Method of treating ischemic stroke at risk of cerebral edema or cerebellar edema

Abstract

The present invention relates to a method of treating ischemic stroke at risk of cerebral edema or cerebellar edema. Specifically, the invention relates to treatment of ischemic stroke with brain swelling risk by using an SUR1-TRPM4 channel inhibitor in combination with mechanical thrombus removal. In some embodiments, the methods include treating a patient with a large area of hemispherical infarction. In certain embodiments, the patient's lesion volume is less than 140 cm < 3 > or less than 125 cm < 3 > as measured by MRI DWI or CTP. Patients may experience post-waking stroke. Some embodiments relate to treating patients also receiving reduced pressure therapy.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 637,163, filed on April 22, 2024, U.S. Provisional Application No. 63 / 642,492, filed on May 3, 2024, and U.S. Provisional Application No. 63 / 644,658, filed on May 9, 2024, the disclosures of which are incorporated herein by reference in their entireties. Background Art

[0003] After a large ischemic stroke, patients may develop space-occupying brain edema (swelling). For example, life-threatening brain swelling occurs in up to 8% of all hospitalized ischemic stroke patients and in up to 15% of all patients with middle cerebral artery stroke. This brain swelling (also called edema) usually develops within a few days after the stroke and typically peaks on the second or third day.

[0004] Brain swelling increases intracranial pressure and may block blood flow to the brain, thereby starving the brain of oxygen. Brain swelling can also block drainage pathways from the brain and prevent fluid from leaving the brain. In addition, as intracranial pressure within the skull increases, previously healthy brain tissue is damaged, and transtentorial or uncal herniation can occur. Swelling in and around the brain can also lead to morbidity and brain death, as well as secondary neurological disorders and the death of the subject.

[0005] Brain swelling may be related to two independent molecular and physiological processes, namely, cell swelling of neurons and astrocytes, and the influx of ions and fluids into the injury site across capillaries. Cell swelling of neurons and astrocytes is the result of changes in the ion gradient between the cell and the extracellular space. One ion channel involved in cell swelling is NC CA-ATP channel, also known as the SUR1-TRPM4 channel. This channel is a non-selective Ca 2+ ATP-sensitive cation channels activated when intracellular ATP is depleted in neuronal cells. CA-ATP The channel is thought to be composed of regulatory subunits, which include the sulfonylurea receptor 1 (SUR1) and a pore subunit related to the transient receptor potential cation channel subfamily M member 4 (TRPM4).

[0006] In treating a subject with a condition or disease that can present with brain edema, the physician is primarily concerned with minimizing the extent of brain swelling. However, treating brain edema is particularly difficult due to the length of time the swelling persists, the overall functioning of the brain, and the location of the brain within the skull, among other reasons. Wake-up stroke is an ischemic stroke in which neurological symptoms first appear upon waking. Thus, the last known well time for the patient corresponds to the time of sleep onset the night before the onset of the stroke. Due to the uncertainty of when the stroke occurred, these patients are often not eligible for certain interventions, such as tPA and other thrombolytic agents, which have a narrow window of time in which they can be used without causing undue harm. Thus, there is a pressing need for a treatment that can be applied to the wake-up stroke population. Furthermore, mechanical thrombectomy is underutilized in patients with large vessel occlusion, in part due to concerns that rapid reperfusion over such a large area will lead to hemorrhage or other adverse effects. Thus, providing a treatment that reduces the extent of brain edema would be a step forward in the art. SUMMARY

[0007] Embodiments of the invention include methods of using a SUR1-TRPM4 channel inhibitor in combination with mechanical thrombectomy to improve outcomes in patients with ischemic stroke. The patient can have a lesion volume of less than 140 cm 3 or less than 125 cm 3 and greater than 50 cm. The lesion volume can be measured by diffusion weighted imaging (DWI) or computed tomography perfusion (CTP) imaging. Embodiments of the invention include administering to the subject a therapeutically effective amount of a SUR1-TRPM4 channel inhibitor. The SUR1-TRPM4 inhibitor can be administered by at least one continuous infusion for a cumulative treatment time of at least 72 hours. The SUR1-TRPM4 channel inhibitor can be glibenclamide. The treatment can be initiated within 10 hours or onset of the first stroke symptoms.

[0008] In some embodiments, the minimum lesion volume can be 85 cm 3 and in other cases, the maximum lesion volume can be 180 cm 3 . In some embodiments, the maximum lesion volume can be 125 cm 3 . The patient can be between 18 and 70 years of age at the start of treatment. The patient can have undergone thrombectomy prior to treatment, or the treatment can be initiated prior to thrombectomy, or it can be initiated at the time the patient undergoes thrombectomy. The patient can undergo decompressive craniectomy prior to, during, or after treatment. In other embodiments, the patient experiences a wake-up stroke. In aspects involving a wake-up stroke, the treatment is initiated within 10 hours of the midpoint between the time of sleep onset (or last known normal time) and the time of waking.

[0009] Other embodiments can involve administering one or more continuous infusions for at least 72 hours, 96 hours, at least 120 hours, or 168 hours. A bolus can be administered prior to any first continuous infusion. Certain embodiments can involve two or more continuous infusion doses, where the first continuous infusion dose is higher than the second continuous infusion dose. Some embodiments contemplate administering a bolus dose and two or more continuous infusion doses, where the first continuous infusion dose is higher than the second continuous infusion dose.

[0010] Exemplary SUR1-TRPM4 channel inhibitors include glibenclamide (also known as glyburide), 4-trans-hydroxy-glibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, gliquidone, LY397364, LY389382, gliclazide, glimepiride, metabolites thereof that interact with SUR1, and combinations thereof.

[0011] In one aspect, the disclosure includes a method of administering a formulation comprising: glibenclamide or a pharmaceutically acceptable salt thereof; a buffer; a base; and a sugar alcohol, wherein the formulation has a pH outside the buffering capacity of the buffer. In some aspects, the formulation does not contain a cyclodextrin. In one aspect, wherein the formulation has a pH outside the buffering capacity of the buffer, and wherein the pKa of the buffer is 7.7 to 9.2.

[0012] In one aspect, the disclosure includes a method of administering an infusion solution comprising 500 ml of a saline solution, 3 mg to 5 mg of glibenclamide, 100 mg to 140 mg of mannitol, 10 mg to 12 mg of Tris, and a pH of 7.8 to 9.

[0013] In one aspect, the disclosure includes a method of administering a solution comprising 10 ml to 30 ml of WFI, 3 mg to 5 mg of glibenclamide, 100 mg to 140 mg of mannitol, 10 mg to 12 mg of Tris, and a pH of 9 to 11, for example, 9.4 to 10.

[0014] In one aspect, the present disclosure includes methods of making and administering a glibenclamide formulation having less than 1% loss of glibenclamide concentration (w / v) due to adsorption to a polymeric container over the course of an infusion period, the method comprising combining glibenclamide with a buffer 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 base to glibenclamide of between 5.0 to 6.7: 1.

[0015] In some aspects, the present disclosure includes reconstituting the formulation of the present invention in a suitable diluent, e.g., saline or water for injection (WFI), such that the reconstituted formulation has a buffer concentration of 4 mM to 60 mM, 5 mM to 50 mM, 6 mM to 40 mM, 7 mM to 30 mM, 8 mM to 25 mM, 9 mM to 23 mM, 10 mM to 21 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, or 20 mM.

[0016] In some aspects, the present disclosure includes diluting the formulation of the present invention in a saline solution, wherein the pH of the formulation is 7.8 to 9.

[0017] In some aspects, the present disclosure includes diluting the formulation in a saline solution, wherein the formulation has a pH that does not vary by more than 0.2 pH units during an infusion period of at least 24 hours.

[0018] In some aspects, the present disclosure includes formulations and methods having high storage stability, e.g., storage stability properties such that the degradation product is less than 0.2% after 6 months storage at 25°C / 60% RH, less than 0.4% after 6 months storage at 40°C / 75% RH; and / or less than 1.0% after 7 days storage at 70°C / 75% RH.

[0019] In some aspects, the present disclosure includes methods of increasing the solubility of a glibenclamide formulation in a saline infusion solution, comprising combining glibenclamide or a pharmaceutically acceptable salt thereof with: a buffer; a base; and a sugar alcohol, wherein the formulation has a pH outside the buffering capacity of the buffer at 4°C, 20°C, or 25°C to form a solubilized glibenclamide formulation having a solubility of glibenclamide in the saline infusion solution of 15 pg / ml, wherein the pH of the glibenclamide formulation in the saline infusion solution is 7.8 to 9.

[0020] In some aspects, the present disclosure includes a method of minimizing the volume of saline infusion solution required to infuse a glibenclamide formulation into a human over a 24-hour period, comprising combining 3 mg to 5 mg of glibenclamide, or a pharmaceutically acceptable salt thereof, with a buffer; a base; and a sugar alcohol, wherein the formulation has a pH outside the buffering capacity of the buffer, wherein the pH of the glibenclamide formulation in the saline infusion solution is 7.8 to 9, and wherein the volume of saline infusion solution for infusing 3 mg to 5 mg of glibenclamide, or a pharmaceutically acceptable salt thereof, into the human is about 500 ml.

[0021] In some aspects, the present disclosure includes a method of increasing the storage stability of a glibenclamide formulation, comprising combining glibenclamide or a pharmaceutically acceptable salt thereof with a buffer; a base; and a sugar alcohol, wherein the formulation has a pH outside the buffering capacity of the buffer, to form a stable glibenclamide formulation, wherein the stable glibenclamide formulation has less than 0.2% degradation products after storage at 25°C / 60% RH for at least 6 months and after storage at 25°C / 60% RH for 6 months.

[0022] The disclosure of US2022 / 0280537 is incorporated herein by reference in its entirety for all purposes. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The clinical efficacy of combined administration of glibenclamide and mechanical thrombectomy in human subjects is shown. DETAILED DESCRIPTION

[0024] The present invention is based on several surprising observations. One of these observations is that when patients diagnosed with ischemic stroke involving large vessel occlusion are treated with a SUR1-TRPM4 inhibitor, the drug's effect is diminished as a function of lesion volume, with a lesion volume of approximately 140 cm 3The effect is zeroed at death. To observe this effect, if a patient is alive but bedridden, incontinent, and completely dependent on care, this is considered an adverse outcome, and the data must be analyzed this way. This concept stems from the development of a class of drugs called lazaroids, which, while saving lives, left patients in a very weakened state, considered a "worse fate than death." Thus, in the modified Rankin Scale (primary functional assessment in stroke studies), a score of 5 (severe disability) is considered an adverse outcome as is death. In this way, any effect that is "merely" to save lives is ignored, ensuring that any drug effect is one that provides a real benefit to the patient. Analysis that includes both decreased mortality (mRS 6) and increased rate of severe disability (mRS 5) distorts reality and is not accepted by the FDA or other regulatory agencies, as it implies that saving a life provides only meaningless quality of life, placing a huge emotional and financial burden on the patient's family.

[0025] Another observation is that SUR1-TRPM4 inhibitors can improve outcomes in patients with large vessel occlusion who receive mechanical thrombectomy to remove the thrombus. Until recently, such patients were excluded from mechanical thrombectomy because of concerns that such a large area of rapid reperfusion would lead to hemorrhage or other adverse reactions. As thrombectomy has begun to be successfully applied to these patients, it is still completely unknown whether these patients are still at risk for edema, and thus, it is unknown whether they would benefit or be harmed by additional treatment with SUR1-TRPM4 inhibitors. Surprisingly, the combination of mechanical thrombectomy and SUR1-TRPM4 inhibitors provides a very good effect.

[0026] Before the present specific embodiments of the application are disclosed and described, it is to be understood that the application is not limited to the particular process and materials disclosed herein as such process and materials can vary somewhat. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only and is not intended to be limiting as the scope of the present application will be limited only by the appended claims and equivalents thereof.

