Low-adsorption glyburide formulations and methods

Abstract

Methods and formulations 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, 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 formulations comprising glyburide or a pharma- ceutically acceptable salt thereof; a buffering agent; a base; and a sugar alcohol, wherein the formulation has a pH outside the range of the buffering capacity of the buffering agent.

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 to treat 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 buffered aqueous solutions. For example, the solubility of glibenclamide in buffered aqueous 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 buffered aqueous solutions were made with distilled water to form potassium chloride (220 mM) solutions buffered with potassium phosphate (29 mM) and pH adjusted with sodium hydroxide to pH 5, 6, or 7. These solutions had an osmolality between about 280 and 310 milliosmolality and a buffering capacity of about 10 ± 2 meq / 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: Solubility of glibenclamide (aqueous) at 37°C. [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 solubilities below 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: Solubility of Glibenclamide (aqueous) at 27°C. [Table 2]

[0006] Applicants have discovered that the concentration of glyburide is reduced 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 presents a challenge to obtain stable glyburide formulations that can be administered to patients over time. It is also necessary and extremely important to control the stability of the stored glyburide formulations and the diluted administration solutions for injection (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 a number of 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 administration and when the patient was last known to be normal 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 will lose 1.9 million neurons per minute if the stroke goes untreated. Thus, the added complexity of handling and administration of intravenous glyburide (i.e., the requirement of specialized infusion components) delays patient administration, adversely affecting patient outcomes. Furthermore, the use of commonly used materials results in significant loss of active pharmaceutical ingredients due to adsorption, resulting in unknown and possibly subtherapeutic administration of glyburide, again adversely affecting patient outcomes. Furthermore, administering an inaccurate amount of glyburide is unsafe, since glyburide is known to cause hypoglycemia. In 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 being reduced 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 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 formulation comprising glyburide or a pharma- ceutically acceptable salt thereof; a buffering agent; a base; and a sugar alcohol, wherein the formulation has a pH outside the range of the buffering capacity of the buffering agent.

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

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

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

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

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

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

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

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

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

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

[0021] In some aspects, the present disclosure provides a compound having the following structure: [ka] and formulations comprising said compounds, including 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.

[0022] In some aspects, the present disclosure provides a compound having the following structure: [ka] (including any active metabolite, salt, ester, hydrate, solvate, crystalline form, co-crystalline form, amorphous form, prodrug (including ester prodrug) form, racemate, polymorph, chelate, tautomer, stereoisomer, or optically active form thereof).

[0023] In some aspects, the present disclosure provides a compound having the following structure: [ka] and formulations comprising said compounds, including 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 following structure: [ka] (including any active metabolite, salt, ester, hydrate, solvate, crystalline form, co-crystalline form, amorphous form, prodrug (including ester prodrug) form, racemate, polymorph, chelate, tautomer, stereoisomer, or optically active form thereof).

[0025] In some aspects, the present disclosure provides a compound having the following structure: [ka] and formulations comprising said compounds, including 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 formulations comprising said compounds, including 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 following structure: [ka] and formulations comprising said compounds, including 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 disclosure includes a kit comprising a first container containing a lyophilized formulation comprising glyburide or a pharma- ceutically acceptable salt thereof; a base; a sugar alcohol; and a buffering agent, and a mixing device configured to reconstitute and transfer the lyophilized formulation between the first container and a second container prior to administration, wherein the lyophilized formulation, when reconstituted in the second container, has a pH outside the range of the buffering capacity of the aqueous buffer.

[0029] In some aspects, the 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.

[0030] In some aspects, the disclosure provides a reconstituted formulation comprising WFI and a lyophilized formulation comprising glyburide or a pharma- ceutically acceptable salt thereof; a buffering agent; a base; and a sugar alcohol, wherein the formulation has a pH outside the range of the buffering capacity of the buffering agent, 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.

[0031] In some aspects, the disclosure includes infusion formulations comprising saline infusion solutions and aqueous or lyophilized formulations comprising glyburide or a pharma- ceutically acceptable salt thereof; a buffering agent; a base; and a sugar alcohol, wherein the formulation has a pH outside the range of the buffering capacity of the buffering agent, and wherein 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.

[0032] In some aspects, the disclosure includes a method for controlling the pH of a glyburide solution diluted in saline infusion solution in a pH range of 8 to 9 over the course of a 24 hour infusion, the method comprising combining glyburide or a pharma- ceutically acceptable salt thereof; a buffering agent; a base; and a sugar alcohol, wherein the formulation has a pH outside the range of the buffering capacity of the buffering agent, to form a stabilized and soluble glyburide formulation, diluting the stabilized and soluble glyburide formulation in the saline infusion solution, and infusing the diluted formulation into a patient, wherein the pH of the diluted formulation is 7.8 to 9, and wherein the pH of the diluted formulation does not change by more than 0.2 pH units over the course of the 24 hour infusion.

[0033] In some aspects, the disclosure includes a method for reducing the infusion rate of a glyburide solution diluted in saline infusion solution over the course of the 24 hour infusion, the method comprising combining 3-5 mg glyburide or a pharma- ceutically acceptable salt thereof; a buffering agent; a base; and a sugar alcohol, wherein the formulation has a pH outside the range of the buffering capacity of the buffering agent, to form a stabilized and soluble glyburide formulation, diluting the stabilized and soluble glyburide formulation in the saline infusion solution, and infusing the diluted formulation into a patient at a rate of less than 16 ml / hour over the course of 24 hours.

[0034] In some aspects, the disclosure encompasses a compounding process comprising sequentially adding glyburide to mannitol to form a first mixture, then adding Tris-base to the first mixture to form a second mixture, then adding Tris-HCl to the second mixture to form a third mixture, then adding a first amount of NaOH to the third mixture to form a fourth mixture comprising glyburide dissolved and solubilized at 1 mg / ml and at a pH of less than 10.0, and then adding a second amount of NaOH to the fourth mixture to form a final formulation comprising glyburide dissolved and solubilized at 1 mg / ml and having a pH of 10.4±0.4.

[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 detailed description and the appended claims, all of which form a part of this specification. [Brief description of the drawings]

[0036] BRIEF DESCRIPTION OF THE DRAWINGS [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 relationship (contour lines) between the vial pH after reconstitution, the initial saline pH, and the pH of the final dosing solution of the formulations of the present disclosure.

[0041] [Figure 6] Figure 6 shows the NaOH:GLY molar ratios required for use in prior art glyburide formulations to eliminate adsorption to PVC administration sets. (Left) With an initial saline solution pH of 4.5, a NaOH:GLY molar ratio of 13.8 is required in the clinical formulation to achieve a pH of 8.8 in the final administration solution. (Right) When a drug product having a NaOH:GLY molar ratio of 13.8 is reconstituted into a saline solution having a pH of 7, the resulting pH in the final administration solution is 9.9, which is outside the pH range of typical infusion solutions (even considering the pH drop in unbuffered systems during infusion).

[0042] [Figure 7] FIG. 7 shows the correlation between the NaOH:GLY molar ratio in the drug product, Tris buffer pH (10 mM), and vial pH after reconstitution (20 ml) for the formulations of the present disclosure.

