How to treat ischemic stroke at risk of 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 of related applications This application claims 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 thereof are incorporated herein by reference in their entirety). [Background technology]

[0002] background Following a widespread ischemic stroke, subjects may develop cerebral edema (swelling) that occupies space. Life-threatening cerebral swelling occurs in, for example, up to 8% of all ischemic stroke hospitalizations and up to 15% of all middle cerebral artery stroke patients. Such cerebral swelling (also known as edema) usually appears a few days after the stroke and generally peaks on the second or third day.

[0003] Brain swelling can increase intracranial pressure, obstructing blood flow to the brain and thereby depriving it of oxygen. Brain swelling can also block brain exit pathways, preventing fluids from leaving the brain. Furthermore, as intracranial pressure rises within the skull, previously healthy brain tissue can be destroyed, potentially leading to tentorinal hernia or uncinate hernia. Swelling within or around the brain can also cause pathological conditions and brain death, as well as secondary neurological damage and death of the subject.

[0004] Brain swelling may be associated with two distinct molecular and physiological processes: cellular swelling of neurons and astrocytes, as well as transcapillary influx of ions and fluids into the injury site. Cellular swelling of neurons and astrocytes occurs as a result of changes in the ion gradient between the cell and the extracellular space. One ion channel associated with cell swelling is NC CA-ATPThis is a channel (also known as the SUR1-TRPM4 channel). This channel is activated when intracellular ATP is depleted in neuronal cells, and is a non-selective Ca2+ channel. 2+ It is an activated ATP-sensitive cation channel. CA-ATP The channel is thought to consist of a regulating subunit, including a pore subunit associated with sulfonylurea-type receptor 1 (SUR1) and transient receptor potential cation channel subfamily M member 4 (TRPM4).

[0005] Minimizing the degree of cerebral edema is a major concern for physicians when treating subjects with conditions or diseases that can lead to cerebral edema. However, managing cerebral edema is particularly challenging due to the long duration associated with the swelling, the overall function of the brain, and the placement of the brain within the skull. Wake-up stroke is an ischemic stroke associated with neurological symptoms only upon waking. Therefore, the patient's last-known-well time corresponds to the start of sleep the night before the presentation. Given the uncertainty of when the stroke occurs, these patients are often ineligible for certain interventions, such as tPA and other thrombolytic agents, which have a narrow time window during which they can be used without excessive harm. Thus, there is an urgent need for interventions that can be applied to the sleep-up stroke population. Furthermore, the use of mechanical thrombectomy in patients with occlusion of large vessels has been underrepresented in some cases due to the fear that rapid perfusion of such large areas may cause bleeding or other adverse effects. Therefore, providing treatments to reduce the degree of cerebral edema represents an advance in this field. [Overview of the project] [Means for solving the problem]

[0006] Abstract The present invention relates to the treatment of ischemic stroke at risk of brain swelling, using a SUR1-TRPM4 channel inhibitor in combination with mechanical thrombectomy. In some embodiments, the method includes treating a patient suffering from a large hemispheric infarction. In certain embodiments, the patient has a lesion volume of less than 140 cm 3 or less than 125 cm 3 when measured by MRI DWI or CTP. The patient may be suffering from a stroke that occurred during sleep. Some embodiments include treating a patient who also undergoes decompressive therapy. Embodiments of the present invention include a method of improving outcomes in a patient diagnosed with ischemic stroke, using a SUR1-TRPM4 channel inhibitor in combination with mechanical thrombectomy. The patient may have a lesion volume of less than 140 cm 3 or less than 125 cm 3 and greater than 50 cm 3 The lesion volume may be measured by diffusion-weighted imaging (DWI) or computed tomography perfusion (CTP) imaging. Embodiments of the present invention include administering to the patient a therapeutically effective amount of a SUR1-TRPM4 channel inhibitor. The SUR1-TRPM4 inhibitor may be administered by at least one continuous infusion that results in a cumulative treatment time of at least 72 hours. The SUR1-TRPM4 channel inhibitor may be glyburide. The treatment may be initiated within 10 hours of the first stroke symptom.

[0007] In some embodiments, the minimum lesion volume may be 85 cm 3 whereas in other cases, the maximum lesion volume may be 180 cm 3 In some embodiments, the maximum lesion volume is 125 cm 3This may be the case. The patient may be between 18 and 70 years old at the start of the procedure. The patient may have undergone thrombectomy before the procedure, or the procedure may begin before or while the patient is undergoing thrombectomy. The patient may have undergone decompressive craniotomy before, during, or after the procedure. In another embodiment, the patient has experienced a sleep-onset stroke. In a particular phase involving a sleep-onset stroke, the procedure begins within 10 hours of the midpoint between falling asleep (or the last known to be normal) and waking up.

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

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

[0010] In one aspect, the present disclosure includes a method comprising the step of administering a formulation comprising a glybride 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 several 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 present disclosure includes a method of administering an infusion solution comprising 500 ml of saline solution, 3-5 mg of glybride, 100-140 mg of mannitol, 10-12 mg of Tris, and a pH of 7.8-9.

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

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

[0014] In some aspects, the Disclosure includes reconstitution of the formulations of the Disclosure in a suitable diluent (e.g., saline or water for injection (WFI)) such that the reconstituted formulation has a buffering agent concentration 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 the formulations of the present disclosure in a saline solution, wherein the formulations have a pH of 7.8 to 9.

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

[0017] In some respects, the present disclosure encompasses formulations and methods having storage stability characteristics such as high storage stability, for example, having less than 0.2% degradation products when stored at 25°C / 60% RH for 6 months, less than 0.4% degradation products when stored at 40°C / 75% RH for 6 months, and / or less than 1.0% degradation products when stored at 70°C / 75% RH for 7 days.

[0018] In some aspects, the present disclosure provides a method for increasing the solubility of a glybrid formulation in a salt-injection solution, the method comprising the steps of combining glybrid 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 glybrid formulation having a glybrid solubility of 15 μg / ml in the salt-injection solution, wherein the glybrid formulation in the salt-injection solution has a pH of 7.8 to 9.

[0019] In some aspects, the present disclosure includes a method for minimizing the volume of a saline injection solution required to inject a glybride formulation into a human over a 24-hour period, the method comprising the steps of combining 3–5 mg of glybride 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 glybride formulation in the saline injection solution has a pH of 7.8–9, and the volume of the saline injection solution used to inject 3–5 mg of glybride or a pharmaceutically acceptable salt thereof into the human is approximately 500 ml.

[0020] In some aspects, the present disclosure includes a method for increasing the storage stability of a glibride formulation, the method comprising the steps of combining a glibride 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% degradation products after storage at 25°C / 60% RH for at least 6 months and during storage at 25°C / 60% RH for 6 months.

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

[0022] [Figure 1] Figure 1 shows the clinical effects of the combination of glybride administration and mechanical thrombectomy in human subjects. [Modes for carrying out the invention]

[0023] Detailed explanation This invention is based on several surprising observations. One such observation is that when patients diagnosed with ischemic stroke involving occlusion of a large vessel are treated with the SUR1-TRPM4 inhibitor, the drug effect decreases as a function of lesion volume (the effect is approximately 140 cm³). 3 This means reducing the risk to zero. To observe this effect, outcomes in which the patient is alive but bedridden, incontinent, and completely dependent on care are considered undesirable outcomes, and the data must be analyzed accordingly. This concept stems from the development of a class of drugs called lazaroids, in which the patient survives but is left in a state of debilitation considered "worse than death." Thus, in the case of the modified Rankin scale (the primary functional assessment in stroke research), a score of 5 (severe disability) is considered a bad outcome, along with death. In this way, any effect that "simply" represents saving a life is not considered, and it is ensured that any drug effect provides a truly meaningful benefit to the patient. Analysis that includes a reduction in death (mRS 6) associated with an increase in severe disability (mRS 5) distorts this reality and is unacceptable to the FDA or other regulatory authorities. Because it only saves lives without providing a meaningful quality of life, and places a heavy emotional and financial burden on the patient's family.

[0024] Another observation is that the SUR1-TRPM4 inhibitor may improve outcomes in patients with large vessel occlusion undergoing mechanical thrombectomy to remove blood clots. Until recently, such patients were excluded from mechanical thrombectomy due to fears that rapid reperfusion of such a large area could cause bleeding or other adverse effects. When thrombectomy began to be successfully used in these patients, it was completely unclear whether further treatment with a SUR1-TRPM4 inhibitor would be beneficial or harmful, as these patients were still at risk of developing edema. Surprisingly, the combination of mechanical thrombectomy and a SUR1-TRPM4 inhibitor yields very good results.

[0025] Before any specific embodiments of the present invention are disclosed and described, it should be understood that the present invention is not limited to the specific processes and materials disclosed herein and is therefore subject to some degree of variation. It should also be understood that the terminology used herein is used solely for the purpose of describing specific embodiments and is not intended to be limiting, for the scope of the present invention is defined solely by the appended claims and their equivalents.

[0026] In one embodiment, a method for improving outcomes in subjects after ischemic stroke is demonstrated. The stroke may be a widespread stroke involving occlusion of a major vessel in the cerebrum or cerebellum. Such patients may be at risk of developing cerebral or cerebellar edema. In the case of a cerebral stroke, infarction of one or more (usually proximal) segments of the internal carotid artery (ICA) and / or the middle cerebral artery (MCA) may be involved. In the case of a cerebellar stroke, infarction of the posterior inferior cerebellar artery (PICA) or superior cerebellar artery (SCA) may be involved. The stroke may be a large hemispheric infarction (LHI) or a large cerebellar infarction (LCI). The stroke may be of at least moderate severity according to the NIH Stroke Scale (NIHSS).

[0027] Extensive strokes requiring treatment are associated with extensive ischemic lesions that may occupy at least one-third of either the MCA or cerebellar region, in the cases of LHI and LCI, respectively. LHI is 50 cm 3 or 60cm 3 It is defined in various ways as having a minimum lesion volume exceeding 70-80 cm², but more typically it is defined as having a minimum lesion volume exceeding 70-80 cm². 3 It is defined as the minimum lesion volume.

[0028] Magnetic resonance imaging (MRI) with diffusion-weighted imaging ("MRI DWI," or simply "DWI" or "MRI") is considered the "gold standard" for evaluating lesion size. MRI DWI with 98% specificity for predicting late neurological deterioration showed a size of 82 cm. 3 The threshold lesion size was associated with cerebral edema in LHI. This threshold was 70–80 cm. 3 This readily matches the thresholds that are more easily (casually) identified by other groups. Computed tomography perfusion (CTP) can similarly be used to accurately identify lesion volume.

