 , or 10 -6 meets the "sterility assurance level" or "SAL" of

[0142] Kits having features of the invention may include a liquid solution of glyburide and / or a liquid solution of glyburide together with one or more compounds and may include instructions for using such a liquid solution. For example, instructions for using such a liquid solution may include instructions for lyophilizing such a solution to obtain a lyophilized formulation of the compound of interest. Alternatively, or in addition, kits having features of the invention may include a lyophilized formulation of glyburide and / or a lyophilized formulation of glyburide together with one or more compounds and / or a lyophilized formulation of glyburide together with one or more reconstitution liquids and may include instructions for using such a lyophilized formulation. For example, instructions for using such a lyophilized formulation may include instructions for reconstituting such a lyophilized formulation to provide a solution suitable for use in pharmaceutical applications, preferably a sterile solution. In some aspects, the vial contains a buffer of the present disclosure at a concentration of 6-40 mM, 7-30 mM, 8-25 mM, 9-20 mM, or 10-15 mM.

[0143] In some aspects, the present disclosure encompasses methods of using the following exemplary items: 1. a) glyburide or a pharmaceutically acceptable salt thereof; b) buffering agents; c) a base; and d) sugar alcohols, A formulation comprising: wherein the formulation has a pH outside the buffering capacity of the buffering agent; wherein the buffering agent has a pKa of 7.7 to 9.2. formulation.

[0144] 2. A formulation according to any of the preceding items, wherein the pharmaceutically acceptable salt thereof is a sodium addition salt.

[0145] 3. A formulation according to any of the preceding items, wherein the glyburide or pharmaceutically acceptable salt thereof is about 2.7 to 3.1% (w / w) of the formulation.

[0146] 4. The formulation according to any of the preceding items, wherein the sugar alcohol is about 84-90% w / w of the formulation.

[0147] 5. A formulation according to any of the preceding items, comprising the sugar alcohol and the glyburide or a pharmaceutically acceptable salt thereof in a weight ratio of 28 to 35:1.

[0148] 6. A formulation according to any of the preceding items, which upon storage for 12 months at 25°C / 60% relative humidity (RH) has a pH that is within about 0.2 pH units of the formulation before storage, or upon storage for 6 months at 40°C / 75% RH has a pH that is within about 0.2 pH units of the formulation before storage, or upon storage for 4 weeks at 70°C / 75% RH has a pH that is within about 0.2 pH units of the formulation before storage.

[0149] 7. A formulation according to any of the preceding items, wherein the buffering agent is a buffer solution having a pH of 7.8 to 9.

[0150] 8. The formulation of any of the preceding items, comprising the base and the glyburide or pharmaceutically acceptable salt thereof in a ratio such that the formulation has a pH of 10.1 to 10.9 when reconstituted in water for injection (WFI).

[0151] 9. The formulation according to any of the preceding items, wherein the formulation comprises the sugar alcohol and the glyburide or a pharmaceutically acceptable salt thereof in a weight ratio of 27 to 40:1.

[0152] 10. A formulation according to any of the preceding items, wherein the formulation comprises the sugar alcohol and the buffering agent in a weight ratio of 8 to 12:1.

[0153] 11. A formulation according to any of the preceding items, wherein the formulation contains 26 to 34 mg / ml of the sugar alcohol.

[0154] 12. The formulation of any of the preceding items, wherein the base and the glyburide or pharmaceutically acceptable salt thereof have a molar ratio of 5.4 to 6.3:1.

[0155] 13. The formulation according to any of the preceding items, wherein the formulation comprises about 8 to 12% (w / w) of the buffering agent.

[0156] 14. The formulation of any of the preceding items, wherein the formulation does not contain cyclodextrin.

[0157] 15. e) glyburide or a pharmaceutically acceptable salt thereof; f) buffering agents; g) a base; and h) sugar alcohols, A formulation comprising: wherein the formulation has a pH outside the buffering capacity of the buffering agent; wherein the formulation does not contain cyclodextrin. formulation.

[0158] 16. The formulation according to item 15, wherein the glyburide or pharmaceutically acceptable salt thereof is about 2.7 to 3.1% (w / w) of the formulation, and the sugar alcohol is about 84 to 90% (w / w) of the formulation.

[0159] 17. The formulation according to item 15, comprising the sugar alcohol and the glyburide or a pharmaceutically acceptable salt thereof in a weight ratio of 28 to 35:1.

[0160] 18. Upon storage for 12 months at 25°C / 60% relative humidity (RH), the formulation has a pH that is within about 0.2 pH units of the formulation before storage, or upon storage for 6 months at 40°C / 75% RH, the formulation has a pH that is within about 0.2 pH units of the formulation before storage, or upon storage for 4 weeks at 70°C / 75% RH, the formulation has a pH that is within about 0.2 pH units of the formulation before storage. 16. The formulation of item 15, having a pH that is within pH units of 0.

[0161] 19. The formulation according to item 15, wherein the buffering agent is a buffer solution having a pH of 7.8 to 9.

[0162] 20. The formulation according to item 15, comprising the base and the glyburide or pharmaceutically acceptable salt thereof in a ratio such that the formulation has a pH of 10.1 to 10.9 when reconstituted in water for injection (WFI).

[0163] 21. The formulation according to item 15, wherein the formulation comprises the sugar alcohol and the glyburide or a pharmaceutically acceptable salt thereof in a weight ratio of 27 to 40:1.

[0164] 22. The formulation according to item 15, wherein the formulation comprises the sugar alcohol and the buffering agent in a weight ratio of 8 to 12:1.

[0165] 23. The formulation according to item 15, wherein the formulation contains 26 to 34 mg / ml of the sugar alcohol.

[0166] 24. The formulation according to item 15, wherein the base and the glyburide or pharmaceutically acceptable salt thereof have a molar ratio of 5.4 to 6.3:1.

