Low-adsorbed glyburide kits, formulations and methods

Abstract

Methods and formulations for minimizing or avoiding adsorption of glyburide to surfaces of delivery tubes, filters, bags, and other containers and materials, thereby storing and delivering a more stable product, delivering a predictable and accurate dose of glyburide while minimizing impurities, avoiding drug wastage, reducing costs, and significantly reducing the amount of administration solution that must be infused into a patient. In one aspect, the disclosure includes a lyophilized formulation in a kit comprising glyburide or a pharma- ceutically acceptable salt thereof; a base; and a sugar alcohol, wherein the lyophilized formulation is configured to be combined or reconstituted with a separate buffer provided in the kit, and wherein the reconstituted formulation has a pH outside the range of the buffering capacity of the buffer.

Description

[Technical field]

[0001] Field of Disclosure The present disclosure relates to the field of medical treatment methods, including methods for intravenous administration of drugs to a subject. [Background technology]

[0002] background Glyburide (also known as glibenclamide) is a sulfonylurea drug used in the treatment of diabetes. The systematic name of glyburide is 5-chloro-N-(4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl)-2-methoxybenzamide. Glyburide binds preferentially to and affects sulfonylurea receptor 1 (SUR1), but at higher concentrations also binds to and affects sulfonylurea receptor 2 (SUR2).

[0003] Glyburide has been suggested as a treatment for a variety of disorders including, but not limited to, Large Hemispherical Infarction (LHI), acute stroke (ischemic and hemorrhagic), traumatic brain injury (TBI), spinal cord injury (SCI), myocardial infarction (MI), cerebral contusion (BC), edema, traumatic brain injury, subarachnoid hemorrhage, spinal cord injury, shock (including hemorrhagic shock), organ ischemia, and ventricular arrhythmias to prevent CNS edema, reduce mortality, and preserve neurological function.

[0004] Glibenclamide solubility in various solutions has been reported, typically with very poor solubility in aqueous buffer solutions. For example, the solubility of glibenclamide in aqueous buffer solutions has been reported by Glomme et al. (Glomme A, Marz J, Dressman J B. Comparison of a miniaturized shake-flask solubility method with automated potentiometric acid / base titrations and calculated solubilities. J Pharm Sci. 2005 January; 94(1):1-16). The aqueous buffer solutions were made with distilled water to form potassium chloride (220 mM) solutions buffered with potassium phosphate (29 mM) and pH adjusted to pH 5, 6, or 7 with sodium hydroxide. These solutions had an osmolality between about 280 and 310 milliosmolar and a buffering capacity of about 10 ± 2 milliequivalents / L / pH. Glomme et al. report that glibenclamide is only marginally soluble in such solutions, with very low solubility at pH 2, 3, 5, 6, and 7, and relatively high (but still very low) solubility at pH 8, 9, and 11.8. These solubilities are shown in Table 1. [Table 1]

[0005] Similarly, low glibenclamide solubility in aqueous solutions was reported by Kaiser et al. (Kaiser DG, Forist, A A. A review of Glibenclamide Metabolism in Man and Laboratory Animals. Physical and Analytical Chemistry Research, The Upjohn Company; 1975) with a solubility of less than 1 mg / mL at all measured pH values ​​from pH 4 to pH 9. Glibenclamide was dissolved in Britton-Robinson buffer (Britton-Robinson buffer is an aqueous buffer containing phosphoric, acetic and boric acids pH adjusted with sodium hydroxide). These solubilities are reported in Table 2. [Table 2]

[0006] Applicants have discovered that the concentration of glyburide decreases in glyburide solutions placed in various types of pharmaceutical containers due to various processes including glyburide instability, degradation, and adsorption to such containers. Glyburide is virtually insoluble within the typical pH range of pharma- ceutically acceptable infusion solutions (pH 5-9), which poses challenges in obtaining stable glyburide formulations that can be administered to patients over time. It is also necessary and important to control the stability of the stored glyburide formulation and its diluted administration solution for infusion (e.g., after approximately 100-fold dilution of the stored glyburide formulation).

[0007] An additional difficulty is that dilute solutions of glyburide readily bind to plastics such as polyvinyl chloride (PVC) or polyurethane (PUR), materials commonly used in infusion components such as saline IV bags and administration sets. In Phase 1-3 clinical trials in the United States, specialized infusion sets (low-adsorption, polyethylene-lined) have been used to address drug-substance compatibility issues, but this stopgap strategy is impractical for multiple reasons, including the difficulty of supplying specialized infusion sets, and the fact that glyburide is intended for use in critical care settings and for indications where minimizing the time between when the patient was last known to be normal and when administered is critical for efficacy (i.e., "time is brain"). The rate of neural circuit loss in human ischemic stroke highlights the critical nature of care for patients suffering from stroke and brain injury. For example, a typical patient loses 1.9 million neurons per minute if the stroke is untreated. Thus, the added complexity in handling and administering intravenous glyburide (i.e., the requirement of specialized infusion components) would delay administration to the patient, adversely affecting patient outcomes. Furthermore, the use of commonly used materials would result in significant loss of the active pharmaceutical ingredient due to adsorption, resulting in administration of unknown and possibly sub-therapeutic doses of glyburide, again adversely affecting patient outcomes. Furthermore, administering an inaccurate amount of glyburide is unsafe, since glyburide is known to result in hypoglycemia. When administering intravenous glyburide formulations at therapeutic concentrations for the treatment of stroke (LHI) or cerebral contusion, the inventors have found that approximately 40-50% of the glyburide is wasted due to, for example, instability, adsorption, and process issues. Thus, there is a need in the art to produce glyburide formulations that prevent the concentration of glyburide from decreasing due to adsorption of glyburide to surfaces of delivery tubing, filters, bags, catheters, syringes, infusion sets, extension sets, and other containers and materials that come into contact with glyburide. There is a need in the art to produce glyburide formulations that have greater stability at lower pH. There is a need in the art to produce glyburide formulations that reduce the production of degradation products. There is a need in the art to produce glyburide formulations that require significantly less saline infusion fluid to administer a therapeutic dose intravenously. There is a need in the art to produce glyburide formulations that have improved storage stability. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Glomme A, Marz J, Dressman J B. Comparison of a miniaturized shake-flask solubility method with automated potentiometric acid / base titrations and calculated solubilities. J Pharm Sci. 2005 January; 94(1):1-16 [Non-Patent Document 2] Kaiser DG, Forist, A A. A review of Glibenclamide Metabolism in Man and Laboratory Animals. Physical and Analytical Chemistry Research, The Upjohn Company; 1975 Summary of the Invention [Means for solving the problem]

[0009] Summary of the Invention The present disclosure includes formulations, kits and methods for minimizing or avoiding adsorption of glyburide to surfaces of delivery tubing, filters, bags, and other containers and materials, thereby storing and delivering a more stable product, predictable and precise doses of glyburide, while minimizing impurities, avoiding drug wastage, reducing costs, and significantly reducing the amount of administration solution (typically saline or Ringer's solution) that must be infused into the patient.

[0010] In one aspect, the disclosure includes a lyophilized formulation in a kit comprising glyburide or a pharma- ceutically acceptable salt thereof; a base; and a sugar alcohol, wherein the lyophilized formulation is configured to be combined or reconstituted with a separate buffer provided in the kit, wherein the reconstituted formulation has a pH outside the range of the buffering capacity of the buffer.

[0011] In one embodiment, the disclosure includes a method of making an infusion solution comprising about 250-1000 ml of saline solution, 3-5 mg of glyburide, 100-140 mg of mannitol, 10-12 mg of Tris, 0.94-2.98 mg of NaOH, and a pH of 7.5 to 9.2. In some embodiments, the infusion solution has a NaOH:glyburide molar ratio in the range of 2.9:1 to 9.2:1.

[0012] In one embodiment, the disclosure includes a method of making a solution comprising 10-30 ml WFI, 3-5 mg glyburide, 100-140 mg mannitol, 10-12 mg Tris, 0.94-2.98 mg NaOH, and a pH of 9-11, e.g., 9.4 to 10. In some embodiments, the solution has a NaOH:glyburide molar ratio in the range of 2.9:1 to 9.2:1.

[0013] In one aspect, the disclosure includes a method of making a solution comprising 3-5 ml of WFI, 3-5 mg of glyburide, 100-140 mg of mannitol, 0.94-2.98 mg of NaOH, and a pH of 9-12.5, e.g., 11.3-12.

[0014] In one aspect, the disclosure includes a method of making a glyburide formulation having less than 1% by weight loss in glyburide concentration (w / v) due to adsorption to a polymeric container over an infusion period, the method comprising combining glyburide with a buffer having a pKa of 7.7-9.2, a sugar alcohol, and a base having a pKb of 0.1-1.5, in a molar ratio between base and glyburide of 2.9:1-9.2:1.

[0015] In some embodiments, the disclosure includes reconstitution of a formulation of the disclosure in a suitable diluent, such as saline or water for injection (WFI), comprising 4-60 mM, 5-50 mM, 6-40 mM, 7-30 mM, 8-25 mM, 9-23 mM, 10-21 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, or 20 mM buffer.

[0016] In some aspects, the disclosure includes diluting a reconstituted formulation of the disclosure in a saline solution, wherein the diluted formulation has a pH of 7.5 to 9.2.