[0029] Surprisingly, the therapeutic effect of the SUR1-TRPM4 drug, glibride (also known as glibenclamide), when measured using the modified Rankin scale (mRS), is approximately 140 cm². 3 In that regard, it decreased to the "no effect" level, approximately 125 cm. 3 And a robust treatment effect was observed below this level, and the treatment effect in the LHI population was when the lesion volume was The smaller It was found that the levels increased. In this case, mRS scores 5 and 6 are combined for analysis, and since severe disability is not considered a good outcome, it means that statistical power is not provided in showing that the drug works. Therefore, ideally treatable LHI patients are 50 cm 3 ~60cm 3 It has a minimum lesion volume of 70 cm 3 It may also have the minimum lesion volume. The therapeutic effect of the SUR1-TRPM4 drug, glybride, in combination with mechanical thrombectomy is 180 cm 3 It was also surprisingly discovered that the level of beneficial effects could be extended to 180cm. 3 LHI patients with lesion volumes up to a certain level are treated according to the methods disclosed herein in order to obtain beneficial effects.

[0030] Stroke patients are routinely assessed using non-contrast computed tomography (NCCT) and may 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 CT scans of the brain to identify signs of ischemia early; a score of 1 is given for normal areas, and a score of 0 is given for areas showing signs of ischemia. A lower score indicates more advanced ischemic changes (i.e., worsening stroke). ASPECTS is determined from assessments of two standardized regions of the MCA area: the basal ganglia level and the supraganglionic level. Involvement of more than one-third of the MCA area 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 treated with a SUR1-TRPM4 inhibitor according to the methods of this 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 bleeding and can be used to generate an ASPECTS score. Bleeding or an ASPECTS score ≤2 generally excludes patients from selection for thrombectomy. In addition, certain forms of angiography, CT angiography or MR angiography, may be employed, typically to confirm that the above patients have a blockage that can be removed using thrombectomy. Patients who have undergone recanalization, whether spontaneously or with the use of a thrombolytic agent such as tPA, are not selected for thrombectomy. Occlusion of a large vessel, such as one of the proximal branches of an ICA or MCA, and / or a large lesion (≥70 cm) 3The presence of ASPECTS ≤ 5) previously excluded thrombectomy, but this is no longer the case, and while 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 more important that such patients are selected for thrombectomy as soon as possible after stroke onset. 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 a patient for thrombectomy depends on medical judgment made based on the patient's specific presentation, including all risk factors and whether the patient is likely to benefit from thrombectomy. This is done habitually and is well within the art of those skilled in the art in 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 is intended to assume that a patient undergoes both thrombectomy and treatment with a SUR1-TRPM4 inhibitor, but that these two interventions may be performed sequentially or simultaneously, in either order.

[0032] Treatment of patients with SUR1-TRPM4 inhibitors selected for thrombectomy may be initiated before, during, or after thrombectomy. If treatment begins after thrombectomy, the patient may undergo non-contrast CT to ensure there is no bleeding before starting the treatment. The patient may also undergo CT perfusion or MRI after thrombectomy to determine the lesion volume before treatment.

[0033] Patients selected for thrombectomy are typically 180cm tall. 3 The maximum ischemic lesion volume was 170, 160, 150, 140, 130, 125, or 120 cm at the start of treatment with the SUR1-TRPM4 inhibitor. 3The maximum lesion volume may be [specify maximum lesion volume]. The above lesion volume is best confirmed using CTP or MRI. The lesion volume may be confirmed before or after thrombectomy. If confirmed 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 that the lesion will expand over the time it takes to perform the 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 above procedure can be performed.

[0034] The treatment of patients experiencing "sleep-onset" stroke is specifically planned. Sleep-onset stroke occurs when the patient is asleep without stroke symptoms, but experiences symptoms upon waking. Since it is considered highly likely that the stroke occurred when the patient woke, any time limits for treatment can be measured from the time of waking or from a reasonably early point between falling asleep and waking.

[0035] The above method involves administering one or more sequential infusions of a SUR1-TRPM4 channel inhibitor to a patient undergoing mechanical thrombectomy. These infusions may continue cumulatively for at least approximately 72 hours after the initiation of the sequential infusions. Administration of the SUR1-TRPM4 channel inhibitor has been found to reduce the incidence of late neurological deterioration or death, thereby improving outcomes as measured by conventional scales used to assess stroke.

[0036] Patients with ischemic stroke are those who meet the following criteria: National Institutes of Health Stroke Scale (NIHSS) score of at least 10; Alberta Stroke Program Early CT score (ASPECTS) of 7 or less; ASPECTS score of 4 or less; and MRI DWI lesion volume of 70 cm³.3 Ultra-high; MRI DWI lesion volume 82 cm³ 3 Super; 50cm 3 Ultra-high CT perfusion core; 70cm 3 Treatment may be considered if the subject exhibits at least one factor selected from the group consisting of: a CT perfusion core that is greater than or equal to; insufficient collateral circulation as determined by CT angiography (or other means); a CT scan showing low density covering at least 33% of the middle cerebral artery region; and / or a CT scan showing low density covering at least 50% of the middle cerebral artery region. In some embodiments, the subject is first assessed as having an NIHSS of 10 or greater and then assessed by one of the other methods outlined above. In some embodiments, the subject is first assessed as having an NIHSS of 10–20 and then assessed by one of the other methods outlined above.

[0037] In some embodiments, the subjects are treated if their ASPECTS score is ≤5, ≤4, ≤3, or ≤2. In some embodiments, the subjects have an MRI DWI lesion volume of 82 cm³. 3 Action is taken if it exceeds a certain limit.

[0038] In particular, patients suffering from extensive cerebral hemispheric infarction are at especially risk of cerebral swelling and can be treated according to the present invention. These subjects typically have middle cerebral artery region stroke and MRI DWI or CT perfusion of at least approximately 70 cm. 3 , at least about 80cm 3Alternatively, further radiological identification may be performed using an ASPECTS score of ≤5, ≤4, ≤3, or ≤2. In the methods contemplated herein for treating subjects with LHI, the subjects are ≤approximately 75 years old, most preferably ≤approximately 70 years old. It is also preferable, but most preferably ≤9 hours, that the subjects have an NIHSS ≥10 and the drug is administered ≤10 hours from the index stroke or time last known well. In some embodiments, the subjects have an NIHSS 10–20. These methods produce improvements of 1 or more on 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 lasaroid problem. These improvements appear at one or more point in time, including approximately 90 days, 180 days / 6 months, and 12 months after the stroke.

[0039] In relation to methods for treating extensive stroke, methods for testing drugs to treat extensive stroke are also considered. According to these methods, patients aged 18 and older are radiologically selected and enrolled as described above. Subjects are preferably those with an NIHSS score of ≥10, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or any score between 10 and 20, e.g., ≥10 and ≤16, ≤17, ≤18, ≤19, ≤20, and are treated with a SUR1-TRPM4 channel inhibitor or a matching placebo (starting within ≤about 10 hours, more preferably ≤9 hours, of stroke (or last asymptomatic time), and continuing for up to about 72 hours). These methods fold mRS 5 and 6 to produce improvement in the drug vs. placebo group with respect to one or more clinically relevant endpoints, including survival / mortality and the modified Rankin scale (as a full ordinal scale and / or bipolar scale). These assessments are performed at one or more time points, including approximately 90 days, approximately 180 days / 6 months, and approximately 12 months post-stroke.

[0040] In evaluating outcomes, the mRS is preferably analyzed using analyses that retain ordinal scales (e.g., Mann-Whitney U test (and similar tests)), ordinal logistic regression under the assumption of proportional odds, and sliding dichotomy). Success is defined in terms of a two-tailed p-value of <0.05, or an odds ratio where the 90% confidence interval does not cross 1. The odds ratio thus calculated should preferably be >1, generally >1.1, more preferably >1.2, and most preferably >1.3, to benefit the drug.

[0041] SUR1-TRPM4 Channel Inhibitor SUR1-TRPM4 channel inhibitors may include any active agent effective in inhibiting SUR1-TRPM4, some examples of which may include glibride (also known as glibenclamide), 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, trazamide, repaglinide, nateglinide, meglitinide, midaglisol, glikidone, 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 may be associated with SUR include, for example, pinkolant, flufenamic acid, mefenamic acid, niflumic acid, limonabant, and SKF 9635. In one embodiment, the SUR1-TRMP4 channel inhibitor is glybride 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 above SUR1-TRPM4 channel inhibitor may be administered as a bolus injection, a series of infusions, or a combination thereof. In some cases, the administration may include multiple bolus injections or multiple series of infusions. In other embodiments, the administration may include one or more series of infusions after a bolus injection. For example, a bolus injection may be given, followed by a first series of infusions, followed by a second series of infusions at a lower infusion rate compared to the first infusion. In another embodiment, a bolus injection is followed by a series of infusions. In yet another embodiment, a first series of infusions is followed by a bolus injection, then a second series of infusions. In yet another embodiment, a first series of infusions is followed by a second series of infusions, and then a third series of infusions.

[0043] The doses described herein may occur over a long period of time. Such doses may occur over periods 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, such doses include one or more consecutive infusions over a cumulative length of at least 72 hours. In another embodiment, such doses include one or more consecutive infusions over at least 96 hours. In yet another embodiment, the administration includes one or more consecutive infusions over a period of at least 120 hours. In alternative examples, the administration of one or more consecutive infusions may 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 body weight, and / or the SUR1-TRMP4 channel inhibitor being administered. Bolus injections are recognized to be administered at approximately 100 μg to approximately 200 μg. In one embodiment, the bolus injection is approximately 110 μg to approximately 140 μg, or approximately 125 μg. In another embodiment, the bolus injection is approximately 140 μg to approximately 160 μg, or approximately 150 μg. In yet another embodiment, the bolus injection is approximately 160 μg to approximately 190 μg, or approximately 175 μg. Continuous infusions are recognized to be administered at infusion rates of approximately 100 μg / hr to approximately 300 μg / hr. In one embodiment, the infusion rate is approximately 110 μg / hr to approximately 140 μg / hr, or approximately 125 μg / hr. In another embodiment, the injection rate is approximately 140 μg / hour to approximately 160 μg / hour, or approximately 150 μg / hour. In yet another embodiment, the injection rate is approximately 160 μg / hour to approximately 190 μg / hour, or approximately 175 μg / hour. In yet another embodiment, the injection rate is approximately 190 μg / hour to approximately 225 μg / hour, or approximately 200 μg / hour. Further embodiments include injection rates of approximately 225 μg / hour to approximately 300 μg / hour, or approximately 250 μg / hour.