[0167] 25. The formulation according to item 15, wherein the formulation comprises about 8-12% (w / w) of the buffering agent, and the buffering agent has a pKa of 7.7-9.2.

[0168] Below is an exemplary dosing schedule: References to mass refer to the SUR1-TRPM4 channel inhibitor in drug only (placebo has none). [Table 1]

[0169] Unlike thrombolytic agents (clot busters) typically administered to subjects with ischemic stroke, SUR1-TRPM4 channel inhibitors do not cause bleeding. Therefore, SUR1-TRPM4 channel inhibitors can be effective both when first administered immediately after the injury or condition, or some time after the injury or condition associated with cerebral edema has occurred. In one embodiment, the first administration of the SUR1-TRPM4 channel inhibitor can be within the first hour, the first two hours, the first three hours, the first four hours, the first six hours, the first eight hours, or the first ten hours after the injury or condition associated with cerebral edema has occurred. In another embodiment, the first administration of the SUR1-TRPM4 channel inhibitor can be at least four hours, at least four and a half hours later (a period when thrombolytic agents may be ineffective or even dangerous), at least six hours, at least eight hours, or at least ten hours after the injury or condition associated with cerebral edema has occurred. In another example, the first administration of the SUR1-TRPM4 channel inhibitor may be within 6 hours after the onset of the injury or condition. In a further embodiment, the first administration of the SUR1-TRPM4 channel inhibitor may be within 6 hours after the onset of the injury or condition. In another embodiment, the first administration may be within 8 hours after the onset of the injury or condition. In a further embodiment, the first administration of the SUR1-TRPM4 channel inhibitor may be within 10 hours after the onset of the injury or condition.

[0170] The methods of the present invention are comparable to existing treatments for ischemic stroke. Thus, it is contemplated that the methods can be employed in conjunction with thrombolytic therapy (e.g., tissue plasminogen activator (tPA) and similar thrombolytic agents). They can also be employed in patients undergoing decompressive craniectomy to address space-occupying edema.

[0171] Outcome assessment Additionally, the present disclosure relates to methods of improving outcome, which is generally assessed by measuring the degree of disability in a subject who has suffered a stroke.

[0172] For example, the improved difference in the degree of disability may be understood to be at least about 10% based on a stroke scoring system. In other embodiments, the reduction in the degree of disability may be at least about 15%, at least about 20%, at least about 25%, or at least about 30%. The scoring system may be based on the National Institutes of Health Stroke Score System (NIHSS), a modified Rankin scale, the Barthel Index, or the size of the lesion as measured by CT and / or MRI. In one example, the first scoring system or test may be based on the NIHSS, and the second scoring system or test may be based on the modified Rankin scale, the Barthel Index, or the NIHSS.

[0173] Modified Rankin Scale The mRS (the most commonly used assessment in stroke) grades global disability after stroke, and the 90-day assessment is the most widely used primary outcome measure used in acute stroke trials. It is an ordinal hierarchical scale that grades disability on a scale from 0 (no symptoms) to 6 (death). 0 - no symptoms. 1 - No significant disability. Some symptoms but able to carry out all daily activities. 2 - Slight impairment. Can care for himself / herself without assistance, but not all previous activities. 3 - Moderate disability. Requires some assistance but can walk unaided. 4 - Moderately severe disability. Unable to care for own physical needs without assistance and unable to walk without assistance. 5 - Severely disabled, requiring constant care and attention, bedridden, and incontinent. 6 - Death.

[0174] Although the mRS is often analyzed as a dichotomous outcome (e.g., defining "good" and "bad" outcomes as above and below a threshold (e.g., 0-3 vs. 4-6)), this approach has often been found to reduce the power to detect effects and, in fact, obscure both positive and negative results. In contrast, ordinal analyses preserve the mRS's sufficient power and better reflect health status by assessing each transition. In the case of severe stroke, the mRS is sometimes analyzed by collapsing the scale at each end (e.g., combining 0-1 and 5-6) on the basis that no meaningful differences exist between these outcomes—the difference between completely normal and functionally normal is meaningless, and the difference between death and being bedridden and unable to perform even basic functions is also meaningless. Thus, the truncated scales, 0-1, 2, 3, 4, and 5-6, can still be analyzed as ordinal scales, e.g., using the Mann-Whitney test or other appropriate statistics that essentially ask whether two distributions differ from each other. A common odds ratio can be estimated, for example, using ordinal logistic regression, to assess the magnitude of any effect detected and whether the effect favors the drug or the placebo. An odds ratio greater than 1 indicates a favorable drug response. Thus, the present invention provides a method for determining whether a drug is associated with a favorable drug response in a treated population. It is contemplated to have an odds ratio versus placebo control of greater than 1. In some cases, odds ratios may exceed 1.2, which is not only strong evidence of efficacy but also represents a clearly clinically meaningful benefit.