[0027] In one embodiment, a method of improving outcomes in a subject following an ischemic stroke is presented. The stroke can be a large vessel stroke involving occlusion of a large vessel of the brain or cerebellum. Such patients can be at risk of developing brain edema or cerebellar edema. In the case of a brain stroke, infarction of one or more (typically proximal) segments of the internal carotid artery (ICA) and / or middle cerebral artery (MCA) can be involved. In the case of a cerebellar stroke, infarction of the posterior inferior cerebellar artery (PICA) or superior cerebellar artery (SCA) can be involved. The stroke can be a large hemispheric infarction (LHI) or a large cerebellar infarction (LCI). The stroke severity can be at least moderate according to the NIH Stroke Scale (NIHSS).

[0028] Large vessel strokes considered for treatment are associated with large ischemic lesions, which for LHI and LCI can occupy at least one third of the MCA or cerebellar territory. The definition of LHI varies, i.e. the minimum lesion volume is more than 50 cm 3 or 60 cm 3 , but a more typical definition is a minimum lesion volume of 70 cm 3 to 80 cm 3 .

[0029] Magnetic resonance imaging diffusion weighted imaging (“MRIDWI” or “DWI” alone or “MRI”) is considered the “gold standard” for assessing lesion size. A threshold lesion size of 82 cm 3 measured by MRIDWI has 98% specificity for predicting late neurological deterioration associated with brain edema in LHI. This threshold is in very close agreement with other groups’ arbitrarily determined thresholds of 70 cm 3 to 80 cm 3 . Computed tomography perfusion (CTP) can likewise be used to accurately identify lesion volume.

[0030] Surprisingly, the therapeutic effect of the SUR1-TRPM4 agent glibenclamide (also known as glibenclamide) using the modified Rankin Scale (mRS) measure decreases to “ineffective” levels at about 140 cm 3 , and significant therapeutic effect can be observed at about 125 cm 3 . The therapeutic effect in the LHI population increases as the lesion volume decreases. In this case, patients with mRS scores of 5 and 6 were combined for analysis, which means that severe disability was not considered a good outcome and therefore did not provide statistical power in validating drug effectiveness. Thus, the minimum lesion volume for an LHI patient that can ideally be treated is 50 cm 3 to 60 cm 3 , but the lesion volume can also be at least 70 cm 3It was also surprisingly found that the combination of the SUR1-TRPM4 agent, glibenclamide, with mechanical thrombectomy treatment can extend the level of beneficial effect to 180 cm 3 Thus, in some aspects, LHI patients with lesion volumes up to 180 cm 3 are treated according to the methods of the present application to obtain a beneficial effect.

[0031] Stroke patients will typically receive a non-contrast computed tomography (NCCT) assessment and can obtain an Alberta Stroke Program Early CT (ASPECTS) score. This score is a 10-point quantitative topographic CT scan score used to systematically examine a brain CT scan for early signs of ischemia; normal regions score 1 and regions showing signs of ischemia score 0. The lower the score, the more severe the ischemic changes (i.e., the more severe the stroke is considered to be). ASPECTS is determined by evaluating two standardized regions of the MCA territory; the basal ganglia level and the supraganglionic level. CT examination showing MCA involvement of more than 1 / 3 indicates early ischemia of more than 2 different lobes of the cerebral hemisphere, basal ganglia, and insular cortex, and the presence of a large lesion (>70 cm

[0032] According to the methods of the present disclosure, patients selected for treatment with a SUR1-TRPM4 inhibitor are also selected for thrombectomy. Patients are typically "selected for thrombectomy" using one or more imaging modalities. Non-contrast CT is almost always used because it can identify hemorrhage and can be used to generate an ASPECTS score. Patients with hemorrhage or an ASPECTS score of <2 are typically not selected for thrombectomy. In addition, some form of angiography, either CT angiography or MR angiography, is typically employed to confirm that the patient has an occlusion that can be removed by thrombectomy. Patients who are recanalized, either spontaneously or using a thrombolytic agent like tPA, are not selected for thrombectomy. Patients with prior large vessel (e.g., ICA or one of the proximal MCA branches) occlusion, and / or the presence of a large lesion (>70 cm 3or ASPECTS < 5) were not candidates for thrombectomy, but now more and more of these patients are selected for thrombectomy, although other factors (e.g. time of stroke onset and other risk factors) become more important. For such patients, it is more important to select for thrombectomy as soon as possible after stroke onset. Patients can also receive a CT perfusion or MRI as part of the selection process and quantitative lesion volume measurements can be obtained as a result. The specific method used by the physician to select a patient for thrombectomy will depend on medical judgment based on the specific presentation of the patient, including all risk factors and whether the patient is likely to benefit from thrombectomy. This is routine practice and well within the skill of the ordinary skilled person in the field of stroke treatment. According to the present application, any patient selected for thrombectomy must actually receive thrombectomy. In other words, this aspect of the present application contemplates that the patient receives both thrombectomy and SUR1-TRPM4 inhibitor treatment, but the two interventions can be performed sequentially or simultaneously.

[0033] For patients selected to receive thrombectomy, SUR1-TRPM4 inhibitor treatment can be initiated before, during or after thrombectomy. If treatment is initiated after thrombectomy, the patient can need to undergo a non-contrast CT to confirm no hemorrhage before treatment is initiated. The patient can also receive a CT perfusion or MRI after thrombectomy to determine lesion volume before treatment.

[0034] The maximum ischemic lesion volume for patients selected for thrombectomy treatment is typically 180 cm3 3 and the maximum lesion volume at the start of treatment with a SUR1-TRPM4 inhibitor can be 170 cm3 3 , 160 cm3 3 , 150 cm3 3 , 140 cm3 3 , 130 cm3 3 , 125 cm3 3 or 120 cm3 3 . It is preferred that CTP or MRI is used to determine the lesion volume. The lesion volume can be determined before or after thrombectomy. If before thrombectomy, the physician should reasonably expect that the lesion will not exceed the maximum lesion volume during the thrombectomy procedure. Therefore, the maximum lesion volume determined before thrombectomy should typically be less than the maximum to allow for expansion of the lesion during thrombectomy. Thus, the maximum lesion volume determined before thrombectomy can be 10%, 20%, 30% or even 40% less than the maximum lesion volume determined after thrombectomy, depending on the speed at which the procedure is performed.

[0035] Particular consideration is given to treating patients who experience a "wake-up" stroke. A wake-up stroke is one in which the patient has no stroke symptoms while sleeping, but develops symptoms upon waking. It is believed that the stroke most likely occurred while the patient was waking, and thus any time limitation for treatment can be calculated from the time of waking or some earlier point in time between the time of falling asleep and the time of waking.

[0036] The method includes one or more continuous infusions of a SUR1-TRPM4 channel inhibitor to a patient undergoing mechanical thrombectomy. The infusions can be continued for a cumulative period of at least about 72 hours after the start of the continuous infusions. It has been found that administration of a SUR1-TRPM4 channel inhibitor can reduce the incidence of late neurological deterioration or death, thereby improving treatment outcomes (as measured by conventional scales for stroke).

[0037] A patient suffering from ischemic stroke can be considered for treatment when they exhibit at least one of the following: a National Institutes of Health Stroke Scale (NIHSS) score of at least 10; an Alberta Stroke Program Early CT Score (ASPECTS) of 7 or less; an ASPECTS of 4 or less; an MRIDWI lesion volume of greater than 70 cm 3 ; an MRIDWI lesion volume of greater than 82 cm 3 ; a CT perfusion core of greater than 50 cm 3 ; a CT perfusion core of greater than 70 cm 3 ; poor 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 territory; and / or a CT scan showing low density covering at least 50% of the middle cerebral artery territory. In some embodiments, the subject is first assessed for a NIHSS of 10 or greater, and then assessed by one of the other methods listed above. In some embodiments, the subject is first assessed for a NIHSS of 10 to 20, and then assessed by one of the other methods listed above.

[0038] In some embodiments, the subject is treated when the ASPECTS score is <5, <4, <3, or <2. In some embodiments, the subject is treated when the MRIDWI lesion volume is greater than 82 cm 3 .

[0039] In particular, patients with large hemispheric infarction, who are at particular risk of brain swelling, can be treated in accordance with the present application. These subjects typically have a middle cerebral artery territory stroke and can be further identified by radiological methods using MRIDWI or CT perfusion as having a lesion volume of at least about 70 cm 3 , at least about 80 cm 3or an ASPECTS score of <5, <4, <3, or <2. In the methods of treating LHI subjects contemplated herein, the subject is preferably < about 75 years of age, most preferably < about 70 years of age. It is also preferred that the subject has a NIHSS of >10, and that the drug is administered <10 hours from the first stroke or last known well time, but most preferably <9 hours. In some embodiments, the subject has a NIHSS of 10 to 20. These methods will improve one or more clinically relevant endpoints on the modified Rankin Scale (as a complete ordinal scale and / or dichotomized) but combine mRS 5 and mRS 6 to avoid the problem with Lazabemide described above. These improvements will be manifested at one or more time points post stroke, including about 90 days, about 180 days / 6 months, and about 12 months.

[0040] In connection with the methods of treating large area strokes, methods of testing drugs for treating large area strokes are also contemplated. According to these methods, patients 18 years of age and older are selected and enrolled by radiological methods as described above. The subjects have a NIHSS of preferably >10, for example 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or any fraction therebetween, for example >10 and <16, <17 <18, <19, <20, and are treated with a SUR1-TRPM4 channel inhibitor or a matching placebo, with treatment beginning < about 10 hours from the stroke (last known well time), more preferably <9 hours, with treatment lasting up to about 72 hours. These methods will result in an improvement in one or more clinically relevant endpoints for the drug relative to the placebo group, including: survival / mortality, modified Rankin Scale (as a complete ordinal scale and / or dichotomized), combined mRS 5 and mRS 6. These assessments are made at one or more time points, including about 90 days, about 180 days / 6 months, and about 12 months post stroke.

[0041] In assessing the results, it is preferred to analyze the mRS using analyses that preserve the ordinal scale, for example Mann Whitney test (and similar tests), ordinal logistic regression under the proportional odds assumption, sliding dichotomization. Success is defined as a two-sided p-value <0.05 or a 90% confidence interval that does not exceed an odds ratio of 1. The odds ratio thus calculated should preferably be >1, typically >1.1, more preferably >1.2, most preferably >1.3, in favor of the drug.

[0042] SUR1-TRPM4 channel inhibitors

[0043] SUR1-TRPM4 channel inhibitors can include any active agent that effectively inhibits SUR1-TRPM4, some examples of which can include glibenclamide (also known as glibenclamide), 4-trans-hydroxyglyburide, 3-cis-hydroxyglyburide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, miglitazole, gliquidone, LY397364, LY389382, gliclazide, glimepiride, metabolites thereof that interact with SUR1, pharmaceutically acceptable salts thereof, and 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, rimonabant, and SKF 9635. In one embodiment, the SUR1-TRPM4 channel inhibitor is glibenclamide 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.

[0044] Dosage and administration

[0045] SUR1-TRPM4 channel inhibitors can be administered as a bolus, continuous infusion, or a combination thereof. In some cases, administration may include multiple boluses or multiple continuous infusions. In other embodiments, administration may include one or more continuous infusions after a bolus. For example, a bolus can be performed, followed by a first continuous infusion, followed by a second continuous infusion at a lower infusion rate than the first infusion. In another embodiment, the bolus is followed by a continuous infusion. In another embodiment, the first continuous infusion is followed by a bolus, followed by a second continuous infusion. In yet another embodiment, the first continuous infusion is followed by a second continuous infusion and a third continuous infusion.