[0045] In some respects, this 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, and the method comprises the step of administering a SUR1-TRPM4 channel inhibitor to the patient.

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

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

[0048] 4. The method according to item 3, wherein the administration step begins before or during the mechanical thrombectomy.

[0049] 5. Treatment is to begin within 9 hours of the midpoint between falling asleep (or the last time the person is known to be normal) and waking up, using the method described in any one of items 1-4.

[0050] 6. The procedure described in item 1, which begins within 10 hours of the midpoint between falling asleep (or the last time known to be normal) and waking up.

[0051] 7. The administration step described above is the method described in any one of items 1 to 6, which begins within 8 hours of the first stroke symptom.

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

[0053] 9. The patient undergoes decompressive craniotomy, according to the method described in any one of items 1 to 8.

[0054] 10. The aforementioned patient is 180cm tall. 3 Or the method described in any one of items 1 to 9, having a smaller lesion volume.

[0055] 11. The patient is 180cm 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 A method according to any one of items 1 to 9, having a lesion volume less than .

[0056] 12. The aforementioned patient is >50cm 3 Also <125cm 3 or >50cm 3 Also <100cm 3 A method according to any one of items 1 to 9, having the lesion volume of the specified amount.

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

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

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

[0060] 16. The procedure is to begin before mechanical thrombectomy, as described in item 15.

[0061] 17. The procedure is to begin during or after mechanical thrombectomy, as described in item 15.

[0062] 18. The aforementioned patient is 180cm tall. 3 , 170cm 3 , 160cm 3 , 150cm 3 , 140cm 3 , 130cm 3 , 125cm 3 , 120cm3 , 110cm 3 , 100cm 3 , 90cm 3 , or 80cm 3 The method described in any one of items 15 to 17, having a lesion volume less than .

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

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

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

[0066] 22. The patient is selected to undergo mechanical thrombectomy using computed tomography perfusion or magnetic resonance imaging, as described in any one of items 15 to 21.

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

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

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

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

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

[0072] 28. The patient has an NIH Stroke Scale (NIHSS) score of 10–18, as described in any one of items 1–26.

[0073] 29. The method according to any one of items 1 to 26, wherein the SUR1-TRPM4 channel inhibitor is a glybrid 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 pharmaceutically acceptable salt thereof is a sodium addition salt, as described in any of the preceding items.

[0075] 31. The method described in any of the preceding items, wherein the above-mentioned glybride or a pharmaceutically acceptable salt thereof is present in an amount of approximately 2.7-3.1% (w / w) of the above-mentioned preparation.

[0076] 32. The above sugar alcohol is approximately 84-90% w / w of the above preparation, as described in any of the above items.

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

[0078] 34. The method according to any of the above items, wherein, after storage for 12 months at 25°C / 60% relative humidity (RH), the pH is within approximately 0.2 pH units of the above-mentioned formulation before storage, or after storage for 6 months at 40°C / 75% RH, the pH is within approximately 0.2 pH units of the above-mentioned formulation before storage, or after storage for 4 weeks at 70°C / 75% RH, the pH is within approximately 0.2 pH units of the above-mentioned formulation before storage.

[0079] 35. The buffering agent is a buffer solution having a pH of 7.8 to 9, as described in any of the above-mentioned items.

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

[0081] 37. The preparation according to any of the above-mentioned items, comprising the sugar alcohol and the glibride or a pharmaceutically acceptable salt thereof in a weight ratio of 27 to 40:1.

[0082] 38. The above-mentioned preparation comprises the above-mentioned sugar alcohol and the above-mentioned buffering agent in a weight ratio of 8 to 12:1, as described in any of the above-mentioned items.

[0083] 39. The above preparation contains 26-34 mg / ml of the above sugar alcohol, as described in any of the above-mentioned methods.

[0084] 40. The method described in any of the preceding items, wherein the above base and the above glibride or a pharmaceutically acceptable salt thereof are present in the above preparation in a molar ratio of 5.4 to 6.3:1.

[0085] 41. The above-mentioned preparation contains approximately 8-12% (w / w) of the above-mentioned buffering agent, as described in any of the above-mentioned methods.

[0086] 42. The above-mentioned preparation is a method described in any of the above-mentioned items, which does not contain cyclodextrin.

[0087] 43. The above preparation is a) Glybrid or a pharmaceutically acceptable salt thereof; b) Buffering agent; c) bases; and d) Sugar alcohols, Includes, Here, the above formulation has a pH outside the buffering capacity of the above buffering agent, Here, the above preparation does not contain cyclodextrin. The method described in any of items 1 through 29.

[0088] 44. The method according to item 43, wherein the above-mentioned glybride or a pharmaceutically acceptable salt thereof is present in an amount of approximately 2.7–3.1% (w / w) of the above-mentioned preparation, and the above-mentioned sugar alcohol is present in an amount of approximately 84–90% (w / w) of the above-mentioned preparation.

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

[0090] 46. ​​The method according to item 43, wherein, after 12 months of storage at 25°C / 60% relative humidity (RH), the pH is within approximately 0.2 pH units of the formulation before storage, or after 6 months of storage at 40°C / 75% RH, or after 4 weeks of storage at 70°C / 75% RH, the pH is within approximately 0.2 pH units of the formulation before storage.

[0091] 47. The buffering agent is a buffer solution having a pH of 7.8 to 9, as described in item 43.

[0092] 48. The method according to item 43, comprising the above base and the above glibride or a pharmaceutically acceptable salt thereof in a ratio such that the preparation 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 preparation comprises the sugar alcohol and the glybride or a pharmaceutically acceptable salt thereof in a weight ratio of 27 to 40:1.

[0094] 50. The above preparation comprises the sugar alcohol and the buffering agent in a weight ratio of 8 to 12:1, as described in item 43.

[0095] 51. The above preparation is the method described in item 43, comprising 26-34 mg / ml of the above sugar alcohol.

[0096] 52. The above base and the above glybrid or pharmaceutically acceptable salt thereof, having a molar ratio of 5.4 to 6.3:1, as described in item 43.

[0097] 53. The above formulation contains approximately 8-12% (w / w) of the above buffering agent, wherein the buffering agent has a pKa of 7.7-9.2, as described in item 43.

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

[0099] Examples of suitable pharmaceutically acceptable diluents (e.g., solutions containing WFI (water for injection) and isotonic saline) are known in the art. Examples of 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 / salt 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 Ringer's lactated solution. A typical 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, and 0.027% calcium chloride).

[0102] As used herein, a pharmaceutically acceptable saline solution is a solution suitable for administration to a patient, comprising water and sodium chloride, and may contain, as necessary, buffers, preservatives, or other components, typically in small amounts. Examples of pharmaceutically acceptable saline solutions include 0.9% saline (containing 150 mM sodium and 150 mM chloride, with 9 g NaCl in 100 ml of distilled filtered water) and saline solutions containing 154 mM sodium and 154 mM chloride.

[0103] In general, in this specification, the term "or" includes "and / or". Where used herein, multiple compounds, elements, or processes may be presented in common lists for convenience. However, these lists should be interpreted as if each member of the above list were individually identified as a distinct and unique member. Accordingly, individual members of such lists should not be interpreted, without contrary indication, as de facto equivalents of any other member of the same list, solely on the basis of their presentation in a common group.

[0104] Furthermore, certain compositions, elements, excipients, components, problems, conditions, specifications, processes, etc., may be considered within the context of one particular embodiment or aspect, or in 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 in any part of this disclosure and the claims, all of which form the filing specification and the present invention. For example, a list of method processes, active agents, kits, or compositions described in relation to a formulation or method for treating a particular subject is intended to provide direct support for any other embodiments relating to compositions, formulations, and methods described in any other part of this disclosure, even if those method processes, active agents, kits, or compositions are not reprinted in the context or section of that embodiment or aspect.

[0105] The inventors have found that glibrid in conventional intravenous glibrid 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 special infusion sets are impractical for several reasons, including the difficulty in supplying them, and the fact that intravenous glibrid is intended for use in emergency treatment situations and for indications where minimizing the time from the last known normal state of the patient to administration is critical to efficacy (i.e., "time is brain"). Therefore, presenting further complexity in the handling and administration of intravenous glibrid, i.e., requiring the strict use of special infusion components in emergency situations, delays patient administration and has adverse effects on patient outcomes. Furthermore, the use of substances commonly used with prior art intravenous glibrid formulations results in the loss of a significant amount of the active pharmaceutical component due to adsorption, and the administration of unknown and possibly sub-thermal doses of glibrid. Furthermore, the use of substances commonly used with prior art intravenous glibrid formulations results in instability and degradation, leading to drug products of unacceptable quality. Moreover, administering unknown amounts of glibrid, or attempting to increase the volume of the drug to be administered, is unsafe because higher doses of glibrid (e.g., at rates greater than the average rate of 0.25 mg / hour (6 mg / day)) can cause hypoglycemia. Furthermore, performing complex, time-consuming, inaccurate, wasteful, and potentially contaminating flushing procedures is undesirable. In addition, the inventors have found that glibrid in prior art intravenous glibrid formulations readily and broadly binds to all filter components (data not shown).Therefore, there is a need to provide a novel intravenous glibride formulation that avoids binding to commonly used infusion sets and filter materials, avoids complexity, avoids drug waste, and reduces the amount of infusion fluid administered to the patient, while using commonly used medical supplies, enabling healthcare providers to treat patients with the correct dose within an appropriate time frame (such as immediately after a stroke, infarction, or injury).

[0106] In the first aspect, the present disclosure provides formulations containing stable therapeutic doses of glybrid having a loss of less than 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, 0.1%, 0.05%, and 0.01% of the glybrid concentration (w / v) due to adsorption to polymer 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 disclosure provides formulations containing stable therapeutic doses of glybrid with loss of less than 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, 0.1%, 0.05%, and 0.01% of the glybrid concentration (w / v) due to adsorption to an in-line filter material.

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

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

[0110] In a fifth aspect, the Disclosure provides methods and formulations for reducing the infusion rate, reducing drug waste, and reducing salt uptake by a subject being treated with intravenous glibride.

[0111] In a sixth aspect, the Disclosure provides a method and formulation for maintaining a sufficiently high concentration of glybrid in solution during formulation compounding, which can enable filling into appropriately sized containers to achieve the above therapeutic dose (e.g., 3-5 mg / day of glybrid).