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

[0018] In some embodiments, the disclosure includes formulations and methods that have high storage stability, e.g., storage stability properties such as less than 0.2% decomposition products over 6 months storage at 25° C. / 60% RH, less than 0.4% decomposition products over 6 months storage at 40° C. / 75% RH, and / or less than 1.0% decomposition products over 7 days storage at 70° C. / 75% RH.

[0019] In some aspects, the disclosure includes a method of increasing the solubility of a glyburide formulation in saline infusion, the method comprising combining glyburide or a pharma- ceutically acceptable salt thereof with a buffer; a base; and a sugar alcohol, wherein the formulation has a pH outside the range of the buffering capacity of the buffer at 4° C., 20° C., or 25° C. to form a solubilized glyburide formulation having a glyburide solubility of 15 μg / ml in the saline infusion, and wherein the glyburide formulation in the saline infusion has a pH of 7.5 to 9.2.

[0020] In some aspects, the disclosure includes a method of minimizing the volume of saline infusion required to infuse a glyburide formulation into a human over a 24 hour period, the method comprising combining 3-5 mg of glyburide, 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, and wherein the glyburide formulation in the saline infusion has a pH of 7.5-9.2, and the volume of saline infusion used to infuse 3-5 mg of glyburide, or a pharmaceutically acceptable salt thereof into a human is about 250-500 ml.

[0021] In some aspects, the disclosure includes a method of increasing the storage stability of a glyburide formulation, the method comprising combining glyburide or a pharma- ceutically acceptable salt thereof with a base and a sugar alcohol, the formulation having a pH outside the range of the buffering capacity of a buffer to form a stabilized glibenclamide formulation, the stabilized glibenclamide formulation having less than 0.2% decomposition products after storage for at least 6 months at 25°C / 60% RH.

[0022] In some aspects, the present disclosure provides a compound having the structure: [ka] and any active metabolites, salts, esters, hydrates, solvates, crystalline forms, co-crystalline forms, amorphous forms, prodrug (including ester prodrug) forms, racemates, polymorphs, chelates, tautomers, stereoisomers, or optically active forms thereof.

[0023] In some aspects, the present disclosure provides a compound having the structure: [ka] and further comprising any active metabolites, salts, esters, hydrates, solvates, crystalline forms, co-crystalline forms, amorphous forms, prodrug (including ester prodrug) forms, racemates, polymorphs, chelates, tautomers, stereoisomers, or optically active forms thereof.

[0024] In some aspects, the present disclosure provides a compound having the structure: [ka] and any active metabolites, salts, esters, hydrates, solvates, crystalline forms, co-crystalline forms, amorphous forms, prodrug (including ester prodrug) forms, racemates, polymorphs, chelates, tautomers, stereoisomers, or optically active forms thereof.

[0025] In some aspects, the present disclosure provides a compound having the structure: [ka] and further comprising any active metabolites, salts, esters, hydrates, solvates, crystalline forms, co-crystalline forms, amorphous forms, prodrug (including ester prodrug) forms, racemates, polymorphs, chelates, tautomers, stereoisomers, or optically active forms thereof.

[0026] In some aspects, the present disclosure provides a compound having the structure: [ka] and any active metabolites, salts, esters, hydrates, solvates, crystalline forms, co-crystalline forms, amorphous forms, prodrug (including ester prodrug) forms, racemates, polymorphs, chelates, tautomers, stereoisomers, or optically active forms thereof.

[0027] In some aspects, the present disclosure provides a compound having the structure: [ka] and any active metabolites, salts, esters, hydrates, solvates, crystalline forms, co-crystalline forms, amorphous forms, prodrug (including ester prodrug) forms, racemates, polymorphs, chelates, tautomers, stereoisomers, or optically active forms thereof.

[0028] In some aspects, the present disclosure provides a compound having the structure: [ka] and any active metabolites, salts, esters, hydrates, solvates, crystalline forms, co-crystalline forms, amorphous forms, prodrug (including ester prodrug) forms, racemates, polymorphs, chelates, tautomers, stereoisomers, or optically active forms thereof.

[0029] In some embodiments, the present disclosure includes a kit comprising a first container containing a lyophilized formulation comprising glyburide or a pharma- ceutically acceptable salt thereof; a base; and a sugar alcohol; and a second container containing an aqueous buffer of the present disclosure, wherein the lyophilized formulation, when reconstituted, has a pH outside the range of the buffer capacity of the aqueous buffer of the present disclosure. In some embodiments, the kit further comprises a mixing device configured to reconstitute and transfer the lyophilized formulation between the first container and the second container prior to administration.

[0030] In some aspects, the present disclosure includes methods of treating a patient suffering from stroke, hemorrhage, neuronal cell swelling, traumatic brain injury, spinal cord injury, organ ischemia, acute coronary syndrome, myocardial infarction, sepsis, cerebral contusion, shock, ischemia, or ventricular arrhythmia.

[0031] In some aspects, the disclosure includes a reconstituted formulation comprising a lyophilized formulation comprising glyburide or a pharma- ceutically acceptable salt thereof; a base; and a sugar alcohol, wherein the formulation is reconstituted in a buffer of the disclosure, wherein the reconstituted formulation has a pH outside the buffer capacity of the buffer, and wherein the reconstituted formulation comprises at least 95%, 96%, 97%, 98%, or 99% of the amount of glyburide or a pharma-ceutically acceptable salt thereof in the lyophilized formulation.

[0032] In some aspects, the disclosure includes an infusion formulation comprising a saline infusion solution and a reconstituted lyophilized formulation comprising glyburide or a pharma- ceutically acceptable salt thereof; a base; and a sugar alcohol, wherein the lyophilized formulation is reconstituted in a buffer of the disclosure, the reconstituted formulation has a pH outside the buffer capacity of the buffer, and the infusion solution comprises at least 95%, 96%, 97%, 98%, or 99% of the amount of glyburide or a pharma-ceutically acceptable salt thereof in the lyophilized formulation.

[0033] In some embodiments, the disclosure includes a method for controlling the pH of a diluted glyburide solution in saline infusion within a pH range of 8-9 over a 24 hour infusion period, the method comprising reconstituting a lyophilized formulation comprising glyburide or a pharma- ceutically acceptable salt thereof; a base; and a sugar alcohol with a buffer of the disclosure, wherein the reconstituted formulation has a pH outside the range of the buffering capacity of the buffer to form a stabilized soluble glyburide formulation; diluting the stabilized soluble glyburide formulation in saline infusion; and infusing the diluted formulation into a patient, wherein the pH of the diluted formulation is between 7.5 and 9.2, and wherein the pH of the diluted formulation does not change by more than 0.2 pH units over the 24 hour infusion period. In an alternative aspect, the disclosure includes reconstituting a lyophilized formulation with water for injection (WFI) such that the reconstituted formulation has a pH outside the range of the buffering capacity of the buffer; introducing the buffer into a saline IV infusion container to form a buffered saline IV infusion solution; and diluting the reconstituted formulation in the buffered saline IV infusion solution to form an infusion solution having a pH of 7.5 to 9.2.

[0034] In some aspects, the disclosure includes a method for reducing the infusion rate of a glyburide solution diluted in saline infusion fluid during a 24 hour infusion, the method comprising combining 3-5 mg of glyburide or a pharma- ceutically acceptable salt thereof; a base; and a sugar alcohol with a buffer, wherein the formulation has a pH outside the buffering capacity of the buffer to form a stabilized soluble glyburide formulation; diluting the stabilized soluble glyburide formulation in saline infusion fluid; and infusing the diluted formulation into a patient at a rate of less than 16 ml / hour for 24 hours in a 500 mL bag and at or about 8 ml / hour for 24 hours in a 250 mL bag. In an alternative embodiment, the disclosure includes combining 3-5 mg of glyburide or a pharma- ceutically acceptable salt thereof; a base; and a sugar alcohol with water for injection (WFI), wherein the formulation has a pH outside the range of the buffering capacity of the buffer; introducing the buffer into a saline IV infusion container to form a buffered saline IV infusion solution; diluting the formulation in the buffered saline IV infusion solution to form an infusion solution having a pH of 7.5-9.2; and infusing the diluted formulation into a patient at a rate of less than 16 ml / hour for 24 hours in a 500 mL bag and at or about 8 ml / hour for 24 hours in a 250 mL bag.

[0035] Other features and characteristics of the subject matter of the present disclosure, as well as its method of operation, function of its associated elements of structure and combination of parts, and economies of manufacture, will become more apparent from a consideration of the following description and appended claims, all of which form a part of this specification. [Brief description of the drawings]

[0036] [Figure 1] FIG. 1 shows the adsorption of a prior art intravenous formulation of glyburide to a medical substance.

[0037] [Diagram 2] FIG. 2 shows the effect of various base:glyburide ratios on the adsorption of prior art intravenous glyburide formulations to PVC administration sets.

[0038] [Diagram 3] FIG. 3 shows the effect of final dosage formulation pH in formulations of the present disclosure on adsorption to PVC administration sets.

[0039] [Figure 4] FIG. 4 shows glyburide solubility of formulations of the present disclosure in 10 mM Tris / 0.9% mannitol solution, which mimics the buffer system after drug product reconstitution.