[0043] [Figure 8] FIG. 8 shows the correlation between Tris concentration in the formulations versus formulation pH, Tris pH, and NaOH content based on the nonlinear neural network model (training data set: R2=0.96; validation data set: R2=0.98) (DOE #1-3).

[0044] [Figure 9] Figure 9 shows the effect of formulation pH on drug product stability at accelerated conditions (70°C / 75RH) for 7 days (left) and 14 days (right). Formulations with different formulation pH were tested. The formulations were filled into vials (6ml / vial) and lyophilized. The stability of DP was evaluated with respect to three major impurities: (top) Impurity A, (middle) Impurity X, and (bottom) Impurity RRT 1.25.

[0045] [Figure 10-1] Figures 10A and 10B show the effect of formulation pH, initial saline pH, and vial fill on the pH of the final dose solution based on a linear regression model (actual by predicted plot: R2=0.91). Figure 10A (top and bottom) shows the minimum and maximum pH of the final dose solution based on a 6 ml vial fill. Figure 10B (top and bottom) shows the minimum and maximum pH of the final dose solution based on a 4 ml vial fill. [Figure 10-2] Same as above.

[0046] [Figure 11] 11 shows a mock injection experiment with a formulation of the present disclosure and a PVC / PUR administration set. (Left) The concentration of glyburide was monitored in two different administration sets as indicated. (Right) The pH of the administration solution from the distal end of the administration set was measured at the indicated time points.

[0047] [Figure 12]FIG. 12 shows the effect of the weighing variance of TRIS buffer and NaOH on the formulation pH. As the variance in the weighting of these components increases, the variance in the formulation pH also increases. A weighting variance of 2% by weight or less results in a range of formulation pH that is still within the target specification range of 10 to 10.8. However, as the weighting variance increases above 2% by weight, the formulation pH deviates from its target range at both ends of the variance of the weighting of these components.

[0048] [Figure 13] Figure 13 shows the correlation of reconstitution pH with formulation pH, vial fill, and reconstitution volume based on a nonlinear neural network model (training data: R2=0.98; validation data: R2=0.97). (Right) Post-reconstitution vial pH correlates primarily with formulation pH within the intended target fill volume and reconstitution volume. Most of the variance in reconstitution pH is predicted to come from formulation pH (Left). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0049] Detailed Description Although aspects of the subject matter of the present disclosure may be embodied in a variety of forms, the following detailed description is intended to disclose only some of these forms as illustrative examples of the subject matter encompassed by the present disclosure, and thus is not intended to limit the subject matter of the present disclosure to the forms or embodiments so described.

[0050] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0051] The term "treating" or "treatment" refers to an approach to obtain beneficial or desired results (including clinical results) as used herein and as well understood in the art. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration 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, improvement or palliation of the disease state, reduction in recurrence of disease, and remission (whether partial or total). "Treating" and "treatment" may also mean prolonging survival compared to expected survival if not receiving treatment. In addition to being useful as a method of treatment, the methods described herein may be useful for the prevention or prophylaxis of disease.

[0052] 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 as if each numerical value and subrange were explicitly set forth, so as to include not only the numerical ranges explicitly set forth as boundaries of the ranges, but also all of the individual numerical values ​​or subranges subsumed within the ranges. By way of illustration, a numerical range of "about 0.01 to 2.0" should be interpreted not only to include the explicitly set forth 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 encompassed within this numerical range. Moreover, such an interpretation should apply regardless of the breadth of the range or the properties being described. Furthermore, it is noted that all percentages are by weight unless otherwise specified.

[0053] 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 specifying the presence of stated features, elements, components, groups, integers, and / or steps, but not excluding the presence of other unstated features, elements, components, groups, integers, and / or steps. The foregoing also applies to words having 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 specifying the presence of stated features, elements, components, groups, integers, and / or steps, but not excluding the presence of other unstated features, elements, components, groups, integers, and / or steps. The term "consisting essentially of," as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps, as well as those that do not substantially affect the basic and novel characteristics of the features, elements, components, groups, integers, and / or steps. Reference to any one of these transitional terms (i.e., "comprises," "consists of," or "consistes essentially of") is understood to provide direct support for replacement with any of the other transitional terms not specifically used. For example, amendment of the term "comprises" to "consistes essentially of" finds direct support due to this definition.

[0054] 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 common sense of a person skilled in the art to determine based on experience and the relevant explanations herein. For example, in one aspect, the degree of flexibility may be within about ±10% of the numerical value. In another aspect, the degree of flexibility may be within about ±5% of the numerical value. In a further aspect, the degree of flexibility may be within about ±2%, ±1%, or ±0.05% of the numerical value. The numerical quantities indicated are approximate values, meaning that the terms "around", "about" or "approximately" may be inferred unless explicitly stated.

[0055] As used herein, the term "pharmaceutical acceptable" refers to solvents, cosolvents, surfactants, carriers, diluents, excipients, buffers, salts, and / or other components that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In some aspects, 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.

[0056] As used herein, the term "lyophilized" and grammatical variations thereof refer to a material (e.g., a powder) that has been dried by freeze-drying (freezing a liquid containing dissolved or suspended material and drying while frozen by sublimation) from a liquid containing solid or dissolved material 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, biological material can be lyophilized from a solution or suspension that has been mixed with a protective agent. Such a solution or suspension can then be frozen and subsequently dehydrated by sublimation. Sublimation can be followed by a further drying step, if necessary. Typically, lyophilization methods include freeze-drying a liquid solution or suspension to provide a dry residue that contains a high concentration of the dissolved or suspended compound. In some cases, the solid provided by lyophilization can be or contain a salt. The freeze-drying process provides a solid, such as a powder, dry film, or cake, from which small particles can be obtained, if desired, by procedures such as grinding or flaking.

[0057] 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.

[0058] Examples of suitable pharma- ceutically acceptable diluents, including, for example, 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 (D2.5W (i.e., 2.5% dextrose in water) and 0.45% N saline).

[0059] As used herein, "Ringer's solution" refers to a pharma- ceutically acceptable buffered saline solution having sodium chloride, potassium chloride, and calcium chloride salts.

[0060] As used herein, "Hartmann's solution" refers to lactated Ringer's solution. A representative Hartmann's solution contains 131 mM sodium, 5 mM potassium, 2 mM calcium, 11 mM chloride, and 29 mM lactate (0.6% sodium chloride, 0.25% sodium lactate, 0.04% potassium chloride, and 0.027% calcium chloride).

[0061] As used herein, a pharma- ceutically acceptable saline solution is a solution suitable for administration to a patient that contains water and sodium chloride, and may optionally contain buffers, preservatives, or other components (typically in small amounts). For example, pharma- ceutically acceptable saline solutions include 0.9% saline (9 g NaCl in 100 ml distilled, filtered water (containing 150 mM sodium and 150 mM chloride)) and saline having 154 mM sodium and 154 mM chloride.

[0062] Generally, in this specification, the term "or" includes "and / or."