[0175] Barthel Index The Barthel Index ("BI") assesses functionality based on activities of daily living. The BI employs 10 domains that describe activities of daily living and mobility. Higher scores are better and indicate a higher level of functional independence. The BI assesses the following 10 different domains and a 100-point scoring system: Presence or absence of fecal incontinence 0 = incontinent (or needing an enema) 5=Sometimes I wet myself 10 = Continent Presence or absence of urinary incontinence · 0 = Incontinent or catheterized and unable to care for themselves. 5=Sometimes I wet myself · 10 = Ability to control bowel movements. Do you need help getting dressed? 0 = Need help with personal care 5 = Independent face / hair / teeth / shave (tools provided) Do you need help using the toilet? 0=dependent 5 = Some help required, but some independence 10 = Independent (getting dressed, getting dressed, cleaning) Do you need help eating? 0 = No 5 = Needs help with cutting, buttering, etc. or requires modified diet 10=Independent Do you need help moving (for example, from a chair to a bed)? 0 = No, unable to balance 5 = Major assistance (one or two people, physical), able to sit. 10 = Minor assistance (verbal or physical) 15=Independent Do you need help walking? 0 = immobile or <50 yards 5 = Independent in wheelchair (including turns), >50 yards 10 = Walk with one person's assistance (verbal or physical) >50 yards 15 = Independent (but may use some assistive device; e.g., cane) >50 yards Do you need help getting dressed? 0=dependent 5 = Needs some help, but can do about half the task without assistance 10 = Stands alone (including buttoning, zipping, tying laces, etc.) Do you need help climbing stairs? 0 = No 5 = Needs assistance (verbal, physical, carrying aid) 10=Independent Do you need help bathing? 0=dependent 5 = Standing alone (or showering)

[0176] NIH Stroke Scale score The NIH Stroke Scale score (NIHSS) is used to quantify the level of disability in stroke patients. The NIHSS consists of 11 items, each scored between 0 and 4, with a score of 0 typically indicating normal function and higher scores indicating some level of disability. The NIHSS is typically used to assess stroke severity at baseline / presentation, but the numbers are also used to assess improvement in individual stroke patients or to compare relative improvement between two groups of patients (e.g., placebo and drug-treated groups). The items assessed are as follows:

[0177] Item 1a: Level of Consciousness (LOC) Indication The investigator must select a response if obstacles such as an endotracheal tube, language barriers, or orotracheal trauma / bandages prevent a full assessment. A 3 is scored only if the patient does not move (other than reflex posturing) in response to noxious stimuli. Item 1a is scored as follows: · 0 = Awake; alert; responsive. · 1 = Not aroused; but aroused by small stimuli to obey, answer, or respond. 2 = Not arousable; requires repetitive stimulation to attract attention or is obtunded, requires strong or painful stimulation to perform movements (not stereotyped). · 3 = Responds only with reflex movements or autonomic effects or is completely unresponsive, flaccid, and areflexic.

[0178] Item 1b: LOC Question The patient is asked the month and his / her age. The answer must be exact - no partial credit is given for close calls. Aphasic and stuporous patients who do not understand the question are given a score of 2. Patients who cannot speak due to endotracheal intubation, orotracheal trauma, severe dysarthria of any cause, language barrier, or any other problem not secondary to aphasia are given a score of 1. It is important that only the first answer is graded and that the examiner does not "help" the patient with verbal or nonverbal cues. Item 1b is scored as follows: · 0 = Answer both questions correctly. · 1 = Answer one question correctly. · 2 = Did not answer any of the questions correctly.

[0179] Item 1c: LOC instruction The patient is asked to open and close their eyes, then grasp and open with their non-paretic hand. If the hand is not available, another one-step command is substituted. Credit is given if an explicit attempt is made but not completed due to weakness. If the patient does not respond to the command, the task should be demonstrated (pantomime) to him or her and the result scored (i.e., no command, one command, two commands). Patients with trauma, amputations, or other physical disabilities should be given the appropriate one-step command. Item 1c is scored as follows: 0 = Perform both tasks accurately. 1 = Perform one task accurately. 2 = Does not perform any task accurately.

[0180] Item 2: Best Gaze Only horizontal eye movements are tested. Voluntary or reflex (eye rotation) eye movements are scored, but caloric testing is not performed. If the patient has conjugate eye deviation that can be overcome by voluntary or reflex activity, the score is 1. If the patient has isolated peripheral nerve palsy (CN III, IV, or VI), the score is 1. Gaze can be tested in all aphasic patients. Patients with ocular trauma, bandages, previous blindness, or other impairments of visual acuity or visual field should be tested with reflex movements; the selection should be made by the investigator. Establishing eye contact and then moving the patient from side to side occasionally reveals the presence of partial gaze palsy. Item 2 is scored as follows: · 0=normal. 1 = partial gaze paresis; gaze is abnormal in one or both eyes, but there is no forced deviation or total gaze paresis. 2 = Forced displacement or complete gaze palsy not overcome by oculocephalic maneuvers.

[0181] Item 3: Visual Instruction The visual field (upper and lower quadrants) is examined by confrontation, using finger counting or visual scare, if appropriate. The patient can be encouraged, but if they look properly towards the side of the moving finger, this can be scored as normal. In the case of unilateral blindness or enucleation, the visual field of the remaining eye is scored. A score of 1 is given only if there is a clear asymmetry, including quadrantanopsy. If the patient is blind from any cause, a score of 3 is given. At this point, simultaneous bilateral stimulation is administered. If there is extinction, the patient is given a score of 1, and the result is used to answer item 11. Item 3 is scored as follows: · 0 = no visual field loss. · 1=Partial hemianopia. · 2=complete hemianopia. · 3 = Bilateral hemianopsia (blindness including cortical blindness).

[0182] Item 4: Facial Palsy Instruction The patient is asked to show their teeth or raise their eyebrows and close their eyes, or is prompted to do so using pantomime. In patients who are poorly responsive or do not understand, score the symmetry of grimacing in response to the noxious stimulus. If facial trauma / bandages, an orotracheal tube, tape, or other physical barriers obscure the face, these should be removed to the extent possible. Item 4 is scored as follows: · 0 = normal symmetrical movement. · 1 = slight numbness (flattening of nasolabial folds, asymmetry when smiling). · 2 = Partial paralysis (total or near total paralysis of the lower face). · 3 = Complete paralysis on one or both sides (no movement of the upper or lower face).

