Low adsorption glibenclamide kits, formulations and methods

Abstract

The methods and formulations provided herein are useful for minimizing or avoiding adsorption of glibenclamide to the surfaces of delivery tubes, filters, bags, and other containers and materials, thereby storing and delivering more stable products, delivering predictable and precise doses of glibenclamide, and improving the bioavailability of glibenclamide. Meanwhile, impurities are minimized, medicine waste is avoided, cost is reduced, and the amount of the medicine administration solution which must be infused into a patient is remarkably reduced.

Description

Technical Field

[0001] The present invention relates to the field of medical methods of treatment, including intravenous methods of administering a drug to a subject. Background Art

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

[0003] Glyburide has been proposed as a therapy for a variety of conditions, 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, ventricular arrhythmias, to prevent CNS edema, reduce mortality and preserve neurological function.

[0004] Glyburide solubility in various solutions has been reported, and is generally reported to be very insoluble in buffered aqueous solutions. For example, Glyburide solubility 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). Buffered aqueous solutions are made with distilled water to form a potassium chloride (220 mM) solution buffered with potassium phosphate (29 mM), and the pH is adjusted to pH 5, 6 or 7 with sodium hydroxide. These solutions have an osmotic pressure concentration (osmolarity) between about 280 and 310 milliosmolars, and have a buffer capacity of about 10 ± 2 milliequivalents / L / pH. Glomme et al. reported that glyburide is only slightly soluble in such solutions, with very low solubility at pH 2, 3, 5, 6 and 7, and relatively greater solubility (although still very low) at pH 8, 9 and 11.8. These solubilities are shown in Table 1:

[0005] Table 1: Solubility of glyburide at 37°C (aqueous)

[0006] pH Solubility (mg / ml) 2 0.00007 3 0.00006 5 0.0001 6 0.00062 7 0.00562 8 0.0512 9 0.0986 11.8 0.5316

[0007] Similarly, Kaiser et al. reported lower solubility of glyburide in aqueous solution (Kaiser DG, Forist, AA. A review of Glibenclamide Metabolism in Man and Laboratory Animals. Physical and Analytical Chemistry Research, The Upjohn Company; 1975), with solubility below 1 mg / mL at all measured pH values ​​from pH 4 to pH 9. Glyburide was dissolved in Britton-Robinson buffer. (Britton-Robinson buffer is an aqueous buffer solution containing phosphoric acid, acetic acid, and boric acid, with sodium hydroxide used to adjust the pH). These solubilities are shown in Table 2.

[0008] Table 2: Solubility of Glyburide at 27°C (aqueous)

[0009] pH Solubility (mg / ml) 4 0.004 6 0.005 7 0.011 8 0.080 9 0.600

[0010] Applicants have found that in solutions of glibenclamide placed in various types of pharmaceutical containers, the concentration of glibenclamide is reduced due to various processes including instability, degradation, and adsorption of glibenclamide to such containers. In the typical pH range of pharmaceutically acceptable infusion solutions (pH 5-9), glibenclamide is almost insoluble, thus presenting a difficult problem for obtaining a stable glibenclamide formulation that can be administered to patients over time. It is also necessary and critical to control the stability of stored glibenclamide formulations and diluted dosing solutions for infusion (e.g., after about 100-fold dilution of the stored glibenclamide formulation).

[0011] Another challenge is that the dilute solution of glibenclamide is easily bonded to plastics, such as polyvinyl chloride (PVC) or polyurethane (PUR), which are materials commonly used in infusion components such as saline IV bags and application kits. Although in the 1-3 phase clinical trials in the United States, dedicated infusion kits (low adsorption, polyethylene lining) have been used to solve drug-material compatibility issues, this temporary strategy is not practical for multiple reasons, including the difficulty in obtaining dedicated infusion kits, glibenclamide is intended for emergency care situations, and for patients to know that the time from last-know-normal to administration is minimized to the indications that are crucial to efficacy (i.e., "time is brain"). The speed of neural circuit loss in human ischemic stroke emphasizes the time urgency of nursing patients with stroke and brain injury. For example, in the case of untreated stroke, a typical patient loses 1.9 million neurons per minute. Therefore, the additional complexity of processing and administering intravenous glibenclamide (i.e., requiring a dedicated infusion component) will delay patient administration and adversely affect patient results. Furthermore, the use of commonly used materials will result in the loss of significant amounts of the active pharmaceutical ingredient due to adsorption, resulting in the administration of unknown and potentially subtherapeutic doses of glibenclamide, again adversely affecting patient outcomes. Furthermore, the administration of inaccurate amounts of glibenclamide is unsafe because glibenclamide is known to cause hypoglycemia. The inventors have found that administering intravenous glibenclamide formulations at therapeutic concentrations for the treatment of stroke (LHI) or cerebral contusion, approximately 40% to 50% of glibenclamide is wasted due to, for example, instability, adsorption, and process issues.

[0012] Therefore, it is necessary to produce glibenclamide preparations in the art, which prevent glibenclamide concentration reduction due to glibenclamide adsorbed to the surface of other containers and materials in contact with glibenclamide, such as conveying tubes, filters, bags, catheters, syringes, infusion sets, extension sets and glibenclamide. It is necessary to produce glibenclamide preparations with improved stability at lower pH in the art. It is necessary to produce glibenclamide preparations that reduce the generation of degradation products in the art. It is necessary to produce glibenclamide preparations that require significantly less saline infusion to administer intravenous therapeutic doses in the art. It is necessary to produce glibenclamide preparations with improved storage stability in the art. Summary of the invention

[0013] The present invention 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 waste, reducing costs and significantly reducing the amount of dosing solution (typically saline or Ringer's solution) that must be infused into a patient.

[0014] In one aspect, the present invention includes a lyophilized formulation comprising: glibenclamide or a pharmaceutically acceptable salt thereof; a base; and a sugar alcohol, contained in a kit, the lyophilized formulation being configured to be combined or reconstituted with a separate buffer provided in the kit, wherein the reconstituted formulation has a pH value outside the buffering capacity of the buffer.

[0015] In one aspect, the invention includes a method for manufacturing an infusion solution comprising about 250 ml to 1000 ml of saline solution, 3 mg to 5 mg of glibenclamide, 100 mg to 140 mg of mannitol, 10 mg to 12 mg of Tris, 0.94 mg to 2.98 mg of NaOH, and a pH of 7.5 to 9.2. In some aspects, the molar ratio of NaOH:glibenclamide in the infusion solution is 2.9:1 to 9.2:1.

[0016] In one aspect, the invention includes a method of making an infusion solution comprising 10 ml to 30 ml WFI, 3 mg to 5 mg glibenclamide, 100 mg to 140 mg mannitol, 10 mg to 12 mg Tris, 0.94-2.98 mg NaOH, and a pH of 9 to 11, e.g., 9.4 to 10. In some aspects, the molar ratio of NaOH:glibenclamide in the solution is 2.9:1 to 9.2:1.

[0017] In one aspect, the invention includes a method of making an infusion solution comprising 3 ml to 5 ml WFI, 3 mg to 5 mg glibenclamide, 100 mg to 140 mg mannitol, 0.94 mg to 2.98 mg NaOH, and pH 9 to 12.5, e.g., 11.3 to 12.

[0018] In one aspect, the invention includes a method of making a glibenclamide formulation having a glibenclamide concentration loss of less than 1% by weight (w / v) due to adsorption to a polymer container during an infusion period, the method comprising combining glibenclamide with a buffer having a pKa of 7.7 to 9.2, a base having a sugar alcohol pKb of 0.1 to 1.5, in a molar ratio of base to glibenclamide of 2.9:1 to 9.2:1.

[0019] In some aspects, the invention includes reconstitution of the formulations of the invention in a suitable diluent, e.g., saline or water for injection (WFI), and comprising a buffer concentration of 4mM to 60mM, 5mM to 50mM, 6mM to 40mM, 7mM to 30mM, 8mM to 25mM, 9mM to 23mM, 10mM to 21mM, 11mM, 12mM, 13mM, 14mM, 15mM, 16mM, 17mM, 18mM, 19mM or 20mM.

[0020] In some aspects, the invention comprises diluting a reconstituted formulation of the invention in a saline solution, wherein the pH of the reconstituted formulation is between 7.5 and 9.2.

[0021] In some aspects, the invention comprises diluting the reconstituted formulation in a saline solution, wherein the pH of the diluted formulation does not exceed 0.2 pH units of pH over an infusion period of at least 24 hours.

[0022] In some aspects, the invention includes formulations and methods having high storage stability, for example, such that after storage for 6 months at 25°C / 60% RH, the degradation products are less than 0.2%, after storage for 6 months at 40°C / 75% RH, the degradation products are less than 0.4%; and / or after storage for 7 days at 70°C / 75% RH, the degradation products are less than 1.0% storage stability properties.

[0023] In some aspects, the present invention includes a method of increasing the solubility of a glibenclamide formulation in a saline infusion solution, comprising combining glibenclamide or a pharmaceutically acceptable salt thereof with: a buffer; a base; and a sugar alcohol, wherein the formulation has a pH value outside the buffering capacity of the buffer at 4°C, 20°C, or 25°C to form a dissolved glibenclamide formulation having a glibenclamide solubility of 15 μg / ml in the saline infusion solution, wherein the pH of the glibenclamide formulation in the saline infusion solution is 7.5 to 9.2.