[0040] [Diagram 5] FIG. 5 shows the correlation between the NaOH:GLY molar ratio in the drug product, the Tris buffer pH (10 mM) in the custom diluent, and the vial pH after reconstitution (20 ml) in the formulation of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] Detailed Description Although aspects of the subject matter of the present disclosure may be embodied in a variety of forms, the following description is intended to disclose only some of these forms as illustrative examples of the subject matter encompassed by the present disclosure, and therefore, the subject matter of the present disclosure is not intended to be limited to the forms or embodiments so described.

[0042] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0043] The term "treating" or "treatment" as used herein and as well understood in the art, refers to an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or relief of one or more symptoms or conditions, whether detectable or undetectable, reduction in the extent of disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, reduction or palliation of pathology, reduction in recurrence of disease, and remission (whether partial or total). "Treating" and "treatment" may also mean prolonging survival compared to expected survival in the absence of treatment. In addition to being useful as a method of treatment, the methods described herein may be useful for the prevention or prophylaxis of disease.

[0044] Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It should be understood that such range formats are used merely for convenience and ease, and therefore should be interpreted flexibly to include not only the numerical values ​​explicitly recited as boundaries of the range, but also all of the individual numerical values ​​or subranges contained within the range as if each numerical value and subrange were explicitly recited. By way of illustration, a numerical range of "about 0.01 to 2.0" should be interpreted not only to include the explicitly recited values ​​of about 0.01 to about 2.0, but also to include the individual values ​​and subranges within the indicated range. Thus, individual values ​​such as 0.5, 0.7, and 1.5, as well as subranges such as 0.5 to 1.7, 0.7 to 1.5, and 1.0 to 1.5, are included in this numerical range. Moreover, such an interpretation should apply regardless of the breadth of the range or the properties being described. In addition, it is noted that all percentages are by weight unless otherwise specified.

[0045] In understanding the scope of the present disclosure, the terms "including" or "comprising" and their derivatives, as used herein, are intended to be open-ended terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers, and / or steps. The above also applies to words with similar meanings, such as the terms "including", "having" and their derivatives. The term "consisting" and its derivatives, as used herein, are intended to be closed-ended terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but exclude the presence of other unstated features, elements, components, groups, integers, and / or steps. The term "consisting essentially of," as used herein, is intended to specify that which does not substantially affect the presence of the stated features, elements, components, groups, integers, and / or steps, as well as the basic and novel characteristics of the features, elements, components, groups, integers, and / or steps. Reference to any one of these transitional terms (i.e., "comprising," "consisting," or "consisting essentially of") is understood to provide direct support for the substitution of any of the other transitional terms not specifically used. For example, amendment of the term "comprising" to "consisting essentially of" will find direct support due to this definition.

[0046] As used herein, the term "about" is used to provide flexibility for numerical range endpoints by providing that a given value may be "a little above" or "a little below" that endpoint. The degree of flexibility of this term may be determined by the particular variable and is within the knowledge of a person skilled in the art to determine based on experience and the relevant explanations herein. For example, in one embodiment, the degree of flexibility may be within about ±10% of the numerical value. In another embodiment, the degree of flexibility may be within about ±5% of the numerical value. In further embodiments, the degree of flexibility may be within about ±2%, ±1%, or ±0.05% of the numerical value. The numerical quantities indicated are approximate, meaning that the terms "approximately", "about" or "approximately" may be inferred unless expressly stated.

[0047] As used herein, the term "pharmaceutical acceptable" refers to a solvent, co-solvent, surfactant, carrier, diluent, excipient, buffer, salt, and / or other component that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In some embodiments, the glyburide formulations of the present disclosure may contain one or more sugar alcohols, including, but not limited to, allitol, arabitol, dextrose, dulcitol, erythritol, galactitol, glycol, glycerol, iditol, isomalt, lactitol, maltitol, mannitol, sorbitol, threitol, xylitol, and combinations thereof.

[0048] As used herein, the term "lyophilized" and its grammatical variations refer to a material (such as a powder) that has been dried from a liquid containing solid or dissolved material by freeze-drying (freezing a liquid containing dissolved or suspended material and drying while frozen by sublimation) to provide a dry solid containing the dissolved or suspended material in solid form. Typically, an aqueous solution is used in lyophilization, but mixed aqueous / solvent solutions and other liquid solutions can be used. For example, a biological material can be lyophilized from a solution or suspension in which it is mixed with a protective agent. Such a solution or suspension can then be frozen and subsequently dehydrated by sublimation. Sublimation can be followed by an additional drying step, if necessary. Typically, the lyophilization method involves freeze-drying a liquid solution or suspension to provide a dry residue containing a high concentration of dissolved or suspended compounds. In some cases, the solid provided by lyophilization can be or include a salt. The lyophilization process provides a solid such as a powder, a dry film, or a cake. If desired, small particles may be obtained from such powders, films or cakes by procedures such as grinding or flaking.

[0049] The methods and formulations provided herein provide pharma- ceutically acceptable formulations of glyburide, including concentrated solutions, diluted solutions, and lyophilized formulations, that overcome the problems of adsorption, degradation, instability, and low solubility associated with glyburide in prior art pharmaceutical formulations.

[0050] Examples of suitable pharma- ceutically acceptable diluents, such as solutions containing WFI (water for injection) and isotonic saline, are known in the art. Pharmaceutically acceptable aqueous solutions include Ringer's solution, Hartmann's solution, 0.9% saline, 0.45% N saline, WFI (water for injection), D5W (5% dextrose in water), phosphate buffered saline (PBS), and dextrose / saline solutions (D2.5W (i.e., 2.5% dextrose in water) and 0.45% N saline).

[0051] The present disclosure includes the use of a buffer of the present disclosure to reconstitute a lyophilized drug product. The present disclosure includes a solution of a lyophilized drug product reconstituted in a buffer of the present disclosure. The present disclosure includes diluting the reconstituted solution in a pharma- ceutically acceptable diluent.

[0052] As used herein, "Ringer's solution" refers to a pharma- ceutically acceptable buffered saline solution having sodium chloride, potassium chloride, and calcium chloride salts.

[0053] 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 (0.6% sodium chloride, 0.25% sodium lactate, 0.04% potassium chloride, and 0.027% calcium chloride).

[0054] As used herein, a pharma- ceutically acceptable saline solution is a solution suitable for administration to a patient, containing water and sodium chloride, and may contain, if necessary, buffers, preservatives, or other components, typically in small amounts. For example, pharma- ceutically acceptable saline solutions include 0.9% saline (9 g NaCl (containing 150 mM sodium and 150 mM chloride) in 100 ml of distilled filtered water) and saline solutions having 154 mM sodium and 154 mM chloride.

[0055] Generally, in this specification, the term "or" includes "and / or."

[0056] As used herein, a plurality of compounds, elements, or steps may be presented in a common list for convenience. However, these lists should be construed as if each member of the list were individually identified as a separate and unique member. Thus, the individual members of such lists should not be construed as being effectively equal to any other member of the same list simply based on their presentation in a common group, without indication to the contrary.

[0057] Furthermore, certain compositions, elements, excipients, ingredients, disorders, conditions, characteristics, steps, or the like may be discussed in the context of one specific embodiment or aspect, or in a separate paragraph or section of this disclosure. It is understood that this is merely for convenience and brevity, and that any such disclosure is intended to be combined with any other embodiment or aspect found anywhere in this disclosure and claims that are equally applicable and all form the present application and claimed invention as of the filing date. For example, a list of method steps, active agents, kits, or compositions described in relation to a formulation or method of treating a particular subject is intended, and does, be found as direct support for the embodiments related to the compositions, formulations, and methods described anywhere else in this disclosure, even if those method steps, active agents, kits, or compositions are not re-listed in the context or section of that embodiment or aspect.

[0058] The inventors have found that glyburide in conventional intravenous glyburide formulations readily and extensively binds to the polymeric containers that contain, for example, polyvinyl chloride (PVC) and polyurethane (PUR) infusion sets. See FIG. 1. While the use of low-adsorption polyethylene-lined infusion sets would minimize adsorption, such specialized infusion sets are impractical for multiple reasons, including the difficulty of supplying such specialized infusion sets, and the fact that intravenous glyburide is intended for use in critical care settings and for indications where minimizing the time between when the patient was last known to be normal and when administered is critical for efficacy (i.e., "time is brain"). Thus, presenting additional complications in the handling and administration of intravenous glyburide, i.e., requiring strict use of specialized infusion components in critical care settings, would delay administration to patients and adversely affect patient outcomes. Furthermore, the use of materials commonly used with prior art intravenous glyburide formulations would result in the loss of significant amounts of the active pharmaceutical ingredient due to adsorption, resulting in the administration of unknown and possibly subtherapeutic doses of glyburide. In addition, the use of commonly used substances with prior art intravenous glyburide formulations results in instability and degradation, leading to drug products of unacceptable quality. Furthermore, it is unsafe to administer unknown amounts of glyburide or to attempt to increase the volume of drug to be administered, because administration of glyburide at higher doses (e.g., at rates higher than the average rate of 0.25 mg / hour (6 mg / day)) can result in hypoglycemia. As shown in FIG. 1, the change in the amount of glyburide in prior art intravenous glyburide formulations that binds to commonly used infusion sets over the infusion period is a significant and unpredictable change. Furthermore, it is undesirable to perform a flushing procedure that is complicated, time-consuming, inaccurate, high in wear, and may pose a risk of contamination. Furthermore, the inventors have found that glyburide in prior art intravenous glyburide formulations binds readily and extensively to all filter components (data not shown).Therefore, there is a need to provide a new intravenous glyburide formulation that avoids binding to commonly used infusion sets and filter materials, allowing healthcare providers to treat patients with accurate doses within the appropriate administration window (close to the immediate aftermath of a stroke, infarction, injury, etc.) using commonly used medical supplies while avoiding complications, avoiding drug wastage, and reducing the amount of infusion fluid administered to the patient. Additional advantages of the present invention include improved safety and reduced contamination. In addition, the present disclosure allows for the use of infusion sets with filters while avoiding adsorption of glyburide to the filters.