[0046] The administration presented herein can be carried out over an extended period of time. The administration can be carried out for > 12 hours, > 24 hours, > 48 hours, > 72 hours, > 76 hours, > 80 hours, > 84 hours, > 88 hours, > 92 hours, > 96 hours, > 100 hours, > 104 hours, > 108 hours, > 112 hours, > 116 hours, > 120 hours, > 124 hours, > 128 hours, > 132 hours, > 136 hours, > 140 hours, > 144 hours, > 148 hours, > 152 hours, > 156 hours, > 160 hours, > 164 hours, > 168 hours, or > 172 hours. In one embodiment, the administration comprises one or more continuous infusions for a cumulative time of at least 72 hours. In another embodiment, the administration comprises one or more continuous infusions for at least 96 hours. In yet another embodiment, the administration comprises one or more continuous infusions for at least 120 hours. In other embodiments, the administration of one or more continuous infusions can be carried out for < 72 hours, < 48 hours, or < 24 hours.

[0047] The specific dose will vary based on the underlying condition, the extent of swelling, the weight of the subject, and / or the SUR1-TRMP4 channel inhibitor being administered. The bolus of administration is expected to be about 100 pg to about 200 pg. In one embodiment, the bolus is about 110 pg to about 140 pg, or about 125 pg. In another embodiment, the bolus is about 140 pg to about 160 pg, or about 150 pg. In yet another embodiment, the bolus is about 160 pg to about 190 pg, or about 175 pg. The infusion rate of the continuous infusion of administration is expected to be about 100 pg / hour to about 300 pg / hour. In one embodiment, the infusion rate is about 110 pg / hour to about 140 pg / hour, or about 125 pg / hour. In another embodiment, the infusion rate is about 140 pg / hour to about 160 pg / hour, or about 150 pg / hour. In yet another embodiment, the infusion rate is about 160 pg / hour to about 190 pg / hour, or about 175 pg / hour. In a further embodiment, the infusion rate is about 190 pg / hour to about 225 pg / hour, or about 200 pg / hour. Additional embodiments include infusion rates of about 225 pg / hour to about 300 pg / hour, or about 250 pg / hour.

[0048] In some aspects, the present application includes any of the following exemplary items:

[0049] 1. A method of improving outcomes in a patient diagnosed with ischemic stroke, wherein the patient has experienced a wake-up stroke, comprising administering to the patient a SUR1-TRPM4 channel inhibitor.

[0050] 2. The method of item 1, wherein the patient is 18 years to 70 years of age at the time of treatment initiation.

[0051] 3. The method of item 1 or item 2, wherein the patient has undergone mechanical thrombectomy prior to the administration step.

[0052] 4. The method of item 3, wherein the administration is initiated prior to or during the mechanical thrombectomy.

[0053] 5. The method of any one of items 1 to 4, wherein the treatment is initiated within 9 hours of the midpoint between the time of sleep onset (or last known normal time) and wake time.

[0054] 6. The method of item 1, wherein the treatment is initiated within 10 hours of the midpoint between the time of sleep onset (or last known normal time) and wake time.

[0055] 7. The method of any one of items 1 to 6, wherein the administration is initiated within 8 hours of the first stroke symptom.

[0056] 8. The method of any one of items 1 to 7, wherein the SURl-TRPM4 inhibitor is administered as one or more continuous infusions for a total duration of at least 72 hours.

[0057] 9. The method of any one of items 1 to 8, wherein the patient undergoes decompressive hemicraniectomy.

[0058] 10. The method of any one of items 1 to 9, wherein the patient has a lesion volume of 180 cm 3 .

[0059] 11. The method of any one of items 1 to 9, wherein the patient has a lesion volume of less than 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 .

[0060] 12. The method of any one of items 1 to 9, wherein the patient has a lesion volume of > 50 cm 3and < 125 cm 3 or > 50 cm 3 and < 100 cm 3 .

[0061] 13. The method of any one of items 1 to 12, wherein the SURl-TRPM4 channel inhibitor comprises a member selected from the group consisting of: glibenclamide, 4-trans hydroxyglibenclamide, 3-cis hydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, mitiglinide, glipizide, LY397364, LY389382, gliclazide, glimepiride, pharmaceutically acceptable salts thereof, metabolites thereof that interact with SURl, and combinations thereof.

[0062] 14. The method of any one of items 1 to 13, wherein the SURl-TRPM4 channel inhibitor is glibenclamide.

[0063] 15. A method of treating ischemic stroke in a patient who has experienced post- wake stroke, comprising treating the patient with a therapeutically effective amount of a SURl-TRPM4 inhibitor.

[0064] 16. The method of item 15, wherein the treatment is initiated prior to mechanical thrombectomy.

[0065] 17. The method of item 15, wherein the treatment is initiated during or after mechanical thrombectomy.

[0066] 18. The method of any one of items 15 to 17, wherein the patient has a lesion volume of less than 180 cm3 3 , 170 cm3 3 , 160 cm3 3 , 150 cm3 3 , 140 cm3 3 , 130 cm3 3 , 125 cm3 3 , 120 cm3 3 , 110 cm3 3 , 100 cm3 3 , 90 cm3 3 , or 80 cm3 3 .

[0067] 19. The method of any one of items 1 to 18, wherein the patient is selected for mechanical thrombectomy using non-contrast computed tomography.

[0068] 20. The method of any one of items 1 to 18, wherein the patient is treated with tissue plasminogen activator.

[0069] 21. The method of item 20, wherein the patient has an ASPECTS score of < 7.

[0070] 22. The method of any one of items 15 to 21, wherein the patient is selected for mechanical thrombectomy using computed tomography perfusion imaging or magnetic resonance imaging.

[0071] 23. The method of any one of items 18 to 22, wherein the lesion volume is measured by using computed tomography perfusion or magnetic resonance imaging.

[0072] 24. The method of any one of items 17 to 23, wherein the patient receives a non-contrast computed tomography after mechanical thrombectomy but before starting treatment with a SURl-TRPM4 inhibitor.

[0073] 25. The method of any one of items 17 to 23, wherein the lesion volume is determined prior to mechanical thrombectomy.

[0074] 26. The method of any one of items 17 to 23, wherein the lesion volume is determined after mechanical thrombectomy.

[0075] 27. The method of any one of items 1 to 26, wherein the patient has a National Institutes of Health Stroke Scale (NIHSS) score of 10 to 20.

[0076] 28. The method of any one of items 1 to 26, wherein the patient has a National Institutes of Health Stroke Scale (NIHSS) score of 10 to 18.

[0077] 29. The method of any one of items 1 to 26, wherein the SURl-TRPM4 channel inhibitor is glibenclamide or a pharmaceutically acceptable salt thereof in a formulation comprising a buffer, a base, and a sugar alcohol, wherein the formulation has a pH value outside the buffering capacity of the buffer,

[0078] wherein the pKa of the buffer is 7.7 to 9.2.

[0079] 30. The method of any preceding item, wherein the pharmaceutically acceptable salt thereof is a sodium addition salt.

[0080] 31. The method of any preceding item, wherein the glibenclamide or the pharmaceutically acceptable salt thereof is about 2.7% (w / w) to 3.1% (w / w) of the formulation.

[0081] 32. The method of any preceding item, wherein the sugar alcohol is about 84% w / w to 90% w / w of the formulation.

[0082] 33. The method of any one of the preceding items, comprising a sugar alcohol and glibenclamide or a pharmaceutically acceptable salt thereof in a weight ratio of 28 to 35: 1.

[0083] 34. The method of any one of the preceding items, wherein the formulation has a pH within about 0.2 pH units of the pH prior to storage of the formulation after 12 months storage at 25 °C / 60% relative humidity (RH), or wherein the formulation has a pH within about 0.2 pH units of the pH prior to storage of the formulation after 6 months storage at 40 °C / 75% RH, or wherein the formulation has a pH within about 0.2 pH units of the pH prior to storage of the formulation after 4 weeks storage at 70 °C / 75% RH.

[0084] 35. The method of any one of the preceding items, wherein the buffering agent is a buffer having a pH of 7.8 to 9.

[0085] 36. The method of any one of the preceding items, wherein the formulation comprises a ratio of base and glibenclamide or a pharmaceutically acceptable salt thereof such that the formulation has a pH of 10.1 to 10.9 when reconstituted in water for injection (WFI).

[0086] 37. The method of any one of the preceding items, wherein the formulation comprises a sugar alcohol and glibenclamide or a pharmaceutically acceptable salt thereof in a weight ratio of 27 to 40: 1.

[0087] 38. The method of any one of the preceding items, wherein the formulation comprises a sugar alcohol and a buffering agent in a weight ratio of 8 to 12: 1.

[0088] 39. The method of any one of the preceding items, wherein the formulation comprises 26 mg / ml to 34 mg / ml of a sugar alcohol.

[0089] 40. The method of any one of the preceding items, wherein the molar ratio of base and glibenclamide or a pharmaceutically acceptable salt thereof in the formulation is 5.4 to 6.3: 1.

[0090] 41. The method of any one of the preceding items, wherein the formulation comprises about 8 to 12% (w / w) of a buffering agent.

[0091] 42. The method of any one of the preceding items, wherein the formulation is free of a cyclodextrin.

[0092] 43. The method of any one of items 1 to 29, wherein the formulation comprises:

[0093] a) glibenclamide or a pharmaceutically acceptable salt thereof;

[0094] b) a buffering agent;

[0095] c) a base; and

[0096] d) a sugar alcohol,

[0097] wherein the formulation has a pH outside of the buffering capacity of the buffering agent, and

[0098] wherein the formulation does not contain a cyclodextrin.

[0099] 44. The method of item 43, wherein the glibenclamide or pharmaceutically acceptable salt thereof is about 2.7% (w / w) to 3.1% (w / w) of the formulation, and / or wherein the sugar alcohol is about 84% (w / w) to 90% (w / w) of the formulation.

[0100] 45. The method of item 43, comprising a sugar alcohol and glibenclamide or pharmaceutically acceptable salt thereof in a weight ratio of 28 to 35: 1.

[0101] 46. The method of item 43, wherein the formulation has a pH within about 0.2 pH units of the pH of the formulation prior to storage after storage at 25 °C / 60% relative humidity (RH) for 12 months, or wherein the formulation has a pH within about 0.2 pH units of the pH of the formulation prior to storage after storage at 40 °C / 75% RH for 6 months, or wherein the formulation has a pH within about 0.2 pH units of the pH of the formulation prior to storage after storage at 70 °C / 75% RH for 4 weeks.

[0102] 47. The method of item 43, wherein the buffering agent is a buffer having a pH of 7.8 to 9.

[0103] 48. The method of item 43, comprising a base and glibenclamide or pharmaceutically acceptable salt thereof in a ratio such that the formulation has a pH of 10.1 to 10.9 when reconstituted in water for injection (WFI).

[0104] 49. The method of item 43, wherein the formulation comprises a sugar alcohol and glibenclamide or pharmaceutically acceptable salt thereof in a weight ratio of 27 to 40: 1.

[0105] 50. The method of item 43, wherein the formulation comprises a sugar alcohol and a buffering agent in a weight ratio of 8 to 12: 1.

[0106] 51. The method of item 43, wherein the formulation comprises 26 mg / ml to 34 mg / ml of a sugar alcohol.

[0107] 52. The method of item 43, wherein the molar ratio of base to glibenclamide or pharmaceutically acceptable salt thereof in the formulation is 5.4 to 6.3: 1.

[0108] 53. The method of claim 43, wherein the formulation comprises about 8% to 12% (w / w) buffer, and wherein the buffer has a pKa of 7.7 to 9.2.

[0109] preparation

[0110] The methods and formulations provided herein provide pharmaceutically acceptable glibenclamide formulations, including concentrated solutions, diluted solutions, and lyophilized formulations, thereby solving the adsorption, degradation, instability, and low solubility problems associated with prior art pharmaceutical formulations of glibenclamide.

[0111] Examples of suitable pharmaceutically acceptable diluents such as WFI (water for injection) and solutions containing isotonic saline are known in the art. Pharmaceutically acceptable aqueous solutions include Ringer's solution, Hartmann's solution, 0.9% saline, 0.45% N saline, WFI (water for injection), D5W (5% dextrose in water), phosphate buffered saline (PBS), and dextrose / saline solutions (D2.5W (i.e., 2.5% dextrose in water) and 0.45% N saline).