[0063] As used herein, multiple compounds, elements, or steps are presented in a common list for convenience. However, these lists should be construed as if each member of the list is 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 merely based on their presentation in a common group, without indication to the contrary.

[0064] Furthermore, certain compositions, elements, excipients, ingredients, disorders, conditions, properties, steps, etc. 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 equally applicable and intended to be combined with any other embodiment or aspect found anywhere in this disclosure and claims, all of which form the present application and the 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, find direct support for the embodiments related to compositions, formulations, and methods described anywhere else in this disclosure, even if those method steps, active agents, kits, or compositions are not relisted in the context or section of that embodiment or aspect.

[0065] The inventors have found that glyburide in conventional intravenous glyburide formulations readily and extensively binds to polymeric containers including, 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 a number of reasons, including the difficulty of supplying such specialized infusion sets, and intravenous glyburide is intended for use in critical care settings and for indications where minimizing the time between administration from when the patient was last known to be normal is critical for efficacy (i.e., "stroke is a race against the clock"). Thus, presenting additional complications in the handling and administration of intravenous glyburide, i.e., requiring the use of specialized infusion components in a critical care setting, would result in delayed administration to the patient 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 active pharmaceutical ingredient due to adsorption, resulting in the administration of unknown and possibly subtherapeutic doses of glyburide. Furthermore, the use of commonly used materials with prior art intravenous glyburide formulations results in instability and degradation, resulting in 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, in prior art intravenous glyburide formulations that bind to commonly used infusion sets over the course of an infusion period, the change in the amount of glyburide is substantial and unpredictable. Furthermore, it is undesirable to perform a flushing procedure that is complicated, time-consuming, imprecise, 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).Thus, there is a need to provide a new intravenous glyburide formulation that avoids binding to commonly used infusion sets and filter materials and allows healthcare providers to treat patients with accurate doses within the appropriate dosing window (close to the aftermath of a stroke, infarction, injury, etc.) using commonly used medical supplies, while avoiding complications, avoiding drug wastage, and reducing the amount of infusate administered to the patient.

[0066] In a first aspect, the present disclosure provides formulations comprising stable therapeutic doses of glyburide having less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.05%, less than 0.01% loss of glyburide concentration (w / v) due to adsorption to polymeric containers (including, for example, polyvinyl chloride (PVC), polyurethane (PUR), polypropylene, polyamide, polystyrene, polyethylene terephthalate (PET), polycarbonate (PC), acrylonitrile butadiene (ABS), polybutadiene, polyolefins, ethylene vinyl acetate, polyether ether ketone (PEEK), and mixtures, combinations, and copolymers thereof).

[0067] In a second aspect, the present disclosure provides formulations comprising a stable therapeutic dose of glyburide having less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.05%, less than 0.01% loss of glyburide concentration (w / v) due to adsorption to in-line filter materials.

[0068] 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 of the infusion fluid.

[0069] In a fourth aspect, the disclosure provides methods and formulations for minimizing or avoiding the formation of degradants in stored glyburide solutions.

[0070] 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.

[0071] 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 / day glyburide).

[0072] In a seventh aspect, the present disclosure provides methods and formulations to provide sufficient solubility, stability, and a desired pH upon reconstitution to achieve desirable high concentrations during drug preparation.

[0073] 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., in a saline bag at a concentration of 6-10 μg / ml) for administration over a period of 3 hours, 4 hours, 6 hours, 12 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, 72 hours, 96 hours, or 120 hours.

[0074] In one aspect, the disclosed methods and formulations include formulating a glyburide formulation comprising glyburide, a buffering agent, and a base as described herein. In one aspect, the buffering agent has a pKa of 7.7-9.2, 7.8-9.1, 7.9-9.0, 8.0-8.9, 8.05-8.8, 8.1-8.7, or any specified pKa in a specified range. For example, and without limiting the foregoing disclosure, the buffering agent can be Tris, lysine, arginine, ethylenediamine, imidazole, 4-(2-hydroxyethyl)morpholine, triethanolamine, glucamine, deanol (dimethylaminoethanol), phosphate, phosphate buffered saline (PBS), or combinations thereof. In one aspect, the disclosed buffering agent has a buffering capacity in the pH range of 7-9. In one aspect, the Tris can be a combination of Tris-HCl and Tris-base. In one aspect, the lysine is lysine-HCl. In one aspect, the arginine is arginine-HCl.

[0075] In one aspect, the disclosure includes methods and formulations comprising glyburide, a buffering agent, a base, and a sugar alcohol, where the formulation has a pH outside the range of the buffering capacity of the buffering agent, and the formulation is 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 buffering agent has a buffering capacity in the pH range of 7-9.

[0076] In some embodiments, the formulation can maintain a stable pH. For example, the formulation has a pH that is within about 0.1 or about 0.2 pH units after storage at or near 25°C / 60% relative humidity (RH), 40°C / 75%RH, or 70°C / 75%RH for 1 week, 2 weeks, or 4 weeks, or 3 months, 6 months, or 12 months. In some embodiments, the glyburide has increased stability compared to the same formulation that either lacks a buffering agent or has a buffering agent with a buffering capacity that overlaps with the pH of the formulation. In some aspects, the stability can be determined by measuring the production of degradation products. For example, the degradation products can be measured by HPLC. In some aspects, the degradation products are quantified based on the relative retention time (RRT) on HPLC.

[0077] 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.

[0078] In some aspects, the lyophilized glyburide formulation comprises about 5-15%, 6-14%, 7-13%, 8-12%, 9-13%, or 10-12% (w / w) of the buffering agent. In some aspects, the reconstituted glyburide formulation comprises about 5-15%, 6-14%, 7-13%, 8-12%, 9-13%, or 10-12% (w / w) of the buffering agent. In some aspects, the reconstituted glyburide formulation 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 of the buffering agent. In some aspects, the reconstituted glyburide formulation comprises about 1-5 mg / ml, 1.2-4 mg / ml, 1.5-3.5 mg / ml, or 2-3 mg / ml of the buffering agent.

[0079] In some aspects, the buffering agent is a buffer 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.

[0080] In some aspects, 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 can be a needleless device. The mixing device can 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 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 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 by reference in its entirety. TM, and / or a method of using the MIX2VIAL® mixing device to reconstitute and transfer a lyophilized formulation between a vial and an IV bag prior to administration.

[0081] In a second aspect, 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 foregoing disclosure, the base may be NaOH, CaOH, or KOH.

[0082] In a third aspect, the formulations of the present disclosure include a specific weight ratio between the glyburide and the base to achieve a target pH 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.

[0083] In some aspects, the formulations of the present disclosure include a specific molar ratio between the base and the glyburide, which in the formulation is 5.0-6.7:1, 5.1-6.6:1, 5.2-6.5:1, 5.3-6.4:1, 5.4-6.3:1, 5.5-6.2:1, 5.6-6.1:1, 5.7-6.0:1, or 5.2:1, 5.3:1, 5.4:1, 5.5:1, or 5.6:1. The molar ratios used in accordance with the present disclosure are unexpectedly about 2-fold higher than those used in prior art glyburide formulations.