[0059] In a first aspect, the disclosure provides formulations containing a stable therapeutic dose of glyburide that have less than 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01% loss of glyburide concentration (w / v) due to adsorption to polymeric containers containing, for example, 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.

[0060] In a second aspect, the disclosure provides formulations containing a stable therapeutic dose of glyburide with less than 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01% loss of glyburide concentration (w / v) due to adsorption to an in-line filter material. In some aspects, the filter may comprise a material such as polyethersulfone or polyvinylidene difluoride (PVDF).

[0061] In a third aspect, the disclosure provides methods and formulations for controlling the pH of a glyburide solution within a desired narrow range, both before and after dilution in an infusion fluid.

[0062] In a fourth aspect, the disclosure provides methods and formulations for minimizing or avoiding the formation of degradants in stored glyburide solutions.

[0063] In a fifth aspect, the disclosure provides methods and formulations for reducing infusion rates, reducing drug wastage, and reducing saline uptake in subjects being treated with intravenous glyburide.

[0064] In a sixth aspect, the disclosure provides methods and formulations for maintaining a sufficiently high concentration of glyburide in solution during formulation compounding that can enable filling into appropriately sized containers to achieve a therapeutic dose, e.g., 3-5 mg glyburide / day.

[0065] In a seventh aspect, the present disclosure provides methods and formulations to provide sufficient solubility, stability, and a desired pH upon reconstitution to achieve a desired high concentration during drug preparation.

[0066] In an eighth aspect, the disclosure provides methods and formulations for providing sufficient solubility, stability, and a desired pH upon further dilution of a reconstituted glyburide formulation into an infusion fluid (e.g., at a concentration of 6-20 μg / ml in a saline bag) for administration over a period of 3, 4, 6, 12, 24, 30, 36, 48, 72, 96, or 120 hours.

[0067] In one embodiment, the disclosed method and formulation includes compounding a glyburide formulation comprising glyburide and a base as defined herein to form a lyophilized powder. In one embodiment, the disclosed method and formulation includes combining the lyophilized powder with a buffer of the disclosed method. In one embodiment, the disclosed method and formulation includes reconstituting the lyophilized powder in a buffer of the disclosed method. In one embodiment, the buffer has a pKa of 7.7-9.2, 7.8-9.1, 7.9-9.0, 8.0-8.9, 8.05-8.8, 8.1-8.7, or any specified pKa within a specified range. For example, and without limiting the disclosure above, the buffer can be Tris, lysine, arginine, ethylenediamine, imidazole, 4-(2-hydroxyethyl)morpholine, triethanolamine, glucamine, deanol (dimethylaminoethanol), phosphate, phosphate buffered saline (PBS), or a combination thereof. In one embodiment, the buffer of the present disclosure has a buffering capacity in the pH range of 7 to 9. In one embodiment, the Tris can be a combination of Tris-HCl and Tris-base. In one embodiment, the lysine is lysine-HCl. In one embodiment, the arginine is arginine-HCl.

[0068] In one aspect, the disclosure includes methods and lyophilized formulations comprising glyburide, a base, and a sugar alcohol combined with a separate buffer of the disclosure, the combination having a pH outside the range of the buffer capacity of the buffer, the combination being suitable (including safe, sustained therapeutically effective, and tolerable) for infusion into humans over a period of 24 hours or longer. In one aspect, the formulation (reconstituted formulation) has a pH greater than 9.0, greater than 9.5, greater than 10.0, or greater than 10.5, e.g., 9.3-11, while the buffer has a buffer capacity in the pH range of 7-9.

[0069] In some embodiments, the formulation can maintain a stable pH upon reconstitution.For example, the formulation has a pH within about 0.1 or about 0.2 pH units after storage at 25°C / 60% relative humidity (RH), 40°C / 75%RH, or 70°C / 75%RH or at about 25°C / 60% relative humidity (RH), about 40°C / 75%RH, or about 70°C / 75%RH for 1, 2, or 4 weeks, or 3, 6, or 12 months.In some aspects, stability can be determined by measuring the generation 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.

[0070] In some embodiments, the buffer is a combination of Tris-HCl and Tris-base. In some embodiments, 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.

[0071] In some embodiments, the reconstituted glyburide formulation comprises about 5-15%, 6-14%, 7-13%, 8-12%, 9-13%, or 10-12% (w / w) buffer. In some embodiments, the reconstituted glyburide formulation comprises about 1-100 mM, 2-80 mM, 3-70 mM, 4-60 mM, 5-50 mM, 6-40 mM, 7-30 mM, 8-25 mM, 9-23 mM, 10-21 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, or 20 mM buffer. In some embodiments, the reconstituted glyburide formulation contains about 1-5 mg / ml, 1.2-4 mg / ml, 1.5-3.5 mg / ml, or 2-3 mg / ml of buffer.

[0072] In some embodiments, the buffering agent is a buffer solution having a pH of 7.8-9, 8.1-8.9, 8.2-8.8, 8.3-8.7, 8.4-8.6, or 8.5.

[0073] In some embodiments, the lyophilized formulation comprising glyburide, base, and sugar alcohol may be reconstituted, if necessary, using, for example, WFI or other suitable diluent, and then diluted in an IV bag containing an aqueous diluent containing a buffer of the present disclosure.

[0074] In some embodiments, the disclosure includes the use of a mixing device that allows for the reconstitution and transfer of a lyophilized formulation between a vial and an IV bag prior to administration. The mixing device may be a needleless device. The mixing device may be a needleless device, as described in USP <797> The mixing device may have a dual channel design that provides a dedicated fluid path in and out of the IV bag. In one aspect, the present disclosure includes the use of a mixing device as described in U.S. Pat. No. 8,551,067 (Zinger), which is incorporated herein by reference in its entirety. In one aspect, the present disclosure includes the use of a mixing device as described in U.S. Pat. No. 10,688,295 (Lev), which is incorporated herein by reference in its entirety. In some aspects, the present disclosure includes the use of a mixing device as described in U.S. Pat. No. 10,688,295 (Lev), which is incorporated herein by reference in its entirety. TM and / or a method of using a MIX2VIAL® mixing device to reconstitute and transfer a lyophilized formulation between a vial and an IV bag prior to administration. In some aspects, the disclosure includes kits, formulations, containers, and methods of using a mixing device to reconstitute and transfer a lyophilized formulation comprising glyburide, a base, and a sugar alcohol with a buffer.

[0075] In a second embodiment, the base is a strong base with a pKb of 0.1 to 1.5. Any pharma- ceutically acceptable strong base may be used. For example, and without limiting the above disclosure, the base may be NaOH, Ca(OH)2, or KOH.

[0076] In a third aspect, the formulations of the present disclosure include a specific weight ratio between glyburide and base to achieve a pH target in the formulation in the range of 9.8-11.2, 9.9-11.1, 10.0-11.0, 10.1-10.9, 10.2-10.8, 10.3-10.7, or 10.4-10.6.

[0077] In some embodiments, the formulations of the present disclosure include specific molar ratios between the base and glyburide, which are 2.9:1-9.2:1, 3:1-9:1, 3.2:1-8.8:1, 3.4:1-8.5:1, 3.6:1-8.2:1, 3.8:1-8:1, 4:1-7.8:1, 4.4:1-7.5:1, 4.6:1-7.2:1, 4.8:1-7:1, 5.0-6.7:1, 5.1-6.6:1, 5.2-6.5:1, 5.3-6.4:1, 5.4-6.3:1, 5.5-6.7:1, 5.8-6.7:1, 5.9-6.8:1, 5.1-6.8:1, 5.2-6.8:1, 5.3-6.8:1, 5.4-6.8:1, 5.5 ... .2:1, 5.6-6.1:1, 5.7-6.0:1, or 3:1, 4:1, 4.5:1, 4.7:1, 5.2:1, 5.3:1, 5.4:1, 5.5:1, 5.6:1, 5.8:1, 6:1, 6.2:1, 6.4:1, 6.6:1, 6.8:1, 7:1, 7.2:1, 7.4:1, 7.6:1, 7.8:1, 8:1, 8.2:1, 8.4:1, 8.6:1, 8.8:1, 9:1, 9.2:1, or any ratio or range encompassed by the endpoints 2.9:1 to 9.2:1. The molar ratios used according to the present disclosure are unexpectedly about 2-fold higher than those used in prior art glyburide formulations.