[0112] As used herein, "Ringer's solution" refers to a pharmaceutically acceptable buffered saline solution having sodium chloride, potassium chloride, and calcium chloride salts.

[0113] As used herein, "Hartmann's solution" refers to lactated Ringer's solution. A typical Hartmann's solution contains 131 mM sodium, 5 mM potassium, 2 mM calcium, 11 mM chloride, and 29 mM lactate (sodium chloride 0.6%, sodium lactate 0.25%, potassium chloride 0.04%, calcium chloride 0.027%).

[0114] As used herein, a pharmaceutically acceptable saline solution is a solution suitable for administration to a patient that comprises water and sodium chloride and may optionally contain a buffer, preservative, or other component, typically in small amounts. For example, pharmaceutically acceptable saline solutions include 0.9% saline (9 g NaCl in 100 ml distilled, filtered water, containing 150 mM sodium and 150 mM chloride) and a saline solution having 154 mM sodium and 154 mM chloride.

[0115] In general, the term "or" herein includes "and / or".

[0116] For convenience, as used herein, multiple compounds, elements, or steps may be presented in a common list. However, these lists should be interpreted as if each member of the list were individually identified as a separate and unique member. Therefore, unless otherwise indicated, individual members of such lists should not be construed as being de facto equivalents to any other member of the same list solely based on their presentation in the same group.

[0117] Furthermore, certain compositions, elements, excipients, ingredients, disorders, conditions, properties, and procedures, among others, can be discussed in the context of one particular embodiment or aspect or in separate paragraphs or sections of the application. It will be understood that this is merely for convenience and that any such application is equally applicable in combination with any other embodiment or aspect found anywhere in the application and claims, all of which form part of the application and claimed application as of the application date. For example, a list of method steps, active agents, kits, or compositions described in relation to a formulation or method for treating a subject is intended to and does directly support embodiments relating to compositions, formulations, and methods described in any other part of the application, even if those method steps, active agents, kits, or compositions are not re-listed in the context or section of that embodiment or aspect.

[0118] The inventors have found that glibenclamide in conventional intravenous glibenclamide formulations readily and extensively binds to polymeric containers, for example, infusion sets containing polyvinyl chloride (PVC) and polyurethane (PUR). While the use of low-adsorbing polyethylene lined infusion sets minimizes adsorption, such specialized infusion sets are not practical for a number of reasons, including the difficulty in obtaining such specialized infusion sets and the fact that intravenous glibenclamide is intended for use in emergency care situations and for indications in which minimizing the time from the patient's last known normal to administration is critical for efficacy (i.e., "time is brain"). Thus, additional complexity is introduced in the handling and administration of intravenous glibenclamide, i.e., the need for strict use of specialized infusion components in emergency situations, which will delay patient administration and adversely affect patient outcomes. Furthermore, for prior art intravenous glibenclamide formulations, the use of commonly used materials will result in a loss of significant active pharmaceutical ingredient due to adsorption, resulting in the administration of an unknown and potentially sub-therapeutic dose of glibenclamide. In addition, for prior art intravenous glibenclamide formulations, the use of commonly used materials will result in instability and degradation, resulting in a drug product of unacceptable quality. Furthermore, the administration of an unknown amount of glibenclamide or the attempt to increase the volume of drug to be administered is not safe, as the administration of glibenclamide at higher doses (e.g., at a rate greater than 0.25 mg / hour (6 mg / day) average rate) can result in hypoglycemia. In addition, the implementation of a flushing procedure is undesirable, as flushing procedures can be complex, time consuming, imprecise, wasteful, and at risk for contamination. Furthermore, the inventors have found that glibenclamide in prior art intravenous glibenclamide formulations readily and extensively binds to all filter components (data not shown). Thus, there is a need to provide a novel intravenous glibenclamide formulation that avoids binding to commonly used infusion set and filter materials and allows the medical care provider to treat the patient with a precise dose within the appropriate administration window (close to immediately after stroke, infarction, injury, etc.) using commonly used medical supplies, while avoiding complications, avoiding waste of drug, and reducing the amount of infusion fluid administered to the patient.

[0119] In a first aspect, the present disclosure provides a formulation containing a stable therapeutic dose of glibenclamide with less than 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, 0.1%, 0.05%, 0.01% loss of glibenclamide concentration (w / v) due to adsorption to polymeric containers, for example, containing 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.

[0120] In a second aspect, the present disclosure provides formulations containing stable therapeutic doses of glibenclamide with less than 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, 0.1%, 0.05%, 0.01% loss of glibenclamide concentration (w / v) due to adsorption to inline filter material.

[0121] In a third aspect, the present disclosure provides methods and formulations for controlling the pH of glibenclamide solutions within a narrow desired range before and after dilution in an infusion fluid.

[0122] In a fourth aspect, the present disclosure provides methods and formulations for minimizing or avoiding the formation of degradation products in stored glibenclamide solutions.

[0123] In a fifth aspect, the present disclosure provides methods and formulations for reducing infusion rates, reducing drug wastage, and reducing the amount of saline intake in subjects treated with intravenous glibenclamide.

[0124] In a sixth aspect, the present disclosure provides methods and formulations for maintaining a sufficiently high concentration of glibenclamide in solution during formulation of the preparation to allow filling into appropriately sized containers to achieve therapeutic doses, e.g., 3 mg to 5 mg / day of glibenclamide.

[0125] In a seventh aspect, the present disclosure provides methods and formulations for providing sufficient solubility, stability, and desired pH after reconstitution to achieve the desired high concentration during drug preparation.

[0126] In an eighth aspect, the present disclosure provides methods and formulations for providing sufficient solubility, stability, and desired pH after further dilution of the reconstituted glibenclamide formulation in an infusion fluid, e.g., in a saline bag to a concentration of 6 pg / ml to 10 pg / ml, for administration over a 3, 4, 6, 12, 24, 30, 36, 48, 72, 96, or 120 hour time period.

[0127] In one aspect, the methods and formulations of the present application include formulating a glibenclamide formulation comprising glibenclamide, a buffer, and a base as specified herein. In one aspect, the buffer has a pKa of 7.7 to 9.2, 7.8 to 9.1, 7.9 to 9.0, 8.0 to 8.9, 8.05 to 8.8, 8.1 to 8.7, or any particular pKa of the specified ranges. For example, and without limiting the foregoing application, the buffer can be Tris, lysine, arginine, ethylenediamine, imidazole, 4-(2-hydroxyethyl)morpholine, triethanolamine, glucosamine, diethylaminoethanol, phosphate, phosphate buffered saline (PBS), or combinations thereof. In one aspect, the buffer of the present application has a buffering capacity in the pH range of 7 to 9. In one aspect, the Tris can be a combination of Tris-HCl and Tris-base. In one aspect, the lysine is lysine-HCl. In one aspect, the arginine is arginine-HCl.

[0128] In one aspect, the present application includes methods and formulations comprising glibenclamide, a buffer, a base, and a sugar alcohol, wherein the formulation has a pH outside of the buffering capacity of the buffer, and the formulation is suitable for (including safe at a sustained therapeutically effective amount, and tolerable) infusion into a human for a period of 24 hours or more. In one aspect, the pH of the formulation (reconstituted formulation) is 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 buffer has a buffering capacity in the pH range of 7 to 9.

[0129] In some embodiments, the formulation is capable of maintaining a stable pH. For example, the formulation has a pH within about 0.1 or about 0.2 pH units after storage at or about 25 °C / 60% relative humidity (RH), 40 °C / 75% RH, or 70 °C / 75% Rh for one week, two weeks, or four weeks, or 3 months, 6 months, or 12 months. In some embodiments, the glibenclamide has increased stability compared to the same formulation lacking a buffer or having a buffer with a buffering capacity overlapping the pH of the formulation. In some aspects, stability can be determined by measuring production of degradation products. For example, degradation products can be measured by HPLC. In some aspects, degradation products are quantified based on relative retention time (RRT) on HPLC.

[0130] In some aspects, the buffer is a combination of Tris-HCl and Tris-base. In some aspects, the weight ratio between Tris-HCl and Tris-base is 7:4, 6.7:4.5, 6.5:4.7, 6.4:4.8, 6.3:4.9, 6.2:5.0, or 6.1:5.1.

[0131] In some aspects, the lyophilized glyburide formulation comprises about 5% (w / w) to 15% (w / w), 6% (w / w) to 14% (w / w), 7% (w / w) to 13% (w / w), 8% (w / w) to 12% (w / w), 9% (w / w) to 13% (w / w), or 10% (w / w) to 12% (w / w) buffer. In some aspects, the reconstituted glyburide formulation comprises about 5% (w / w) to 15% (w / w), 6% (w / w) to 14% (w / w), 7% (w / w) to 13% (w / w), 8% (w / w) to 12% (w / w), 9% (w / w) to 13% (w / w), or 10% (w / w) to 12% (w / w) buffer. In some aspects, the reconstituted glyburide formulation comprises about 1 mM to 100 mM, 2 mM to 80 mM, 3 mM to 70 mM, 4 mM to 60 mM, 5 mM to 50 mM, 6 mM to 40 mM, 7 mM to 30 mM, 8 mM to 25 mM, 9 mM to 23 mM, 10 mM to 21 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, or 20 mM buffer. In some aspects, the reconstituted glyburide formulation comprises about 1 mg / ml to 5 mg / ml, 1.2 mg / ml to 4 mg / ml, 1.5 mg / ml to 3.5 mg / ml, or 2 mg / ml to 3 mg / ml buffer.

[0132] In some aspects, the buffer is a buffer having a pH of 7.8 to 9, 8.1 to 8.9, 8.2 to 8.8, 8.3 to 8.7, 8.4 to 8.6, or 8.5.

[0133] In some aspects, the present disclosure includes use of a mixing device that enables reconstitution and transfer of a lyophilized formulation between a vial and an IV bag prior to administration. The mixing device can be a needleless device. The mixing device can meet the requirements of USP <797>. The mixing device can have a dual channel design that provides a dedicated fluid channel into and out of the IV bag. In one aspect, the present disclosure includes use of a mixing device as described in U.S. Patent No. 8,551,067 (Zinger), which is incorporated by reference herein in its entirety. In one aspect, the present disclosure includes use of a mixing device as described in U.S. Patent No. 10,688,295 (Lev), which is incorporated by reference herein in its entirety. In some aspects, the present disclosure includes use of a mixing device to reconstitute and transfer a lyophilized formulation between a vial and an IV bag prior to administration. VIAL2BAGADVANCED TM and / or A method of using a mixing device to reconstitute and transfer a lyophilized formulation between a vial and an IV bag prior to administration.

[0134] In a second aspect, the base is a strong base having a pKb of 0.1 to 1.5. Any pharmaceutically acceptable strong base can be used. By way of example, and without limitation to the foregoing disclosure, the base can be NaOH, CaOH, or KOH.

[0135] In a third aspect, the formulation of the present disclosure comprises a particular weight ratio between glibenclamide and base to achieve a pH target in the formulation ranging from 9.8 to 11.2, 9.9 to 11.1, 10.0 to 11.0, 10.1 to 10.9, 10.2 to 10.8, 10.3 to 10.7, or 10.4 to 10.6.

[0136] In some aspects, the formulation of the present disclosure comprises a particular molar ratio between base and glibenclamide in the formulation of 5.0 to 6.7: 1, 5.1 to 6.6: 1, 5.2 to 6.5: 1, 5.3 to 6.4: 1, 5.4 to 6.3: 1, 5.5 to 6.2: 1, 5.6 to 6.1: 1, 5.7 to 6.0: 1, or 5.2: 1, 5.3: 1, 5.4: 1, 5.5: 1, or 5.6: 1. Unexpectedly, the molar ratio used by the present disclosure is about 2-fold higher than the molar ratio used in glibenclamide formulations in the prior art.

[0137] In some aspects, the lyophilized glibenclamide formulation comprises about 2% to 3.5%, 2.5% to 3.3%, 2.7% to 3.1%, 2.8% to 2.98%, 2.9% to 2.97%, or 2.94% to 2.96% (w / w) glibenclamide.