[0183] Item 5: Motor Arm Instruction The limb is positioned appropriately: the arm is extended (palm down) at 90° (if sitting) or 45° (if supine). A drift is scored if the arm falls in less than 10 seconds. The aphasic patient is prompted using vocal urgency and pantomime, but no noxious stimuli are used. Each limb is tested in turn, starting with the nonparetic arm. Only if there is amputation or joint fusion at the shoulder should the examiner record the score as Unable to Test (UN) and provide an explanation for this choice. Item 5 is scored as follows: 0 = no drift; limb held at 90° (or 45)° for a full 10 seconds. 1 = Drift; limb held at 90° (or 45)° but drifted down before the full 10 seconds; did not hit the bed or other support. 2 = Some resistance to gravity; limb cannot reach or maintain 90° (or 45°) (when commanded) and drops toward bed, but some resistance to gravity. 3 = Unable to resist gravity; limbs fall. · 4=No movement. UN = Amputation or Arthrodesis.

[0184] Item 6: Motor Leg Instruction Position the limb appropriately: hold the leg at 30° (always tested in supine position). A drift is scored if the leg falls in less than 5 seconds. The aphasic patient is prompted using vocal urgency and pantomime, but no noxious stimuli are used. Each limb is tested in turn, starting with the nonparetic leg. Only if there is a hip amputation or arthrodesis should the examiner record the score as Unable to Test (UN) and provide an explanation for this choice. Item 6 is scored as follows: 0 = no drift; leg held at 30° for a full 5 seconds. 1 = Drift; by the end of the 5 seconds, the leg falls but does not hit the bed. 2 = Some resistance to gravity; legs fall to bed by 5 seconds, but some resistance to gravity. 3 = Unable to resist gravity; legs fall immediately onto bed. · 4=No movement. UN = Amputation or Arthrodesis.

[0185] Item 7: Limb Ataxia Instruction This item aims to find evidence of unilateral cerebellar lesions. The test is performed with the eyes open. If visual impairment is present, ensure that the visual field is intact when the test is performed. Finger-nose-finger and heel-shin tests are performed bilaterally, and ataxia is scored only if present out of proportion to the weakness. Ataxia is absent in patients who are unable to comprehend or who are paralyzed. Only in the presence of an amputation or arthrodesis should the examiner record a score as Unable to Test (UN) and provide an explanation for this choice. In the case of blindness, the test is performed by having the patient touch their nose from an outstretched arm position. Item 7 is scored as follows: 0=None. · 1 = present in one limb. · 2 = present in both limbs. UN = Amputation or Arthrodesis.

[0186] Item 8: Sensory Instruction When tested, sensitivity to pinprick stimuli or grimacing, or withdrawal from noxious stimuli in patients who are blunted or aphasic. Only sensory losses attributed to stroke are scored as abnormal, and the examiner should test as many body regions (arms (not hands), legs, trunk, face) as necessary to accurately check for unilateral sensory loss. A score of 2, "severe or complete sensory loss," should be given only if severe or complete sensory loss can be clearly demonstrated. Stuporous and aphasic patients would therefore likely score 1 or 0. A brainstem stroke patient with bilateral sensory loss is scored 2. If the patient is unresponsive and quadriplegic, the score is 2. A comatose patient (item 1a = 3) automatically receives a 2 in this item. Item 8 is scored as follows: 0 = normal; no sensory loss. 1 = Mild to moderate loss of sensation; patient feels pinprick sensation but it is less sharp or dull on the affected side; or there is loss of superficial pain with pinprick sensation but patient is aware of being touched. 2 = Severe or complete loss of sensation; patient is unaware of touch on face, arms, and legs.

[0187] Item 9: Best Language Instruction Much information about comprehension is obtained during the preceding sections of the test. For this scale item, patients are asked to describe what is happening in the accompanying picture, name the item on the accompanying naming form, and read from the accompanying sentence list. See pages 9 and 10 of the NIH Stroke Scale document (ninds.nih.gov / health-information / public-education / know-stroke / health-professionals / nih-stroke-scale). Comprehension is determined from responses here and to all commands in the general neurological examination described above. If visual loss interferes with the test, patients are asked to identify, repeat, and vocalize an object placed in their hand. Intubated patients should be asked to complete the questionnaire. Comatose patients (item 1a = 3) are automatically scored 3 on this item. The examiner must select a score for patients with stupor or limited cooperation; a score of 3 should only be used if the patient is mute and does not follow one-step commands. Item 9 is scored as follows: · 0=no aphasia; normal. 1 = Mild to moderate aphasia; some clear loss of fluency or comprehension, but no significant limitation in expressed ideas or form of expression. However, the reduction in speech and / or comprehension makes conversation about provided material difficult or impossible. For example, in conversation about provided material, the examiner may be able to identify the contents of pictures or name cards from the patient's responses. 2 = Severe aphasia; all communication is fragmented; there is a great deal of inference, questioning, and speculation required from the listener. The range of information exchanged is limited; the listener bears the communication burden. The examiner is unable to identify the material provided from the patient's responses. · 3 = mute, total aphasia; no usable speech or auditory comprehension.

[0188] Item 10: Dysarthria Instruction If the patient is considered normal, an adequate sample of speech should be obtained by asking the patient to read or repeat the words on pages 11 and 12 of the NIH Stroke Scale document. If the patient has severe aphasia, the intelligibility of spontaneous speech may be graded. Only if the patient is intubated or has other physical barriers to vocalization should the examiner record the score as Unable to Test (UN) and provide an explanation for this choice. The patient should not be told why he / she is being tested. Item 10 is scored as follows: · 0=normal. 1 = Mild to moderate dysarthria; the patient slurs at least some words and, at worst, can understand them with some difficulty. 2 = Severe dysarthria; the patient's speech is so slurred or mute / anarthric that it is incomprehensible and out of proportion to the absence or presence of any dysphasia. UN = Intubated or other physical barrier. Description:

[0189] Item 11: Disappearance and inattention to instructions (previously, ignored) Sufficient information to identify neglect may be obtained during prior testing. If the patient has severe visual loss that prevents visual dual simultaneous stimulation and cutaneous stimulation is normal, the score is normal. If the patient has aphasia but appears to be attentive bilaterally, the score is normal. The presence of visual spatial neglect or anosagnosia may also be considered as evidence of abnormality. The item is never untestable, as abnormalities are scored only if present. Item 11 is scored as follows: 0 = No abnormality. · 1 = visual, tactile, auditory, spatial, or personal inattention, or extinction to bilateral simultaneous stimulation in one of the sensory modalities. 2 = Marked hemi-inattention or loss of focus in more than one modality; no awareness of own hand or orientation to only one side in space.