[0024] In some aspects, the present invention includes a method of minimizing the volume of saline infusion solution required to infuse a glibenclamide formulation into a human for 24 hours, comprising combining 3 mg to 5 mg of glibenclamide or a pharmaceutically acceptable salt thereof with a buffer; a base; and a sugar alcohol, wherein the formulation has a pH value outside the buffering capacity of the buffer, wherein the pH of the glibenclamide formulation in the saline infusion solution is 7.5 to 9.2, and wherein the volume of saline infusion solution for infusing 3 mg to 5 mg of glibenclamide or a pharmaceutically acceptable salt thereof into a human is about 250 ml to 500 ml.

[0025] In some aspects, the present invention includes a method of increasing the storage stability of a glibenclamide formulation, comprising combining glibenclamide or a pharmaceutically acceptable salt thereof with a buffer; a base; and a sugar alcohol, wherein the formulation has a pH outside the buffering capacity of the buffer to form a stabilized glyburide formulation, wherein the stabilized glyburide formulation has less than 0.2% degradation products after storage at 25°C / 60% RH for at least 6 months and after storage at 25°C / 60% RH for 6 months.

[0026] In one aspect, the invention includes compounds having the structure:

[0027]

[0028] and preparations containing the compound, 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.

[0029] In some aspects, the invention includes a composition of the invention further comprising a compound having the structure:

[0030] It includes 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.

[0031] In one aspect, the invention includes compounds having the structure:

[0032] and preparations containing the compound, 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.

[0033] In some aspects, the invention includes a composition of the invention further comprising a compound having the structure: It includes 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.

[0034] In one aspect, the invention includes compounds having the structure: and preparations containing the compound, 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.

[0035] In one aspect, the invention includes compounds having the structure: and preparations containing the compound, 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.

[0036] In one aspect, the invention includes compounds having the structure: and preparations containing the compound, 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.

[0037] In some aspects, the present invention includes a kit comprising a first container containing a lyophilized formulation, the lyophilized formulation comprising: glibenclamide or a pharmaceutically acceptable salt thereof; a base; and a sugar alcohol; and a second container containing an aqueous buffer of the present invention, wherein the lyophilized formulation has a pH value outside the buffering capacity of the aqueous buffer of the present invention when reconstituted. In some aspects, the kit includes a mixing device configured to reconstitute and transfer the lyophilized formulation between the first container and the second container prior to administration.

[0038] In some aspects, the invention 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, brain contusion, shock, ischemia, or ventricular arrhythmia.

[0039] In some aspects, the present invention includes a reconstituted formulation comprising a lyophilized formulation containing glibenclamide or a pharmaceutically acceptable salt thereof; a base; and a sugar alcohol, wherein the formulation is reconstituted in a buffer of the present invention, wherein the reconstituted formulation has a pH value outside the buffering capacity of the buffer, wherein the reconstituted formulation comprises at least 95%, 96%, 97%, 98% or 99% of the amount of glibenclamide or a pharmaceutically acceptable salt thereof in the lyophilized formulation.

[0040] In some aspects, the invention includes an infusion formulation comprising a saline infusion solution and a reconstituted lyophilized formulation comprising glibenclamide or a pharmaceutically acceptable salt thereof; a buffer; a base; and a sugar alcohol, wherein the lyophilized formulation is reconstituted in a buffer of the invention, wherein the reconstituted formulation has a pH value outside the buffering capacity of the buffer, wherein the infusion solution comprises at least 95%, 96%, 97%, 98% or 99% of the amount of glibenclamide or a pharmaceutically acceptable salt thereof in the lyophilized formulation.

[0041] In some aspects, the present invention includes a method for controlling the pH of a solution of glyburide diluted in a saline infusion solution within a pH range of 8 to 9 during a 24-hour infusion, comprising reconstituting a lyophilized formulation containing glyburide or a pharmaceutically acceptable salt thereof; a base; and a sugar alcohol in a buffer of the present invention, wherein the reconstituted formulation has a pH value outside the buffering capacity of the buffer to form a stabilized and soluble glyburide formulation, diluting the stabilized and soluble glyburide formulation in a saline infusion solution, and infusing the diluted formulation into a patient, wherein the pH of the diluted formulation is 7.5 to 9.2 and the pH of the diluted formulation does not vary by more than 0.2 pH units during a 24-hour infusion. In other aspects, the present invention includes reconstituting a lyophilized formulation with water for injection (WFI) such that the reconstituted formulation has a pH value outside the buffering capacity of the buffer, introducing the buffer into a saline IV infusion container to form a buffered saline infusion solution, and diluting the reconstituted formulation in a buffered saline IV infusion solution to form an infusion solution having a pH of 7.5 to 9.2.

[0042] In some aspects, the present invention includes a method for reducing the infusion rate of a glibenclamide solution diluted in a saline infusion solution during a 24-hour infusion, comprising combining 3 mg to 5 mg of glibenclamide or a pharmaceutically acceptable salt thereof; a base; and a sugar alcohol and a buffer, wherein the formulation has a pH value outside the buffering capacity of the buffer to form a stabilized and soluble glibenclamide formulation, diluting the stabilized and soluble glibenclamide formulation in the saline infusion solution, and infusing the diluted formulation into a patient in a 500 mL bag at a rate of less than 16 ml / hour for 24 hours, or infusing the patient in a 250 mL bag at a rate of less than about 8 ml / hour for 24 hours. In an alternative aspect, the invention comprises combining 3 mg to 5 mg of glibenclamide or a pharmaceutically acceptable salt thereof; a base; and a sugar alcohol; with water for injection (WFI), wherein the formulation has a pH outside the buffering capacity of the buffer, introducing the buffer into a saline IV infusion container to form a buffered saline IV infusion solution, diluting the formulation in the buffered saline IV infusion solution to form an infusion solution having a pH of 7.5 to 9.2, and infusing the diluted formulation into a patient at a rate of less than 16 ml / hour in a 500 mL bag for 24 hours, or at a rate of about 8 ml / hour or less in a 250 mL bag for 24 hours.

[0043] Other features and characteristics of the invention, as well as the method of operation, the function of the related structural elements and combinations of parts, and the economy of manufacture, will become more apparent from a consideration of the following description and appended claims, all of which form a part of this specification. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1The adsorption of a prior art intravenous formulation of glibenclamide onto a medical material is shown.

[0045] Figure 2 The effect of different base to glyburide ratios on the adsorption of prior art glyburide intravenous formulations onto a PVC administration set is shown.

[0046] Figure 3 The effect of the pH of the final administration formulation on adsorption onto a PVC administration kit is shown for formulations of the present invention.

[0047] Figure 4 The solubility of glibenclamide of the formulation of the present invention in a 10 mM Tris / 0.9% mannitol solution simulating a buffer system is shown after reconstitution of the drug product.

[0048] Figure 5 Shown is the correlation between the NaOH:GLY molar ratio in the drug product, the Tris buffer pH (10 mM) in the custom diluent, and the vial pH after reconstitution (20 ml) in the formulation of the invention. DETAILED DESCRIPTION

[0049] Although aspects of the subject matter of the present invention can be implemented in various forms, the following description is intended only to disclose some forms as specific examples of the subject matter encompassed by the present invention. Therefore, the subject matter of the present invention is not limited to the described forms or embodiments.

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

[0051] As used herein and well known in the art, the term "treatment" refers to a method for obtaining a beneficial or desired result (including clinical results). A beneficial or desired clinical result may include, but is not limited to, mitigation or improvement of one or more symptoms or conditions, reduction of disease extent, stabilization (i.e., no deterioration) of the disease state, delay or slow disease progression, improvement or alleviation of the disease state, reduction of recurrence and alleviation (whether partial or complete) of the disease, whether detectable or undetectable. "Treatment" may also refer to prolonged survival compared to the expected survival without treatment. In addition to being used as a therapeutic method, the methods described herein may be applicable to preventing or preventing a disease.

[0052] Concentration, amount and other numerical data can be expressed or provided in range format herein.It should be understood that such range format is only for the purpose of convenience and simplicity, and therefore should be flexibly interpreted as not only including the numerical value clearly stated as the limit of the range, but also including all individual numerical values ​​or sub-ranges contained in the range, as if each numerical value and sub-range are clearly stated.For example, the numerical range of "about 0.01 to 2.0" should be interpreted as not only including the value clearly stated from about 0.01 to about 2.0, but also including individual values ​​and sub-ranges within the indicated range.Therefore, the numerical range includes individual values, such as 0.5, 0.7 and 1.5, and sub-ranges, such as 0.5 to 1.7, 0.7 to 1.5 and 1.0 to 1.5.In addition, regardless of the breadth of the range or the described features, this explanation should be applied.In addition, it should be noted that unless otherwise specified, all percentages are by weight.

[0053] In understanding the scope of the present invention, the terms "include" or "comprising" and their derivatives used herein are meant to be open terms, which clearly indicate the existence of stated features, elements, components, groups, integers and / or steps, but do not exclude the existence of other unstated features, elements, components, groups, integers and / or steps. The foregoing also applies to words with similar meanings, such as the terms "include", "have" and their derivatives. As used herein, the term "consisting of..." and its derivatives are intended to be closed terms, which clearly indicate the existence of stated features, elements, components, groups, integers and / or steps, and exclude the existence of other unstated features, elements, components, groups, integers and / or steps. As used herein, the term "consisting essentially of..." is intended to clearly indicate the existence of stated features, elements, components, groups, integers and / or steps and those that do not substantially affect the basic and novel characteristics of features, elements, components, groups, integers and / or steps. It should be understood that any one of these transitional terms (i.e., "include", "consisting of..." or "consisting essentially of...") is provided direct support for replacing any other transitional terms that are not specifically used. For example, modifying the term from "comprising" to "consisting essentially of" would find direct support due to this definition.