[0078] In some embodiments, the lyophilized glyburide formulation comprises about 2-3.5%, 2.5-3.3%, 2.7-3.1%, 2.8-2.98%, 2.9-2.97%, or 2.94-2.96% (w / w) glyburide.

[0079] In some embodiments, the lyophilized glyburide formulation comprises about 70-93%, 75-92%, 80-91%, 84-90%, 86-89%, or 87-89% (w / w) of a sugar alcohol of the present disclosure. In some embodiments, the sugar alcohol is mannitol, sorbitol, xylitol, or a combination thereof. In some embodiments, the sugar alcohol is mannitol.

[0080] In some aspects, the formulations of the present disclosure comprise a specific weight ratio between the sugar alcohol and the glyburide in the formulation.

[0081] In some embodiments, the reconstituted formulations of the present disclosure include a specific weight ratio between the sugar alcohol and the buffering agent, which is 5-15:1, 6-14:1, 7-13:1, 8-12:1, 9-11:1, 9.5:1, 10:1, or 10.5:1 in the formulation.

[0082] In some embodiments, the reconstituted glyburide formulation contains about 20-40 mg / ml, 24-36 mg / ml, 26-34 mg / ml, 38-32 mg / ml, 29 mg / ml, 30 mg / ml, or 31 mg / ml of sugar alcohol.

[0083] In some embodiments, the reconstituted glyburide formulation has a pH of about 9.3-11, 9.4-10.9, 9.5-10.8, 9.6-10.7, 9.7-10.6, 9.6-10.5, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, or 10.4. In some embodiments, the reconstituted glyburide formulation has a pH of 9.5-10.0.

[0084] In some embodiments, glyburide is a free acid or a pharma- ceutically acceptable salt thereof. In some embodiments, the glyburide formulation comprises a sodium addition salt of glyburide. As used throughout this disclosure, reference to "glyburide" may also refer to its salts, esters, hydrates, solvates, racemates, tautomers, stereoisomers, and / or optically active forms.

[0085] In some aspects, the present disclosure includes preparing an aqueous solution of the glyburide of the present disclosure at a concentration described herein, adding a base of the present disclosure at a weight ratio to the glyburide described herein, and freeze-drying the solution to obtain a lyophilized solid composition. In some aspects, the aqueous solution may further contain a sugar alcohol of the present disclosure at a concentration described herein.

[0086] In some embodiments, the formulations of the present disclosure include cyclodextrins, meglumine, sugars such as fructose, mannose, galactose, arabinose, xylose, and ribose, as well as oligosaccharides such as disaccharides (maltose, lactose, sucrose, trehalose, and the like) and trisaccharides (e.g., raffinose, maltotriose, and the like), salts, alcohols such as ethanol, diethanolamine, Britton-Robinson buffer, lactose, malt ... The composition is free of one or more of the following: stearate, 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, salicylic acid and the like, choline, n-methylglucamine, diethylamine, procaine and the like.

[0087] In some embodiments, the reconstituted formulations of the present disclosure have an osmolarity of between about 250 milliosmoles per liter (mOsm) and about 350 mOsm; or between about 280 mOsm and about 320 mOsm; or between about 290 mOsm and about 310 mOsm.

[0088] The present disclosure provides methods and formulations that allow for the provision of glyburide formulations with significantly higher glyburide solubility in the administration solution, i.e., approximately three times higher than prior art intravenous glyburide administration solutions (i.e., greater than 15 μg / ml as opposed to less than 5.7 μg / ml in prior art intravenous glyburide administration solutions), and further, even at these three-fold higher concentrations, there is no detectable loss of glyburide due to precipitation or adsorption.

[0089] In some embodiments, the diluted (or also referred to herein as the "final dose" formulation) glyburide formulation according to the present disclosure has a glyburide concentration of 7.2 (±0.2) μg / mL and an injection pH of up to about 8.3 (±0.1).

[0090] In some embodiments, the final administered glyburide formulation has a pH of 7.8-9.0, 7.9-9.0, 8.0-9.0. In some embodiments, the final administered glyburide formulation has a pH of 7.8-9, 7.9.8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, or 8.9.

[0091] In some embodiments, the final administered glyburide formulation has a buffer concentration of about 0.1-0.5 mM, about 0.15-0.4 mM, about 0.2-0.3 mM, or about 0.2 mM.

[0092] In some embodiments, the diluted glyburide formulations of the present disclosure are diluted into an IV infusion bag, thereby reducing the amount of infusion fluid administered to a subject. For example, in some embodiments, the diluted glyburide formulations of the present disclosure are diluted into a 250 mL IV infusion bag. In some embodiments, the diluted glyburide formulations of the present disclosure are diluted into a 500 mL IV infusion bag. Given the increased solubility, stability, and minimized adsorption to medical containers, the formulations of the present disclosure allow for the use of more concentrated dosage formulations, thereby delivering a consistent therapeutic dose over the infusion period while using significantly less infusion fluid.

[0093] In some aspects, the disclosure provides methods for reducing the volume of infusion fluid administered to a subject by about 25-50% over the infusion period, e.g., from about 2 L to about 1 L over a 4 day infusion period, or from about 1.5 L to about 0.75 L over a 3 day infusion period.

[0094] In some embodiments, due to the advantages of the present invention, the diluted glyburide formulation can be administered at a slower rate than prior art intravenous glyburide formulations, for example, the infusion rate can be reduced to about 40% of the infusion rate used to inject prior art intravenous glyburide formulations, for example, 11.5 ml / hr for the first 6 hours and 8 ml / hr thereafter versus 29 ml / hr for the first 6 hours and 20 ml / hr thereafter compared to prior art intravenous glyburide formulations.

[0095] In some embodiments, the disclosure includes sterilizing the formulation of the disclosure. In some embodiments, the formulation may be sterile filtered. In some embodiments, the formulation may be sterilized to have zero bioburden. In some embodiments, the product of the disclosure may be terminally sterilized. In some embodiments, the product is sterilized with gamma irradiation. In some embodiments, the product is sterilized with electron beam, x-ray, hydrogen peroxide, or ethylene oxide. In some embodiments, the product may be a powder, solution, vial, kit, pre-filled syringe, injection device, cartridge, on body injector, autoinjector, infusion bag, or any other container or set of containers suitable for storage, infusion, and / or injection of the product of the disclosure. In some embodiments, the product may be sterilized in a 10-ml container. -3 , 10 -4 , or 10 -6 Meet the "sterility assurance level" or "SAL" of the

[0096] In some aspects, the present disclosure provides a compound having the following structure: [ka] The present invention provides a compound having the formula:

[0097] In some aspects, the disclosure provides a compound comprising glyburide and the following structure: [ka] The present invention provides a formulation comprising a compound having the formula:

[0098] In some aspects, the present disclosure provides a compound having the following structure: [ka] In some embodiments, the formulation may contain less than 1% by weight, less than 0.5% by weight, less than 0.3% by weight, less than 0.1% by weight, less than 0.05% by weight, e.g., 0.001-0.04% by weight, 0.01-0.03% by weight, 0.01% by weight, 0.02% by weight, or 0.03% by weight of the compound.

[0099] A kit having features of the present invention may include a lyophilized formulation of the present disclosure, or may include a lyophilized formulation of the present disclosure together with a buffer of the present disclosure in a separate container, and may include instructions for the use of such formulation and buffer. A kit having features of the present invention may include a lyophilized formulation of glyburide, and / or may include a lyophilized formulation of glyburide together with one or more compounds, and / or may include a lyophilized formulation of glyburide together with one or more liquids for reconstitution, and may include instructions for the use of such lyophilized formulation. For example, instructions for the use of such lyophilized formulation may include instructions for reconstituting such lyophilized formulation to provide a solution suitable for use in pharmaceutical applications, preferably a sterile solution. In some embodiments, a kit may include lyophilized glyburide, base, and sugar alcohol in one container, e.g., a vial, syringe, pen, or bag, and a buffer of the present disclosure in a separate container. In some embodiments, the vial contains a buffer of the present disclosure at a concentration of 6-40 mM, 7-30 mM, 8-25 mM, 9-20 mM, or 10-15 mM. In some embodiments, the kit may also include a mixing device for reconstituting and transferring a reconstituted formulation according to the present disclosure.

[0100] Thus, the formulations and kits disclosed herein provide improved medicaments and treatments, and the methods disclosed herein provide improved methods for making medicaments and for treating patients. The present disclosure includes a method for treating a patient suffering from a disorder selected from the group consisting of stroke, neuronal cell swelling, traumatic brain injury, spinal cord injury, organ ischemia, acute coronary syndrome, myocardial infarction, sepsis, and diabetes, comprising intravenously administering to a patient in need thereof an effective amount of the aqueous pharmaceutical composition described herein. In certain cases, the disorder is stroke. In certain cases, the patient is a human. In certain other cases, the disorder is stroke, ischemia, hypoxia / ischemia, spinal cord injury, brain trauma, or other brain injury. The patient in need of treatment may be, for example, a patient suffering from diabetes, or hemorrhage, or other disorder or condition. The patient in need of treatment may be, for example, a patient suffering from ischemia of any organ or organs or system. Such a system may be, for example, the nervous system, including a part of the nervous system, or the cardiovascular system, or a part of the cardiovascular system. Such an organ may be, for example, the brain, the heart, muscle, or other organ. The patient in need of treatment may be any patient who may benefit from administration of the formulation, composition, and / or kit contents disclosed herein. Further examples of patients in need of treatment include patients suffering from disorders selected from the group consisting of stroke, hemorrhage, neuronal cell swelling, traumatic brain injury, spinal cord injury, organ ischemia, acute coronary syndrome, myocardial infarction, and sepsis.