[0084] In some aspects, the lyophilized glyburide formulation comprises about 2-3.5%, 2.5-3.3%, 2.7-3.1%, 2.8-2.98%, 2.9-2.97%, or 2.94-2.96% (w / w) of the glyburide.

[0085] In some aspects, the lyophilized glyburide formulation comprises about 70-93%, 75-92%, 80-91%, 84-90%, 86-89%, or 87-89% (w / w) of a sugar alcohol of the present disclosure. In some aspects, the sugar alcohol is mannitol, sorbitol, xylitol, or a combination thereof. In some aspects, the sugar alcohol is mannitol.

[0086] In some aspects, the formulations of the present disclosure include a specific weight ratio between the sugar alcohol and the glyburide in the formulation.

[0087] In some aspects, the formulations of the present disclosure include a specific weight ratio between the sugar alcohol and the buffering agent, which in the formulation 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.

[0088] In some aspects, the reconstituted glyburide formulation contains about 20-40 mg / ml, 24-36 mg / ml, 26-34 mg / ml, 38-32 mg / ml, 29 mg / ml, 30 mg / ml, or 31 mg / ml of the sugar alcohol.

[0089] In some aspects, the reconstituted glyburide formulation has a pH of about 9.3-11, 9.4-10.9, 9.5-10.8, 9.6-10.7, 9.7-10.6, 9.6-10.5, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, or 10.4. In some aspects, the reconstituted glyburide formulation has a pH of 9.5-10.0.

[0090] In some aspects, the glyburide is a free acid or a pharma- ceutically acceptable salt thereof. In some aspects, the glyburide formulation comprises a sodium addition salt of glyburide. As used throughout this disclosure, reference to "glyburide" may also refer to salts, esters, hydrates, solvates, racemates, tautomers, stereoisomers, and / or optically active forms thereof.

[0091] In some aspects, the present disclosure includes preparing an aqueous solution of glyburide in a buffer of the present disclosure at a concentration described herein, adding a base of the present disclosure at the weight ratio to glyburide described herein, and freeze-drying the solution to provide a lyophilized solid composition. In some aspects, the aqueous solution may further include a sugar alcohol of the present disclosure at a concentration described herein.

[0092] In some aspects, the formulations of the present disclosure include, but are not limited to, cyclodextrins, meglumine, sugars (such as, for example, fructose, mannose, galactose, arabinose, xylose, and ribose), as well as oligonucleotides (such as disaccharides (maltose, lactose, sucrose, trehalose, and the like) and trisaccharides (e.g., raffinose, maltotriose, and the like)), salts, alcohols (such as, for example, ethanol), diethanolamine, Britton-Robi The composition does not include one or more of the following: nson buffer, lactate, acetate, glutamate, glycine, citrate, succinate, surfactants, polysorbates, solubilizing polymers (e.g., polyethylene glycol), inorganic or organic acids (e.g., methanesulfonic acid, lactic acid, tartaric acid, citric acid, succinic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.), choline, n-methylglucamine, diethylamine, procaine, etc.

[0093] In some aspects, 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.

[0094] The present disclosure provides methods and formulations that allow for the provision of glyburide formulations with significantly higher glyburide solubility in the administration solution (i.e., approximately three-fold higher than prior art intravenous glyburide administration solutions (i.e., greater than 15 μg / ml as opposed to less than 5.7 μg / ml in prior art intravenous glyburide administration solutions). Moreover, even at these three-fold higher concentrations, there is no detectable loss of glyburide due to precipitation or adsorption.

[0095] In some aspects, a diluted (or referred to herein as a "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 about 8.3 (±0.1).

[0096] In some aspects, the final dose glyburide formulation has a pH of 7.8-9.0, 7.9-9.0, 8.0-9.0 In some aspects, the final dose 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.

[0097] In some aspects, the final administered glyburide formulation has a buffer concentration of about 0.1-0.5 mM, about 0.15-0.4 mM, about 0.2-0.3 mM, or about 0.2 mM.

[0098] In some aspects, the diluted glyburide formulations of the present disclosure are diluted into a 500 ml IV infusion bag, thereby reducing the amount of infusion fluid administered to the subject. In view of the increased solubility, stability, and minimized adsorption to medical containers, the formulations of the present disclosure allow for the use of a more concentrated dosage formulation, thereby using significantly less infusion fluid, while at the same time delivering a consistent therapeutic dose over the infusion period.

[0099] In some aspects, the disclosure provides methods for reducing 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 over a 4 day infusion period, or from about 1.5 L to 1.1 L over a 3 day infusion period.

[0100] In some aspects, due to the advantages of the present invention, the diluted glyburide formulation can be administered at a slower rate than prior art intravenous glyburide formulations, for example, the infusion rate can be reduced to about 80% of the infusion rate used to inject prior art intravenous glyburide formulations, e.g., 23 ml / hr for the first 6 hours and 15.9 ml / hr thereafter, compared to 29 ml / hr for the first 6 hours and 20 ml / hr thereafter, as compared to prior art intravenous glyburide formulations.

[0101] In some aspects, the disclosure includes sterilizing the formulation of the disclosure. In some aspects, the formulation can be sterile filtered. In some aspects, the formulation can be sterilized to have zero bioburden. In some aspects, the product of the disclosure can be terminally sterilized. In some aspects, the product is sterilized with gamma irradiation. In some aspects, the product is sterilized by electron beam, x-ray, hydrogen peroxide, or ethylene oxide. In some aspects, the product can 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 aspects, the product can be sterilized in a container that is 100% soluble in water. -3 , 10 -4 , or 10 -6 Meet the "sterility assurance level" or "SAL" of the

[0102] In some aspects, the present disclosure provides a compound having the following structure: [ka] The present invention provides a compound having the formula:

[0103] 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:

[0104] In some aspects, the present disclosure provides a compound having the following structure: [ka] In some aspects, 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.

[0105] A kit having features of the invention may include a liquid solution of glyburide, and / or a liquid solution of glyburide with one or more compounds, and may include instructions for the use of such liquid solution. For example, instructions for the use of such liquid solution may include instructions for freeze-drying such liquid to obtain a lyophilized formulation of the compound of interest. Alternatively, or in addition, a kit having features of the invention may include a lyophilized formulation of glyburide, and / or a lyophilized formulation of glyburide with one or more compounds, and / or a lyophilized formulation of glyburide 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 (preferably a sterile solution) suitable for use in pharmaceutical applications. In some aspects, the vial includes a buffer of the disclosure at a concentration of 6-40 mM, 7-30 mM, 8-25 mM, 9-20 mM, or 10-15 mM.

[0106] 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 administering an effective amount of the aqueous pharmaceutical composition described herein intravenously to a patient in need thereof. 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 organ, 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 above-mentioned 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.

[0107] In some aspects, the formulations, methods, and kits of the disclosure provide tolerable, safe, effective, and predictable infusion administration to patients over extended periods of time (e.g., 3 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours or longer).

[0108] The present disclosure encompasses liquid formulations, including undiluted liquid formulations and final dosing solutions for bolus administration.