[0054] As used herein, the term "about" is used to provide flexibility to a numerical range endpoint by specifying that a given value may be "slightly above" or "slightly below" the endpoint. The degree of flexibility of this term may be dictated by the particular variable and will be within the knowledge of one skilled in the art to determine based on experience and the relevant description 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 yet another aspect, the degree of flexibility may be within about ±2%, ±1%, or ±0.05% of the numerical value. The numerical amounts given are approximate, and if not expressly stated, the term "around," "about," or "approximately" may be inferred.

[0055] As used herein, the term "pharmaceutically acceptable" refers to solvents, cosolvents, surfactants, carriers, diluents, excipients, buffers, salts and / or other components that are compatible with the other ingredients of the preparation and harmless to its recipient. In some aspects, the glibenclamide preparation of the present invention may include one or more sugar alcohols, including but not limited to allitol, arabitol, dextrose, dulcitol, erythritol, galactitol, ethylene glycol, glycerol, iditoluol, isomalt, lactitol, maltitol, mannitol, sorbitol, threitol, xylitol and combinations thereof.

[0056] As used herein, the term "lyophilized" and its grammatical variants refer to the process of obtaining a dry material, such as a powder, from a liquid containing a solid or dissolved material by freeze drying (freezing a liquid containing a dissolved or suspended material and drying by sublimation while freezing). The process is carried out by freeze drying (freezing a liquid containing a dissolved or suspended material and drying by sublimation while freezing). The process is carried out by freeze drying to provide a dry solid containing a dissolved or suspended material in solid form. Typically, an aqueous solution is used in freeze drying, but mixed aqueous / solvent solutions, as well as other liquid solutions, can be used. For example, a biological material can be freeze dried from a solution or suspension mixed with a protective agent. Such a solution or suspension can then be frozen and subsequently dehydrated by sublimation. A further drying step can be optionally performed after sublimation. Typically, a freeze drying method includes freeze drying a liquid solution or suspension to provide a dry residue containing a high concentration of dissolved or suspended compounds. In some cases, the solid provided by freeze drying can be or include a salt. The freeze drying process provides a solid, such as a powder, a dry film or a cake. If desired, small particles can be obtained from such a powder, a film or a cake by a procedure such as grinding or flaking.

[0057] The methods and formulations provided herein provide pharmaceutically acceptable glibenclamide formulations, including concentrated solutions, diluted solutions, and lyophilized formulations, thereby solving the adsorption, degradation, instability, and low solubility problems associated with prior art pharmaceutical formulations of glibenclamide.

[0058] Examples of suitable pharmaceutically acceptable diluents such as WFI (water for injection) and solutions containing isotonic saline are known in the art. Pharmaceutically acceptable aqueous solutions include Ringer's solution, Hartmann's solution, 0.9% saline, 0.45% N saline, WFI (water for injection), D5W (5% dextrose in water), phosphate buffered saline (PBS), and dextrose / saline solutions (D2.5W (i.e., 2.5% dextrose in water) and 0.45% N saline).

[0059] The invention includes reconstituting a lyophilized drug product using a buffer of the invention. The invention includes reconstitution solutions of lyophilized drug products in a buffer of the invention. The invention includes diluting the reconstitution solutions with a pharmaceutically acceptable diluent.

[0060] As used herein, "Ringer's solution" refers to a pharmaceutically acceptable buffered saline solution having sodium chloride, potassium chloride, and calcium chloride salts.

[0061] As used herein, "Hartmann's solution" refers to lactated Ringer's solution. Typical Hartmann's solution contains 131 mM sodium, 5 mM potassium, 2 mM calcium, 11 mM chloride, and 29 mM lactate (sodium chloride 0.6%, sodium lactate 0.25%, potassium chloride 0.04%, calcium chloride 0.027%).

[0062] As used herein, a pharmaceutically acceptable saline solution is a solution suitable for administration to a patient, comprising water and sodium chloride, and may optionally contain a buffer, preservative or other component, usually in small amounts. For example, a pharmaceutically acceptable saline solution comprises 0.9% saline (9 g NaCl in 100 ml distilled, filtered water, containing 150 mM sodium and 150 mM chloride) and a saline solution having 154 mM sodium and 154 mM chloride.

[0063] Generally, the term "or" herein includes "and / or".

[0064] For purposes of convenience, as used herein, multiple compounds, elements, or steps may be presented in a common list. However, these lists should be interpreted as if each member of the list were individually identified as a separate and unique member. Therefore, unless otherwise indicated, a single member of such a list should not be interpreted as being de facto equivalent to any other member of the same list based solely on its presentation in the same group.

[0065] In addition, certain compositions, elements, excipients, ingredients, disorders, conditions, properties, steps, etc. may be discussed in the context of a particular embodiment or aspect or in a separate paragraph or section of the present invention. It should be understood that this is for convenience and brevity purposes only, and that any such inventive content is equally applicable and intended to be combined with any other embodiment or aspect found anywhere in the present invention 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 with respect to a formulation or method for treating a subject is intended to and does directly support embodiments related to compositions, formulations, and methods described in any other part of the present invention, even if those method steps, active agents, kits, or compositions are not re-listed in the context or section of that embodiment or aspect.

[0066] The inventors have discovered that glyburide in conventional intravenous glyburide formulations is readily and extensively incorporated into polymeric containers, for example, infusion sets containing polyvinyl chloride (PVC) and polyurethane (PUR). Figure 1 . Although the use of low-absorption polyethylene lined infusion sets minimizes adsorption, such dedicated infusion sets are impractical for a number of reasons, including the difficulty in obtaining such dedicated infusion sets and the fact that intravenous glibenclamide is intended for use in emergency care situations and for indications where minimizing the time from the patient's last known normality to administration is critical to efficacy (i.e., "time is brain"). Therefore, additional complexity is created in the operation and administration of intravenous glibenclamide, i.e., the need to strictly use dedicated infusion sets in emergency situations will delay patient dosing and adversely affect patient outcomes. In addition, for prior art intravenous glibenclamide preparations, the use of commonly used materials will result in the loss of a large amount of active pharmaceutical ingredients due to adsorption, resulting in the administration of unknown and possibly untreated doses of glibenclamide. In addition, for prior art intravenous glibenclamide preparations, the use of commonly used materials will result in instability and degradation, resulting in a drug product of unacceptable quality. Furthermore, administering an unknown amount of glyburide or attempting to increase the volume of medication to be administered is unsafe because administration of glyburide at higher doses (e.g., at an average rate greater than 0.25 mg / hour (6 mg / day)) can result in hypoglycemia. Figure 1As shown, during the infusion time period, the amount of glibenclamide in the prior art intravenous glibenclamide preparation that is attached to the commonly used infusion kit has significant and unpredictable changes. In addition, it is undesirable to implement a flushing procedure, which may be complicated, time-consuming, imprecise, wasteful and contaminating. In addition, the inventor has found that the glibenclamide in the prior art intravenous glibenclamide preparation is easily and widely attached to all filter components (data not shown). Therefore, it is necessary to provide a new intravenous glibenclamide preparation, avoid being attached to a commonly used infusion kit and a filter material, and allow a healthcare provider to use commonly used medical supplies to treat a patient with an accurate dose in a suitable dosing window (close to immediately after a stroke, infarction, injury, etc.), while avoiding complications, avoiding wasting medicine and reducing the amount of the infusion solution applied to the patient. Other advantages of the present invention also include improved safety and reduced pollution. In addition, the present invention can also use an infusion kit with a filter, while avoiding glibenclamide from being adsorbed to the filter.

[0067] In a first aspect, the present invention provides a formulation containing a stable, therapeutic dose of glibenclamide, which has a glibenclamide concentration (w / v) loss due to adsorption to a polymer container (for example, containing 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.

[0068] In a second aspect, the present invention provides a formulation containing a stable, therapeutic dose of glibenclamide having a glibenclamide concentration (w / v) loss due to adsorption to an in-line filter material of less than 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, 0.1%, 0.05%, 0.01%. In some aspects, the filter may comprise a material such as polyethersulfone or polyvinylidene fluoride (PVDF).

[0069] In a third aspect, the present invention provides methods and formulations for controlling the pH of a glibenclamide solution within a narrow desired range before and after dilution in an infusion fluid.

[0070] In a fourth aspect, the present invention provides methods and formulations for minimizing or avoiding the formation of degradation products in storage solutions of glibenclamide.

[0071] In a fifth aspect, the present invention provides methods and formulations for reducing infusion rates, reducing drug waste, and reducing saline intake in subjects treated with intravenous glibenclamide.

[0072] In a sixth aspect, the present invention provides methods and formulations for maintaining a sufficiently high concentration of glyburide in solution during formulation to enable filling into appropriately sized containers to achieve a therapeutic dose, for example, 3 mg to 5 mg / day of glyburide.

[0073] In a seventh aspect, the invention provides methods and formulations for providing sufficient solubility, stability and desired pH after reconstitution to achieve desired high concentrations during drug manufacture.