[0190] The individual scores of the above 11 items are added to obtain the patient's total NIHSS score. The maximum possible score is 42 and the minimum is 0. The NIHSS can be adapted to stroke severity as follows: [Table 2]

[0191] Patients treated according to the present invention may have an NIHSS score of at least 10, for example, 10-20. Life-threatening swelling can occur in up to 8% of hospitalized patients with ischemic stroke and up to 15% of all middle cerebral artery (MCA) strokes. Patients who progress to such swelling typically have a National Institute of Health Stroke Score (NIHSS) of greater than 20 if the dominant hemisphere is involved, and greater than 15 if the non-dominant hemisphere is involved. In other examples, the majority of cases (probably greater than 99%) that progress to the development of significant swelling have an NIHSS score of ≥ 10. Patients with an NIHSS score below 10 are not prone to developing life-threatening swelling.

[0192] Definitions and Interpretation In describing and claiming the present invention, the following terminology will be used.

[0193] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a SUR1-TRPM4 channel inhibitor" includes reference to one or more such SUR1-TRPM4 channel inhibitors.

[0194] As used herein, the term "active agent" refers to a compound or mixture of compounds that, when added to a composition, tends to produce a particular therapeutic effect.

[0195] As used herein, the term "Large Hemispheric Infarction" or "LHI" refers to an ischemic stroke affecting the entire or less than the entire middle cerebral artery (MCA), with or without involvement of adjacent (i.e., anterior cerebral artery [ACA] or posterior cerebral artery [PCA]) territories.

[0196] The term "lesion" refers to an abnormality in the tissue of the brain. In some cases, a lesion may be a space-occupying lesion with a discernible volume and may invade nearby tissue and blood vessels.

[0197] As used herein, the term "placebo" refers to a formulation that does not contain a SUR1-TRPM4 antagonist or is compositionally similar except that the amount (wt%) of a SUR1-TRPM4 channel inhibitor is replaced with the same amount (wt%) of another inactive ingredient (e.g., water). Furthermore, a "placebo" may have slight formulation differences that are typical due to the absence of a drug, as understood by those skilled in the art.

[0198] The term "subject", as used herein, includes all members of the animal kingdom, including mammals, and most typically refers to human patients.

[0199] The term "sulfonylurea" includes sulfonylureas, sulfonylurea mimetics, and any other compositions that are effective to block or reduce activity associated with the SUR1 channel.

[0200] " Stroke " occurs when blood flow to the brain is insufficient, which can cause cell death.As defined herein, there are essentially two known types of stroke: ischemic stroke or hemorrhagic stroke.Ischemic stroke occurs when blood flow to the brain is lacking, and hemorrhagic stroke occurs when there is bleeding in the cranial vault or in brain tissue, and includes subarachnoid hemorrhage and intracerebral hemorrhage.Both forms can cause cerebral edema.

[0201] The terms "treating" or "treatment," as used herein and as well understood in the art, refer to an approach for obtaining beneficial or desired results (including clinical results). Beneficial or desired clinical results may include, but are not limited to, the alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, a reduction in the extent of the disease, a stabilization of the disease state (i.e., not worsening), a delay or slowing of disease progression, an improvement or palliation of the disease state, a reduction in disease recurrence, and remission (whether partial or complete). "Treating" and "treatment" may also mean prolonging survival compared to expected survival if not receiving treatment. In addition to being useful as a method of treatment, the methods described herein may be useful for the prevention or prophylaxis of disease.

[0202] As used herein, the term "about" is used to provide flexibility to the endpoints of a numerical range by providing that a given value may be "a little above" or "a little below" that endpoint. The degree of flexibility of this term may be determined by the particular variable and is within the knowledge of one of ordinary skill in the art to determine based on experience and the relevant descriptions herein. For example, in one embodiment, the degree of flexibility may be within about ±10% of the numerical value. In another embodiment, the degree of flexibility may be within about ±5% of the numerical value. In further embodiments, the degree of flexibility may be within about ±2%, ±1%, or ±0.05% of the numerical value.

[0203] Generally, in this specification the term "or" includes "and / or".

[0204] As used herein, for convenience, multiple active agents, compounds, injuries or conditions, etc. may be presented in a common list. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Accordingly, the individual members of such lists should not be construed as de facto equivalents to any other members of the same list solely by virtue of their presentation within a common group, unless indicated to the contrary.

[0205] Concentrations, amounts, and other numerical data may be described or presented herein in a range format. It should be understood that such range formats are used merely for convenience and ease and should be interpreted flexibly to include not only the numerical values ​​expressly recited as the limits of the range, but also all individual numerical values ​​or subranges subsumed within that range, as if each numerical value and subrange were expressly recited. By way of example, a numerical range of "about 0.01 to 2.0" should be interpreted not only to include the explicitly recited value of about 0.01 to about 2.0, but also to include each individual numerical value or subrange within that recited range. Accordingly, included within this numerical range are individual values ​​such as 0.5, 0.7, and 1.5, as well as subranges such as 0.5 to 1.7, 0.7 to 1.5, and 1.0 to 1.5. Furthermore, such interpretation should apply regardless of the breadth of the range or the properties being described. Furthermore, it should be noted that all percentages are by weight unless otherwise specified.