[0109] 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 patient 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 patient is at risk of brain swelling or neuronal cell swelling.Administration of glyburide via liquid formulations, and 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.

[0110] In developing an intravenous glyburide formulation, the inventors encountered many confounding challenges, especially for use in an emergency medical environment. Glyburide is practically insoluble in water at physiological pH and has low stability in that it precipitates and adsorbs to plastic medical containers, tubing, and filters, especially at low pH and physiological pH. In addition, the inventors found degradation products formed. In particular, the percentage of degradation products formed increases when the ratio of base to glyburide is relatively low. Although higher pH is used to solubilize glyburide, it is not possible to administer formulations with such high pH intravenously. Furthermore, due to low solubility and unpredictable adsorption to medical plastic materials, the inventors 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 the materials rather than being infused to the patient; and 3) the need to administer large amounts of saline infusion solution to the patient.

[0111] 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 is largely unpredictable how much of the drug product will be administered to a given patient at any given time depending on a variety of factors.

[0112] Additionally, as shown in FIG. 2, we tested glyburide formulations containing 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 after the start of the infusion, and that the recovery rate of glyburide concentration over the course of 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 high 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 (and expressed as a percentage of the initial concentration of glyburide in the IV bag) at the indicated time points. The lower the NaOH:GLY ratio, the longer the period required for drug concentration to recover. However, it was not possible to use a higher base to glyburide ratio in prior art glyburide formulations to avoid adsorption problems because using a high enough base to glyburide ratio would have resulted in a reconstituted formulation having a pH that was too high for injection into human patients (i.e., having 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.

[0113] Thus, the present disclosure provides formulations, including lyophilized, reconstituted, and diluted (final dose) formulations, that solve the aforementioned confounding problems including adsorption to medical containers, extremely low solubility, low stability, high wear, and the need to inject large amounts of saline solution to deliver the drug.

[0114] It has been found through experimentation that in order to create 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 injection solutions to deliver a therapeutic dose, it is necessary to use specific combinations of the disclosed specific buffering agents, bases, glyburide, and sugar alcohols in specific ranges of amounts and in specific ratios relative to each other. Unexpectedly, it has been found that it is necessary to use buffering agents that have buffering capacities outside the pH range of the glyburide formulation.

[0115] To avoid the initial dip in glyburide concentration caused by adsorption to the administration set, 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 administration) 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 consistently maintaining a pH of at least 7.8 and producing a glyburide formulation of the present disclosure that has a pH of 9.0 or lower when diluted into an infusion solution (e.g., saline). As shown in Figure 6 (left), with an initial saline pH of 4.5, a NaOH:GLY molar ratio of 13.8 is required in the prior art glyburide formulation to achieve a pH of 8.8 in the final administration solution. (Right) When a drug product with a NaOH:GLY molar ratio of 13.8 is reconstituted into a saline solution with a pH of 7, the resulting pH of the final dosing solution is 9.9, which is outside the pH range of acceptable infusion solutions.

[0116] A further important requirement was that after reconstitution, the reconstituted formulation must remain sufficiently stable and soluble. As an example, in an experiment using 10 mM Tris and 0.9% mannitol, it was determined that for a drug product vial containing 6 mg glyburide and a reconstitution volume of 20 ml, the resulting concentration was 0.3 mg / ml glyburide, as shown in Figure 4. 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. Using a Tris concentration lower than 10 mM was also sufficient to protect against instability, adsorption, and low solubility. For example, reconstitution of a 6 mg / vial 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. Based on these data, the necessary parameters for minimum reconstituted glyburide formulation pH relative to the initial saline infusion pH were determined, as shown in FIG.

[0117] The inventors have unexpectedly found that a buffering agent with a pKa between 7.7 and 9.2 provides critical properties for creating a formulation that balances many factors: more soluble, more stable, avoids adsorption to medical grade plastics, and has the proper pH when diluted with an infusion solution so that it can be administered by injection into humans. It was unexpected that such a buffer would work in the claimed formulation since glyburide is virtually insoluble within the pH range buffered by such agents.

[0118] Additionally, it was necessary to determine a molar ratio of base to glyburide to remain sufficiently stable and soluble and avoid adsorption to medical plastic materials. As shown in FIG. 6, when using prior art glyburide formulations, it was necessary to use a NaOH:GLY molar ratio of 13.8 to maintain sufficient stability, solubility, and avoid adsorption (which was too high to use as it resulted in a diluted (final dose) formulation that was unsafe for injection into humans (pH approx. 10)), whereas the formulations of the present disclosure were found to require a much lower ratio of base to glyburide to provide sufficient stability, solubility, avoid adsorption, and provide that when diluted into an injection solution is safe for injection into humans (final dose pH between 7.8-9.0). As shown in FIG. 7, the base content in the drug product vial (e.g., 6 mg glyburide / vial) and the pH of the (presently disclosed) buffer used for reconstitution can be correlated to produce a formulation that has sufficient stability, solubility, and lacks adsorption, based on the inventors' findings. For example, within the target design space of vial pH (9.1-10.2), critical NaOH:GLY molar ratio regions at vial and buffer pH were determined. For example, in Figure 7, it is determined that when using NaOH as the base and a buffer at pH 8.5, a NaOH:GLY molar ratio of 5.3 should be used (as indicated by the star).

[0119] 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.

[0120] Example 1 The solubility and stability of glyburide was tested in formulations with pHs outside the buffering capacity of Tris buffer. The pKa value of Tris is 8.08 at 25°C, which has buffering capacity in the pH range of 7.0-9.0. In formulation experiments, a minimum formulation pH of 9.1 was found to be required to maintain bulk solution stability at 1 mg / ml for at least 24 hours at room temperature (RT). For formulations with formulation pH<8.9, cloudy solutions were observed indicating precipitation of glyburide. For formulations with formulation pH>9, the formulation pH changes rapidly depending on the buffer and base to glyburide molar ratio. For example, as shown in Figure 8, rapid changes in compound pH depending on Tris pH and NaOH:GLY molar ratio were observed as illustrated by the steep slopes of both these components. This is because Tris effectively buffers in the pH range of 7-9 (i.e., ±1 pH unit from a pKa of 8.1). Outside this pH range, the bulk solution is no longer buffered by the addition of Tris. In order to maintain the stability of the bulk solution, it is necessary to increase the formulation pH above 9, which is outside the buffering range of Tris.

[0121] Example 2 Solutions with a range of pH were filled into vials (6 ml / vial) and lyophilized. Stability studies at accelerated conditions (70° C. / 75 RH) at 7 and 14 days were used to evaluate the effect of formulation parameters on impurity formation. A clear dependence of impurity formation on formulation pH was observed for impurity A and impurity X, as shown in FIG. 9. The production of both impurities decreased with increasing formulation pH. For impurity A, above a formulation pH of 9.8, levels were ≦0.5% at 7 days and ≦1.0% at 14 days. For impurity X, above a formulation pH of 9.8, levels were ≦0.5% at 7 and 14 days. Above a formulation pH of 10.3, impurity X levels were essentially 0%. For the impurity with an RRT of 1.25, overall levels were low (<0.2%) at both 7 and 14 days. As formulation pH increased, impurities with RRT 1.25 showed a weak positive correlation. Based on accelerated stability studies, a minimum formulation pH of 9.8 limits the formation of impurities A and X. The overall levels of impurities with RRT 1.25 were low at all tested pHs.