[0074] In an eighth aspect, the present invention provides methods and formulations for providing sufficient solubility, stability, and desired pH for administration over a 3, 4, 6, 12, 24, 30, 36, 48, 72, 96, or 120 hour period upon further dilution of a reconstituted glibenclamide formulation in an infusion fluid (e.g., at a concentration of 6 μg / ml to 20 μg / ml in a saline bag).

[0075] On the one hand, the methods and formulations of the present invention include mixing a glibenclamide formulation comprising glibenclamide, a base specified herein, to form a lyophilized powder. On the one hand, the methods and formulations of the present invention include combining the lyophilized powder with the buffer of the present invention. On the one hand, the methods and formulations of the present invention include reconstructing the lyophilized powder in the buffer of the present invention. On the one hand, the buffer has a pKa of 7.7 to 9.2, 7.8 to 9.1, 7.9 to 9.0, 8.0 to 8.9, 8.05 to 8.8, 8.1 to 8.7, or any specific pKa of a specified range. For example, and without limiting the foregoing invention, the buffer may be Tris, lysine, arginine, ethylenediamine, imidazole, 4-(2-hydroxyethyl)morpholine, triethanolamine, glucosamine, diarno (dimethylaminoethanol), phosphate, phosphate buffered saline (PBS) or a combination thereof. On the one hand, the buffer of the present invention has a buffering capacity within a pH range of 7 to 9. On the one hand, Tris can be a combination of Tris-HCl and Tris-base. In one aspect, lysine is lysine-HCl. In one aspect, arginine is arginine-HCl.

[0076] In one aspect, the invention includes methods and lyophilized formulations comprising glibenclamide, a base and a sugar alcohol, in combination with a separate buffer of the invention, wherein the combination has a pH value outside the buffering capacity of the buffer, and the combination is suitable for (including being safe and tolerable at a sustained therapeutically effective amount) infusion into a human for 24 hours or longer. In one aspect, the pH of the formulation (reconstituted formulation) is greater than 9.0, greater than 9.5, greater than 10.0 or greater than 10.5, for example 9.3 to 11, and the buffer has a buffering capacity in the pH range of 7 to 9.

[0077] In some embodiments, the preparation can maintain stable pH when reconstructed.For example, after being stored for one week, two weeks, or four weeks, or 3 months, 6 months or 12 months at or about 25 ℃ / 60% relative humidity (RH), 40 ℃ / 75% RH or 70 ℃ / 75% Rh, the preparation has a pH in about 0.1 or about 0.2pH units.In some aspects, stability can be determined by measuring the generation of degradation products.For example, degradation products can be measured by HPLC.In some aspects, degradation products are quantified based on the relative retention time (RRT) on HPLC.

[0078] 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.

[0079] In some aspects, the reconstituted glibenclamide formulation comprises about 5% to 15%, 6% to 14%, 7% to 13%, 8% to 12%, 9% to 13% or 10% to 12% (w / w) of buffer. In some aspects, the reconstituted glibenclamide formulation comprises about 1mM to 100mM, 2mM to 80mM, 3mM to 70mM, 4mM to 60mM, 5mM to 50mM, 6mM to 40mM, 7mM to 30mM, 8mM to 25mM, 9mM to 23mM, 10mM to 21mM, 11mM, 12mM, 13mM, 14mM, 15mM, 16mM, 17mM, 18mM, 19mM or 20mM of buffer. In some aspects, the reconstituted glibenclamide formulation comprises about 1 mg / ml to 5 mg / ml, 1.2 mg / ml to 4 mg / ml, 1.5 mg / ml to 3.5 mg / ml, or 2 mg / ml to 3 mg / ml of buffer.

[0080] In some aspects, the buffer is a buffer having a pH of 7.8 to 9, 8.1 to 8.9, 8.2 to 8.8, 8.3 to 8.7, 8.4 to 8.6, or 8.5.

[0081] In some aspects, a lyophilized formulation comprising glibenclamide, base, and sugar alcohol can be optionally reconstituted, for example using WFI or other suitable diluent, and then diluted in an IV bag containing an aqueous diluent containing a buffer of the invention.

[0082] In some aspects, the invention includes the use of a mixing device to reconstitute and transfer a lyophilized formulation between a vial and an IV bag prior to administration. The mixing device may be a needle-free device. The mixing device may meet USP <797> The mixing device may have a dual channel design that provides dedicated fluid channels into and out of the IV bag. In one aspect, the invention includes the use of a mixing device as described in U.S. Pat. No. 8,551,067 (Zinger), which is incorporated herein by reference in its entirety. In one aspect, the invention includes the use of a mixing device as described in U.S. Pat. No. 10,688,295 (Lev), which is incorporated herein by reference in its entirety. In some aspects, the invention includes the use of VIAL2BAGADVANCED TM and / or Mixing device to reconstitute and transfer lyophilized formulations between vials and IV bags prior to administration. In some aspects, the invention includes kits, formulations, containers, and methods of reconstitution and transfer of lyophilized formulations comprising glibenclamide, base, and sugar alcohol with a buffer using a mixing device.

[0083] In a second aspect, the base is a strong base having a pKb of 0.1 to 1.5. Any pharmaceutically acceptable strong base can be used. For example, and without limiting the foregoing invention, the base can be NaOH, Ca(OH)2 or KOH.

[0084] In a third aspect, the formulation of the invention comprises a specific weight ratio between glibenclamide and base to achieve a pH target in the range of 9.8 to 11.2, 9.9 to 11.1, 10.0 to 11.0, 10.1 to 10.9, 10.2 to 10.8, 10.3 to 10.7 or 10.4 to 10.6 in the formulation.

[0085] In some aspects, the formulations of the present invention comprise a specific molar ratio between base and glibenclamide in the formulation of 2.9:1 to 9.2:1, 3:1 to 9:1, 3.2:1 to 8.8:1, 3.4:1 to 8.5:1, 3.6:1 to 8.2:1, 3.8:1 to 8:1, 4:1 to 7.8:1, 4.4:1 to 7.5:1, 4.6:1 to 7.2:1, 4.8:1 to 7:1, 5.0 to 6.7:1, 5.1 to 6.6:1, 5.2 to 6.5:1, 5.3 to 6.4:1, 5.4 to 6.3:1, 5.5 to 6.6:1. 2: 1, 5.6 to 6.1: 1, 5.7 to 6.0: 1, or 3: 1, 4: 1, 4.5: 1, 4.7: 1, 5.2: 1, 5.3: 1, 5.4: 1, 5.5: 1, 5.6: 1, 5.8: 1, 6: 1, 6.2: 1, 6.4: 1, 6.6: 1, 6.8: 1, 7: 1, 7.2: 1, 7.4: 1, 7.6: 1, 7.8: 1, 8: 1, 8.2: 1, 8.4: 1, 8.6: 1, 8.8: 1, 9: 1, 9.2: 1, or any ratio or range encompassed by endpoints 2.9: 1 to 9.2: 1. Unexpectedly, the molar ratio used in the present invention is about 2 times higher than the molar ratio used in the prior art glibenclamide formulations.

[0086] In some aspects, the lyophilized glyburide formulation comprises about 2% to 3.5%, 2.5% to 3.3%, 2.7% to 3.1%, 2.8% to 2.98%, 2.9% to 2.97%, or 2.94% to 2.96% (w / w) glyburide.

[0087] In some aspects, the lyophilized glibenclamide formulation comprises about 70% to 93%, 75% to 92%, 80% to 91%, 84% to 90%, 86% to 89% or 87% to 89% (w / w) of the sugar alcohol of the present invention. In some aspects, the sugar alcohol is mannitol, sorbitol, xylitol or a combination thereof. In some aspects, the sugar alcohol is mannitol.

[0088] In some aspects, the formulations of the present invention comprise a specific weight ratio between the sugar alcohol and glibenclamide in the formulation.

[0089] In some aspects, the reconstituted formulations of the invention comprise a specific weight ratio between sugar alcohol and buffer in the formulation of 5 to 15:1, 6 to 14:1, 7 to 13:1, 8 to 12:1, 9 to 11:1, 9.5:1, 10:1, or 10.5:1.

[0090] In some aspects, the reconstituted glibenclamide formulation comprises about 20 mg / ml to 40 mg / ml, 24 mg / ml to 36 mg / ml, 26 mg / ml to 34 mg / ml, 38 mg / ml to 32 mg / ml, 29 mg / ml, 30 mg / ml, or 31 mg / ml of a sugar alcohol.

[0091] In some aspects, the reconstituted glibenclamide formulation has a pH of about 9.3 to 11, 9.4 to 10.9, 9.5 to 10.8, 9.6 to 10.7, 9.7 to 10.6, 9.6 to 10.5, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3 or 10.4. In some aspects, the reconstituted glibenclamide formulation has a pH of 9.5 to 10.0.

[0092] In some aspects, glibenclamide is a free acid or a pharmaceutically acceptable salt thereof. In some aspects, the glibenclamide preparation comprises a sodium addition salt of glibenclamide. As used throughout the present invention, reference to "glibenclamide" may also describe its salts, esters, hydrates, solvates, racemates, tautomers, stereoisomers and / or optically active forms.