[0101] In some embodiments, the disclosed formulations, methods, and kits provide for tolerable, safe, effective, and predictable infusion administration to patients over extended periods of time, e.g., 3, 6, 12, 24, 48, 72, 96, 120 hours or longer.

[0102] The present disclosure encompasses liquid formulations, including reconstituted liquid formulations as well as final (diluted) dosing solutions for bolus administration.

[0103] The liquid formulations disclosed herein can be used for infusion (e.g., infusion over an extended period of time) into the vascular system, cerebrospinal fluid, or other administration destinations of patients suffering from stroke, head trauma, spinal cord injury, cardiac arrest resulting in interruption of blood flow to the brain, or other conditions in which the affected individual is at risk of brain swelling or neuronal cell swelling.In yet a further example, the liquid formulations disclosed herein can be used for intraventricular or intrathecal administration to patients suffering from stroke, head trauma, spinal cord injury, cardiac arrest resulting in interruption of blood flow to the brain, or other conditions in which the affected individual is at risk of brain swelling or neuronal cell swelling.Administration of glyburide via liquid formulations, particularly via intra-arterial or intravenous administration, provides a rapid and easy controlled increase in circulating glyburide concentration, providing a rapid onset of treatment that allows for rapid adjustment and easy maintenance of circulating glyburide concentration.

[0104] The inventors have encountered many confounding challenges in developing an intravenous glyburide formulation, especially for use in an emergency care environment. Glyburide is practically insoluble in water at physiological pH and has low stability in that it precipitates and adsorbs to plastic medical containers, tubes, and filters, especially at low and physiological pH. Furthermore, the inventors have found degradation products formed. In particular, when the ratio of base to glyburide is relatively low, the percentage of degradation products formed increases. Although higher pH is used to solubilize glyburide, it is not possible to administer formulations with such higher pH intravenously. Furthermore, due to low solubility and unpredictable adsorption to medical plastic materials, the inventors have encountered problems including, but not limited to, 1) inability to administer therapeutic doses quickly and predictably; 2) wastage of drug product that is adsorbed to materials rather than infused to the patient; and 3) the need to administer large amounts of saline infusion to the patient.

[0105] As shown in Figure 1, in mock infusion studies with various dosing materials using prior art glyburide formulations, there is significant adsorption and concentration changes immediately at the beginning of the infusion that do not recover throughout the infusion period. Furthermore, the change in glyburide concentration varies depending on the dosing set material. Thus, it was largely unpredictable how much of the drug product would be administered to a given patient at any given time depending on a variety of factors.

[0106] Additionally, as shown in Figure 2, we tested glyburide formulations containing the prior art components, but varying the ratio of NaOH to glyburide to determine the effect of that ratio on adsorption. We found that there was significant adsorption immediately at the beginning of the infusion, and that the rate of recovery of glyburide concentration over the infusion period varied significantly between formulations with various ratios of base to glyburide. There was an initial drop in glyburide concentration of at least 10%, which was as much as about 40% when the NaOH:GLY ratio was 3:1. Specifically, prior art formulations of glyburide with various NaOH:GLY molar ratios were reconstituted and diluted into 1 L saline bags. Mock IV infusions were set up using a PVC administration set, and the glyburide concentration of the infusion was measured at the indicated time points (and expressed as a percentage of the initial concentration of glyburide in the IV bag). The lower the NaOH:GLY ratio, the longer the period required for drug concentration to recover. However, it was not possible to use higher ratios of base to glyburide in prior art glyburide formulations to avoid adsorption problems because using a high enough ratio of base to glyburide would have resulted in a reconstituted formulation having a pH that was too high for injection into human patients, i.e., a pH of about 10, whereas the maximum pH considered acceptable for human injection by the industry is pH 9, according to the 2016 Infusion Therapy Standards of Practice.

[0107] Thus, the present disclosure provides formulations, including lyophilized, reconstituted, and diluted (final dose) formulations, that solve the confounding problems mentioned above including adsorption to medical containers, extremely low solubility, low stability, high wear, and the need to inject large amounts of saline to deliver the drug.

[0108] It has been found through experimentation that in creating a formulation that can provide sufficient solubility, stability, therapeutic efficacy, and safety for injection into humans while avoiding adsorption to medical containers, formation of degradation products, and the need to administer large volumes of saline injections to deliver a therapeutic dose, it is necessary to use specific combinations of the disclosed specific buffers, bases, glyburide, and sugar alcohols in specific ranges of amounts and in specific ratios to each other. Unexpectedly, it has been found that it is necessary to use buffers that have buffering capacities outside the pH range of the glyburide formulation.

[0109] To avoid the initial drop in glyburide concentration caused by adsorption to administration sets, a pH increase experiment was conducted using a formulation according to the present disclosure. As shown in Figure 3, it was found that there was at least a 10% dip in glyburide concentration when the pH of the diluted (final dose) formulation according to the present disclosure was less than 7.8. Thus, it was recognized that it is possible to eliminate adsorption to PVC administration sets by producing a glyburide formulation of the present disclosure that consistently maintains a pH of at least 7.8 and has a pH of 9.0 or less when diluted into an infusion fluid (e.g., saline solution). When a drug product with a NaOH:GLY molar ratio of 13.8 is reconstituted into saline with a pH of 7, the resulting pH in the final dose solution is 9.9, which is outside the acceptable infusion pH range.

[0110] A further important requirement was that the reconstituted formulation must remain sufficiently stable and soluble after reconstitution. As an example, in an experiment using 10 mM Tris and 0.9% mannitol, for a drug product vial containing 6 mg of glyburide and with a reconstitution volume of 20 ml, as shown in Figure 4, the resulting concentration was determined to be 0.3 mg / ml of glyburide. Assuming a 20% buffer at the concentration (0.360 mg / ml), a minimum vial pH of 9.14 was required to ensure solution stability after reconstitution. Also, using a Tris concentration lower than 10 mM was sufficient to protect against instability, adsorption, and low solubility, e.g., reconstitution of 6 mg / vial of drug product with 20 ml of 5 mM solution, further dilution into a 1 L saline bag; a buffer concentration of about 0.1 mM Tris in the final dosing solution was sufficient.

[0111] The inventors have unexpectedly found that buffers having a pKa between 7.7 and 9.2 provide important properties for creating a formulation that balances many factors such as being more soluble, more stable, avoiding adsorption to medical plastics, and having the appropriate pH when diluted with an infusion fluid to be administered by injection into humans. Such buffers were not predicted to work in the claimed formulations since glyburide is virtually insoluble within the pH range buffered by such agents.

[0112] Additionally, it was necessary to determine a molar ratio of base to glyburide that would remain sufficiently stable and soluble and avoid adsorption to medical plastic materials. As shown in Figure 5, the base content in the drug product vial (e.g., 6 mg glyburide / vial) and the pH of the buffer (of the present disclosure) used for reconstitution can be correlated based on our findings to produce a formulation that has sufficient stability, solubility, and lacks adsorption. For example, within the target design space of vial pH (9.1-10.2), the critical NaOH:GLY molar ratio region in the vial, and buffer pH were determined. For example, in Figure 7, it is determined that when using NaOH as the base and a buffer of pH 8.5, a NaOH:GLY molar ratio of 5.3 should be used (as indicated by the star).

[0113] In certain embodiments, the kit, method, infusion solution or reconstituted formulation according to the present disclosure may be provided in a container configured to shield the glyburide solution from light. In some embodiments, an amber or brown light-blocking cover or package is used. In some embodiments, a light-blocking cover or package that blocks 90% or more of UV is used. In some embodiments, an aluminum protective cover is used. For example, a light-blocking cover is used to cover an IV bag. This maximizes the stability of the glyburide solution of the present invention over the infusion period.