[0138] In some aspects, the lyophilized glibenclamide formulation comprises about 70% to 93%, 75% to 92%, 80% to 91%, 84% to 90%, 86% to 89%, or 87% to 89% (w / w) sugar alcohol of the present disclosure. In some aspects, the sugar alcohol is mannitol, sorbitol, xylitol, or a combination thereof. In some aspects, the sugar alcohol is mannitol.

[0139] In some aspects, the formulation of the present disclosure comprises a particular weight ratio between sugar alcohol and glibenclamide in the formulation.

[0140] In some aspects, the formulation of the present disclosure comprises a particular weight ratio between sugar alcohol and buffer in the formulation of 5 to 15: 1, 6 to 14: 1, 7 to 13: 1, 8 to 12: 1, 9 to 11: 1, 9.5: 1, 10: 1, or 10.5: 1.

[0141] In some aspects, the reconstituted glibenclamide formulation comprises about 20 mg / ml to 40 mg / ml, 24 mg / ml to 36 mg / ml, 26 mg / ml to 34 mg / ml, 38 mg / ml to 32 mg / ml, 29 mg / ml, 30 mg / ml, or 31 mg / ml sugar alcohol.

[0142] In some aspects, the reconstituted glyburide formulation has a pH of about 9.3 to 11, 9.4 to 10.9, 9.5 to 10.8, 9.6 to 10.7, 9.7 to 10.6, 9.6 to 10.5, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, or 10.4. In some aspects, the reconstituted glyburide formulation has a pH of 9.5 to 10.0.

[0143] In some aspects, the glyburide is the free acid or a pharmaceutically acceptable salt thereof. In some aspects, the glyburide formulation comprises the sodium addition salt of glyburide. As used throughout this disclosure, reference to "glyburide" can also describe salts, esters, hydrates, solvates, racemates, tautomers, stereoisomers, and / or optically active forms thereof.

[0144] In some aspects, the present application includes preparing an aqueous solution of glyburide in the buffer of the present application at the concentrations described herein, adding the base of the present application at the weight ratio to glyburide described herein, and lyophilizing the solution to provide a lyophilized solid composition. In some aspects, the aqueous solution can further contain a sugar alcohol of the present application at the concentrations described herein.

[0145] In some aspects, the formulation of the present application does not contain one or more of the following: cyclodextrins, meglumine, sugars such as, for example, fructose, mannose, galactose, arabinose, xylose, and ribose, and oligosaccharides such as disaccharides (maltose, lactose, sucrose, trehalose, etc.) and trisaccharides (e.g., raffinose, maltotriose, etc.), salts, alcohols such as, for example, ethanol, diethanolamine, Britton-Robinson buffer, lactate, acetate, glutamate, glycine, citrate, succinate, surfactants, polysorbates, solubilizing polymers such as polyethylene glycol, inorganic or organic acids such as methanesulfonic acid, lactic acid, tartaric acid, citric acid, succinic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, etc., choline, n-methylglucamine, diethylamine, and procaine, etc.

[0146] In some aspects, the reconstituted formulation of the present application has an osmolarity of between about 250 milliosmole per liter (mOsm) and about 350 mOsm; or between about 280 mOsm and about 320 mOsm; or between about 290 mOsm and about 310 mOsm.

[0147] The present disclosure provides methods and formulations that are capable of providing glibenclamide formulations having significantly higher solubility of glibenclamide in the administration solution, i.e., about 3 times that of prior art intravenous glibenclamide administration solutions (i.e., greater than 15 μg / ml as compared to less than 5.7 μg / ml in prior art intravenous glibenclamide administration solutions). Moreover, even at these triple higher concentrations, there is no detectable loss of glibenclamide due to precipitation or adsorption.

[0148] In some aspects, the diluted (referred to herein as "final administration" formulations) glibenclamide formulations of the present disclosure have a glibenclamide concentration of 7.2 (± 0.2) μg / mL and an infusion pH of about 8.3 (± 0.1).

[0149] In some aspects, the final administration glibenclamide formulations have a pH of 7.8 to 9.0, 7.9 mM to 9.0, 8.0 to 9.0. In some aspects, the final administration glibenclamide formulations have a pH of 7.8 to 9, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, or 8.9.

[0150] In some aspects, the final administration glibenclamide formulations have a buffer concentration of about 0.1 mM to 0.5 mM, about 0.15 mM to 0.4 mM, about 0.2 mM to 0.3 mM, or about 0.2 mM.

[0151] In some aspects, the diluted glibenclamide formulations of the present application are diluted in a 500 mL IV infusion bag, thereby reducing the amount of infusion fluid administered to a subject. Given the increased solubility, stability, and minimized medical container adsorption of the formulations of the present application, more concentrated administration formulations can be used, thereby providing a consistent therapeutic dose over the infusion period while using significantly less infusion fluid.

[0152] In some aspects, the present application provides methods that reduce the volume of infusion fluid administered to a subject by about 25-30% over the infusion period, e.g., from about 2 L to 1.5 L for a four day infusion period, or from about 1.5 L to 1.1 L for a three day infusion period.

[0153] In some aspects, due to the advantages of the present application, the diluted glibenclamide formulations can be administered at a slower rate than prior art intravenous glibenclamide formulations. For example, the infusion rate can be reduced to about 80% of the infusion rate used for infusion of prior art intravenous glibenclamide formulations, e.g., a first six hour infusion rate of 23 ml / hour followed by 15.9 ml / hour, as compared to a first six hour infusion rate of 29 ml / hour followed by 20 ml / hour for prior art intravenous glibenclamide formulations.

[0154] In some aspects, the present disclosure includes sterilizing the formulations of the present application. In some aspects, the formulations can be filter sterilized. In some aspects, the formulations can be sterilized to have a zero bioburden. In some aspects, the products of the present application can be terminally sterilized. In some aspects, the products are sterilized with gamma irradiation. In some aspects, the products are sterilized by electron beam, X-ray, hydrogen peroxide, or ethylene oxide. In some aspects, the products can be a powder, a solution, a vial, a kit, a pre-filled syringe, an injection device, a cartridge, an on body injector, an auto-injector, an infusion bag, or any other container or container set suitable for storing, infusing, and / or injecting the products of the present disclosure. In some aspects, the products meet the "Sterility Assurance Level" or "SAL" of 10 -3 , 10 -4 , or 10 -6 .

[0155] Kits having features of the present application can comprise a liquid solution of glibenclamide, and / or a liquid solution of glibenclamide and one or more compounds, and can comprise instructions for using such liquid solution. For example, instructions for using such liquid solution can comprise instructions for freeze-drying such solution to obtain a lyophilized formulation of the compound(s) of interest. Alternatively or additionally, kits having features of the present application can comprise a lyophilized formulation of glibenclamide, and / or a lyophilized formulation of glibenclamide and one or more compounds, and / or a lyophilized formulation of glibenclamide and one or more liquids for reconstitution, and can comprise instructions for using such lyophilized formulation. For example, instructions for using such lyophilized formulation can comprise instructions for reconstituting such lyophilized formulation to provide a solution, preferably a sterile solution, suitable for use in a medical application. In some aspects, the vial contains a concentration of 6 mM to 40 mM, 7 mM to 30 mM, 8 mM to 25 mM, 9 mM to 20 mM, or 10 mM to 15 mM of the buffer of the present disclosure.

[0156] In some aspects, the present disclosure includes methods of using the following exemplary items:

[0157] 1. A formulation comprising:

[0158] a) glibenclamide or a pharmaceutically acceptable salt thereof;

[0159] b) a buffer;

[0160] c) a base; and

[0161] d) a sugar alcohol,

[0162] wherein the formulation has a pH outside of the buffering capacity of the buffer, and

[0163] wherein the pKa of the buffering agent is 7.7 to 9.2.

[0164] 2. The formulation according to any one of the preceding items, wherein the pharmaceutically acceptable salt thereof is a sodium addition salt.

[0165] 3. The formulation according to any one of the preceding items, wherein the glibenclamide or the pharmaceutically acceptable salt thereof is about 2.7% (w / w) to 3.1% (w / w) of the formulation.

[0166] 4. The formulation according to any one of the preceding items, wherein the sugar alcohol is about 84% w / w to 90% w / w of the formulation.

[0167] 5. The formulation according to any one of the preceding items, comprising a sugar alcohol and glibenclamide or the pharmaceutically acceptable salt thereof in a weight ratio of 28 to 35: 1.

[0168] 6. The formulation according to any one of the preceding items, wherein the pH is within about 0.2 pH units of the pH prior to storage of the formulation after storage at 25 °C / 60% relative humidity (RH) for 12 months, or wherein the pH is within about 0.2 pH units of the pH prior to storage of the formulation after storage at 40 °C / 75% RH for 6 months, or wherein the pH is within about 0.2 pH units of the pH prior to storage of the formulation after storage at 70 °C / 75% RH for 4 weeks.

[0169] 7. The formulation according to any one of the preceding items, wherein the buffering agent is a buffer having a pH of 7.8 to 9.

[0170] 8. The formulation according to any one of the preceding items, comprising a base and glibenclamide or the pharmaceutically acceptable salt thereof in a ratio such that the formulation has a pH of 10.1 to 10.9 when reconstituted in water for injection (WFI).

[0171] 9. The formulation according to any one of the preceding items, wherein the formulation comprises a sugar alcohol and glibenclamide or the pharmaceutically acceptable salt thereof in a weight ratio of 27 to 40: 1.

[0172] 10. The formulation according to any one of the preceding items, wherein the formulation comprises a sugar alcohol and a buffering agent in a weight ratio of 8 to 12: 1.

[0173] 11. The formulation according to any one of the preceding items, wherein the formulation comprises 26 mg / ml to 34 mg / ml of a sugar alcohol.

[0174] 12. The formulation according to any one of the preceding items, wherein the molar ratio of base and glibenclamide or the pharmaceutically acceptable salt thereof in the formulation is 5.4 to 6.3: 1.

[0175] 13. The formulation according to any of the preceding items, wherein the formulation comprises about 8 to 12% (w / w) of a buffering agent.

[0176] 14. The formulation according to any of the preceding items, wherein the formulation does not contain a cyclodextrin.

[0177] 15. A formulation comprising:

[0178] e) glibenclamide or a pharmaceutically acceptable salt thereof;

[0179] f) a buffering agent;

[0180] g) a base; and

[0181] h) a sugar alcohol,

[0182] wherein the formulation has a pH outside the buffering capacity of the buffering agent, and

[0183] wherein the formulation does not contain a cyclodextrin.

[0184] 16. The formulation according to item 15, wherein the glibenclamide or a pharmaceutically acceptable salt thereof is about 2.7% (w / w) to 3.1% (w / w) of the formulation and / or wherein the sugar alcohol is about 84% (w / w) to 90% (w / w) of the formulation.

[0185] 17. The formulation according to item 15, comprising a sugar alcohol and glibenclamide or a pharmaceutically acceptable salt thereof in a weight ratio of 28 to 35: 1.

[0186] 18. The formulation according to item 15, wherein after storage at 25 °C / 60% relative humidity (RH) for 12 months, has a pH within about 0.2 pH units of the pH prior to storage of the formulation, or wherein after storage at 40 °C / 75% RH for 6 months, has a pH within about 0.2 pH units of the pH prior to storage of the formulation, or wherein after storage at 70 °C / 75% RH for 4 weeks, has a pH within about 0.2 pH units of the pH prior to storage of the formulation,

[0187] 19. The formulation according to item 15, wherein the buffering agent is a buffer having a pH of 7.8 to 9.

[0188] 20. The formulation according to item 15, comprising a ratio of base and glibenclamide or a pharmaceutically acceptable salt thereof such that the formulation has a pH of 10.1 to 10.9 when reconstituted in water for injection (WFI).

[0189] 21. The formulation according to item 15, wherein the formulation comprises a sugar alcohol and glibenclamide or a pharmaceutically acceptable salt thereof in a weight ratio of 27 to 40: 1.