[0093] In some aspects, the present invention includes preparing an aqueous solution of glibenclamide of the present invention at a concentration described herein, adding a base of the present invention at a weight ratio with glibenclamide described herein, and freeze-drying the solution to provide a freeze-dried solid composition. In some aspects, the aqueous solution may further contain a sugar alcohol of the present invention at a concentration described herein.

[0094] In some aspects, the formulations of the invention do not contain one or more of the following: cyclodextrins, meglumine, sugars such as, for example, fructose, mannose, galactose, arabinose, xylose and ribose, and oligosaccharides such as disaccharides (maltose, lactose, sucrose, trehalose, etc.) and trisaccharides (e.g., raffinose, maltotriose, etc.), salts, alcohols such as, for example, ethanol, diethanolamine, Britton-Robinson buffer, lactate, acetate, glutamate, glycine, citrate, succinate, surfactants, polysorbates, solubilizing polymers such as polyethylene glycol, inorganic or organic acids such as methanesulfonic acid, lactic acid, tartaric acid, citric acid, succinic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid, choline, n-methylglucamine, diethylamine, and procaine, etc.

[0095] In some aspects, the reconstituted formulations of the invention 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.

[0096] The present invention provides methods and formulations capable of providing a glibenclamide formulation having a significantly higher glibenclamide solubility in a dosing solution, i.e., about 3 times that of prior art intravenous glibenclamide dosing solutions (i.e., greater than 15 μg / ml compared to less than 5.7 μg / ml in prior art intravenous glibenclamide dosing solutions). Furthermore, even at these three-fold higher concentrations, there is no detectable loss of glibenclamide due to precipitation or adsorption.

[0097] In some aspects, the diluted (referred to herein as the "final dosing" formulation) glibenclamide formulation of the invention has a glibenclamide concentration of 7.2 (± 0.2) μg / mL and an infusion pH of about 8.3 (± 0.1).

[0098] In some aspects, the final administered glibenclamide formulation has a pH of 7.8 to 9.0, 7.9 mM to 9.0, 8.0 to 9.0. In some aspects, the final administered glibenclamide formulation has a pH of 7.8 mM to 9, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8 or 8.9.

[0099] In some aspects, the final dosed glibenclamide formulation has a buffer concentration of about 0.1 mM to 0.5 mM, about 0.15 mM to 0.4 mM, about 0.2 mM to 0.3 mM, or about 0.2 mM.

[0100] In some aspects, the diluted glibenclamide preparation of the present invention is diluted in an IV infusion bag to reduce the amount of the infusion liquid administered to the subject. For example, in some aspects, the diluted glibenclamide preparation of the present invention is diluted in a 250mL IV infusion bag. In some aspects, the diluted glibenclamide preparation of the present invention is diluted in a 500mL IV infusion bag. In view of the fact that the preparation of the present invention has increased solubility, stability, and minimized medical container adsorption, a more concentrated dosing preparation can be used to provide a consistent therapeutic dose in the infusion time period while using significantly less infusion liquid.

[0101] In some aspects, the invention provides methods for reducing the volume of infusion fluid administered to a subject by about 25% to 50% over an infusion period, for example, from about 2 L to 1 L over a four day infusion period, or from about 1.5 L to 0.75 L over a three day infusion period.

[0102] In some aspects, due to the advantages of the present invention, the diluted glibenclamide formulation can be administered at a slower rate than the prior art intravenous glibenclamide formulation. For example, the infusion rate can be reduced to about 40% of the infusion rate used to infuse the prior art intravenous glibenclamide formulation, for example, the infusion rate is 11.5 ml / hour for the first six hours and 8 ml / hour thereafter, compared to 29 ml / hour for the prior art intravenous glibenclamide formulation and 20 ml / hour thereafter.

[0103] In some aspects, the invention includes sterilizing the formulations of the invention. In some aspects, the formulations can be filter sterilized. In some aspects, the formulations can be sterilized to have zero bioburden. In some aspects, the products of the invention can be terminally sterilized. In some aspects, the products are sterilized with gamma irradiation. In some aspects, the products are sterilized by electron beam, X-ray, hydrogen peroxide, or ethylene oxide. In some aspects, the product can be a powder, solution, vial, kit, prefilled syringe, injection device, cartridge, on body injector, auto-injector, infusion bag, or any other container or container kit suitable for storage, infusion and / or injection of the product of the invention. In some aspects, the product meets 10 -3 , 10 -4 or 10 -6 The “Sterility Assurance Level” or “SAL”.

[0104] In some aspects, the present invention provides compounds having the following structure:

[0105]

[0106] In some aspects, the present invention provides a formulation comprising glibenclamide and a compound having the following structure:

[0107]

[0108] In some aspects, the invention provides a lyophilized formulation containing a compound having the following structure:

[0109] In some aspects, the formulation may contain less than 1 wt%, less than 0.5 wt%, less than 0.3 wt%, less than 0.1 wt%, less than 0.05 wt%, e.g., 0.001 to 0.04 wt%, 0.01 to 0.03 wt%, 0.01 wt%, 0.02 wt%, or 0.03 wt% of the compound.

[0110] The kit with the features of the present invention may include the lyophilized preparation of the present invention or the lyophilized preparation of the present invention contained in a separate container and the buffer of the present invention, and may include the instructions for use of these preparations and buffers. The kit with the features of the present invention may include the lyophilized preparation of glibenclamide, and / or the lyophilized preparation of glibenclamide and one or more compounds, and / or the lyophilized preparation of glibenclamide and one or more liquids for reconstruction, and may include the instructions for use of such lyophilized preparations. For example, the instructions for use of such lyophilized preparations may include instructions for reconstructing such lyophilized preparations to provide a solution suitable for use in medical applications, preferably a sterile solution. In some aspects, the kit may include lyophilized glibenclamide, alkali and sugar alcohol in a container (such as a vial, a syringe, a pen or a bag), and a buffer of the present invention in a separate container. In some aspects, the buffer of the present invention containing a concentration of 6mM to 40mM, 7mM to 30mM, 8mM to 25mM, 9mM to 20mM or 10mM to 15mM in a vial. In some aspects, the kit may further comprise a mixing device for reconstitution and transfer of the reconstituted formulations of the invention.

[0111] Thus, the formulations and kits disclosed herein provide improved medicines and treatments, and the methods disclosed herein provide improved methods for making medicines and treating patients. The present invention includes methods for treating patients suffering from a condition selected from the following: stroke, neuronal cell swelling, traumatic brain injury, spinal cord injury, organ ischemia, acute coronary syndrome, myocardial infarction, sepsis, and diabetes, the method comprising intravenously administering an effective amount of an aqueous pharmaceutical composition described herein to a patient in need thereof. In some cases, the condition is a stroke. In some cases, the patient is a human. In certain other cases, the condition is a 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 bleeding, or other conditions or conditions. The patient in need of treatment may be, for example, a patient suffering from ischemia of any one or more organs or systems. Such systems may be, for example, the nervous system, including a portion of the nervous system, or the cardiovascular system, or a portion of the cardiovascular system. Such organs may be, for example, the brain, heart, muscle, or other organs. The patient in need of treatment may be any patient who may benefit from administering the formulations, compositions, and / or contents of the kit disclosed herein. Other examples of patients in need of treatment include patients suffering from a condition 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.

[0112] In some aspects, the formulations, methods and kits of the invention provide tolerable, safe, effective and predictable infusion dosing to patients for extended periods of time, e.g., 3, 6, 12, 24, 48, 72, 96, 120 hours or longer.

[0113] The present invention includes liquid formulations comprising a reconstituted liquid formulation and a final (diluted) dosing solution for bolus administration.

[0114] Liquid formulations disclosed herein can be used for infusion, such as infusion over an extended period of time, to the vasculature, cerebrospinal fluid or other destinations of administration 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 nerve cell swelling. In another embodiment, 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 nerve cell swelling. Glyburide is administered by liquid formulations, particularly by intra-arterial or intravenous administration, providing a rapid and easily controlled increase in circulating glibenclamide concentrations, providing a rapid start of treatment, thereby being able to quickly adjust and maintain circulating glibenclamide concentrations at all times.

[0115] In developing intravenous glibenclamide formulations, especially intravenous glibenclamide formulations for emergency medical situations, the inventors encountered many complex challenges. Glyburide is almost insoluble in water at physiological pH, has low stability, makes it easy to precipitate, and adsorbs to plastic medical containers, tubes and filters, especially at low pH and physiological pH. In addition, the inventors found that degradation products were formed. Especially at relatively low base to glibenclamide ratios, the percentage of degradation products formed increased. Although higher pH is used to solubilize glibenclamide, it is impossible to administer preparations with such higher pH intravenously. In addition, due to low solubility and unpredictable adsorption to medical plastic materials, the inventors encountered problems including but not limited to the following: 1) the inability to quickly and predictably administer therapeutic doses; 2) waste of drug products adsorbed to the material rather than injected into the patient; and 3) the need to administer a large amount of saline infusion solution to the patient.

[0116] like Figure 1 As shown, in simulated infusion tests with various administration materials using prior art glibenclamide formulations, significant adsorption occurred immediately at the start of the infusion, with concentration changes, but no recovery throughout the entire infusion period. In addition, depending on the materials of the administration kit, the concentration changes of glibenclamide are different. Therefore, depending on various factors, there is significant unpredictability in how much drug product is administered to a given patient at any given time.