[0206] As used herein, all percent compositions are given as weight percentages unless otherwise stated. When solutions of components are referred to, the percentages refer to weight percentages of the composition including solvent (e.g., water) unless otherwise indicated.

[0207] In understanding the scope of the present disclosure, the term "comprising" and its derivatives, as used herein, are intended to be open-ended terms specifying the presence of stated features, elements, components, groups, integers, and / or steps, but not excluding the presence of other unstated features, elements, components, groups, integers, and / or steps. The foregoing also applies to words of similar meaning, such as the terms "including," "having," and their derivatives. The term "consisting" and its derivatives, as used herein, are intended to be closed-ended terms specifying the presence of the stated features, elements, components, groups, integers, and / or steps, but excluding the presence of other unstated features, elements, components, groups, integers, and / or steps. The term "consisting essentially of," as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps, and that do not materially affect the basic and novel characteristics of the features, elements, components, groups, integers, and / or steps. Reference to any one of these transitional terms (i.e., "comprise," "consist," or "essentially consist of") is understood to provide direct support for substitution of any of the other transitional terms not specifically used. For example, amending the wording from "comprise" to "consist essentially of" finds direct support due to this definition.

[0208] As used herein, for convenience, multiple compounds or processes may be presented in a common list. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Accordingly, the individual members of such lists should not be construed as de facto equivalents to any other members of the same list solely by virtue of their presentation within a common group, unless indicated to the contrary.

[0209] Furthermore, certain compositions, injuries or conditions, steps, etc. may be discussed in the context of one particular embodiment.This is merely for convenience, and it is understood that such disclosure is equally applicable to other embodiments found herein.For example, the list of active agents or drugs described in relation to the method for treating late neurological deterioration or death finds direct support for the embodiment of the method for reducing cerebral midline shift, even if these drugs are not re-listed herein in the context of that embodiment.

[0210] Embodiments of the present disclosure will now be described with reference to the following examples, which are provided for illustrative purposes only and should not be used to limit the scope or interpret the invention. [Example]

[0211] Example The CHARM trial evaluated the safety and efficacy of intravenous glibenclamide as a treatment for patients with large hemispheric infarction (LHI) who are at high risk for cerebral edema.

[0212] Patients who met the following criteria were included: · Clinical diagnosis of acute ischemic stroke in the middle cerebral artery (MCA) territory. Extensive hemispheric infarction was defined as 80 to 300 cubic centimeters (cm) on magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), or computed tomography perfusion (CTP). 3 ) lesion volume or Alberta Stroke Program Early CT score (ASPECTS) 1–5 with involvement of at least two defined cortical regions. · National Institutes of Health Stroke Scale (NIHSS) screening >=10. At the time of randomization, and in the investigator's judgment, it must be possible to start the study drug treatment infusion at the time of symptom onset, if known, or within 10 hours after the last known time of normal. Participants awakened by stroke may be included if neurological and other exclusion criteria are met. The time of stroke onset is considered to be the midpoint between sleep onset (or last known normal time) and wake-up time. For participants undergoing thrombectomy, inclusion in the trial must be based on post-thrombectomy MRI-DWI.

[0213] Patients were excluded if they met the following criteria: · On the first day, participants may be discontinued from supportive care. · Committed to decompressive craniectomy (DC) before enrollment. · Evidence of a concurrent infarct in the contralateral cerebral hemisphere severe enough to affect functional outcome.

[0214] Pre-specified primary endpoint Modified Rankin Scale (mRS) scores at 90 days were analyzed as a shift analysis using a 5-category ordinal scale, with 0 / 1 and 5 / 6 collapsed. The primary efficacy analysis was pre-specified to occur among participants aged 18-70 years (inclusive) who were randomized and received study treatment (modified intention-to-treat [mITT] population).

[0215] 535 subjects were enrolled, 268 were treated with placebo, and 267 were treated with intravenous glyburide. The mITT population (primary analysis population) (participants ≤70 years of age who received any study drug) consisted of 431 subjects.

[0216] Analysis was performed for CTP or DWI volumes >80 cm 3To examine the effect on lesion volume in subjects enrolled in the mITT population (ASPECTS enrollment was excluded because it does not assess lesion volume), an interaction term between treatment arm and stroke volume was included in an ordinal logistic regression model with 90-day mRS as the dependent variable. Independent variables included age, sex, baseline NIHSS, world region, tissue plasminogen activator, and thrombectomy.

[0217] Of the 431 subjects comprising the mITT population, 280 (65%) had baseline stroke volumes assessed by CTP or DWI. Baseline infarct volume was 154 ± 146 mL, which did not differ by treatment arm. The common odds ratio (cOR) decreased with increasing lesion volume, reaching approximately 140 cm. 3 The "no effect" point (cOR = 1.0) is crossed at 140 cm, above which threshold indicates no drug effect. 3 Below 85cm, the cOR increases with decreasing lesion volume. 3 The cOR for the group of patients with lesion volumes between 120 cm and 120 cm was approximately 6, suggesting a very robust effect for patients with smaller lesion volumes. 3 There was a statistically significant interaction (p=0.031) between baseline stroke volume and ≤120cm 3 A subgroup (cOR 2.31, 95% CI 1.07-5.01, p=0.034) had a favorable outcome among glibenclamide-treated subjects.