[0122] A maximum final dose 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 formulation pH. Drug reconstitution and dilution experiments were performed. Experiments were performed using glyburide and a vial fill volume of 6 ml (i.e., 6 mg of glyburide). Vials were reconstituted with 20 ml water for injection (WFI) and transferred to 500 ml saline bags (instead of a typical 1 L saline bag to ensure that the formulations of the present disclosure can be safely administered with less saline than is used in prior art glyburide formulations) with an initial pH of either 4.5 or 7 (adjusted with HCl or NaOH). The correlation between formulation pH, initial saline pH, and vial fill at the final dose solution pH is shown in FIG. 10. With a low formulation pH specification of 10.0 (based on accelerated stability testing to limit impurity formation) and an initial starting saline solution pH of 4.5, the predicted pH of the final dosing solution is approximately 8.7 (based on a 6 ml vial fill). A maximum formulation pH of 10.8 results in a pH of 9.2 for the final dosing solution (based on a 6 ml vial fill), which represents the maximum pH of the solution that can be safely injected into a patient. Such a formulation avoids significant amounts of glyburide adsorption to the PVC dosing components, as will be demonstrated below.

[0123] The pH of the final dosing solution is also dependent on the drug product vial fill (Figure 10, right). A formulation with a reduced vial fill of 4 ml (of a 1 mg / ml solution) is generated to reduce glyburide wastage after each day of dosing as shown in the table below. [Table 3-1] [Table 3-2]

[0124] Example 3 Further reconstitution and dilution studies with drug product using 4 ml fills were performed to evaluate the effect of formulation pH on the pH of the final dose solution. Using saline solutions within the target formulation pH range of 10-10.8 and through the possible pH range or 4.5-7, the final dose pH ranged from 8.1-8.7. It was possible to produce a final dose formulation that was soluble, stable, avoided adsorption to the PVC / PUR dose components, and was at a pH suitable for injection into humans.

[0125] Throughout the experiments, it was found that the buffering agent 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 specific pKa within the specified range. For example, and without limiting the foregoing disclosure, the buffering agent can be Tris, lysine, arginine, ethylenediamine, imidazole, 4-(2-hydroxyethyl)morpholine, triethanolamine, glucamine, deanol (dimethylaminoethanol), phosphate, phosphate buffered saline (PBS), or combinations thereof. In tests conducted with buffering agents such as phosphate (pKa 7.21) and glycine (pKa 9.8), it was found that these buffering agents did 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 formulation was then diluted in saline injection solution.

[0126] Thus, based on these studies, the present disclosure includes the following formulations:

[0127] Formulation A (reconstituted, undiluted): 1 mg / ml glyburide, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, or 40 mg / ml mannitol, 1 N NaOH to 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.

[0128] Formulation B (reconstituted, undiluted): 1 mg / ml glyburide, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 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.

[0129] Formulation C (reconstituted, undiluted): 1 mg / ml glyburide, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 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.

[0130] Formulation D (reconstituted, undiluted): 1 mg / ml glyburide, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, or 40 mg / ml mannitol, 1 N KOH or CaOH to formulation pH of 10.4 ± 0.6, 1.20 mg / ml Tris-base, 1.59 mg / ml Tris-HCl, and water.

[0131] Formulation E (reconstituted, undiluted): 1 mg / ml glyburide, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, or 40 mg / ml mannitol, 1 N KOH or CaOH to a formulation pH of 10.4 ± 0.6, 2.5 to 5 mg / ml arginine, and water.

[0132] Formulation F (reconstituted, undiluted): 1 mg / ml glyburide, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, or 40 mg / ml mannitol, 1 N KOH or CaOH to a formulation pH of 10.4 ± 0.6, 2.5 to 5 mg / ml lysine, and water.

[0133] 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 saline for injection.

[0134] Example 4 Stability studies were performed on Formulation A with 30 mg / ml mannitol at pH 9.8, 10.3, and 10.8 for up to 6 months at 25° C. / 60% RH and 40° C. / 75% RH as shown in the table below: [Table 4]

[0135] Impurity A levels were below the proposed release specifications of either 0.5 or 1%; impurity X and impurity RRT 1.25 were found to be below the specified threshold of 0.5%.

[0136] The above formulation procedure was carried out over a temperature range of 15-25° C. It was found that formulations could be successfully carried out over that temperature range. At 15° C., a NaOH:GLY molar ratio of 5.78-6.4 was found to be suitable. At 21.4° C., a NaOH:GLY molar ratio of 5.9-6.6 was found to be suitable. At 25° C., a NaOH:GLY molar ratio of 6.11-6.63 was found to be suitable.

[0137] Example 5 To confirm the elimination of adsorption to administration sets, a mock infusion was performed using a glyburide formulation of the present disclosure (target formulation pH 9.8). After reconstitution and dilution into an IV bag, the infusion was performed over a 4-hour period using a PVC administration set with an in-line 0.2 μm filter and a PUR administration set (FIG. 11). As shown in FIG. 11, (left graph) the concentration of glyburide was monitored in two different administration sets as indicated, and (right graph) the pH of the administration solution from the distal end of the administration set was measured at the indicated time points. No adsorption was observed over the infusion period. The pH of the administration solution was also tracked at the distal end of the administration set. For the PUR administration set, the pH was maintained at 8.6 throughout the test. For the PVC administration set, the pH dropped from approximately 8.6 to 8.3. This confirms that the incorporation of a buffer of the present disclosure in the final administration solution effectively eliminates adsorption of glyburide to the administration components.

[0138] Example 6 Further experiments revealed that the blend pH was strongly dependent on the TRIS concentration, buffer pH, and base content in the formulation (Figure 8). Variations in buffer and base weightings could potentially cause changes to the predicted blend pH, resulting in batch-to-batch process variation. An analysis of the effect of weighting inputs, and therefore the variation in blend pH, was obtained (Figure 12). A weighting variance of 2% for TRIS buffer and NaOH results in a blend pH distribution that is still within the target specification of 10-10.8 (0.5% of the blend pH variation is outside the target range). A weighting variance at 2.5% could result in a blend pH outside the target specification range, resulting in batch-to-batch process variation. Alternatively, in the case of a very high blend pH (i.e., >10.8), the batch is discarded because there is no mechanism to reduce the pH in the blend process. Therefore, formulation pH was controlled within a specified range of 10-10.8 by establishing weighted control of 2% or less of critical formulation components that affect formulation pH (TRIS-base, TRIS-HCl, 1N NaOH).