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

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

[0114] In one aspect, the methods and formulations of the present disclosure encompass the step of formulating a glybrid formulation comprising a glybrid, 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, 8.1–8.7, or any specific pK within the specified range. For example, and without limiting the foregoing disclosure, the buffering agent may 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 buffering agent of the present disclosure has buffering capacity in the pH range of 7–9. In one aspect, the Tris may be a combination of Tris-HCl and Tris-base. In one aspect, the above lysine is lysine-HCl. In another aspect, the above arginine is arginine-HCl.

[0115] In one aspect, the present disclosure provides a method and formulation comprising a glybride, 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 a human over a period of 24 hours or longer (including being safe and tolerable in a sustained therapeutically effective dose). 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, for example, 9.3 to 11, while the buffering agent has buffering capacity in the pH range of 7 to 9.

[0116] In some embodiments, the formulation can maintain a stable pH. For example, the formulation has a pH of about 0.1 or about 0.2 pH units after storage for 1, 2, or 4 weeks, or 3, 6, or 12 months, at or around 25°C / 60% relative humidity (RH), 40°C / 75% RH, or 70°C / 75% RH. In some embodiments, the glybrid 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 generation of degradation products. For example, the degradation products can be measured by HPLC. In some aspects, the degradation products are quantified based on the relative retention time (RRT) in HPLC.

[0117] In some cases, the buffering agent is a combination of Tris-HCl and Tris-base. In some cases, 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 cases, the lyophilized glybrid formulation contains approximately 5-15%, 6-14%, 7-13%, 8-12%, 9-13%, or 10-12% (w / w) of the buffering agent. In some cases, the reconstituted glybrid formulation contains approximately 5-15%, 6-14%, 7-13%, 8-12%, 9-13%, or 10-12% (w / w) of the buffering agent. In some cases, the reconstituted glibride formulation contains approximately 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 cases, the reconstituted glibride formulation contains approximately 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 cases, the buffering agent is a buffer solution having a pH of 7.8-9, 8.1-8.9, 8.2-8.8, 8.3-8.7, 8.4-8.6, or 8.5.

[0120] In some aspects, this disclosure includes the use of a mixing device that allows for the reconstitution and transfer of a lyophilized formulation from a vial to an IV bag prior to administration. The mixing device may be a needleless device. The mixing device is subject to USP <797> The requirements may be met. The mixing device may have a dual-channel design that provides a dedicated fluid path for inflow and outflow of the IV bag. In one aspect, this disclosure includes the use of a mixing device as described in U.S. Patent No. 8,551,067 (Zinger), which is incorporated herein by reference in its entirety. In one aspect, this disclosure includes the use of a mixing device as described in U.S. Patent No. 10,688,295 (Lev), which is incorporated herein by reference in its entirety. In several aspects, this disclosure includes the use of VIAL2BAG®, VIAL2BAG ADVANCED, etc., for reconstituting and transferring lyophilized formulations between vials and IV bags prior to administration. TM This includes methods of using, and / or MIX2VIAL® mixing devices.

[0121] In the 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 may be NaOH, CaOH, or KOH.

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

[0123] In some aspects, the formulations of the present disclosure include specific molar ratios between the base and the glybride, such as 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. Unexpectedly, the molar ratios used in accordance with the present disclosure are about twice as high as those used in prior art glybride formulations.

[0124] In some cases, the above-mentioned lyophilized glybrid formulation contains approximately 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 above-mentioned glybrid.

[0125] In some aspects, the lyophilized glybrid formulation contains approximately 70-93%, 75-92%, 80-91%, 84-90%, 86-89%, or 87-89% (w / w) of the sugar alcohols of the 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 glybrid 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, which 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 cases, the reconstituted glybride formulation contains the above sugar alcohols in amounts of approximately 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.

[0129] In some cases, the reconstituted glybride formulation has a pH of approximately 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 cases, the reconstituted glybride formulation has a pH of 9.5–10.0.

[0130] In some contexts, the glybrid is a free acid or a pharmaceutically acceptable salt thereof. In some contexts, the glybrid formulation comprises a sodium-added salt of the glybrid. Where used throughout this disclosure, the term “glybrid” may also describe its salts, esters, hydrates, solvates, racemates, tautomers, stereoisomers, and / or optically active forms.

[0131] In some aspects, the Disclosure includes preparing an aqueous solution of glybride in a buffer of the Disclosure at concentrations described herein, adding a base of the Disclosure in a weight ratio to the glybride as described herein, and lyophilizing the solution to provide a lyophilized solid composition. In some aspects, the aqueous solution may further contain a sugar alcohol of the Disclosure at concentrations described herein.

[0132] In some aspects, the formulations of this disclosure include cyclodextrins, meglumines, sugars (e.g., fructose, mannose, galactose, arabinose, xylose, and ribose), and similarly oligosaccharides (e.g., disaccharides (maltose, lactose, sucrose, trehalose, etc.) and trisaccharides (e.g., raffinose, maltotriose, etc.)), salts, alcohols (e.g., ethanol), diethanolamine, Britton-Robi It does not contain one or more of the following: NSON buffer, lactate, acetate, glutamate, glycine, citrate, succinate, surfactant, polysorbate, solubilizing polymer (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 reconfigured formulations of the present disclosure have a volume osmolality between approximately 250 milliosmoles / liter (mOsm) and approximately 350 mOsm; or between approximately 280 mOsm and approximately 320 mOsm; or between approximately 290 mOsm and approximately 310 mOsm.

[0134] This disclosure provides a method and formulation that enables the provision of a glibrid formulation having significantly higher glibrid solubility in the administration solution (i.e., about three times higher than the prior art intravenous glibrid administration solution (i.e., higher than 15 μg / ml, in contrast to less than 5.7 μg / ml in the prior art intravenous glibrid administration solution)). Furthermore, even at these three times higher concentrations, there is no detectable loss of glibrid due to precipitation or adsorption.

[0135] In some aspects, the diluted glybride formulations according to this disclosure (also referred to herein as “final dosing” formulations) have a glybride concentration of 7.2 (±0.2) μg / mL and an injection pH up to approximately 8.3 (±0.1).

[0136] In some cases, the final administered glybride preparation has a pH of 7.8–9.0, 7.9–9.0, or 8.0–9.0. In some cases, the final administered glybride preparation has a pH of 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 several scenarios, the final administered glybride preparation has a buffer concentration of approximately 0.1–0.5 mM, approximately 0.15–0.4 mM, approximately 0.2–0.3 mM, or approximately 0.2 mM.

[0138] In several aspects, the diluted glybride formulations of the present disclosure are diluted into 500 mL IV infusion bags, 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 enable the use of more concentrated administration 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 a method for reducing the volume of an infusion fluid administered to a subject over an infusion period by approximately 25-30%, for example, from approximately 2 L to 1.5 L during a 4-day infusion period or from approximately 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 glibride formulation can be administered at a slower rate than the prior art intravenous glibride formulation. For example, the infusion rate can be reduced to about 80% of the infusion rate used to infuse the prior art intravenous glibride formulation (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 the prior art intravenous glibride formulation).

[0141] In some aspects, the Disclosure encompasses sterilization of the formulations of the Disclosure. In some aspects, the formulations may be filter-sterilized. In some aspects, the formulations may be sterilized to have a bioburden of 0. In some aspects, the products of the Disclosure may be terminally sterilized. In some aspects, the products may be sterilized by gamma irradiation. In some aspects, the products may be sterilized by electron beam, X-ray, hydrogen peroxide, or ethylene oxide. In some aspects, the products may be powders, solutions, vials, kits, pre-filled syringes, injection devices, cartridges, on-body injectors, auto-injectors, injection bags, or any other containers or sets of containers suitable for storage, injection, and / or injection of the products of the Disclosure. In some aspects, the products may be 10 -3 , 10 -4 , or 10 -6 Meets the "sterility assurance level" or "SAL".

[0142] A kit featuring the present invention may contain a liquid solution of glybrid and / or a liquid solution of glybrid combined with one or more compounds, and may include instructions for the use of such liquid solution. For example, instructions for the use of such liquid solution may include instructions for lyophilizing such solution to obtain a lyophilized formulation of the compound of interest. Alternatively, or in addition, a kit featuring the present invention may contain a lyophilized formulation of glybrid and / or a lyophilized formulation of glybrid combined with one or more compounds, and / or a lyophilized formulation of glybrid combined with one or more reconstitution liquids, and may include instructions for the use of such lyophilized formulation. For example, instructions for the use of such lyophilized formulation may include instructions for reconstituting such lyophilized formulation to provide a solution suitable for use in pharmaceutical applications, preferably a sterile solution. In some aspects, the vial contains the buffer of the present disclosure at concentrations of 6–40 mM, 7–30 mM, 8–25 mM, 9–20 mM, or 10–15 mM.

[0143] In several aspects, this disclosure includes ways of using the following exemplary items: 1. a) Glybrid or a pharmaceutically acceptable salt thereof; b) Buffering agent; c) bases; and d) Sugar alcohols, A formulation containing, Here, the above formulation has a pH outside the buffering capacity of the above buffering agent, Here, the buffering agent has a pKa of 7.7 to 9.2. formulation.

[0144] 2. The pharmaceutically acceptable salt of the above is a sodium addition salt, as described in any of the items above.

[0145] 3. The preparation described in any of the above items, wherein the above-mentioned glibride or a pharmaceutically acceptable salt thereof is present in an amount of approximately 2.7-3.1% (w / w) of the preparation.

[0146] 4. The sugar alcohol is the formulation described in any of the above items, in an amount of approximately 84-90% w / w of the formulation.

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

[0148] 6. A formulation described in any of the above items, which, when stored for 12 months at 25°C / 60% relative humidity (RH), has a pH within approximately 0.2 pH units of the formulation before storage, or when stored for 6 months at 40°C / 75% RH, has a pH within approximately 0.2 pH units of the formulation before storage, or when stored for 4 weeks at 70°C / 75% RH, has a pH within approximately 0.2 pH units of the formulation before storage.

[0149] 7. The buffering agent is a buffer solution having a pH of 7.8 to 9, as described in any of the items above.

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

[0151] 9. The preparation described in any of the preceding items, comprising the sugar alcohol and the glibride or a pharmaceutically acceptable salt thereof in a weight ratio of 27 to 40:1.

[0152] 10. The above-mentioned preparation is the preparation described in any of the above-mentioned items, comprising the above-mentioned sugar alcohol and the above-mentioned buffering agent in a weight ratio of 8 to 12:1.

[0153] 11. The above-mentioned preparation is a preparation described in any of the above-mentioned items, containing 26 to 34 mg / ml of the above-mentioned sugar alcohol.