[0190] 22. The formulation according to item 15, wherein the formulation comprises a sugar alcohol and a buffering agent in a weight ratio of 8 to 12: 1.

[0191] 23. The formulation according to item 15, wherein the formulation comprises 26 mg / ml to 34 mg / ml of a sugar alcohol.

[0192] 24. The formulation according to item 15, wherein the molar ratio of base to glibenclamide or a pharmaceutically acceptable salt thereof in the formulation is 5.4 to 6.3: 1.

[0193] 25. The formulation according to item 15, wherein the formulation comprises about 8 to 12% (w / w) of a buffering agent, and wherein the pKa of the buffering agent is 7.7 to 9.2.

[0194] The following are exemplary dosing regimens. Reference to mass refers only to the SUR1-TRPM4 channel inhibitor in the drug (none in the placebo).

[0195] Table 1 - Dosing Regimens

[0196]

[0197]

[0198] Unlike clot busters, which are typically administered to subjects with ischemic stroke, SUR1-TRPM4 channel inhibitors do not cause hemorrhage. Thus, SUR1-TRPM4 channel inhibitors can be effective whether administered for the first time promptly after the injury or condition occurs, or at a time period after the injury or condition occurs that is associated with brain edema. In one embodiment, the SUR1-TRPM4 channel inhibitor can be administered for the first time within the first hour, within the first 2 hours, within the first 3 hours, within the first 4 hours, within the first 6 hours, within the first 8 hours, or within the first 10 hours after the injury or condition occurs. In another embodiment, the SUR1-TRPM4 channel inhibitor can be administered for the first time at least 4 hours, at least 4.5 hours (a time period in which clot busters can be ineffective or even dangerous), at least 6 hours, at least 8 hours, or at least 10 hours after the injury or condition occurs that is associated with brain edema. In other examples, the SUR1-TRPM4 channel inhibitor can be administered for the first time within a time period of 6 hours after the injury or condition occurs. In a further embodiment, the SUR1-TRPM4 channel inhibitor can be administered for the first time within a time period of 6 hours after the injury or condition occurs. In another embodiment, the SUR1-TRPM4 channel inhibitor can be administered for the first time within 8 hours of the injury or condition occurring. In yet another embodiment, the SUR1-TRPM4 channel inhibitor can be administered for the first time within a time period of 10 hours of the injury or condition occurring.

[0199] The methods of the present application are compatible with existing methods of treatment of ischemic stroke. Thus, it is contemplated that the methods can be used in conjunction with thrombolytic therapy, such as tissue plasminogen activator (tPA) and similar thrombolytic agents. They can also be used in patients who have undergone decompressive hemicraniectomy to address mass effect edema.

[0200] Assessment of Results

[0201] In addition, the present application relates to a method of improving outcome, typically assessed by measuring the degree of disability in a patient suffering from stroke.

[0202] For example, a difference in degree of disability of at least about 10% improvement can be achieved based on a stroke rating system. In other embodiments, the decrease in degree of disability can be at least about 15%, at least about 20%, at least about 25%, or at least about 30%. The rating system can be based on the National Institutes of Health Stroke Scale (NIHSS), the modified Rankin Scale, the Barthel Index, or lesion size (e.g., CT and / or MRI measurements). In one example, a first rating system or test can be based on the NIHSS, and a second rating system or test can be based on the modified Rankin Scale or the Barthel Index or the NIHSS.

[0203] Modified Rankin Scale

[0204] The mRS is the most commonly used assessment of stroke, used to assess global disability after stroke, with 90-day assessment being the most commonly used primary outcome in acute stroke trials. It is an ordinal scale, with disability rated on a scale of 0 (no symptoms) to 6 (death).

[0205] 0 - No symptoms.

[0206] 1 - No significant disability. Is able to carry out all usual activities.

[0207] 2 - Slight disability. Able to look after own affairs; unable to carry out all usual activities.

[0208] 3 - Moderate disability. Requires some help; able to walk without assistance.

[0209] 4 - Moderately severe disability. Disabled; able to walk with assistance; able to attend to own bodily functions.

[0210] 5 - Severe disability. Bedridden; incontinent; not entirely capable of communicating.

[0211] 6 - Death.

[0212] While the mRS is often analyzed as a dichotomous outcome (e.g., defining "good" and "bad" outcomes as above a threshold and below a threshold, e.g., 0-3 vs. 4-6), this approach typically reduces the power to detect effects, and in fact, has been found to obscure positive and negative effects. In contrast, ordinal analysis preserves the full power of the mRS and better reflects health status by assessing each transition. In the case of severe stroke, mRS analysis is sometimes performed by collapsing the scale at both ends (e.g., collapsing 0-1 and 5-6), as there is no meaningful difference between these outcomes - there is no meaningful difference between being completely normal and functioning normally, and there is no meaningful difference between being dead, bedridden, or even unable to perform basic functions. Thus, the simplified scale 0-1, 2, 3, 4, 5-6 can still be analyzed as an ordinal scale, e.g., using the Mann-Whitney test or other suitable test of the nature to assess whether two distributions differ. Ordinal logistic regression can be used, e.g., to estimate the common odds ratio to assess the size of any effect detected, and whether the effect favors the drug or placebo. An odds ratio greater than 1 indicates a favorable drug response. Thus, the present invention expects that the odds ratio of the drug in the population of people receiving the treatment relative to the population of people receiving the placebo control will be greater than 1. In some cases, the odds ratio can be greater than 1.2, which is not only strong evidence of efficacy, but also represents a clear clinical benefit.

[0213] Barthel Index

[0214] The Barthel Index ("BI") assesses function in terms of activities of daily living. The BI uses 10 domains to describe activities of daily living and mobility. The higher the score, the better, indicating a higher level of functional independence. The BI assesses the following ten different domains, using a 100-point scale:

[0215] Presence of fecal incontinence

[0216] • 0 = incontinent (or requiring enemas)

[0217] • 5 = occurs occasionally

[0218] • 10 = self-controlled

[0219] Presence of urinary incontinence

[0220] • 0 = incontinent, or catheterized and unable to manage alone

[0221] • 5 = occurs occasionally

[0222] • 10 = self-controlled

[0223] Need help with personal hygiene

[0224] • 0 = needs help with personal care

[0225] • 5 = independent in washing face / brushing hair / brushing teeth / shaving (tools provided)

[0226] Need help with toileting

[0227] • 0 = dependent

[0228] • 5 = needs some help but can do some things alone

[0229] • 10 = independent (in and out, dressing, wiping)

[0230] Need help with feeding

[0231] • 0 = unable

[0232] • 5 = needs help cutting, spreading butter, etc., or needs diet adjusted

[0233] • 10 = independent

[0234] Need help with transfers (e.g., from chair to bed)

[0235] • 0 = unable to balance in sitting position

[0236] • 5 = needs a lot of help (one to two people, physically), can sit

[0237] • 10 = minimal assistance (verbal or physical)

[0238] • 15 = independent

[0239] Requires assistance walking

[0240] • 0 = unable to move or < 50 yards

[0241] • 5 = independent wheelchair, including corners, > 50 yards

[0242] • 10 = walks > 50 yards with one person assistance (verbal or physical)

[0243] • 15 = independent (but can use any assistive device; e.g. cane) > 50 yards

[0244] Requires assistance dressing

[0245] • 0 = dependent

[0246] • 5 = requires assistance but can accomplish about half independently

[0247] • 10 = independent (including buttons, zippers, shoelaces, etc.)

[0248] Requires assistance climbing stairs

[0249] • 0 = unable

[0250] • 5 = requires assistance (verbal, physical, carrying assistive device)

[0251] • 10 = independent

[0252] Requires assistance bathing

[0253] • 0 = dependent

[0254] • 5 = independent (or shower)

[0255] NIH Stroke Scale score

[0256] The NIH Stroke Scale score (NIHSS) is used to quantify the extent of impairment in a stroke patient. The NIHSS consists of 11 items, each scored between 0 and 4, with a score of 0 typically indicating normal function and higher scores indicating some degree of impairment. The NIHSS is typically used to assess the severity of stroke at baseline / onset, but the numerical value can also be used to assess improvement in an individual stroke patient or to compare relative improvement between two groups of patients (e.g., placebo and drug treatment groups). The following items are assessed:

[0257] Item 1a: Level of Consciousness (LOC) Indicator

[0258] If a full assessment is prevented by endotracheal intubation, speech impediment, oral endotracheal trauma / tape, etc., the investigator must choose a response. Score 3 only if the patient does not make any movement in response to noxious stimuli (except reflexive posturing). Score for item 1a is as follows:

[0259] • 0 = Alert; responsive to stimuli.

[0260] • 1 = Not alert; but easily aroused and compliant with commands, answering questions, or responding to mild stimuli.

[0261] • 2 = Not alert; requires repeated stimuli to attend, or is confused, requiring strong or painful stimuli to make a movement (not stereotypic).

[0262] • 3 = Only reflexive movements or autonomic responses, or no response at all, flaccid and unresponsive.

[0263] Project 1b: LOC Issues

[0264] Ask the patient for the month and the year. The answers must be correct - partial credit cannot be given for answers that are close. Score 2 for aphasic and comatose patients who cannot understand the question. Score 1 for patients who cannot speak due to endotracheal intubation, oral endotracheal trauma, severe dysarthria of any cause, speech impediment, or any other problem not secondary to aphasia. It is important that only the initial answers be scored, the examiner must not "help" the patient by verbal or non-verbal cues. Score for item 1b is as follows:

[0265] • 0 = Correctly answers both questions.

[0266] • 1 = Correctly answers one question.

[0267] • 2 = Does not correctly answer either question.

[0268] Item 1c: LOC Directive

[0269] Ask the patient to open and close their eyes, then to hold and release the non-paretic hand. If the hand cannot be used, substitute another single-step command. If an explicit attempt is made but not completed due to weakness, score as attempted. If the patient does not respond to the command, demonstrate the task to him or her (in pantomime), and score the result (i.e., no command executed, one command executed, or two commands executed). For patients with trauma, amputations, or other physical impediments, give the appropriate single-step command. Score for item 1c is as follows:

[0270] 0 = Correctly performs both tasks.

[0271] 1 = Correctly performs one task.

[0272] 2 = Neither task performed correctly.

[0273] Project 2: Best Look

[0274] Only horizontal eye movements are tested. Voluntary or reflexive (oculoccephalic) eye movements are scored, but no thermal testing is performed. Score 1 if the patient's eyes are conjugately deviated but can be overcome by voluntary or reflexive activity. Score 1 if the patient has isolated peripheral nerve palsy (CN III, IV, or VI). All aphasic patients can be tested for gaze. Patients with ocular trauma, bandaged eyes, previous blindness, or other visual or visual field impairment should receive reflexive movement testing, and the choice is made by the investigator. Establishing eye contact and then moving from one side of the patient to the other can sometimes clarify whether partial gaze palsy is present. Scoring for item 2 is as follows:

[0275] • 0 = Normal.

[0276] • 1 = Partial gaze palsy; monocular or binocular gaze abnormalities, but no forced deviation or complete gaze palsy.

[0277] • 2 = Forced deviation or complete gaze palsy and cannot be overcome by oculoccephalic movements.

[0278] Project 3: Visual Instructions

[0279] Test visual fields (upper and lower quadrants) by having the patient face the examiner, using finger counting or visual threat, as appropriate. Patients can be encouraged, but if they appropriately observe the side of the moving finger, they can be scored as normal. If there is unilateral blindness or enucleation of the eye, the visual field of the remaining eye is scored. Score 1 only if a clear asymmetry is found (including quadrant blindness), and 3 if the patient is blind for any reason. Stimulate both eyes simultaneously at this time.

[0280] If ignored, the patient gets a score of 1, and this result is also used for item 11. Scoring for item 3 is as follows:

[0281] • 0 = No visual deficit.

[0282] • 1 = Partial hemianopia.

[0283] • 2 = Complete hemianopia.