[0114] The invention of this disclosure will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention, and are not intended to limit the scope of the invention of this disclosure. EXAMPLES

[0115] Example 1 The solubility and stability of glyburide after reconstitution with Tris buffer was tested. To obtain the correct reconstitution pH to obtain the desired solubility and stability characteristics, it was necessary to use a NaOH:GLY molar ratio between 2.9:1 and 9.2:1 along with the appropriate pH of the Tris buffer, as shown in Figure 5, to generate the resulting reconstituted solution within the design space shown in Figure 5. Example 2 A maximum final administration pH of 9.2 (after injection, there is a slight drop in pH to about 9, which is the maximum pH of the solution that can be safely injected into a patient) was used as an upper constraint on the pH of the reconstituted and diluted solutions. Drug reconstitution and dilution experiments were performed. Experiments were performed using glyburide and a vial fill volume of 6 ml (i.e., 6 mg glyburide). Vials were reconstituted with 20 ml water for injection (WFI) and transferred to a 500 ml saline bag (instead of a typical 1 L saline bag to ensure that the formulation of the present disclosure can be safely administered with less saline than used in prior art glyburide formulations) with an initial pH of either 4.5 or 7 (adjusted with HCl or NaOH). This procedure was also performed using a 250 ml saline bag, demonstrating successful and safe delivery of glyburide, thereby allowing even higher glyburide concentrations. It was found that when the vial reconstitution pH was less than 9.14, the final IV bag pH was less than 7.8, resulting in adsorption. If the vial reconstitution pH exceeds 10.2, the final IV bag pH will be greater than 9.2, which is outside the range of pH that can be safely administered to patients. Such a formulation avoids the adsorption of significant amounts of glyburide to the PVC dosing components, as demonstrated below. Example 3

[0116] Through experimentation, it has been found that the buffer should have a pKa of 7.7-9.2, 7.8-9.1, 7.9-9.0, 8.0-8.9, 8.05-8.8, 8.1-8.7, or any particular pKa within the specified range. For example, and without limiting the above disclosure, the buffer may be Tris, lysine, arginine, ethylenediamine, imidazole, 4-(2-hydroxyethyl)morpholine, triethanolamine, glucamine, deanol (dimethylaminoethanol), phosphate, phosphate buffered saline (PBS), or combinations thereof. In tests conducted with buffers such as phosphate (pKa 7.21) and glycine (pKa 9.8), it was found that these buffers do not effectively stabilize glyburide and prevent its adsorption to the medical substance. Specifically, lyophilized glyburide samples containing various amounts of NaOH were reconstituted in 20 ml of sodium phosphate buffer (10 mM, pH 8.0), the pH was measured, and the reconstituted formulations were then diluted in saline injection solution.

[0117] Thus, based on these studies, the present disclosure includes the following formulations:

[0118] Formulation A (reconstituted, undiluted): 1 mg / ml glyburide, 10, 15, 20, 25, 30, 35, or 40 mg / ml mannitol, 1 N NaOH to a formulation pH of 10.4±0.4, 1.20 mg / ml Tris-base, 1.59 mg / ml Tris-HCl (total 20 mM Tris), and water.

[0119] Formulation B (reconstituted, undiluted): 1 mg / ml glyburide, 10, 15, 20, 25, 30, 35, or 40 mg / ml mannitol, 1 N NaOH to a formulation pH of 10.4 ± 0.6, 2.5 to 5 mg / ml arginine, and water.

[0120] Formulation C (reconstituted, undiluted): 1 mg / ml glyburide, 10, 15, 20, 25, 30, 35, or 40 mg / ml mannitol, 1 N NaOH to a formulation pH of 10.4 ± 0.6, 2.5 to 5 mg / ml lysine, and water.

[0121] Formulation D (reconstituted, undiluted): 1 mg / ml glyburide, 10, 15, 20, 25, 30, 35, or 40 mg / ml mannitol, 1 N KOH or Ca(OH)2 to a formulation pH of 10.4 ± 0.6, 1.20 mg / ml Tris-base, 1.59 mg / ml Tris-HCl, and water.

[0122] Formulation E (reconstituted, undiluted): 1 mg / ml glyburide, 10, 15, 20, 25, 30, 35, or 40 mg / ml mannitol, 1 N KOH or Ca(OH)2 to a formulation pH of 10.4 ± 0.6, 2.5 to 5 mg / ml arginine, and water.

[0123] Formulation F (reconstituted, undiluted): 1 mg / ml glyburide, 10, 15, 20, 25, 30, 35, or 40 mg / ml mannitol, 1 N KOH or Ca(OH)2 to a formulation pH of 10.4 ± 0.6, 2.5 to 5 mg / ml lysine, and water.

[0124] Formulation G (reconstituted, diluted): 7.2 μg / ml glyburide, 0.216 mg / ml mannitol, diluted formulation pH of 8.3±0.1, 0.2 mM Tris, water, and 500 mL of saline for injection. Example 4

[0125] The ratio of NaOH:GLY affects important quality attributes of the drug product including impurity formation during storage, adsorption to dosing components, and stability during infusion. A robust process control strategy has been developed for the formulation process that allows control of formulation parameters. Vial pH after reconstitution (20 ml) can be used to ensure that the proper formulation pH is achieved during manufacturing. The target reconstitution pH is 9.8, with a range of 9.2-10.2. In some embodiments, the post-reconstitution concentration is 0.3 mg / ml (6 mg / 20 ml). It has been found that a vial reconstitution pH of at least 9.2 is required when added at a 20% excess concentration (i.e., 0.3 mg / ml x 1.2 = 0.36 mg / ml) to ensure proper stability (Figure 5). Example 5

[0126] The effect of adding Tris buffer to a lyophilized combination of glyburide, NaOH, and mannitol was evaluated. 20 ml of 10 mM Tris buffer was added to a lyophilized combination of glyburide, NaOH, and mannitol. The contents of the vial were dissolved by gentle shaking, and the pH of the solution in the vial after reconstitution was measured with a pH probe. Based on the results, the combination of the lyophilized formulation with 10 mM Tris buffer with 50-65% excess NaOH and pH 8.32-8.65 was able to achieve the desired reconstituted vial pH >9.14, while the use of 20% or 80% NaOH did not provide the desired reconstituted vial pH >9.14.

[0127] The effect of Tris buffer pH and strength on the pH of the BIIB093 DP vial upon reconstitution and the final saline bag pH for infusion was evaluated. Saline bags (0.5 L) were used as is or after adjusting the pH to approximately 7.0 by addition of 1 N NaOH to the saline bag. A total of 45 mL of saline was removed from the bag and 19 mL of reconstituted BIIB093 was added from the vial to the saline bag. The contents of the bag were gently mixed and the final saline bag pH was recorded. Based on the results, the combination of BIIB093 DP at pH 8.44-8.52 with (50-65% excess NaOH) and 10 mM Tris buffer was able to achieve a reconstituted vial pH >9.13 and a final saline bag pH >7.8 and <9.0. When 5 mM Tris was used for reconstitution, it was observed that a small change in buffer pH from 7.95 to 8.19 resulted in approximately a 1 pH unit change in reconstitution vial pH (from 9.13 to 10.13). Example 6

[0128] The stability of glyburide was evaluated after reconstitution with Tris buffer at a pH less than the target pH (9.14) to achieve a solubility of 0.3 mg / mL. 20 mL of Tris buffer was added to the lyophilized formulation of the present disclosure (+50% excess NaOH). The contents of the vial were dissolved by gentle shaking and the pH after reconstitution was measured. Approximately 1 mL samples were removed 0, 1, 2 and 24 hours after reconstitution, filtered through a 0.22 um membrane filter and analyzed by HPLC. No precipitation of glyburide was observed throughout the 24 hours at both the 8.65 and 8.78 reconstitution pH. [Table 3] Example 7

[0129] The pH of the reconstituted vial and saline bag was evaluated. A saline bag (0.5 L) was used after adjusting the pH to approximately 4.5 or 7.0 in the saline bag by adding 1 N HCl or 1 N NaOH, respectively. A total of 60 mL of saline was removed from the bag and 9 mL of reconstituted glyburide was added from the vial to the saline bag. The bag contents were gently mixed and the final saline bag pH was recorded. In these experiments, 10 mM Tris pH 8.5-8.3 (10 mL with 50% excess NaOH) achieved a target pH of >9.37 (corresponding to a glyburide solubility of 0.720 mg / mL) as well as final saline bag pH >7.8 and <9.0. [Table 4] Example 8

[0130] Vial pH and final saline bag pH after reconstitution with 10 mM Tris were evaluated. 6 mL of Tris buffer was added to the lyophilized formulation of the present disclosure (6 mg glyburide and 50% excess NaOH per vial). The contents of the vial were dissolved by gentle shaking, and 2 mL of solution was discarded from the vial. An additional 6 mL or 16 mL of Tris buffer was then added to achieve a final reconstitution volume of 10 mL and 20 mL, respectively. Saline bags (0.5 L) were used after adjusting the pH to approximately 4.5 or 7.0 by adding 1 N HCl or 1 N NaOH, respectively, to the saline bag.

[0131] For the 10 mL vial reconstitution volume: A total of 17 mL of saline was removed from the bag and 9.5 mL of the reconstituted lyophilized formulation of the present disclosure was added from the vial to the saline bag. The bag contents were gently mixed and the final saline bag pH was recorded. Based on the results, 10 mL of 10 mM Tris pH 8.4-8.8 could be used to reconstitute the lyophilized formulation of the present disclosure (containing 50%-65% excess NaOH) to achieve a target pH of >9.25 (corresponding to a glyburide solubility of 0.480 mg / mL) and a final saline bag pH of >7.8 and <9.0. [Table 5]

[0132] For the 20 mL vial reconstitution volume: 20 mL of reconstituted BIIB093 was added from the vial to the saline bag. The bag contents were gently mixed and the final saline bag pH was recorded. Based on the results, 20 mL of 10 mM Tris pH 8.5-8.8 could be considered for reconstitution (containing 80% excess NaOH) to achieve a target pH of >9.25 (corresponding to a glyburide solubility of 0.480 mg / mL) and a final saline bag pH of >7.8 and <9.0. [Table 6]

[0133] The present disclosure provides methods and formulations to address the confounding challenges associated with intravenous glyburide formulations, including low solubility, poor stability, adsorption to dosing materials, degradation, drug wastage, and the need to administer large amounts of saline for injection. It has been found that using the described combination of formulations according to the present disclosure using a specific base, a specific ratio of base to glyburide, and a sugar alcohol, as well as a specific buffer, the solubility requirements of the final dosing solution can be met and solution stability can be ensured throughout the entire infusion period. Furthermore, drug adsorption to dosing components made of PVC or PUR is eliminated, allowing for the expanded use of any commonly used medical dosing components. To achieve precise control of the final dosing solution, the reconstituted formulations of the present disclosure contain the specific buffers of the present disclosure in the specific amounts, ratios, and pHs described above. The buffers, in combination with the appropriate molar ratio of base to glyburide, are important among the process control parameters that affect drug product stability as well as solubility and adsorption. It has been found that when reconstituted using the buffers of the present disclosure, a molar ratio of base to glyburide in the range of 2.9:1 to 9.2:1 is necessary to achieve key quality attributes of the drug product. In summary, the formulation and process elements of the present disclosure provide a robust, stable, and soluble drug product that eliminates the difficulties associated with existing formulations and methods, and also provides a method of administering significantly less saline to patients due to reduced drug wastage and increased solubility.