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

[0155] 13. The above-mentioned formulation is a formulation described in any of the above-mentioned items, containing approximately 8-12% (w / w) of the above-mentioned buffering agent.

[0156] 14. The above-mentioned preparation is a preparation that does not contain cyclodextrin and is one of the preparations described in any of the preceding items.

[0157] 15. e) Glybrid or a pharmaceutically acceptable salt thereof; f) Buffering agent; g) bases; and h) Sugar alcohols, A formulation containing, Here, the above formulation has a pH outside the buffering capacity of the above buffering agent, Here, the above preparation does not contain cyclodextrin. formulation.

[0158] 16. The preparation described in item 15, wherein the above-mentioned glybride or a pharmaceutically acceptable salt thereof is present in an amount of approximately 2.7–3.1% (w / w) of the preparation, and the above-mentioned sugar alcohol is present in an amount of approximately 84–90% (w / w) of the preparation.

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

[0160] 18. The formulation described in item 15, wherein, after 12 months of storage at 25°C / 60% relative humidity (RH), the pH is within approximately 0.2 pH units of the formulation before storage, or after 6 months of storage at 40°C / 75% RH, the pH is within approximately 0.2 pH units of the formulation before storage, or after 4 weeks of storage at 70°C / 75% RH, the pH is within approximately 0.2 pH units of the formulation before storage.

[0161] 19. The above buffering agent is a buffer solution having a pH of 7.8 to 9, as described in item 15.

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

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

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

[0165] 23. The above preparation is the preparation described in item 15, containing 26-34 mg / ml of the above sugar alcohol.

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

[0167] 25. The above formulation contains approximately 8-12% (w / w) of the above buffering agent, wherein the above buffering agent has a pKa of 7.7-9.2, as described in item 15.

[0168] The following is an exemplary dosing schedule. References to mass refer only to the SUR1-TRPM4 channel inhibitor in the drug (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 may be effective both when administered immediately after the injury or condition, or some time after the injury or condition related to cerebral edema has occurred. In one embodiment, the initial administration of the SUR1-TRPM4 channel inhibitor may be within the first 1, 2, 3, 4, 6, 8, or 10 hours after the injury or condition has occurred. In another embodiment, the initial administration of the SUR1-TRPM4 channel inhibitor may be at least 4 hours, at least 4.5 hours (a period during which thrombolytic agents may be ineffective or even dangerous), at least 6 hours, at least 8 hours, or at least 10 hours after the injury or condition related to cerebral edema has occurred. In other embodiments, the initial administration of the SUR1-TRPM4 channel inhibitor may occur within 6 hours after the injury or condition occurs. In further embodiments, the initial administration of the SUR1-TRPM4 channel inhibitor may occur within 6 hours after the injury or condition occurs. In yet another embodiment, the initial administration may occur within 8 hours of the injury or condition occurring. In further embodiments, the initial administration of the SUR1-TRPM4 channel inhibitor may occur within 10 hours of the injury or condition occurring.

[0170] The method of the present invention is comparable to existing treatments for ischemic stroke. Therefore, it is intended that the method may be employed in conjunction with thrombolytic therapy (e.g., tissue plasminogen activator (tPA) and similar thrombolytic agents). These may also be employed in patients undergoing decompressive craniotomy to address space-occupying edema.

[0171] Evaluation of Outcomes Furthermore, this disclosure relates to methods for improving outcomes, which are generally evaluated by measuring the degree of disability in subjects suffering from 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 or the Barthel Index or the NIHSS.

[0173] Modified Rankin scale The above mRS (most commonly used assessment in stroke) grades overall disability after stroke, and the 90-day assessment is the most widely used primary outcome measure in acute stroke clinical 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 impairment. Although there are some symptoms, all daily activities can be performed. 2 - Slight disability. The individual can manage their personal care independently, but is not able to perform all activities they previously could. 3 - Moderate disability. Requires some assistance, but can walk independently. 4 - Moderately severe disability. Unable to take care of one's own physical needs without assistance, and unable to walk without assistance. 5 - Severe disability. Requires constant nursing care and attention, is bedridden, and experiences incontinence. 6 - Death.

[0174] 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)), but 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 analysis retains sufficient power for mRS and better reflects health status by evaluating each transition. In the case of severe stroke, mRS is sometimes analyzed by folding each end of the scale (e.g., combining 0–1 and 5–6) on the grounds that there is no meaningful difference between those outcomes—the difference between perfectly 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 omitted scales, 0–1, 2, 3, 4, and 5–6, can still be analyzed as an ordinal scale using, for example, the Mann-Whitney U test or other appropriate statistics that essentially ask whether two distributions differ from each other. The common odds ratio can be estimated, for example, using ordinal logistic regression, to assess the magnitude of any effect detected and whether that effect is favorable to the drug or placebo. An odds ratio greater than 1 indicates a favorable drug response. Accordingly, the present invention assumes that the drug has an odds ratio greater than 1 in the treatment population versus the placebo control. In some cases, the odds ratio may exceed 1.2, which not only represents strong evidence of efficacy but also clearly indicates a clinically meaningful benefit.

[0175] Barthel Index The Barthel Index ("BI") assesses functional ability based on activities of daily living (ADL). The BI employs 10 domains that describe ADL and motor skills. Higher scores indicate better performance and a higher level of functional independence. The BI assesses the following 10 distinct domains and uses a 100-point scoring system: Presence or absence of fecal incontinence • 0 = Incontinence (or enema required) 5 = Occasionally wets the bed • 10 = Able to control excretion (continent) Presence or absence of urinary incontinence • 0 = Incontinence or catheterization is present and cannot be managed independently. 5 = Occasionally wets the bed • 10 = Able to control excretion. Do you need help getting ready? • 0 = Needs assistance with personal care. • 5 = Self-service face / hair / teeth / shaving (tools provided) Do you need assistance using the toilet? • 0 = Dependent • 5 = Some help is needed, but there are things that can be done on one's own. • 10 = Independent (dressing / undressing, changing clothes, cleaning) Do you need help with meals? 0 = Not possible 5 = Needs assistance with tasks such as cutting or spreading butter, or requires a modified diet. 10 = Independent Do you need assistance with moving (for example, from a chair to a bed)? • 0 = Unable to do so, unable to maintain balance while sitting. • 5 = Significant assistance (by one or two people, physically), able to sit. • 10 = Mild assistance (speech or physical) 15 = Independent Do you need help walking? • 0 = Unable to move or <50 yards • 5 = Independent in a wheelchair (including around corners), >50 yards • 10 = Can walk (verbally or physically) with the help of one person > 50 yards • 15 = Independent (but may use some form of assistive device; e.g., a cane) > 50 yards Do you need help getting dressed? • 0 = Dependent • 5 = Assistance is needed, but about half of the tasks can be done without assistance. • 10 = Self-sufficient (including fastening buttons, zipping up zippers, tying strings, etc.) Do you need help climbing the stairs? 0 = Not possible • 5 = Needs assistance (speech, physical, or using assistive devices to maintain posture (carrying aid)) 10 = Independent Do you need assistance with bathing? • 0 = Dependent • 5 = Independent (or takes a shower)

[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, where a score of 0 indicates typical normal function, and higher scores indicate some level of disability. While the NIHSS is typically used to assess the severity of stroke at baseline / presentation, its scores can also be used to assess improvement in individual stroke patients or to compare relative improvement between two groups of patients (e.g., placebo and drug treatment groups). The items assessed are as follows:

[0177] Item 1a: Level of Consciousness (LOC) Instructions The principal investigator must select responses if a complete assessment is hindered by obstacles such as an endotracheal tube, language barrier, or orotracheal trauma / bandages. Item 3 is scored only if the patient does not move in response to the harmful stimulus (other than a reflex posture). Item 1a is scored as follows: • 0 = Awakened; highly sensitive. • 1 = Not awake; but will become awake and obey, respond, or reply to a small stimulus. • 2 = Not awake; requires repetitive stimulation to attract attention, or is obtuned and requires strong or painful stimulation to perform actions (not stereotypic). • 3 = Responds only with reflex movements or autonomic nervous system effects, or does not respond at all, is flaccid, and is areflexive.

[0178] Item 1b: LOC Question The patient is asked the month and his / her age. The answer must be accurate – no partial credit is given for close answers. Patients with aphasia or stupor who do not understand the question are scored 2. Patients who are unable to speak due to endotracheal intubation, oral intratracheal trauma, severe dysarthria of any cause, language barrier, or any other problem not secondary to aphasia are given 1. Only the first answer is graded, and it is important that the examiner does not "help" the patient with verbal or nonverbal cues. Item 1b is scored as follows: • 0 = Answer both questions accurately. • 1 = Answer one of the questions accurately. • 2 = Do not answer any of the questions accurately.

[0179] Item 1c: LOC instruction The patient is asked to open and close their eyes, and then to grasp and open their hand with the non-paralyzed hand. If the hand is unusable, another one-step command is used as a substitute. A unit is awarded if a clear attempt is made but is not completed due to weakness. If the patient does not respond to a command, the task is performed (pantomime) for him or her, and the result should be scored (i.e., does not follow the command, follows one command, follows both commands). Patients with trauma, amputation, or other physical disabilities should be given appropriate one-step commands. Item 1c is scored as follows: 0 = Perform both tasks correctly. 1 = Perform one of the tasks accurately. 2 = None of the tasks are performed accurately.

[0180] Item 2: Best Gaze Only horizontal eye movements are tested. Voluntary or reflex (oculotropic) eye movements are scored, but caloric testing is not performed. If the patient has conjugate gaze deviation that can be overcome by voluntary or reflexive 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 eye trauma, bandages, a history of blindness, or other impairments of visual acuity or visual field should be tested with reflex movements, and the selection should be made by the principal investigator. After establishing eye contact and then moving the patient from side to side, the presence of partial gaze palsy is sometimes evident. Item 2 is scored as follows: · 0=normal. • 1 = Partial gaze paresis; gaze is abnormal in one or both eyes, but forced deviation or total gaze paresis is absent. • 2 = Forced displacement or complete gaze paralysis cannot be overcome by an oculocephalic maneuver.

[0181] Item 3: Visual Instruction The visual field (upper and lower quadrants) is examined face-to-face, using, if appropriate, counting fingers or visual scares. If the patient may be encouraged but properly looks to the side of the moving finger, this can be scored as normal. If there is unilateral blindness or enucleation, the visual field of the remaining eye is scored. A score of 1 is given only if obvious asymmetry is found, including quarter-opia. A score of 3 is given if the patient is blind for any reason. At this point, simultaneous bilateral stimulation is performed. If extinction occurs, 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 defects. · 1=Partial hemianopia. · 2=complete hemianopia. • 3 = Bilateral hemianopsia (including cortical blindness).