[0117] In addition, if Figure 2 As shown, the inventors tested the glibenclamide preparation containing prior art components, but changed the ratio of NaOH to glibenclamide to determine the influence of the ratio for adsorption. The inventors found that significant adsorption occurred immediately when the infusion was started, and between the preparations with different bases and glibenclamide ratios, the recovery rate of glibenclamide concentration during the infusion time period changed significantly. Glibenclamide concentration initially decreased by at least 10%, and when the NaOH:GLY ratio was 3:1, the decrease was up to about 40%. Specifically, the prior art glibenclamide preparation with different NaOH:GLY molar ratios was reconstructed and diluted in a 1L saline bag. The simulated IV infusion was established using a PVC application kit and the glibenclamide concentration (and expressed as the percentage of the initial concentration of glibenclamide in the IV bag) of the infusion at the indicated time point was measured. At a lower NaOH:GLY ratio, drug concentration recovery requires a longer time period. However, to avoid adsorption issues, it is not possible to use higher base to glyburide ratios in prior art glyburide formulations because using sufficiently high base to glyburide ratios results in a pH of the reconstituted formulation that is too high for infusion into human patients, i.e., a pH of approximately 10, while the industry considers the maximum acceptable pH for human infusion to be pH 9 according to the 2016 Infusion Therapy Standards of Practice.

[0118] Thus, the present invention provides formulations, including lyophilized, reconstituted and diluted (final dosing) formulations, which solve the aforementioned complex problems, including adsorption to medical containers, very low solubility, low stability, high losses and the need to infuse large amounts of saline to deliver the drug.

[0119] It was found experimentally that it is necessary to use a specific combination of a specific buffer, base, glibenclamide and sugar alcohol of the present invention in a specific range of amounts and in a specific ratio to each other in the preparation of a formulation that provides sufficient solubility, stability, therapeutic effect, safety for human infusion while avoiding adsorption to medical containers, formation of degradation products, and the need to administer a large volume of saline infusion solution to deliver a therapeutic dose. It was unexpectedly found that it is necessary to use a buffer with a buffering capacity outside the pH of the glibenclamide formulation.

[0120] In order to avoid an initial drop in the concentration of glibenclamide due to adsorption to the administration kit, a pH ramp experiment was performed using the formulation of the present invention. Figure 3As shown, it was found that if the pH of the diluted (final dosing) formulation of the present invention is less than 7.8, the concentration of glibenclamide decreases by at least 10%. Therefore, it is recognized that adsorption to the PVC administration set can be eliminated by producing a glibenclamide formulation of the present invention that always maintains a pH of at least 7.8 and is below 9.0 when diluted in an infusion solution (e.g., saline solution). If a drug product having a NaOH:GLY molar ratio of 13.8 is reconstituted in saline at pH 7, the resulting pH in the final dosing solution is 9.9, which is outside the acceptable pH range for infusion solutions.

[0121] Another key requirement is that after reconstitution, the reconstituted formulation must remain sufficiently stable and soluble. For example, in experiments using 10 mM Tris and 0.9% mannitol, Figure 4 As shown, it is determined that for a vial containing 6 mg of glibenclamide and a reconstitution volume of 20 ml, the resulting concentration is 0.3 mg / ml glibenclamide. Assuming a concentration of 20% buffer (0.360 mg / ml), a minimum vial pH of 9.14 is required to ensure solution stability after reconstitution. Using a Tris concentration below 10 mM is also sufficient to prevent instability, adsorption, and low solubility, for example, 20 ml of a 5 mM solution is used to reconstitute a 6 mg / vial of drug product and further diluted in a 1 L saline bag; a buffer concentration in the final dosing solution of about 0.1 mM Tris is sufficient.

[0122] The inventors have surprisingly discovered that buffers with pKas of 7.7 to 9.2 provide key properties for preparing formulations that have a balance of many factors to be more soluble, more stable, avoid adsorption to medical plastics, and have a suitable pH when diluted with an infusion solution so that they can be administered to humans by infusion. Unexpectedly, such buffers work in the claimed formulations because glibenclamide is virtually insoluble in the pH range buffered by such agents.

[0123] Furthermore, the molar ratio of base to glibenclamide must be determined to maintain sufficient stability, solubility and avoid adsorption to medical plastic materials. Figure 5 As shown, based on the inventors' findings, the base content in the vial of the drug product (e.g., 6 mg glibenclamide / vial) and the pH of the buffer used for reconstitution (the buffer of the present invention) can be linked to produce a formulation with sufficient stability, solubility, and no adsorption. For example, within the target design space of vial pH (9.1–10.2), the critical NaOH:GLY molar ratio region and buffer pH in the vial are determined. For example, in FIG7 , when NaOH is used as the base and a buffer of pH 8.5, it is determined that a NaOH:GLY molar ratio of 5.3 should be used (as indicated by the star).

[0124] In some aspects, the kit, method, infusion solution or reconstituted formulation of the present invention can be provided in a container configured to protect the glibenclamide solution from light. In some aspects, an amber or brown light-proof cover or packaging can be used. In some aspects, a light-proof cover or packaging that blocks more than 90% of UV is used. In some aspects, an aluminum protective cover can be used. For example, a light-proof cover can be used to cover an IV bag. The stability of the glibenclamide solution of the present invention during the infusion process can thus be improved to the greatest extent.

[0125] The invention of the present invention will be more readily understood by referring to the following examples, which are merely provided to illustrate certain aspects and embodiments of the present invention and are not intended to limit the scope of the disclosed invention.

[0126] Example 1

[0127] The solubility and stability of glibenclamide after reconstitution with Tris buffer were tested. To obtain the appropriate reconstitution pH, and thus the desired solubility and stability, a molar ratio of NaOH:GLY between 2.9:1 and 9.2:1 and a Tris buffer of the appropriate pH (e.g. Figure 5 As shown), Figure 5 Reconstituted solutions were produced within the design space shown.

[0128] Example 2

[0129] The maximum final dosing pH of 9.2 (after infusion, the pH slightly drops to about 9, which is the maximum pH of the solution that can be safely infused into the patient) is used as the upper limit of the pH of the reconstituted solution and the dilution solution. Drug reconstitution and dilution experiments were performed. The experiment was performed using a vial filled with a volume of 6 ml of glibenclamide (i.e., 6 mg of glibenclamide). The vial was reconstituted with 20 ml of water for injection (WFI) and transferred to a 500 ml saline bag (replacing a typical 1 L saline bag to ensure that the preparation of the present invention can be safely administered with less saline compared to the saline used in the prior art glibenclamide preparation), wherein the initial pH was 4.5 or 7 (adjusted with HCl or NaOH). This operation was also performed using a 250 ml saline bag, and the results showed that glibenclamide could be successfully and safely delivered, thereby achieving a higher concentration of glibenclamide. The structure shows that if the vial reconstitution pH is lower than 9.14, the final IV bag pH will be less than 7.8, resulting in adsorption. If the vial reconstitution pH is higher than 10.2, the final IV bag pH will be greater than 9.2, which exceeds the pH range that can be safely administered to patients. Such formulations avoid the adsorption of significant amounts of glyburide to the PVC application component, as demonstrated below.

[0130] Example 3

[0131] Through experiments, it is found that the buffer should have a pKa of 7.7 to 9.2, 7.8 to 9.1, 7.9 to 9.0, 8.0 to 8.9, 8.05 to 8.8, 8.1 to 8.7, or any specific pKa within a specified range. For example, and without limiting the foregoing invention, the buffer can be Tris, lysine, arginine, ethylenediamine, imidazole, 4-(2-hydroxyethyl)morpholine, triethanolamine, glucosamine, diarno (dimethylaminoethanol), phosphate, phosphate buffered saline (PBS) or a combination thereof. In studies using buffers such as phosphate (pKa 7.21) and glycine (pKa 9.8), it was found that these buffers could not effectively stabilize glibenclamide and did not prevent adsorption to medical materials. Specifically, freeze-dried glibenclamide samples containing different amounts of NaOH were reconstituted in 20ml of sodium phosphate buffer (10mM, pH 8.0), pH was measured, and the reconstituted formulation was then diluted in a saline infusion solution.

[0132] Therefore, based on these studies, the present invention includes the following formulations:

[0133] Formulation A (reconstituted, undiluted): 1 mg / ml glibenclamide, 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 ± 0.4, 1.20 mg / ml Tris-base, 1.59 mg / ml Tris-HCl (20 mM Tris total), and water.

[0134] Formulation B (reconstituted, undiluted): 1 mg / ml glibenclamide, 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 mg / ml to 5 mg / ml arginine, and water.

[0135] Formulation C (reconstituted, undiluted): 1 mg / ml glibenclamide, 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 mg / ml to 5 mg / ml lysine, and water.

[0136] Formulation D (reconstituted, undiluted): 1 mg / ml glibenclamide, 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 Ca(OH)2 to a formulation pH of 10.4 ± 0.6, 1.20 mg / ml Tris-base, 1.59 mg / ml Tris-HCl, and water.

[0137] Formulation E (reconstituted, undiluted): 1 mg / ml glibenclamide, 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 Ca(OH)2 to a formulation pH of 10.4 ± 0.6, 2.5 mg / ml to 5 mg / ml arginine, and water.

[0138] Formulation F (reconstituted, undiluted): 1 mg / ml glibenclamide, 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 Ca(OH)2 to a formulation pH of 10.4 ± 0.6, 2.5 mg / ml to 5 mg / ml lysine, and water.