[0139] Further process control of the formulation pH is through the implementation of a pH adjustment step in the formulation process to achieve a target pH specification of 10.4 (±0.4). The order of addition of the formulation components that controls the formulation pH to maintain bulk solution stability throughout the formulation process has been found to be Tris-base, Tris-HCl, and then 1N NaOH. Importantly, the 1N NaOH is added in two portions. The first portion is to allow for glyburide solubility and dissolution in addition to mitigating the drop in pH after the addition of Tris-HCl. The resulting pH after Tris-HCl addition is designed to maintain glyburide solubility (at 1 mg / ml) and below the target formulation pH of 10.4. The second portion of 1N NaOH is used in the pH adjustment step to achieve the target formulation pH. In some aspects, the order of addition of formulation components that controls the formulation pH to maintain bulk solution stability throughout the compounding process is water, mannitol, first part of 1 N NaOH, glyburide, Tris-base, Tris-HCl, second part of 1 N NaOH. In summary, the combination of weighted control of critical formulation components and compounding process steps (order of addition and implementation of pH adjustment steps) is useful for process control parameters that affect critical quality attributes of the drug product.

[0140] Example 7 The compounding pH affects critical quality attributes of the drug product, including impurity formation during storage, adsorption to dosage components, and stability during injection. A robust process control strategy was developed for the commercial compounding process to allow control of compounding parameters. As part of drug product release testing, vial pH after reconstitution (10 ml) can be used to ensure that the proper compounding pH was achieved during manufacturing. The relationship between compounding pH and vial pH after reconstitution, as well as the predicted variation, is shown in FIG. 13. From the developmental testing, compounding pH was found to correlate well with reconstitution pH. Vial fill volume also affects reconstitution pH, but within the target fill volume (4 ml ± 4%), essentially no dependence exists. Thus, the majority of the predicted variation in reconstitution pH is predicted to come from compounding pH variation. The target reconstitution pH is 9.8 with a range of 9.5-10.0. In some aspects, the concentration after reconstitution is 0.4 mg / ml (4 mg / 10 ml). It was found that a 20% excess in concentration (i.e., 0.4 mg / ml x 1.2 = 0.48 mg / ml) was added and a vial reconstitution pH of at least 9.3 was required to ensure adequate stability (Figure 5).

[0141] The present disclosure provides methods and formulations to address the confounding challenges associated with intravenous glyburide formulations, including low solubility, low stability, adsorption to the dosing material, degradation, drug wastage, and the need for large amounts of saline solution for injection. It has been found that using the described combination of a specific base, a specific buffer, a specific ratio of base to glyburide, and sugar alcohol, and formulations according to the present disclosure, the solubility requirements of the final dosing solution can be met and ensure solution stability 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 formulations of the present disclosure include the specific buffering agents of the present disclosure in the specific amounts described above. The buffering agents, in combination with the appropriate molar ratio of base to glyburide, are critical among the process control parameters that affect drug product stability and its solubility and adsorption. It has been found that a formulation pH target of 10.4 (±0.4) is necessary to achieve the critical quality attributes of the drug product. Taken together, 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 solution to patients due to reduced drug wastage and increased solubility.

[0142] Any of the above protocols or similar variants thereof may be described in various documents associated with pharmaceutical products. These documents may include, but are not limited to, protocols, statistical analysis plans, investigator's brochures, clinical guidelines, drug guides, risk evaluation and mediation programs, prescribing 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.

[0143] Although the subject matter of the present disclosure has been described and illustrated in some detail with reference to certain illustrative embodiments (including various combinations and subcombinations of features), those skilled in the art will readily recognize other embodiments and variations and modifications thereof as 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 any features or combinations of features other than those expressly recited in the claims. Thus, the scope of the present disclosure is intended to encompass all modifications and variations encompassed within the spirit and scope of the following appended claims.

Claims

1. a) glyburide or a pharma- ceutically acceptable salt thereof; b) a buffering agent; c) a base; and d) sugar alcohols, wherein when reconstituted in water for injection (WFI), the lyophilized formulation has a pH outside the range of the buffering capacity of the buffering agent, the buffering agent having a pKa of 7.7 to 9.

2.

2. The lyophilized formulation of claim 1 , wherein the pharma- ceutically acceptable salt thereof is a sodium addition salt.

3. a) the glyburide or a pharma- ceutically acceptable salt thereof is about 2-3.5%, 2.5-3.3%, 2.7-3.1%, 2.8-2.98%, 2.9-2.97%, or 2.94-2.96% (w / w) of the lyophilized formulation; b) the lyophilized formulation comprises about 70-93%, 75-92%, 80-91%, 84-90%, 86-89%, or 87-89% (w / w) of the sugar alcohol; c) the lyophilized formulation comprises the sugar alcohol and the glyburide or a pharma- ceutically acceptable salt thereof in a weight ratio of 25-50:1, 26-45:1, 27-40:1, 28-35:1, 29-33:1, 30:1, 31:1, or 32:1; d) the lyophilized formulation comprises the sugar alcohol and the buffering agent in a weight ratio of 5-15:1, 6-14:1, 7-13:1, 8-12:1, 9-11:1, 9.5:1, 10:1, or 10.5:1; e) the base and the glyburide or pharma- ceutically acceptable salt thereof have a molar ratio of 5.0-6.7:1, 5.1-6.6:1, 5.2-6.5:1, 5.3-6.4:1, 5.4-6.3:1, 5.5-6.2:1, 5.6-6.1:1, 5.7-6.0:1, or 5.2:1, 5.3:1, 5.4:1, 5.5:1, or 5.6:1; f) the lyophilized formulation comprises about 5-15%, 6-14%, 7-13%, 8-12%, 9-13%, or 10-12% (w / w) of the buffering agent; or g) any combination of a) to f); A lyophilized formulation according to claim 1 or claim 2.

4. 2. The lyophilized formulation of claim 1, wherein the sugar alcohol is mannitol, sorbitol, xylitol, or a combination thereof.

5. 2. The lyophilized formulation of claim 1, wherein the base is NaOH, CaOH, KOH, or a combination thereof.

6. 2. The lyophilized formulation of claim 1, wherein the buffering agent is Tris, lysine, arginine, ethylenediamine, imidazole, 4-(2-hydroxyethyl)morpholine, triethanolamine, glucamine, deanol (dimethylaminoethanol), or a combination thereof.

7. 2. The lyophilized formulation of claim 1, wherein the buffering agent is a combination of Tris-HCl and Tris-base.

8. having a weight ratio between Tris-HCl and Tris-base of 7:4; or having a weight ratio between Tris-HCl and Tris-base of 6.2:5.0; The lyophilized formulation of claim 7.

9. 2. The lyophilized formulation of claim 1, comprising the base and the glyburide or a pharma- ceutically acceptable salt thereof in a ratio such that the lyophilized formulation, when reconstituted in WFI, has a pH 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.

10. 10. The lyophilized formulation of claim 1 having a solubility of at least 15 μg / ml in saline injection solution.

11. 10. The lyophilized formulation of claim 1, having 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 when reconstituted in saline injection solution.

12. a) has less than 0.2% decomposition products when stored for 6 months at 25°C / 60% RH; b) have less than 0.4% decomposition products when stored for 6 months at 40°C / 75% RH; c) have less than 1.0% decomposition products upon storage for 7 days at 70° C. / 75% RH; or d) any combination of a) to c); The lyophilized formulation of claim 1 having such storage stability characteristics.