[0182] Item 4: Facial Palsy Instruction Ask the patient to show their teeth or raise their eyebrows and close their eyes, or encourage them to do so using pantomime. In patients who are unresponsive or do not understand, score the symmetry of the grimace in response to the adverse stimulus. If the face is obscured by facial trauma / bandages, oral endotracheal tubes, tape, or other physical barriers, these should be removed to the extent possible. Item 4 is scored as follows: • 0 = Normal, symmetrical movement. • 1 = Mild paralysis (flattening of the nasolabial folds, asymmetry when smiling). • 2 = Partial paralysis (complete or near-complete paralysis of the lower part of the face). • 3 = Complete paralysis on one or both sides (no movement of the upper and lower parts of the face).

[0183] Item 5: Motor Arm Instruction Position the limb correctly: extend the arm at a 90° angle (seated) or 45° angle (supine) with the palm facing down. A drift is scored if the arm drops in less than 10 seconds. Patients with aphasia should be prompted using vocal urgency and pantomime, but no harmful stimuli should be used. Each limb should be examined sequentially, starting with the non-paralyzed arm. Only in cases of shoulder amputation or joint fusion should the examiner score it as Untestable (UN) and clearly state the reason for this selection. Item 5 is scored as follows: • 0 = No drift; hold the limb completely at 90° (or 45°) for 10 seconds. • 1 = Drift; hold the limb at a 90° (or 45°) angle but let it drop down before the full 10 seconds are up; do not hit the bed or other support. • 2 = To some extent resists gravity; the limbs cannot be bent or maintained at 90° (or 45°) (when signaled) and hang down to the bed, but to some extent resists gravity. • 3 = Unable to resist gravity; the limb falls. 4 = No movement. • UN = Amputation or joint fixation. Explanation:

[0184] Item 6: Motor Leg Instruction Position the limb correctly: Hold the leg at a 30° angle (always in a supine position). Drift is scored if the leg drops faster than 5 seconds. Patients with aphasia should be prompted using vocal urgency and pantomime, but no harmful stimuli should be used. Each limb should be examined sequentially, starting with the non-paralyzed leg. Only in cases of hip amputation or arthrodesis should the examiner score it as Unable to Examine (UN) and specify the reason for this selection. Item 6 is scored as follows: • 0 = No drift; hold the legs completely at a 30° angle for 5 seconds. • 1 = Drift; Legs fall by the end of the 5-second window but do not hit the bed. • 2 = To some extent resists gravity; legs fall to the bed within 5 seconds, but resist gravity to some extent. • 3 = Unable to resist gravity; legs immediately fall to the bed. 4 = No movement. • UN = Amputation or joint fixation. Explanation:

[0185] Item 7: Limb Ataxia Instruction This item aims to find evidence of unilateral cerebellar lesions. The examination should be performed with eyes open. If visual impairment is present, ensure the visual field remains intact during the examination. Perform the finger-to-nose-tooth and heel-to-shin tests bilaterally, and score ataxia only if present without proportionality to weakness. Ataxia is absent in patients who are unable to understand or are paralyzed. Only in cases of amputation or arthrodesis should the examiner record a score of Untested (UN) and clearly state the reason for this selection. In cases of blindness, the test should be performed by having the patient touch their nose from an outstretched arm position. Item 7 is scored as follows: 0 = None. • 1 = Present on one of the limbs. • 2 = Present in both limbs. • UN = Amputation or joint fixation. Explanation:

[0186] Item 8: Sensory Instruction During the examination, the patient responds to a pinprick, either by grimacing or numbing, or withdraws from the harmful stimulus in patients with aphasia. Only loss of sensation attributed to stroke is scored as abnormal, and the examiner should examine as many body areas as necessary to accurately check for unilateral loss of sensation [arms (not hands), legs, trunk, face]. Score 2, “severe or complete loss of sensation,” should only be given if severe or complete loss of sensation is clearly demonstrable. Patients in a stupor and with aphasia will therefore likely score 1 or 0. Patients with brainstem stroke and bilateral loss of sensation are scored 2. If the patient is unresponsive and quadriplegic, the score is 2. Patients in a coma (item 1a=3) are automatically given 2 for this item. Item 8 is scored as follows: • 0 = Normal; no loss of sensation. • 1 = Mild to moderate loss of sensation; the patient feels a pinprickling sensation, but it is not as sharp or dull on the affected side; or there is a loss of superficial pain from the pinprickling sensation, but the patient is aware of being touched. • 2 = Severe or complete loss of sensation; the patient is unaware of being touched on the face, arms, and legs.

[0187] Item 9: Best Language Instruction Much information about comprehension can be obtained during the preceding sections of the examination. For this scale item, the patient is asked to describe what is happening in the attached picture, write the name of the item on the attached naming sheet, and read from the attached list of texts. 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 judged from the response here and to the responses to all commands in the preceding general neurological examination. If visual impairment interferes with the examination, the patient is asked to identify, repeat, and say aloud an object placed in their hand. Intubated patients should be asked to fill in. Patients in a comatose state (item 1a=3) are automatically scored 3 on this item. The examiner must select a score for patients who are stupor or have limited cooperation, but score 3 should only be used if the patient is silent and does not follow one-step commands. Item 9 is scored as follows: • 0 = No aphasia; normal. • 1 = Mild to moderate aphasia; there is some apparent loss of fluency or comprehension, but no significant limitation in the form of thoughts or expressions. However, due to reduced speech and / or comprehension, conversation about the provided material is difficult or impossible. For example, in a conversation about the provided material, the examiner may be able to identify the content of a picture or naming card from the patient's responses. • 2 = Severe aphasia; all communication is in fragmented form; significant listener reasoning, questioning, and inference are required. The range of information that can be exchanged is limited; the listener bears the burden of communication. The examiner cannot identify the material provided from the patient's responses. • 3 = Silent, global aphasia; no usable conversation or auditory comprehension.

[0188] Item 10: Dysarthria Instruction If the patient is considered normal, a suitable 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 clarity of spontaneous speech may be graded. Only if the patient is intubated or has other physical barriers to speaking should the examiner score the patient as Unable to Test (UN) and specify the reason for this selection. 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 pronounces at least some words unclearly, and at worst, is understandable with some difficulty. • 2 = Severe dysarthria; the patient's speech is either very unclear to the point of being unintelligible, without any dysphasia or in proportion to a dysphasia, or silent / anarthric. • UN = Intubated or other physical barrier. Explanation:

[0189] Item 11: Disappearance phenomenon and inattentive instructions (formerly ignored) Sufficient information to identify neglect may be obtained during the preliminary examination. The score is normal if the patient has severe visual loss that interferes with simultaneous visual dual stimulation and skin stimulation is normal. The score is normal if the patient has aphasia but appears to be bilaterally attentive. The presence of visual-spatial neglect or anosagnosia may also be considered evidence of abnormality. Since abnormality is only scored if it is present, the item is never untestable. Item 11 is scored as follows: • 0 = No abnormality. • 1 = Disappearance in response to bilateral simultaneous stimulation in one of the following sensory modalities: visual, tactile, auditory, spatial, or personal inattention. • 2 = Marked hemisacral inattention or loss of awareness of more than 1 modality; failure to recognize one's hands or facing only one side of space.

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

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

[0192] Definitions and Interpretations In describing and claiming the present invention, the following terminology is used.

[0193] The singular forms "a", "an", and "the" include plural referents 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 tends to produce a particular therapeutic effect when added to a composition.

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

[0196] The term "lesion" refers to an abnormality in the tissue of the brain. In some cases, a lesion can be a lesion that occupies a space with a recognizable volume and can invade nearby tissue and blood vessels.

[0197] As used herein, the term "placebo" is a formulation that is compositionally similar except that it does not contain a SUR1-TRPM4 antagonist or the amount (wt%) of the SUR1-TRPM4 channel inhibitor has been replaced by an equal amount (wt%) of other inert components (e.g., water). Further, a "placebo" may have minor 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, but most representatively refers to human patients.

[0199] The term "sulfonylurea" includes sulfonylureas, sulfonylurea mimetic compounds, and any other compositions effective in blocking or reducing the channel-associated activity of SUR1.

[0200] A stroke occurs when blood flow to the brain is insufficient, potentially leading to cell death. As defined herein, there are essentially two known types of stroke: ischemic stroke and hemorrhagic stroke. An ischemic stroke occurs when there is insufficient blood flow to the brain, while a hemorrhagic stroke occurs when there is bleeding in the cranial vault or within brain tissue, including subarachnoid hemorrhage and intracerebral hemorrhage. Both forms can result in cerebral edema.

[0201] The terms “treating” or “treatment,” as used herein and as is well understood in the art, mean an approach to obtain a beneficial or desired outcome (including clinical outcomes). Beneficial or desired clinical outcomes may include, but are not limited to, one or more alleviations or improvements of symptoms or conditions, whether detectable or undetectable; a reduction in the severity of the disease; stabilization of the disease state (i.e., no exacerbations); delay or slowing of disease progression; improvement or mitigation of the disease state; reduction of disease recurrences; and remission (whether partial or complete). “Treatment” and “treatment” may also mean prolonging survival compared to the expected survival without treatment. In addition to being useful as methods of treatment, the methods described herein may be useful for the prevention or prevention of disease.

[0202] As used herein, the term “about” is used to provide flexibility with respect to the endpoints of a numerical range by indicating that a given value may be “a little above” or “a little below” its endpoint. The degree of flexibility in this term may be determined by certain variables and is within the knowledge of those skilled in the art, based on experience and 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 a further embodiment, the degree of flexibility may be within about ±2%, ±1%, or ±0.05% of the numerical value.

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

[0204] Where used herein, multiple active agents, compounds, injuries, or conditions may be shown in common lists for convenience. However, these lists should be interpreted as if each member of the list were individually identified as a distinct and unique member. Therefore, individual members of such lists should not be interpreted as being substantially equivalent to any other member in the same list solely on the basis of their presentation within a common group, unless otherwise indicated.