[0284] • 3 = Bilateral hemianopia (blindness, including cortical blindness).

[0285] Project 4: Facial paralysis instructions

[0286] Ask (or encourage with pantomime) the patient to show teeth or raise eyebrows and close eyes. For patients who do not respond or who do not understand, score according to the symmetry of the grimace in response to noxious stimuli. If the face is obscured by trauma / bandages, endotracheal tube, tape, or other physical barriers, remove as much as possible. Scoring for item 4 is as follows:

[0287] • 0 = Normal symmetrical movement.

[0288] • 1 = Mild paresis (flattening of nasolabial fold, asymmetry in smiling).

[0289] • 2 = Partial paresis (complete or nearly complete paralysis of lower face).

[0290] • 3 = Unilateral or bilateral complete paresis (no facial movement of upper and lower face).

[0291] Item 5: Upper limb exercise instructions

[0292] Position the limb in place: extend the arm (palm down) 90 degrees (if sitting) or 45 degrees (if supine). Score as drift if the arm falls in 10 seconds. Encourage aphasic patients with an urgent tone of voice and pantomime, but do not use noxious stimuli. Test each limb in turn, starting with the non-paretic arm. Only if there is shoulder amputation or joint fusion, the examiner should record the score as not testable (UN) and clearly write the reason for this choice. Scoring for item 5 is as follows:

[0293] • 0 = No drift; limb remains at 90 degrees (or 45 degrees) for the full 10 seconds.

[0294] • 1 = Drift; limb remains at 90 degrees (or 45 degrees) but drifts before the full 10 seconds; does not touch the bed or other support.

[0295] • 2 = Some anti-gravity effort; limb cannot achieve or maintain (if prompted) 90 degrees (or 45 degrees), drifts onto the bed but shows some anti-gravity effort.

[0296] • 3 = Unable to resist gravity; limb falls.

[0297] • 4 = No movement.

[0298] • UN = Amputation or joint fusion, specify:

[0299] Project 6: Lower limb exercise instructions

[0300] Position the extremity: Keep the leg at 30 degrees (always test in supine position). Score as sliding if the leg falls in less than 5 seconds. Encourage the aphasic patient with a forceful voice and mime, but do not use noxious stimuli. Test each extremity in turn, starting with the non-paretic leg. Only if there is a hip amputation or joint fusion, the examiner should record the score as not testable (UN) and clearly write the reason for this choice. Score for item 6 is as follows:

[0301] • 0 = No slippage; extremity remains at 30 degrees for the full 5 seconds.

[0302] • 1 = Slippage; leg falls after 5 seconds but does not touch the bed.

[0303] • 2 = Some anti-gravity effort; leg falls to the bed in less than 5 seconds but still shows some anti-gravity effort.

[0304] • 3 = Unable to oppose gravity; leg falls immediately to the bed.

[0305] • 4 = No movement.

[0306] • UN = Amputation or joint fusion, explain:

[0307] Item 7: Limb Ataxia Indications

[0308] This item is designed to find evidence of unilateral cerebellar lesion. Test with eyes open. If there is a visual defect, make sure the test is performed within the intact visual field. Both sides are tested for finger-to-nose and heel-shin tests, and only if ataxia is out of proportion to weakness is the score assigned. Patients who are unable to understand or paralyzed do not have ataxia. Only if there is an amputation or joint fusion, the examiner should record the score as not testable (UN) and clearly write the reason for this choice. If the patient is blind, have the patient reach out with the arm to touch the nose for the test. Score for item 7 is as follows:

[0309] • 0 = None.

[0310] • 1 = One extremity on one side.

[0311] • 2 = Extremities on both sides.

[0312] • UN = Amputation or joint fusion, explain:

[0313] Project 8: Sensory Indications

[0314] Tests for pinprick or makes a contorted facial expression, or for patients with confusion or aphasia, withdraws from noxious stimuli. Only sensory loss attributable to stroke is rated as abnormal. The examiner should test as many body parts as necessary [arms (not hands), legs, trunk, face] to accurately check for hemisensory loss. Only when clear evidence of severe or complete sensory loss is present should a score of 2 be assigned, "severe or complete sensory loss." Thus, patients who are stuporous and aphasic will most likely score 1 or 0. Patients with brainstem strokes and bilateral sensory loss score 2. If the patient has no response and is quadriplegic, score 2. Patients in a coma (item 1a = 3) automatically score 2 on this item. Scoring for item 8 is as follows:

[0315] • 0 = Normal; no sensory loss.

[0316] • 1 = Mild to moderate sensory loss; patient feels pinprick on affected side to be less sharp or dull; or surface pain is absent with pinprick, but patient can feel being touched.

[0317] • 2 = Severe or complete sensory loss; patient cannot feel being touched on face, arms, and legs.

[0318] Project 9: Best Language Instructions

[0319] Much information about comprehension has been obtained in the preceding examination section. For this scale item, the patient is asked to describe what is happening in the attached pictures, name the objects on the attached naming sheet, and read the attached list of sentences. 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 by the patient's response to all the instructions here, as well as in the general neurological examination described previously. If visual loss affects the testing, the patient is asked to identify objects placed in the hand, repeat and make sounds. Patients with intubation are asked to write. Patients in a coma (item 1a = 3) will automatically score 3 on this item. The examiner must choose a score for patients who are comatose or have limited cooperation, but a score of 3 should only be used if the patient is mute and does not follow any single-step instructions. Scoring for item 9 is as follows:

[0320] • 0 = No aphasia; normal.

[0321] • 1 = Mild to moderate aphasia; fluent or comprehension abilities are markedly impaired, but there are no obvious restrictions in expressing ideas or in form of expression. However, the decline in speech and / or comprehension makes it very difficult or impossible to have a conversation about the material presented. For example, in a conversation about the material presented, the examiner can identify the content of the picture or naming cards from the patient's responses.

[0322] • 2 = Severe aphasia; all communication is by piecemeal expression; the listener needs to infer, question, and guess very much. The range of exchangeable information is limited, and the listener bears the burden of communication. The examiner cannot identify the presented material from the patient's responses.

[0323] • 3 = Mutism, complete aphasia; no usable speech or auditory comprehension.

[0324] Item 10: Dysarthria Indication

[0325] If the patient is considered normal, the patient must be asked to read or repeat the words in the NIH Stroke Scale document, pages 11 and 12, to obtain an adequate speech sample. If the patient has severe aphasia, the articulation clarity of spontaneous speech can be scored. Only if the patient is intubated or there is another physical impediment to speech should the examiner record a score of UN, and clearly write the explanation for this choice. Do not tell the patient why he / she is being tested. The score for item 10 is as follows:

[0326] • 0 = Normal.

[0327] • 1 = Mild to moderate dysarthria; the patient has at least some words that are not clearly articulated, and in the worst case, can be somewhat difficult to understand.

[0328] • 2 = Severe dysarthria; the patient's speech is so slurred that it is unintelligible without any speech disorder or out of proportion to any speech disorder, or mutism / dysarthria.

[0329] • UN = intubated or other physical impediment, explanation:

[0330] Item 11: Extinction and failure to pay attention to indications (formerly known as neglect)

[0331] Enough information can be obtained in the foregoing tests to identify neglect. If the patient has severe visual loss and cannot simultaneously receive visual double stimulation, and the skin stimulation is normal, score normal. If the patient has aphasia but appears to be indeed able to attend to both sides, score normal. The presence of visual spatial neglect or agnosia can also be taken as evidence of abnormality. Since abnormality is scored only if it is present, this item is never untestable. The score for item 11 is as follows:

[0332] • 0 = No abnormality.

[0333] • 1 = visual, tactile, auditory, spatial, or personal attentional neglect, or bilateral simultaneous stimulation neglect for a certain sensory modality.

[0334] • 2 = severe hemi-neglect for more than one sense or neglect; unable to recognize own hand or orient to only one side of space.

[0335] The individual scores for the 11 items are added to obtain the patient's total NIHSS score. The highest score is 42 and the lowest score is 0. Stroke severity can be determined by the NIHSS according to the following:

[0336] NIHSS Severity 0 No stroke symptoms 1–4 Mild stroke 5–15 moderate stroke 16–20 moderate to severe stroke 21–42 severe stroke

[0337] The NIHSS of a patient treated according to the present application can be at least 10, for example, 10 to 20. Up to 8% of hospitalized ischemic stroke patients and up to 15% of all middle cerebral artery (MCA) strokes develop life-threatening swelling. Patients who progress to such swelling can present with a National Institutes of Health Stroke Score (NIHSS) typically greater than 20 when the dominant hemisphere is involved and greater than 15 when the non-dominant hemisphere is involved. In other examples, the majority (perhaps more than 99%) of cases that continue to form significant swelling have an NIHSS > 10. Patients with an NIHSS score less than 10 do not tend to form life-threatening swelling.

[0338] Definitions and explanations

[0339] The following terms will be used in describing and claiming the present application.

[0340] 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 a single or multiple such SUR1-TRPM4 channel inhibitors.

[0341] 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.

[0342] As used herein, the term "large hemispheric infarction" or "LHI" refers to an ischemic stroke affecting all or nearly all territory of the middle cerebral artery (MCA), with or without involvement of adjacent territories (i.e., anterior cerebral artery [ACA] or posterior cerebral artery [PCA] territories).

[0343] The term "lesion" refers to an abnormality in brain tissue. In some cases, the injury can be a space-occupying lesion, which has an identifiable volume and can involve nearby tissues and blood vessels.

[0344] As used herein, the term "placebo" refers to a formulation that does not contain a SUR1-TRPM4 antagonist, or a formulation that is similar in composition, except that the amount (wt%) of the SUR1-TRPM4 channel inhibitor is replaced by the same amount (wt%) of another inert ingredient (e.g., water). In addition, as understood by one of skill in the art, a "placebo" can result in a formulation that is slightly different due to the absence of a drug in general.

[0345] The term "subject" as used herein includes all members of the animal kingdom, including mammals, most typically referring to a human patient.

[0346] The term "sulfonylureas" includes sulfonylureas, sulfonylurea mimetics, and any other composition effective to block or reduce activity associated with the SUR1 channel.

[0347] A "stroke" occurs when there is an inadequate blood flow to the brain and can result in cell death. As defined herein, there are essentially two known types of stroke, i.e., ischemic stroke or hemorrhagic stroke. Ischemic strokes occur when there is a lack of blood flow to the brain and hemorrhagic strokes occur when there is bleeding in the brain, or there is bleeding within the brain tissue and includes subarachnoid hemorrhage and intracerebral hemorrhage. Both forms can result in cerebral edema.

[0348] As used herein, the terms "treat" or "treatment" are art-recognized and refer to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the recurrence of disease, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. In addition to use as a therapeutic method, the methods described herein can be useful in preventing or prophylaxis of a disease.

[0349] As used herein, the term "about" is used to provide leeway for endpoints of a range of values by providing that a given value can be "a little above" or "a little below" the endpoint. The leeway of this term can be specified by the particular variable and will be within the knowledge of the skilled artisan depending on experience and the relevant description herein. For example, in one embodiment, the leeway can be within about ±10% of the value. In another embodiment, the leeway can be within about ±5% of the value. In another embodiment, the leeway can be within about ±2%, ±1%, or ±0.05% of the value.

[0350] Generally, the term "or" as used herein encompasses "and / or".

[0351] As used herein, a variety of active agents, compounds, injuries, or conditions, etc. can be presented in one general list for convenience. However, these lists should be interpreted as if each member of the list is separately identified as a separate and unique member. Thus, unless indicated to the contrary, individual members of such a list should not be construed as being factually equivalent to any other member of the same list merely based on their presentation in the same group.