[0134] Any of the above protocols or similar variants may be described in various documents associated with pharmaceutical products. These documents may include, but are not limited to, protocols, statistical analysis plans, investigator profiles, clinical guidelines, drug guides, risk assessment and drug therapy programs, prescription information and other documents that may be associated with pharmaceutical products. It is specifically contemplated that such documents may be physically packaged with pharmaceutical products according to the present disclosure as kits, as they may be useful or indicated by regulatory authorities.

[0135] Although the subject matter of the present disclosure has been described and illustrated in some detail with reference to certain exemplary embodiments, including various combinations and subcombinations of features, those skilled in the art will readily recognize that other embodiments and variations and modifications thereof are encompassed within the scope of the present disclosure. Moreover, the description of such embodiments, combinations, and subcombinations is not intended to convey that the claimed subject matter requires features or combinations of features other than those expressly recited in the claims. Accordingly, the scope of the present disclosure is intended to include all variations and modifications encompassed within the spirit and scope of the following appended claims.

Claims

1. a. i. glyburide or a pharmaceutically acceptable salt thereof; ii. sugar alcohol; and iii. Base a lyophilized formulation comprising: b. a separate container containing a buffer having a pKa between 7.7 and 9.2; c. instructions for reconstituting the lyophilized formulation in the buffer; Kit including:

2. a. The pharmaceutically acceptable salt thereof is a sodium addition salt. b. the sugar alcohol is mannitol, sorbitol, xylitol, or a combination thereof; or c. Both a) and b); The kit of claim 1.

3. a. The sugar alcohol and glyburide or a pharmaceutically acceptable salt thereof are contained in a weight ratio of 20 to 50:1, 23 to 45:1, 25 to 40:1, 28 to 35:1, 29 to 33:1, 30:1, 31:1, or 32:1, b. The glyburide or a pharmaceutically acceptable salt thereof and the base are in a weight ratio of 4.5 to 1.2:1, 4 to 1.3:1, 3.5 to 1.5:1, 3 to 1.8:1, 2.7 to 2:1, 2.6 to 2.1:1, 2.5:1, 2.4:1, or 2.3:1; c. the sugar alcohol and the base are in a weight ratio of 45 to 75:1, 48 to 70:1, 50 to 67:1, 53 to 65:1, 55 to 63:1, 58:1, 60:1, or 62:1; or d. any combination of a), b) and c); The kit of claim 1.

4. 2. The kit of claim 1, wherein the buffer has a pKa of 8 to 9.

5. a. The base is NaOH, Ca(OH) ２ , KOH, or a combination thereof; b. the buffering agent is Tris, lysine, arginine, ethylenediamine, imidazole, 4-(2-hydroxyethyl)morpholine, triethanolamine, glucamine, deanol (dimethylaminoethanol), or a combination thereof; c. Both a) and b); The kit of claim 1.

6. 2. The kit of claim 1, wherein the buffer is a combination of Tris-HCl and Tris-base in a weight ratio of 7:4 to 5:5, optionally in a weight ratio of 6.5:4.5 to 6.2:5.

0.

7. a. The lyophilized formulation is in an amount of 3 to 8 mg, 3.5 to 7 mg, 4 to 6 mg, or 4 to 5 mg. b. the second container contains an aqueous buffer at a concentration of 6-40 mM, 7-30 mM, 8-25 mM, 9-20 mM, 10 mM, 15 mM, or 20 mM; c. the second container contains 10-30 mL, 15-25 mL, or 20 mL of the buffer; d. the second container contains the buffer having a pH of 7.5 to 8.8, 7.8 to 8.6, 8 to 8.5, 8.2 to 8.5, 8.3, 8.4, or 8.5; or e. Any combination of a) to d). The kit of claim 1.

8. The freeze-dried preparation is a. 0.2 to 10.8% by weight of glyburide or a pharmaceutically acceptable salt thereof; b. 80 to 98% by weight of the sugar alcohol; c. 0.5 to 2.5 wt. % of said base; or d. Any combination of a), b) and c). The kit of claim 1 , comprising:

9. Prior to lyophilization, the base is a. Between 9.5 and 11.5, or b. Between 10.2 and 10.6 2. The kit of claim 1, wherein the lyophilized formulation is added in an amount sufficient to achieve a pre-lyophilization pH of 0.

1.

10. The second container comprises: a. 10-30 mL, 15-25 mL, or 20 mL of said buffer; b. the buffer has a pH of 7.5 to 8.8, 7.8 to 8.6, 8 to 8.5, 8.2 to 8.5, 8.3, 8.4, or 8.5; c. 5-20 mM, 10 mM-15 mM, or 10 mM combination of Tris-HCl and Tris-base; d. 1.9-3.8 wt. % Tris-base and 2.5-5.0 wt. % Tris-HCl; or e. Any combination of a), b), c) and d). The kit of claim 1 , comprising:

11. The lyophilized powder comprises the glyburide or a pharmaceutically acceptable salt thereof, the sugar alcohol, and the base. a. 0.00038-0.02186: 0.440-0.516: 0.021-0.042, b. 0.001-0.015: 0.46-0.5: 0.025-0.035, or c. 0.005-0.01: 0.47-0.5: 0.027-0.032 The kit of claim 1, comprising:

12. A mixing device for reconstituting the lyophilized formulation with the buffer; b. 【Chemistry 1】 or a combination thereof, or c. Both a) and b) 10. The kit of claim 1, further comprising:

13. The kit of claim 1, wherein the buffer is a liquid for reconstitution.

14. A method for producing a glyburide formulation having a loss of glyburide concentration (w / v) of less than 1% by weight over an infusion period due to adsorption to a polymeric container, the method comprising reconstituting the lyophilized formulation using a kit described in any preceding claim.

15. 1. A method for minimizing the volume of saline infusion required to infuse a glyburide formulation into a human over a 24 hour period, said method comprising: a. 3-5 mg of glyburide or a pharmaceutically acceptable salt thereof i. a base; and ii. Sugar alcohols to form a lyophilized solution; lyophilizing the lyophilized solution to produce a lyophilized powder; providing the lyophilized powder in a kit with a buffer in a separate container with instructions for reconstituting the lyophilized powder with the buffer such that the reconstituted formulation has a pH outside the range of the buffering capacity of the buffer; and providing instructions for diluting the reconstituted formulation in 250-600 mL of saline infusion to form an infusion having a pH of 7.5-9.2; or b. 3-5 mg of glyburide or a pharmaceutically acceptable salt thereof i. a base; and ii. Sugar alcohols to form a lyophilized solution; lyophilizing the lyophilized solution to produce a lyophilized powder; providing the lyophilized powder in a kit with the buffer in a separate container with instructions for reconstituting the lyophilized powder with water for injection (WFI) such that the reconstituted formulation has a pH outside the range of the buffer capacity of the buffer; providing instructions for introducing the buffer into a saline IV infusion container to form a buffered saline IV infusion solution; and providing instructions for diluting the reconstituted formulation in 250-600 mL of the buffered saline IV infusion solution to form an infusion solution having a pH of 7.5-9.

2. A method comprising:

16. A reconstituted formulation or infusion solution produced using the kit of any one of claims 1 to 13, wherein the reconstituted formulation or infusion solution has a pH outside the range of the buffering capacity of the buffer, and the reconstituted formulation contains at least 95, 96, 97, 98, or 99% of the amount of glyburide or a pharmaceutically acceptable salt thereof in the lyophilized formulation.

17. 14. The kit of any one of claims 1 to 13 for use in a method for controlling the pH of a solution of glyburide diluted in saline infusion within a pH range of 8 to 9 over a 24 hour infusion period, the method comprising reconstituting the lyophilized formulation using the buffer of the kit, wherein the reconstituted formulation has a pH outside the buffering capacity of the buffer; diluting the reconstituted formulation in the saline infusion; and infusing the diluted formulation into a patient, wherein the pH of the diluted formulation is between pH 7.8 and 9, and the pH of the diluted formulation does not change by more than 0.2 pH units over the 24 hour infusion period.

18. 14. The kit of any one of claims 1 to 13, wherein the glyburide solution is in a container configured to shield the glyburide solution from light, and optionally the container is configured with a protective cover that blocks the transmission of at least 90% of ultraviolet light.

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