[0205] Concentration, quantity, and other numerical data may be described or presented herein in range format. Since such range format is used only for convenience and simplicity, it should be understood that it should be interpreted flexibly to include not only the numerical values ​​explicitly stated as limits to the range, but also all individual numerical values ​​or subranges contained within that range as if each numerical value and subrange were explicitly stated. For example, the numerical range "approximately 0.01 to 2.0" should be interpreted to include not only the explicitly stated values ​​of approximately 0.01 to approximately 2.0, but also all individual numerical values ​​or subranges within that indicated range. Thus, this numerical range includes 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 characteristic described. Additionally, unless otherwise specified, all percentages are weight percent.

[0206] Where used herein, all percentage compositions are expressed as weight percentages unless otherwise specified. Where a solution of a component is mentioned, the percentage refers to the weight percentage of the composition including the solvent (e.g., water), unless otherwise specified.

[0207] For understanding the scope of this disclosure, the terms “comprising” and its derivatives are intended, as used herein, to be unrestricted terms that identify the existence of any described feature, element, component, group, integer, and / or process, but do not exclude the existence of any other undescribed feature, element, component, group, integer, and / or process. The foregoing also applies to similar terms such as “including,” “having,” and their derivatives. The terms “consisting” and its derivatives are intended, as used herein, to be closed terms that identify the existence of any described feature, element, component, group, integer, and / or process, but do not exclude the existence of any other undescribed feature, element, component, group, integer, and / or process. The term "consisting essentially of," as used herein, is intended to identify the existence of the described feature, element, component, group, integer, and / or process, and any that does not essentially affect the fundamental and novel characteristics of the feature, element, component, group, integer, and / or process. Reference to any one of these transitional terms (i.e., "contains," "consisting of," or "consisting essentially of") is understood to provide direct justification for a substitution of any of the other transitional terms not specifically used. For example, the correction of wording from "contains" to "consisting essentially of" finds direct justification due to this definition.

[0208] Where used herein, multiple compounds or processes may be shown in common lists for convenience. However, these lists should be interpreted as if each member of the list were individually identified as a distinct and unique member. Therefore, individual members of such lists should not be interpreted as being substantially equivalent to any other member in the same list solely on the basis of their presentation within a common group, unless otherwise indicated.

[0209] Furthermore, certain compositions, injuries or conditions, processes, etc., may be considered in the context of a particular embodiment. This is merely for convenience, and it is understood that such disclosures are equally applicable to other embodiments found herein. For example, a list of active agents or drugs described in relation to methods for treating late neurological deterioration or death will find direct support for embodiments relating to methods for reducing cerebral midline shift, even if those drugs are not reproduced herein in the context of their respective embodiments.

[0210] Embodiments of this disclosure are described with reference to the following examples. These examples are provided for illustrative purposes only and should not be used to limit the scope of the invention or to interpret the invention. [Examples]

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

[0212] Including patients who meet the following criteria: • Clinical diagnosis of acute ischemic stroke in the middle cerebral artery (MCA) region. Extensive cerebral hemisphere infarction was defined as: 80–300 cubic centimeters (cm) as measured by magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), or computed tomography perfusion (CTP). 3 Lesion volume of ) or an Alberta Stroke Program Early CT score (ASPECTS) of 1-5 with involvement of at least two defined cortical regions. • Screening score on the National Institutes of Health Stroke Scale (NIHSS) is >= 10. · At the time of randomization and, at the discretion of the principal investigator of the clinical trial, when the infusion of the investigational drug is known, it must be possible to initiate it within 10 hours after the onset of symptoms or the last time when it was known to be normal. · Participants who wake up with a stroke may be included if neurological criteria and other exclusion criteria are met. The time of onset of the stroke is considered to be the midpoint between the time of falling asleep (or the last time when it was known to be normal) and the time of waking up. · For participants undergoing thrombectomy, inclusion in the clinical trial must be based on MRI-DWI after thrombectomy.

[0213] The following criteria were used to exclude patients: · On the first day, it may be possible to discontinue supportive therapy for the participant. · Have promised decompressive craniectomy (DC) prior to enrollment. · Evidence of a concomitant infarction in the contralateral cerebral hemisphere that is severe enough to affect functional outcome.

[0214] Pre-specified primary endpoint · The modified Rankin Scale (mRS) score at 90 days was collapsed for 0 / 1 and 5 / 6 and analyzed as a shift analysis using a 5-category ordinal scale. The primary efficacy analysis was pre-specified to be performed in randomized participants aged 18 - 70 years (including both end values) who received the investigational treatment (modified intention to treat [mITT] population).

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

[0216] Analysis was performed with CTP or DWI volume > 80 cm 3To investigate the effect on lesion volume in subjects enrolled in the mITT population, the study was conducted (ASPECTS enrollment was excluded as it does not assess lesion volume). The interaction term between the treatment arm and stroke volume was included as the dependent variable in an ordinal logistic regression model along with the 90-day mRS. 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 volume as assessed by CTP or DWI. The baseline infarct volume was 154 ± 146 mL, which did not vary between treatment arms. The common odds ratio (cOR) decreased with increasing lesion volume, reaching approximately 140 cm². 3 In this case, crossing the "no effect" point (cOR=1.0) and exceeding that threshold indicates no drug effect. 140cm 3 Below this level, cOR increases as the lesion volume decreases, reaching 85 cm 3 The cOR for the group of patients with lesion volumes between ≤120 cm² was approximately 6. This suggests a very robust effect in patients with smaller lesion volumes. 3 A statistically significant interaction (p=0.031) exists between baseline stroke volume and ≤120 cm². 3 In the lower group (cOR 2.31, 95% CI 1.07-5.01, p=0.034), subjects treated with glibenclamide showed favorable outcomes.

[0218] Beneficial outcomes were remarkably and dramatically higher in subjects (n=81) who received glibrenclamide in combination with thrombectomy. In these patients, a procedure × stroke volume interaction existed (p=0.009), and glibenclamide-treated subjects had favorable outcomes (cOR 4.69, 95% CI 1.10-20.1, p=0.037). In these subjects, the cOR was approximately 180 cm², as shown in Figure 1. 3In this case, the threshold for "no effect" was crossed (cOR=1.0), indicating that there was no drug effect above that threshold. Therefore, the effect of combining glybride administration with mechanical thrombectomy increased the pool of subjects who benefited from the above method and resulted in dramatically higher functional benefits.