[0139] Formulation G (reconstitution, dilution): 7.2 μg / ml glibenclamide, 0.216 mg / ml mannitol, dilution formulation pH of 8.3 ± 0.1, 0.2 mM Tris, water, and 500 mL saline for infusion.

[0140] Example 4

[0141] The ratio of NaOH:GLY affects the critical quality attributes of the drug product, including the formation of impurities during storage, adsorption to the administration component, and stability during infusion. For the formulation process, a robust process control strategy has been developed to achieve control of formulation parameters. The pH of the vial after reconstitution (20 ml) can be used to ensure that the appropriate formulation pH is achieved during manufacturing. The target reconstitution pH is 9.8, with a range of 9.2 to 10.2. In some aspects, the concentration after reconstitution is 0.3 mg / ml (6 mg / 20 ml). A 20% excess concentration (i.e., 0.3 mg / ml*1.2=0.36 mg / ml) is added to ensure appropriate stability, and it is found that the pH of the vial reconstitution needs to be at least 9.2 ( Figure 5 ).

[0142] Example 5

[0143] The effect of adding Tris buffer to a lyophilized combination of glibenclamide, NaOH, and mannitol was evaluated. 20 ml of 10 mM Tris buffer was added to the lyophilized combination of glibenclamide, NaOH, and mannitol. The contents of the vial were gently shaken to dissolve, and the pH of the solution in the reconstituted vial was measured with a pH probe. The results showed that the combination of the lyophilized formulation with 50% to 65% excess NaOH and 10 mM tris buffer at pH 8.32-8.65 was able to achieve the desired reconstituted vial pH>9.14, while the use of 20% or 80% NaOH could not achieve the desired reconstituted vial pH>9.14.

[0144] The effect of the pH and strength of the Tris buffer on the pH of the BIIB093 DP vial upon reconstitution and the final saline bag pH for infusion was evaluated. The saline bag (0.5L) was used as is or after adding 1N NaOH to the saline bag to adjust the pH to approximately 7.0. A total of 45mL of saline was removed from the bag and 19mL of reconstituted BIIB093 was added from the vial to the saline bag. The contents of the saline bag were gently mixed and the final saline bag pH was recorded. The results showed that the use of BIIB093 DP in combination with (50%-65% excess NaOH) and 10mM tris buffer solution at pH 8.44-8.52 resulted in a reconstituted vial pH >9.13 and a final saline bag pH >7.8 and <9.0. When reconstituted with 5 mM tris, a slight shift in buffer pH from 7.95 to 8.19 was observed resulting in a change in reconstitution vial pH of approximately 1 pH unit (9.13 to 10.13).

[0145] Example 6

[0146] After reconstitution with Tris buffer at a pH value lower than the target pH (9.14) to achieve a solubility of 0.3 mg / mL, the stability of glibenclamide was evaluated. 20 ml of Tris buffer (+50% excess NaOH) was added to the lyophilized formulation of the present invention. The contents in the vial were dissolved by gentle shaking, and the pH value after reconstitution was measured. About 1 mL of sample was taken at 0 hours, 1 hour, 2 hours and 24 hours after reconstitution, filtered through a 0.22 um membrane filter, and analyzed by HPLC. Within 24 hours, no precipitation of glibenclamide was observed at reconstitution pH values ​​of 8.65 and 8.78.

[0147]

[0148] Example 7

[0149] The pH of the reconstituted vials and saline bags was evaluated. A saline bag (0.5 L) was used after the pH was adjusted to approximately 4.5 or 7.0 by adding 1N HCl or 1N NaOH, respectively, to the saline bag. A total of 60 ml of saline was taken out from the bag, and then 9 ml of reconstituted glibenclamide was added from the vial to the saline bag. The contents of the bag were gently mixed, and the pH of the final saline bag was recorded. In these experiments, 10 mM tris pH 8.5-8.3 (10 mL, containing 50% excess NaOH) reached a target pH>9.37 (corresponding to a glibenclamide solubility of 0.720 mg / mL), and the pH of the final saline bag was>7.8 and <9.0.

[0150]

[0151] Example 8

[0152] The pH of the vial and the final saline bag after reconstitution with 10mM Tris were evaluated. 6mL tris buffer was added to the lyophilized formulation of the present invention (6mg glibenclamide and 50% excess NaOH per bottle). The contents in the vial were dissolved by gentle shaking, and 2mL of solution was discarded from the vial. Then 6mL or 16mL tris buffer was added to make the final reconstitution volume 10mL and 20mL, respectively. After adding 1N HCl or 1N NaOH to the saline bag to adjust the pH to about 4.5 or 7.0, a saline bag (0.5L) was used.

[0153] For the 10ml vial reconstitution volume: a total of 17mL of saline was taken out from the bag, and then 9.5mL of the reconstituted lyophilized formulation of the present invention was added from the vial to the saline bag. The contents of the saline bag were gently mixed, and the pH of the final saline bag was recorded. The results show that 10mL of 10mM tris with a pH of 8.4-8.8 can be used for the reconstitution of the lyophilized formulation of the present invention (containing 50% to 65% excess NaOH) to achieve a target pH>9.25 (corresponding to a glibenclamide solubility of 0.480mg / mL), and the pH of the final saline bag is>7.8 and <9.0.

[0154]

[0155] For 20 ml vial reconstitution volume: add 20 mL of reconstituted BIIB093 from the vial to the saline bag. Gently mix the contents of the saline bag and record the pH of the final saline bag. The results show that for reconstitution (containing 80% excess NaOH), 20 mL of 10 mM tris at pH 8.5-8.8 can be considered to achieve a target pH>9.25 (corresponding to a glibenclamide solubility of 0.480 mg / mL), with a final saline bag pH>7.8 and <9.0.

[0156]

[0157] The present invention provides methods and formulations for solving the complex challenges of intravenous glibenclamide formulations, which include low solubility, low stability, adsorption to application materials, degradation, drug waste, and the need to administer large amounts of saline for infusion. Using the described specific base, a specific ratio of base to glibenclamide, and a combination of sugar alcohols, and using a specific buffer according to the present invention for preparation, it can be found that the solubility requirements of the final dosing solution are met and the stability of the solution can be ensured throughout the infusion period. In addition, the absorption of the drug on the application component made of PVC or PUR is eliminated, thereby allowing the expansion of the use of any conventionally used medical application components. In order to achieve precise control of the final dosing solution, the disclosed reconstituted formulation contains a specific buffer of the present invention, the specific amount, ratio and pH value of which are described above. Among the process control parameters that affect the stability, solubility and adsorption of the drug product, the combination of the buffer and the appropriate molar ratio of the base to glibenclamide is critical. Studies have found that when reconstituted using the buffer of the present invention, the molar ratio of the base to glibenclamide must be in the range of 2.9:1 to 9.2:1 to achieve the key quality attributes of the drug product. In summary, the disclosed formulations and process elements provide a robust, stable and soluble drug product that eliminates challenges of existing formulations and processes, and also provides a method for administering significantly less saline to patients due to reduced drug waste and increased solubility.

[0158] Any of the above schemes or similar variations thereof can be described in various files related to the pharmaceutical product. Such files may include, but are not limited to, schemes, statistical analysis plans, investigator's brochures, clinical guidelines, medication guides, risk assessment and mediation procedures, prescription information, and other files that may be related to the pharmaceutical product. It is particularly contemplated that such files may be physically packaged with the pharmaceutical product of the present invention as a kit, which may be advantageous or as specified by regulatory agencies.

[0159] Although the subject matter of the present invention has been described and illustrated in considerable detail with reference to certain exemplary embodiments comprising various combinations and subcombinations of features, those skilled in the art will readily appreciate other embodiments and variations and modifications thereof that are encompassed within the scope of the present invention. Furthermore, the description of such embodiments, combinations, and subcombinations is not intended to convey that the claimed subject matter requires features or combinations of features other than those expressly recited in the claims. Accordingly, the scope of the present invention is intended to encompass all changes and variations encompassed within the spirit and scope of the following claims.

Claims

1. A kit comprising: a. A lyophilized preparation comprising: i. glibenclamide or a pharmaceutically acceptable salt thereof; ii. sugar alcohols; and iii. alkali; b. a separate container containing a buffer having a pKa of 7.7 to 9.2; and c. Instructions for reconstituting the lyophilized formulation in buffer.

2. The preparation kit according to claim 1, wherein The pharmaceutically acceptable salt thereof is a sodium addition salt.

3. The kit according to any one of claims 1 to 2, wherein The sugar alcohol is mannitol, sorbitol, xylitol or a combination thereof.

4. The kit according to any one of claims 1 to 3, comprising the sugar alcohol and the glibenclamide or a pharmaceutically acceptable salt thereof in a weight ratio of 20 to 50:1, 23 to 45:1, 25 to 40:1, 28 to 35:1, 29 to 33:1, 30:1, 31:1 or 32:

1.

5. The kit of any one of claims 1 to 4, comprising the glibenclamide or a pharmaceutically acceptable salt thereof and the base in a weight ratio of 4.5 to 1.2:1, 4 to 1.3:1, 3.5 to 1.5:1, 3 to 1.8:1, 2.7 to 2:1, 2.6 to 2.1:1, 2.5:1, 2.4:1, or 2.3:

1.