13. 10. An infusion solution comprising the lyophilized formulation of claim 1 and 500 mL of saline infusion solution.

14. 1. A method of making a glyburide formulation having less than 1% weight loss of glyburide concentration (w / v) due to adsorption to a polymeric container over the course of an infusion period, the method comprising combining glyburide or a pharma- ceutically acceptable salt thereof with a buffering agent having a pKa of 7.7-9.2, a sugar alcohol, and a base having a pKb of 0.1-1.5, in a molar ratio between the base and the glyburide of 5.0-6.7:

1.

15. 15. The method of claim 14, wherein the base is NaOH, CaOH, KOH, or a combination thereof.

16. 16. The method of claim 14 or claim 15, wherein the buffering agent is Tris, lysine, arginine, ethylenediamine, imidazole, 4-(2-hydroxyethyl)morpholine, triethanolamine, glucamine, deanol (dimethylaminoethanol), or a combination thereof.

17. The method of claim 14 or claim 15, wherein the buffering agent is a combination of Tris-HCl and Tris-base.

18. having a weight ratio between Tris-HCl and Tris-base of 7:4; or having a weight ratio between Tris-HCl and Tris-base of 6.2:5.0; 20. The method of claim 17.

19. 16. The method of claim 14 or claim 15, wherein the sugar alcohol is mannitol, sorbitol, xylitol, or a combination thereof.

20. The method of claim 20, wherein the glyburide or a pharma- ceutically acceptable salt thereof is about 2 to about 3.5%, about 2.5 to about 3.3%, about 2.7 to about 3.1%, 2.8 to 2.98%, 2.9 to 2.97%, or 2.94 to 2.96% (w / w) of the glyburide formulation; b) the glyburide formulation comprises about 70-93%, 75-92%, 80-91%, 84-90%, 86-89%, or 87-89% (w / w) sugar alcohol; c) the glyburide formulation comprises the sugar alcohol and the glyburide or a pharma- ceutically acceptable salt thereof in a weight ratio of 25-50:1, 26-45:1, 27-40:1, 28-35:1, 29-33:1, 30:1, 31:1, or 32:1; d) the glyburide formulation comprises a weight ratio of the sugar alcohol to the buffering agent of 5-15:1, 6-14:1, 7-13:1, 8-12:1, 9-11:1, 9.5:1, 10:1, or 10.5:1; e) the glyburide formulation comprises 20-40 mg / ml, 24-36 mg / ml, 26-34 mg / ml, 38-32 mg / ml, 29 mg / ml, 30 mg / ml, or 31 mg / ml of the sugar alcohol; f) the glyburide formulation comprises about 5-15%, 6-14%, 7-13%, 8-12%, 9-13%, or 10-12% (w / w) of the buffering agent; or g) any combination of a) to f); The method according to claim 14 or claim 15.

21. A formulation of glyburide having a pH within about 0.2 pH units of said formulation prior to storage when stored for 12 months at 25° C. / 60% relative humidity (RH); b) upon storage for 6 months at 40° C. / 75% RH, has a pH within about 0.2 pH units of said glyburide formulation prior to storage; c) upon storage for 4 weeks at 70° C. / 75% RH, has a pH within about 0.2 pH units of said glyburide formulation prior to storage; or d) any combination of a) to c); The method according to claim 14 or claim 15.

22. 16. The method of claim 14 or claim 15, wherein the glyburide formulation is a solid powder that, when reconstituted in WFI, has a pH 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.

23. The method of claim 14 or claim 15, wherein the glyburide formulation is in the form of a reconstituted solution having a pH of 9.3 to 11.

24. reconstituting the glyburide formulation in 20 mL of water for injection (WFI); and 16. The method of claim 14 or claim 15, further comprising making a reconstituted formulation 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 of the buffering agent.

25. 25. The method of claim 24, wherein the reconstituted formulation comprises 1-5 mg / ml, 1.2-4 mg / ml, 1.5-3.5 mg / ml, or 2-3 mg / ml of the buffering agent.

26. 16. The method of claim 14 or claim 15, further comprising the step of diluting the glyburide formulation in a saline infusion solution, wherein the formulation has a pH that does not fluctuate by more than 0.2 pH units during an infusion period of at least 24 hours.

27. 27. The method of claim 26, wherein the formulation has a buffer concentration in the saline infusion solution of about 0.1-0.5 mM, about 0.15-0.4 mM, about 0.2-0.3 mM, or about 0.2 mM.

28. a) glyburide or a pharma- ceutically acceptable salt thereof; b) a base; c) a sugar alcohol; and d) a buffering agent; a first container containing a lyophilized formulation comprising: a mixing device configured to reconstitute and transfer the lyophilized formulation between the first container and a second container prior to administration; Kit including:

29. The lyophilized formulation comprises: 0.2 to 10.8% by weight of said glyburide or a pharma- ceutically acceptable salt thereof; 4.4 to 8.8% by weight of said buffering agent; and 80.1 to 94% by weight of the sugar alcohol; 30. The kit of claim 28, comprising:

30. A compound comprising: a) glyburide or a pharma- ceutically acceptable salt thereof; b) a buffering agent; c) a base; and d) sugar alcohols, 1. A liquid intravenous (IV) formulation comprising: wherein said liquid IV formulation has a pH outside the range of the buffering capacity of said buffering agent, wherein said liquid IV formulation comprises said sugar alcohol and said glyburide or a pharma- ceutically acceptable salt thereof in a weight ratio of 27 to 40:1, and / or said base and said glyburide or a pharma-ceutically acceptable salt thereof in a molar ratio of 5.4 to 6.3:1; A liquid IV formulation, wherein the liquid IV formulation does not contain a cyclodextrin.

31. 1. A method for controlling the pH of a glyburide solution diluted in saline infusion solution in the pH range of 8 to 9 over the course of a 24 hour infusion, said method comprising: a) glyburide or a pharma- ceutically acceptable salt thereof; b) a buffering agent; c) a base; and d) sugar alcohols, to form a stabilized and soluble glyburide formulation, wherein the glyburide solution has a pH outside the buffering capacity of the buffering agent, the buffering agent having a pKa of 7.7 to 9.2; and diluting said stabilized and soluble glyburide formulation in said saline infusion solution. wherein the pH of the diluted formulation is between pH 7.8 and 9, and the pH of said diluted formulation does not change by more than 0.2 pH units over the course of said 24 hour infusion. method.

32. A compounding method comprising the steps of: a) adding glyburide to mannitol to form a first mixture and then adding Tris-base to the first mixture to form a second mixture; b) then adding Tris-HCl to said second mixture to form a third mixture; c) then adding a first amount of NaOH to said third mixture to form a fourth mixture containing dissolved and solubilized glyburide at 1 mg / ml and at a pH of less than 10.0; and d) then adding a second amount of NaOH to said fourth mixture to form a final formulation containing glyburide dissolved and solubilized at 1 mg / ml and having a pH of 10.4±0.4; A compounding method comprising:

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