[0219] Therefore, the cOR obtained in mITT patients who underwent thrombectomy was several times higher than in the overall population, and the thrombectomy group showed a particularly good response. In embodiments 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, and the method comprises the step of administering a SUR1-TRPM4 channel inhibitor to the patient. (Item 2) The patient is between 18 and 70 years old at the start of treatment, according to the method described in item 1. (Item 3) The method according to item 1, wherein the patient has undergone mechanical thrombectomy prior to the administration step. (Item 4) The administration step described above is the method described in item 3, which begins before or during the mechanical thrombectomy. (Item 5) The procedure described above is the method described in item 1, and is initiated within nine hours of the midpoint between falling asleep (or the last time known to be normal) and waking up. (Item 6) The procedure described in item 1 is to begin within 10 hours of the midpoint between falling asleep (or the last time known to be normal) and waking up. (Item 7) The administration step described above is the method described in item 1, which begins within 8 hours of the onset of the first stroke symptoms. (Item 8) The method according to item 1, wherein the SUR1-TRPM4 inhibitor is administered in one or more consecutive infusions with a total duration of at least 72 hours. (Item 9) The patient undergoes decompressive craniectomy, the method according to item 1. (Item 10) The patient has a lesion volume of 180 cm 3 or less, the method according to item 1. (Item 11) The patient has a lesion volume of 180 cm 3 , 170 cm 3 , 160 cm 3 , 150 cm 3 , 140 cm 3 , 130 cm 3 , 125 cm 3 , 120 cm 3 , 110 cm 3 , 100 cm 3 , 90 cm 3 , or 80 cm 3 or less, the method according to item 1. (Item 12) The patient has a lesion volume of >50 cm 3 and <125 cm 3 or >50 cm 3 and <100 cm 3 of the lesion volume, the method according to item 1. (Item 13) The SUR1-TRPM4 channel inhibitor includes members selected from the group consisting of glyburide, 4-trans-hydroxy-glyburide, 3-cis-hydroxyglyburide, tolbutamide, chlorpropamide, trazamide, repaglinide, nateglinide, meglitinide, midaglizole, glibonide, LY397364, LY389382, glyclazide, glimepiride, and pharmaceutically acceptable salts thereof, metabolic products thereof that interact with SUR1, and combinations thereof, the method according to item 1. (Item 14) The SUR1-TRPM4 channel inhibitor is glyburide, the method according to item 1. (Item 15) A method for treating ischemic stroke in a patient who has experienced a stroke during sleep, the method comprising treating the patient with a therapeutically effective amount of a SUR1-TRPM4 inhibitor. (Item 16) The treatment begins before mechanical thrombectomy, the method according to item 15. (Item 17) The treatment begins during or after mechanical thrombectomy, the method according to item 15. (Item 18) The patient is 180 cm 3 , 170 cm 3 , 160 cm 3 , 150 cm 3 , 140 cm 3 , 130 cm 3 , 125 cm 3 , 120 cm 3 , 110 cm 3 , 100 cm 3 , 90 cm 3 , or 80 cm 3 The method according to item 15, having a lesion volume less than. (Item 19) The patient is selected to undergo mechanical thrombectomy using non-contrast computed tomography, the method according to item 1. (Item 20) The patient is treated with tissue plasminogen activator, the method according to item 1. (Item 21) The patient has an ASPECTS score ≤ 7, the method according to item 20. (Item 22) The patient is selected to undergo mechanical thrombectomy using computed tomography perfusion or magnetic resonance imaging, the method according to item 15. (Item 23) The lesion volume is measured by using computed tomography perfusion or magnetic resonance imaging, the method according to item 18. (Item 24) The method according to item 17, wherein the patient undergoes mechanical thrombectomy but receives non-contrast computed tomography before treatment with the SUR1-TRPM4 inhibitor begins. (Item 25) The lesion volume is determined before mechanical thrombectomy, according to the method described in item 17. (Item 26) The lesion volume is determined after mechanical thrombectomy, according to the method described in item 17. (Item 27) The patient described above has an NIH Stroke Scale (NIHSS) score of 10-20, as described in item 1. (Item 28) The patient described above has an NIH Stroke Scale (NIHSS) score of 10-18, as described in item 1. (Item 29) The method according to item 1, wherein the SUR1-TRPM4 channel inhibitor is a glybrid 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) The method according to item 29, wherein the glybride or a pharmaceutically acceptable salt thereof is present in an amount of about 2.7–3.1% (w / w) of the formulation, and / or the sugar alcohol is present in an amount of about 84–90% (w / w) of the formulation. (Item 1) A composition for use in a method to improve outcomes in patients diagnosed with ischemic stroke, comprising a SUR1-TRPM4 channel inhibitor, wherein the outcome is assessed by a modified Rankin scale (mRS) score, the patient has experienced a sleep-onset stroke, and the method comprises the step of administering the composition to the patient. a) The patient has undergone mechanical thrombectomy prior to the administration step, b) The administration step is characterized in that it begins before or during the mechanical thrombectomy, composition. (Item 2) The composition according to item 1, wherein the patient has undergone the mechanical thrombectomy procedure prior to the administration step. (Item 3) The composition according to item 1, characterized in that the administration step begins before or during the mechanical thrombectomy. (Item 4) a) The administration step is characterized in that it begins within 9 hours of the midpoint between the last time the person is known to be asleep or normal and the time they are awake. b) The administration step is characterized in that it begins within 10 hours of the midpoint between the last time the person is known to be asleep or normal and the time they wake up, or c) The administration step is characterized in that it begins within 8 hours of the first stroke symptoms. The composition described in item 1. (Item 5) The patient in question has not been administered tissue plasminogen activator (tPA), and the composition is as described in item 1. (Item 6) The composition according to item 1, characterized in that the SUR1-TRPM4 inhibitor is administered in one or more consecutive infusions with a total duration of at least 72 hours. (Item 7) The composition according to item 1, wherein the patient has undergone decompressive craniotomy. (Item 8) The aforementioned patient was 180cm 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 The composition according to item 1, having a lesion volume less than 1. (Item 9) The aforementioned patient, >50cm 3Also <125cm 3 or >50cm 3 Also <100cm 3 The composition described in item 1, having the lesion volume. (Item 10) The composition according to 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, trazamide, repaglinide, nateglinide, meglitinide, midaglisol, glikidone, LY397364, LY389382, gliclazide, glimepiride, pharmaceutically acceptable salts thereof, metabolites thereof that interact with SUR1, and combinations thereof. (Item 11) The composition according to item 1, wherein the SUR1-TRPM4 channel inhibitor is glibenclamide. (Item 12) A composition comprising a SUR1-TRPM4 inhibitor for treating ischemic stroke in patients who have experienced sleep-onset stroke, (a) The procedure is characterized in that it begins before mechanical thrombectomy, or (b) The procedure is characterized in that it begins during or after mechanical thrombectomy, composition. (Item 13) The composition according to item 12, characterized in that the procedure begins before the mechanical thrombectomy. (Item 14) The composition according to item 12, characterized in that the procedure begins during or after the mechanical thrombectomy. (Item 15) The aforementioned patient was 180cm tall. 3 , 170cm 3 , 160cm 3 , 150cm 3 , 140cm 3 , 130cm 3 , 125cm 3 , 120cm 3 , 110cm3 , 100cm 3 , 90cm 3 , or 80cm 3 The composition according to item 12, having a lesion volume less than 1. (Item 16) The composition according to item 1, wherein the patient is selected to undergo mechanical thrombectomy using non-contrast computed tomography. (Item 17) The composition according to item 1, wherein the patient is treated with a tissue plasminogen activator. (Item 18) The composition according to item 17, wherein the patient has an ASPECTS score of ≤7. (Item 19) The composition according to item 12, wherein the patient is selected to undergo mechanical thrombectomy using computed tomography perfusion or magnetic resonance imaging. (Item 20) The composition according to item 15, wherein the lesion volume is measured by computed tomography perfusion or magnetic resonance imaging. (Item 21) The composition according to item 14, wherein the patient has undergone mechanical thrombectomy but has received non-contrast computed tomography before treatment with the SUR1-TRPM4 inhibitor begins. (Item 22) a) The patient has an NIH Stroke Scale (NIHSS) score of 10-20, or b) The patient has an NIHSS score of 10-18, The composition described in item 1. (Item 23) The composition according to item 1, wherein the SUR1-TRPM4 channel inhibitor is a glybrid 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) The composition according to item 23, wherein the glybride or a pharmaceutically acceptable salt thereof is present in an amount of about 2.7–3.1% (w / w) of the formulation, and / or the sugar alcohol is present in an amount of about 84–90% (w / w) of the formulation. (Item 25) A composition for use in a method to improve outcomes in patients diagnosed with ischemic stroke, comprising a SUR1-TRPM4 channel inhibitor, wherein the outcome is assessed by an mRS score, the patient has experienced sleep-onset stroke or extensive cerebral hemisphere infarction, the method comprising the step of administering the composition to the patient, the patient being >50cm 3 Also <125cm 3 It has a lesion volume of, a) The patient has undergone mechanical thrombectomy prior to the administration step, b) The administration step is characterized in that it begins before or during mechanical thrombectomy, composition. (Item 26) The composition according to item 25, wherein the SUR1-TRPM4 channel inhibitor is glibenclamide. (Item 27) A composition comprising the SUR1-TRPM4 inhibitor for treating ischemic stroke in patients who have experienced sleep-onset stroke or extensive cerebral hemispheric infarction, wherein the patient is >50cm 3 Also <125cm 3 It has a lesion volume of, a) The procedure is characterized by beginning before mechanical thrombectomy, or b) The procedure is characterized in that it begins during or after mechanical thrombectomy, a composition. (Item 28) The composition according to item 27, wherein the SUR1-TRPM4 channel inhibitor is glibenclamide. (Item 29) The patient in question has not been administered tPA, and the composition is as described in item 12. (Item 30) The patient in question has not been administered tPA, and the composition is as described in item 25.

Claims

1. A composition for use in a method for improving the outcome of ischemic stroke in a patient diagnosed with ischemic stroke, comprising a SUR1-TRPM4 channel inhibitor, wherein the outcome is assessed by a modified Rankin Scale (mRS) score, the patient has experienced a sleep-onset stroke, the method comprising the step of administering the composition to the patient, wherein the SUR1-TRPM4 channel inhibitor is glybride or a pharmaceutically acceptable salt thereof. a) The patient has undergone mechanical thrombectomy prior to the administration step, b) The administration step is characterized in that it begins before or during the mechanical thrombectomy, composition.

2. The composition according to claim 1, wherein the patient has undergone the mechanical thrombectomy procedure prior to the administration step.

3. The composition according to claim 1, characterized in that the administration step begins before or during the mechanical thrombectomy.

4. a) The administration step is characterized in that it begins within 9 hours of the midpoint between the last time the patient is known to be asleep or normal and the time they are awake. b) The administration step is characterized in that it begins within 10 hours of the midpoint between the last time the patient is known to be asleep or normal and the time they are awake, or c) The composition according to claim 1, characterized in that the administration step begins within eight hours of the onset of the first stroke symptoms.

5. The composition according to claim 1, wherein the patient has not been administered tissue plasminogen activator (tPA).

6. The composition according to claim 1, characterized in that the SUR1-TRPM4 inhibitor is administered in one or more consecutive infusions with a total duration of at least 72 hours.

7. The composition according to claim 1, wherein the patient has undergone decompressive craniotomy.

8. The patient is 180 cm ３ , 170 cm ３ , 160 cm ３ , 150 cm ３ , 140 cm ３ , 130 cm ３ , 125 cm ３ , 120 cm ３ , 110 cm ３ , 100 cm ３ , 90 cm ３ , or less than 80 cm ３ The composition according to claim 1, having a lesion volume of less than 80 cm.

9. The aforementioned patient, >50cm ３ Also <125cm ３ or >50cm ３ Also <100cm ３ The composition according to claim 1, having the lesion volume.

10. A composition for treating ischemic stroke in a patient who has experienced a sleep-onset stroke, comprising a SUR1-TRPM4 inhibitor, wherein the SUR1-TRPM4 channel inhibitor is a glybride or a pharmaceutically acceptable salt thereof. (a) The procedure is characterized in that it begins before mechanical thrombectomy, or (b) The procedure is characterized in that it begins during or after mechanical thrombectomy, composition.

11. The composition according to claim 10, characterized in that the procedure begins before the mechanical thrombectomy.

12. The composition according to claim 10, characterized in that the procedure begins during or after the mechanical thrombectomy.

13. The aforementioned patient was 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 80 cm ３ The composition according to claim 10, having a lesion volume of less than 100%.

14. The composition according to claim 1, wherein the patient is selected to undergo mechanical thrombectomy using non-contrast computed tomography.

15. The composition according to claim 1, wherein the patient has been treated with a tissue plasminogen activator.

16. The composition according to claim 15, wherein the patient has an ASPECTS score of ≤7.

17. The composition according to claim 10, wherein the patient is selected to undergo mechanical thrombectomy using computed tomography perfusion or magnetic resonance imaging.

18. The composition according to claim 13, wherein the lesion volume is measured by computed tomography perfusion or magnetic resonance imaging.

19. The composition according to claim 12, wherein the patient has undergone mechanical thrombectomy but has received non-contrast computed tomography before treatment with the SUR1-TRPM4 inhibitor begins.

20. 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, The composition according to claim 1.

21. The composition according to claim 1, wherein the glybride or a pharmaceutically acceptable salt thereof is 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.

22. The composition according to claim 21, wherein the glybride or a pharmaceutically acceptable salt thereof is present in an amount of about 2.7 to 3.1% (w / w) of the formulation, and / or the sugar alcohol is present in an amount of about 84 to 90% (w / w) of the formulation.

23. A composition comprising a SUR1-TRPM4 channel inhibitor for use in a method for improving the outcome of ischemic stroke in a patient diagnosed with ischemic stroke, wherein the outcome is assessed by an mRS score, the patient has experienced a sleep-onset stroke, and the method comprises the step of administering the composition to the patient, the patient being >50 cm ３ Also <125cm ３ The lesion volume is such that the SUR1-TRPM4 channel inhibitor is glybride or a pharmaceutically acceptable salt thereof. a) The patient has undergone mechanical thrombectomy prior to the administration step, b) The administration step is characterized in that it begins before or during mechanical thrombectomy, composition.

24. A composition comprising a SUR1-TRPM4 inhibitor for treating ischemic stroke in a patient who has experienced sleep-onset stroke, wherein the SUR1-TRPM4 channel inhibitor is glybride or a pharmaceutically acceptable salt thereof, and the patient is >50 cm ３ Also <125cm ３ It has a lesion volume of, a) The procedure is characterized by starting before mechanical thrombectomy, or b) The procedure is characterized by beginning during or after mechanical thrombectomy, composition.

25. The composition according to claim 10, wherein the patient has not been administered tPA.

26. The composition according to claim 23, wherein the patient has not been administered tPA.

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