[0218] The beneficial outcome was surprisingly dramatic in subjects (n=81) who received glyburide in combination with thrombectomy. In those patients, there was a treatment × stroke volume interaction (p=0.009), with glibenclamide-treated subjects having a favorable outcome (cOR 4.69, 95% CI 1.10-20.1, p=0.037). In these subjects, the cOR was approximately 180 cm, as shown in Figure 1. 3The "no effect" point was crossed at 0.05 (cOR=1.0), indicating no drug effect above that threshold. Thus, the effect of combining glyburide administration with mechanical thrombectomy increased the pool of subjects who benefited from the procedure, resulting in dramatically higher functional benefits.

[0219] Thus, in mITT patients who underwent thrombectomy, the resulting cOR was several-fold higher than in the overall population, indicating a particularly favorable response in the thrombectomy population. In an embodiment of the present invention, for example, the following items are provided: (Item 1) A method for improving outcomes in a patient diagnosed with ischemic stroke, wherein the patient has experienced a sleep-onset stroke, the method comprising administering to the patient a SUR1-TRPM4 channel inhibitor. (Item 2) Item 1. The method of item 1, wherein the patient is 18 to 70 years old at the start of treatment. (Item 3) 10. The method of claim 1, wherein the patient has undergone mechanical thrombectomy prior to the administering step. (Item 4) 4. The method of claim 3, wherein the administering step begins before or during the mechanical thrombectomy. (Item 5) 2. The method of item 1, wherein the treatment begins within 9 hours of the midpoint between sleep onset (or last known normal time) and wake-up time. (Item 6) 2. The method of item 1, wherein the treatment begins within 10 hours of the midpoint between sleep onset (or last known normal time) and wake-up time. (Item 7) 2. The method of claim 1, wherein the administering step begins within 8 hours of the first stroke symptom. (Item 8) 2. The method of claim 1, wherein the SUR1-TRPM4 inhibitor is administered in one or more continuous infusions for a total duration of at least 72 hours. (Item 9) Item 10. The method of item 1, wherein the patient undergoes decompressive craniectomy. (Item 10) The patient was 180 cm 3 or a smaller lesion volume. (Item 11) The patient was 180 cm 3 , 170cm 3 , 160cm 3 , 150cm 3 , 140cm 3 , 130cm 3 , 125cm 3 , 120cm 3 , 110cm 3 , 100cm 3 , 90cm 3 , or 80cm 3 2. The method of claim 1, wherein the lesion volume is less than 100 μg / mL. (Item 12) The patient has a 3 and <125cm 3 or >50cm 3 and <100cm 3 Item 1. The method according to item 1, wherein the lesion volume is (Item 13) The method of item 1, wherein the SUR1-TRPM4 channel inhibitor comprises a member selected from the group consisting of glibenclamide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, gliquidone, LY397364, LY389382, gliclazide, glimepiride, and pharmaceutically acceptable salts thereof, metabolites thereof that interact with SUR1, and combinations thereof. (Item 14) Item 2. The method of item 1, wherein the SUR1-TRPM4 channel inhibitor is glibenclamide. (Item 15) A method of treating ischemic stroke in a patient who has experienced a sleep-onset stroke, said method comprising treating said patient with a therapeutically effective amount of a SUR1-TRPM4 inhibitor. (Item 16) 16. The method of item 15, wherein treatment begins before mechanical thrombectomy. (Item 17) 16. The method of item 15, wherein treatment begins during or after mechanical thrombectomy. (Item 18) The patient was 180 cm 3 , 170cm 3 , 160cm 3 , 150cm 3 , 140cm 3 , 130cm 3 , 125cm 3 , 120cm 3 , 110cm 3 , 100cm 3 , 90cm 3 , or 80cm 3 16. The method of item 15, wherein the lesion volume is less than 100 μg / mL. (Item 19) 2. The method of claim 1, wherein the patient is selected to undergo mechanical thrombectomy using non-contrast computed tomography. (Item 20) 2. The method of claim 1, wherein the patient is treated with tissue plasminogen activator. (Item 21) 21. The method of item 20, wherein the patient has an ASPECTS score of ≦7. (Item 22) 16. The method of claim 15, wherein the patient is selected for mechanical thrombectomy using computed tomography perfusion or magnetic resonance imaging. (Item 23) 19. The method of claim 18, wherein the lesion volume is measured by using computed tomography perfusion or magnetic resonance imaging. (Item 24) 18. The method of item 17, wherein the patient undergoes non-contrast computed tomography after mechanical thrombectomy but before treatment with the SUR1-TRPM4 inhibitor begins. (Item 25) 18. The method of claim 17, wherein the lesion volume is determined before mechanical thrombectomy. (Item 26) 18. The method of claim 17, wherein the lesion volume is determined after mechanical thrombectomy. (Item 27) Item 1. The method of item 1, wherein the patient has a National Institutes of Health Stroke Scale (NIHSS) score of 10 to 20. (Item 28) Item 10. The method of item 1, wherein the patient has a National Institutes of Health Stroke Scale (NIHSS) score of 10 to 18. (Item 29) Item 1. The method of item 1, wherein the SUR1-TRPM4 channel inhibitor is glyburide or a pharmaceutically acceptable salt thereof in a formulation comprising a buffering agent, a base, and a sugar alcohol, wherein the formulation has a pH outside the buffering capacity of the buffering agent, and the buffering agent has a pKa of 7.7 to 9.2. (Item 30) 30. The method of claim 29, wherein the glyburide or a pharmaceutically acceptable salt thereof is about 2.7 to 3.1% (w / w) of the formulation, and / or the sugar alcohol is about 84 to 90% (w / w) of the formulation. (Item 1) 1. A composition comprising a SUR1-TRPM4 channel inhibitor for use in a method of improving outcome in a patient diagnosed with ischemic stroke, wherein the outcome is assessed by a modified Rankin Scale (mRS) score, and the patient has experienced a sleep-onset stroke, the method comprising administering the composition to