[0352] Concentrations, amounts, and other numerical data can be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be construed as having been followed to its broadest extent, unless it is understood that when supported by the specification the numerical limits were too narrow to support this broad language. For example, a numerical range expressed as "about 0.01 to 2.0" should be interpreted to include not only individual values explicitly recited as the upper and lower limits of the range, but also to include the entire range based on the individual value. Thus, "about 0.01 to 2.0" means about 0.01 to about 2.0. In this instance, every individual value of about 0.01 to about 2.0 inclusive is incorporated in the range. The same applies to ranges using both endpoints. In addition, it is intended that every combination of the individual values of the ranges should be expressly stated herein. For example, a statement that a composition is between about 1 and 3 or between about 1 and 3, is intended to convey that the composition can be about 1, about 2, about 3, or any other value or sub-range within the specified range. Further, it is intended that every individual value and sub-range should be incorporated in the range as if each is explicitly stated. More specifically, it is intended that the description as a range should be interpreted to be broadly enough to encompass individual values and sub-ranges within the range. Also, the description as a range should be interpreted to include single values within the range and sub-ranges within the range unless the context clearly indicates otherwise. Additionally, it should be noted that all percentages are by weight unless otherwise specified.

[0353] As used herein, all percentage compositions are given as weight percentages, unless otherwise specified. When referring to a solution of a component, the percentages refer to the weight percentage of the composition including the solvent (e.g., water), unless otherwise specified.

[0354] The terms "comprise(s)," "comprising," "include(s)," "including," "contain(s)," "containing," "have(s)," "having," or the like, are open-ended transitional phrases and terms that are intended to convey to a person of ordinary skill in the art the broadest possible interpretation of the terms in the context in which they are used, such that the terms should be interpreted in the manner intended by the person of ordinary skill in the art when using the terms. The terms "consisting of" and "consisting essentially of" are closed transitional phrases and terms that are intended to convey to a person of ordinary skill in the art the narrowest possible interpretation of the terms in the context in which they are used, such that the terms should be interpreted in the manner intended by the person of ordinary skill in the art when using the terms. As used herein, the terms "comprise(s)," "comprising," "include(s)," "including," "contain(s)," "containing," "have(s)," "having," or the like, are open-ended transitional phrases and terms that are intended to convey to a person of ordinary skill in the art the broadest possible interpretation of the terms in the context in which they are used, such that the terms should be interpreted in the manner intended by the person of ordinary skill in the art when using the terms. The terms "consisting of" and "consisting essentially of" are closed transitional phrases and terms that are intended to convey to a person of ordinary skill in the art the narrowest possible interpretation of the terms in the context in which they are used, such that the terms should be interpreted in the manner intended by the person of ordinary skill in the art when using the terms. As used herein, the term "consisting essentially of" means that the composition, method or process can include additional steps, elements, components or species, but only if the additional steps, elements, components or species do not materially alter the basic and novel characteristics of the claimed composition, method or process. It is understood that a recitation of any of these transition terms (i.e., "comprising," "consisting of," or "consisting essentially of") provides direct support for the alternative recitation of any other of these transition terms. For example, a recitation of the term "comprising" would find direct support from a recitation of the term "consisting essentially of" and vice versa, due to this definition.

[0355] As used herein, multiple compounds or steps can be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on its presence on the same general list.

[0356] Further, certain compositions, injuries or conditions, steps, etc. can be discussed in the context of a specific embodiment. It is understood that such discussion does not apply only to the embodiment in question but also to the likewise applicable embodiments found herein. For example, the list of active agents or drugs described in relation to methods of treating late neurological deterioration or death can find direct support in embodiments relating to methods of reducing linear shift in the brain, even if those drugs are not recited in the context of the described embodiment in the specification.

[0357] Embodiments of the present disclosure will be described with reference to the following examples, which are offered merely by way of illustration and not by way of limitation.

[0358] Example

[0359] The CHARM trial evaluated the safety and efficacy of intravenous glibenclamide treatment in patients with large hemispheric infarction (LHI) at high risk of cerebral oedema.

[0360] Patients were included if they met the following criteria:

[0361] • Clinical diagnosis of acute ischemic stroke in the middle cerebral artery (MCA) territory.

[0362] • Large hemispheric infarction was defined as a lesion volume of 80 to 300 cubic centimeters (cm3) on magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) or computed tomography perfusion (CTP), or Alberta Stroke Program Early CT Score (ASPECTS) of 1 to 5 and involvement of at least 2 clearly defined cortical regions. 3

[0363] • Screening National Institutes of Health Stroke Scale (NIHSS) > 10.

[0364] • At randomization, must be able to start study drug treatment infusion within 10 hours of symptom onset (if known) or last known normal time, per investigator’s judgment.

[0365] • Participants who wake with stroke can also be included if they meet the neurological and other exclusion criteria. Stroke onset time should be the midpoint between the time of sleep onset (or last known normal time) and the time of wakefulness.

[0366] • For participants who undergo thrombectomy, must be enrolled in the study based on MRI-DWI after thrombectomy.

[0367] Patients meeting the following criteria were excluded:

[0368] • Participants are likely to discontinue support therapy by Day 1.

[0369] • Commitment to undergo decompressive craniectomy (DC) prior to enrollment.

[0370] • Evidence of a concurrent severe infarction in the contralateral cerebral hemisphere that is sufficiently severe to affect functional outcome.

[0371] Pre-specified primary endpoint

[0372] • Shift analysis of the modified Rankin Scale (mRS) score at 90 days using a 5-category ordinal scale (with 0 / 1 and 5 / 6 combined). The primary efficacy analysis was pre-specified to be conducted in participants 18 to 70 years of age, inclusive, who were randomized and received study treatment (modified intent-to-treat [mITT] population).

[0373] A total of 535 subjects were enrolled, of which 268 were treated with placebo and 267 were treated with intravenous injection of glibenclamide. The mITT population (primary analysis population) consisted of participants ≤ 70 years of age who received any study drug and consisted of 431 subjects.​

[0374] Analyses were conducted in the mITT population to investigate the effect of CTP or DWI volume >80 cm at enrollment. 3 Methods: The effect of lesion volume on treatment-group differences in patients enrolled in the ASPECTS study was not considered (patients enrolled using the ASPECTS study were excluded because lesion volume was not assessed). An interaction term between treatment group and stroke volume was included in an ordinal logistic regression model with the 90-day mRS as the dependent variable. Independent variables included age, sex, baseline NIHSS score, world region, tissue plasminogen activator status, and thrombectomy.

[0375] Of the 431 subjects who comprised the mITT population, 280 (65%) had baseline stroke volume assessed by CTP or DWI. Baseline infarct volume was 154 ± 146 mL and did not differ between treatment groups. The common odds ratio (cOR) decreased with increasing lesion volume and was higher at approximately 140 cm 3 Crossing the "no effect" point (cOR = 1.0) indicates that the drug has no effect if the threshold is exceeded. 3 , cOR increases with decreasing lesion volume, and lesion volume less than 85 cm 3 The cOR for the patient group was approximately 6, indicating a particularly strong effect in patients with smaller lesion volumes. 3 There was a statistically significant interaction (p = 0.031) between the two groups, with 3 In the subgroup of subjects treated with glibenclamide, the outcome was favorable (cOR 2.31, 95% CI 1.07-5.01, p=0.034).

[0376] Surprisingly, the beneficial effect was significantly higher in subjects who received glyburide plus thrombectomy (n=81). In these patients, there was an interaction between treatment and stroke volume (p=0.009), with subjects treated with glyburide having a favorable outcome (cOR 4.69, 95% CI 1.10-20.1, p=0.037). Figure 1 As shown, cOR is at about 180 cm 3 The "no effect" point (cOR = 1.0) was crossed at 1.5, indicating that above this threshold there was no drug effect. Thus, the effect of combining glibenclamide administration with mechanical thrombectomy increases the population of subjects who can benefit from this approach and results in a significantly higher functional benefit.

[0377] Thus, in patients with mITT who underwent thrombectomy, the cOR obtained was several times higher than that in the overall population, indicating that the thrombectomy population responded particularly well.

Claims

1. A method of improving outcomes in a patient diagnosed with ischemic stroke, wherein, The patient has experienced a wake-up stroke, comprising administering to the patient a SUR1-TRPM4 channel inhibitor.

2. The method of claim 1, wherein, The patient is 18 years of age to 70 years of age at the start of treatment.

3. The method of claim 1, wherein, The patient has received mechanical thrombectomy prior to the administering step.

4. The method of claim 3, wherein, The administering begins prior to or during the mechanical thrombectomy.

5. The method of claim 1, wherein, Treatment begins within 9 hours of the midpoint between the start of sleep (or last known normal time) and wake-up time.

6. The method of claim 1, wherein, Treatment begins within 10 hours of the midpoint between the start of sleep (or last known normal time) and wake-up time.

7. The method of claim 1, wherein, The administering begins within 8 hours of the first stroke symptom.

8. The method of claim 1, wherein, The SUR1-TRPM4 inhibitor is administered in one or more continuous infusions for a total duration of at least 72 hours.

9. The method of claim 1, wherein, The patient has received decompressive hemicraniectomy.

10. The method of claim 1, wherein, The patient has a lesion volume of 180 cm 3 The following.

11. The method of claim 1, wherein, The patient has a lesion volume less than 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 .

12. The method of claim 1, wherein, the patient has a lesion volume > 50 cm 3 and < 125 cm 3 or > 50 cm 3 and < 100 cm 3 .

13. The method of claim 1, wherein, The SUR1-TRPM4 channel inhibitor comprises a member selected from the group consisting of: glibenclamide, 4-trans-hydroxyglibenclamide, 3-cis-hydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, mitiglinide, gliquidone, LY397364, LY389382, gliclazide, glimepiride, pharmaceutically acceptable salts thereof, metabolites thereof that interact with SUR1, and combinations thereof.

14. The method of claim 1, wherein, The SUR1-TRPM4 channel inhibitor is glibenclamide.

15. A method of treating ischemic stroke in a patient who has experienced a wake-up stroke, comprising treating the patient with a therapeutically effective amount of a SUR1-TRPM4 inhibitor.

16. The method of claim 15, wherein, The treatment begins prior to mechanical thrombectomy.

17. The method of claim 15, wherein, The treatment begins during or after mechanical thrombectomy.

18. The method of claim 15, wherein, The patient's lesion volume is less than 180 cm 3 , 170cm 3 , 160cm 3 , 150cm 3 , 140cm 3 , 130cm 3 , 125cm 3 , 120cm 3 , 110cm 3 , 100cm 3 , 90cm 3 or 80cm 3 .

19. The method of claim 1, wherein, The patient receiving mechanical thrombectomy is selected using non-contrast computed tomography.

20. The method of claim 1, wherein, The patient is treated with tissue plasminogen activator.

21. The method of claim 20, wherein, The patient has an ASPECTS score of < 7.

22. The method of claim 15, wherein, The patient receiving mechanical thrombectomy is selected using computed tomography perfusion imaging or magnetic resonance imaging.

23. The method of claim 18, wherein, The lesion volume is measured by using computed tomography perfusion or magnetic resonance imaging.

24. The method of claim 17, wherein, The patient receives a non-contrast computed tomography after mechanical thrombectomy but before beginning treatment with a SUR1-TRPM4 inhibitor.

25. The method of claim 17, wherein, The lesion volume is determined prior to mechanical thrombectomy.

26. The method of claim 17, wherein, The lesion volume is determined after mechanical thrombectomy.

27. The method of claim 1, wherein, The patient has a National Institutes of Health Stroke Scale (NIHSS) score of 10 to 20.

28. The method of claim 1, wherein, The patient has a National Institutes of Health Stroke Scale (NIHSS) score of 10 to 18.

29. The method of claim 1, wherein, The SUR1-TRPM4 channel inhibitor is glibenclamide or a pharmaceutically acceptable salt thereof in a formulation comprising a buffer, a base, and a sugar alcohol, wherein the formulation has a pH outside the buffering capacity of the buffer, and wherein the buffer has a pKa of 7.7 to 9.

2.

30. The method of claim 29, wherein, The glibenclamide or pharmaceutically acceptable salt thereof is about 2.7% (w / w) to 3.1% (w / w) of the formulation, and / or wherein the sugar alcohol is about 84% (w / w) to 90% (w / w) of the formulation.

Images