the patient; a) the patient has undergone mechanical thrombectomy prior to the administering step, or b) the administering step begins before or during the mechanical thrombectomy; composition. (Item 2) 2. The composition of claim 1, wherein the patient has undergone mechanical thrombectomy prior to the administering step. (Item 3) 2. The composition of claim 1, wherein the administering step begins before or during the mechanical thrombectomy. (Item 4) a) the administering step begins within 9 hours of the midpoint between the onset of sleep or the last known normal time and the time of awakening; b) the administering step begins within 10 hours of the midpoint between the onset of sleep or the last known normal time and the time of awakening; or c) The composition according to item 1, wherein the administering step begins within 8 hours of the first stroke symptoms. (Item 5) Item 10. The composition of item 1, wherein the patient has not been administered tissue plasminogen activator (tPA). (Item 6) 2. The composition of claim 1, wherein the SUR1-TRPM4 inhibitor is administered in one or more continuous infusions for a total duration of at least 72 hours. (Item 7) Item 1, wherein the patient is undergoing decompressive craniectomy. (Item 8) The patient is 180 cm 3 , 170cm 3 , 160cm 3 , 150cm 3 , 140cm 3 , 130cm 3 , 125cm 3 , 120cm 3 , 110cm 3 , 100cm 3 , 90cm 3 , or 80cm 3 2. The composition of claim 1, wherein the lesion volume is less than 100 μg / ml. (Item 9) The patient has a pelvic floor area >50cm 3 and <125cm 3or >50cm 3 and <100cm 3 2. The composition of item 1, having a lesion volume of (Item 10) The composition of item 1, wherein the SUR1-TRPM4 channel inhibitor comprises a member selected from the group consisting of glibenclamide, 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, gliquidone, LY397364, LY389382, gliclazide, glimepiride, pharmaceutically acceptable salts thereof, metabolites thereof that interact with SUR1, and combinations thereof. (Item 11) Item 2. The composition of item 1, wherein the SUR1-TRPM4 channel inhibitor is glibenclamide. (Item 12) 1. A composition for treating ischemic stroke in a patient who has experienced a sleep-onset stroke, comprising a SUR1-TRPM4 inhibitor, (a) the treatment begins before mechanical thrombectomy; or (b) the treatment begins during or after mechanical thrombectomy; composition. (Item 13) 13. The composition according to item 12, characterized in that the treatment begins before the mechanical thrombectomy. (Item 14) 13. The composition according to item 12, wherein the treatment begins during or after the mechanical thrombectomy. (Item 15) The patient is 180 cm 3 , 170cm 3 , 160cm 3 , 150cm 3 , 140cm 3 , 130cm 3 , 125cm 3 , 120cm 3 , 110cm 3 , 100cm 3, 90cm 3 , or 80cm 3 13. The composition of item 12, having a lesion volume of less than (Item 16) 2. The composition of item 1, wherein the patient is selected to undergo mechanical thrombectomy using non-contrast computed tomography. (Item 17) 2. The composition of claim 1, wherein the patient is being treated with tissue plasminogen activator. (Item 18) 18. The composition of item 17, wherein the patient has an ASPECTS score of ≦7. (Item 19) 13. The composition of item 12, wherein the patient is selected for mechanical thrombectomy using computed tomography perfusion or magnetic resonance imaging. (Item 20) 16. The composition of item 15, wherein the lesion volume is measured by using computed tomography perfusion or magnetic resonance imaging. (Item 21) 15. The composition of claim 14, wherein the patient undergoes non-contrast computed tomography after mechanical thrombectomy but before treatment with the SUR1-TRPM4 inhibitor begins. (Item 22) a) the patient has an NIH Stroke Scale (NIHSS) score of 10 to 20, or b) the patient has an NIHSS score of 10 to 18; Item 1. The composition according to item 1. (Item 23) 2. The composition of claim 1, wherein the SUR1-TRPM4 channel inhibitor is glyburide or a pharmaceutically acceptable salt thereof in a formulation comprising a buffering agent, a base, and a sugar alcohol, wherein the formulation has a pH outside the buffering capacity of the buffering agent, and the buffering agent has a pKa of 7.7 to 9.2. (Item 24) 24. The composition of claim 23, wherein the glyburide or a pharmaceutically acceptable salt thereof is about 2.7 to 3.1% (w / w) of the formulation, and / or the sugar alcohol is about 84 to 90% (w / w) of the formulation. (Item 25) 1. A composition comprising a SUR1-TRPM4 channel inhibitor for use in a method of improving outcome in a patient diagnosed with ischemic stroke, wherein the outcome is assessed by mRS score, and the patient has experienced a sleep-onset stroke or a large hemispheric infarction, the method comprising administering the composition to the patient, and wherein the patient has a stroke of >50 cm. 3 and <125cm 3 and having a lesion volume of a) the patient has undergone mechanical thrombectomy prior to the administering step, or b) the administering step begins before or during mechanical thrombectomy; composition. (Item 26) 26. The composition of claim 25, wherein the SUR1-TRPM4 channel inhibitor is glibenclamide. (Item 27) 1. A composition for treating ischemic stroke in a patient who has experienced a sleep-onset stroke or a large hemispheric infarction comprising a SUR1-TRPM4 inhibitor, wherein the patient has a stroke of >50 cm 3 and <125cm 3 and having a lesion volume of a) the treatment is characterized in that it begins before mechanical thrombectomy, or b) the treatment is initiated during or after mechanical thrombectomy; A composition. (Item 28) 28. The composition of claim 27, wherein the SUR1-TRPM4 channel inhibitor is glibenclamide. (Item 29) Item 13. The composition of item 12, wherein the patient is not receiving tPA. (Item 30) 26. The composition of claim 25, wherein the patient is not receiving tPA.

Claims

[Claim 1] The invention described in the specification.

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