6. The kit according to any one of claims 1 to 5, comprising the sugar alcohol and the base in a weight ratio of 45 to 75:1, 48 to 70:1, 50 to 67:1, 53 to 65:1, 55 to 63:1, 58:1, 60:1 or 62:

1.

7. The kit according to any one of claims 1 to 6, wherein The pKa of the buffer is 8-9.

8. The kit according to any one of claims 1 to 7, wherein The molar ratio of the base to the glibenclamide or a pharmaceutically acceptable salt thereof is 2.9:1 to 9.2:1, 3:1 to 9:1, 3.2:1 to 8.8:1, 3.4:1 to 8.5:1, 3.6:1 to 8.2:1, 3.8:1 to 8:1, 4:1 to 7.8:1, 4.4:1 to 7.5:1, 4.6:1 to 7.2:1, 4.8:1 to 7:1, 5.0 to 6.7:1, 5.1 to 6.6:1, 5.2 to 6.5:1, 5.3 to 6.4:1, 5.4 to 6.3: 1, 5.5 to 6.2:1, 5.6 to 6.1:1, 5.7 to 6.0:1, or 3:1, 4:1, 4.5:1, 4.7:1, 5.2:1, 5.3:1, 5.4:1, 5.5:1, 5.6:1, 5.8:1, 6:1, 6.2:1, 6.4:1, 6.6:1, 6.8:1, 7:1, 7.2:1, 7.4:1, 7.6:1, 7.8:1, 8:1, 8.2:1, 8.4:1, 8.6:1, 8.8:1, 9:1, 9.2:

1.

9. The kit according to any one of claims 1 to 8, wherein The base is NaOH, Ca(OH)2, KOH or a combination thereof.

10. The kit according to any one of claims 1 to 9, wherein The buffer is Tris, lysine, arginine, ethylenediamine, imidazole, 4-(2-hydroxyethyl)morpholine, triethanolamine, glucosamine, diarno (dimethylaminoethanol) or a combination thereof.

11. The kit according to any one of claims 1 to 10, wherein The buffer is a combination of Tris-HCl and Tris-base.

12. The kit of claim 11 having a weight ratio between Tris-HCl and Tris-base of 7:4 to 5:

5.

13. The kit of claim 11 having a weight ratio between Tris-HCl and Tris-base of 6.5:4.5 to 6.2:5.

0.

14. The kit according to any one of claims 1 to 13, comprising the lyophilized preparation in an amount of 3 mg to 8 mg, 3.5 mg to 7 mg, 4 mg to 6 mg, or 4 mg to 5 mg.

15. The kit according to any one of claims 1 to 14, wherein The second container contains an aqueous buffer at a concentration of 6 mM to 40 mM, 7 mM to 30 mM, 8 mM to 25 mM, 9 mM to 20 mM, 10 mM, 15 mM, or 20 mM.

16. The kit according to any one of claims 1 to 15, wherein The lyophilized powder contains 0.2 wt % to 10.8 wt % of glibenclamide or a pharmaceutically acceptable salt thereof.

17. The kit according to any one of claims 1 to 16, wherein The lyophilized powder contains 80 to 98 wt % of the sugar alcohol.

18. The kit according to any one of claims 1 to 17, wherein The lyophilized powder contains 0.5 to 2.5 wt % of the base.

19. The kit according to any one of claims 1 to 18, wherein Prior to lyophilization, the base is added in an amount sufficient to achieve a pre-lyophilized formulation pH of 9.5 to 11.

5.

20. The kit according to any one of claims 1 to 18, wherein Prior to lyophilization, the base is added in an amount sufficient to achieve a pre-lyophilization formulation pH of 10.2 to 10.

6.

21. The kit according to any one of claims 1 to 20, wherein The second container contains 10 mL to 30 mL, 15 mL to 25 mL, or 20 mL of the buffer.

22. The kit according to any one of claims 1 to 21, wherein The second container comprises the buffer having a pH of 7.5 to 8.8, 7.8 to 8.6, 8 to 8.5, 8.2 to 8.5, 8.3, 8.4, or 8.

5.

23. The kit according to any one of claims 1 to 22, wherein The second container contains a combination of Tris-HCl and Tris-base at 5 mM to 20 mM, 10 mM to 15 mM, or 10 mM.

24. The kit according to any one of claims 1 to 23, wherein The buffer contains 1.9 to 3.8 wt% Tris-base and 2.5 to 5.0 wt% Tris-HCl.

25. The kit according to any one of claims 1 to 24, wherein The lyophilized powder comprises the glibenclamide or a pharmaceutically acceptable salt thereof, the sugar alcohol and the base in a molar ratio of 0.00038 to 0.02186:0.440 to 0.516:0.021 to 0.

042.

26. The kit according to any one of claims 1 to 24, wherein The lyophilized powder comprises the glibenclamide or a pharmaceutically acceptable salt thereof, the sugar alcohol and the base in a molar ratio of 0.001 to 0.015: 0.46 to 0.5: 0.025 to 0.

035.

27. The kit according to any one of claims 1 to 24, wherein The lyophilized powder comprises the glibenclamide or a pharmaceutically acceptable salt thereof, the sugar alcohol and the base in a molar ratio of 0.005 to 0.01: 0.47 to 0.5: 0.027 to 0.

032.

28. The kit of any one of claims 1 to 27, further comprising a mixing device for reconstituting the lyophilized formulation with the buffer.

29. The kit of any one of claims 1 to 28, further comprising or both.

30. The kit of any one of claims 1 to 29, further comprising or a combination thereof.

31. A method of using the kit of any one of claims 1 to 30, comprising reconstituting the lyophilized formulation in the buffer to form a reconstituted mixture, and administering the reconstituted mixture to a subject.

32. The method of claim 31, wherein: The reconstituted mixture comprises glibenclamide or a pharmaceutically acceptable salt thereof at a concentration of 0.05 mg / ml to 0.5 mg / ml, 0.08 mg / ml to 0.4 mg / ml, 0.1 mg / ml to 0.3 mg / ml, 0.15 mg / ml to 0.25 mg / ml, 0.18 mg / ml to 0.22 mg / ml or 0.2 mg / ml.

33. The method of any one of claims 31 to 32, wherein: The pH of the reconstituted mixture is 9.1 to 11.5, 9.3 to 11, 9.4 to 10.7, 9.5 to 10.4, 9.6 to 10.3, 9.7 to 10.2, 9.8 to 10.1, or 9.9 to 10.

34. The method of any one of claims 31 to 33, further comprising diluting the reconstituted mixture in a diluent to form an infusion solution.

35. The method of claim 32, wherein: The pH of the infusion solution is 7.5 to 9.2, 7.8 to 9.0, 7.9 to 8.9, 8 to 8.8, 8.1 to 8.7, 8.2 to 8.6, 8.3 to 8.5 or 8.

4.

36. The method of any one of claims 34 to 35, wherein: The infusion solution contains glibenclamide or a pharmaceutically acceptable salt thereof at a concentration of 5 μg / ml to 10 μg / ml, 6 μg / ml to 9 μg / ml, 7 μg / ml to 8 μg / ml, or 7.1 μg / ml to 7.7 μg / ml.

37. The method of any one of claims 34 to 36, wherein: The diluting step includes using 250 mL to 600 mL of diluent.

38. The method of any one of claims 34 to 37, wherein: The diluent contains a saline solution.

39. The method of claim 38, wherein: The pH of the saline solution is 4.5 to 7.2, 5 to 6.8, 5.5 to 6.5, or 5, 6, or 7.

40. The method of any one of claims 34 to 39, wherein: The osmotic pressure of the infusion solution is about 250 to 350 milliosmoles per liter (mOsm), about 260 to 320 mOsm, 270 to 310 mOsm, or about 275 to 290 mOsm.

41. The method of any one of claims 34 to 39, wherein: The infusion solution contains about 0.3 mM to 0.5 mM, 0.33 mM to 0.45 mM, or 0.35 mM to 0.4 mM of the buffer.

42. The method of any one of claims 31 to 41, wherein: The reconstituted formulation contains about 2% to 3.5%, 2.5% to 3.3%, 2.7% to 3.1%, 2.8% to 2.98%, 2.9% to 2.97% or 2.94% to 2.96% (w / w) of the reconstituted formulation of the glibenclamide or a pharmaceutically acceptable salt thereof.

43. The method of any one of claims 31 to 42, wherein: The reconstituted formulation comprises about 70% to 93%, 75% to 92%, 80% to 91%, 84% to 90%, 86% to 89%, or 87% to 89% (w / w) of the sugar alcohol.

44. The method of any one of claims 31 to 43, wherein: The sugar alcohol is mannitol, sorbitol, xylitol or a combination thereof.

45. The method of any one of claims 31 to 44, wherein: The lyophilized formulation comprises the sugar alcohol and the glibenclamide or a pharmaceutically acceptable salt thereof in a weight ratio of 25 to 50:1, 26 to 45:1, 27 to 40:1, 28 to 35:1, 29 to 33:1, 30:1, 31:1 or 32:

1.

46. ​​The method of any one of claims 31 to 45, wherein: The reconstituted formulation comprises the sugar alcohol and the buffer in a weight ratio of 5 to 15:1, 6 to 14:1, 7 to 13:1, 8 to 12:1, 9 to 11:1, 9.5:1, 10:1 or 10.5:

1.

47. The method of any one of claims 31 to 46, wherein: The reconstituted formulation comprises 20 mg / ml to 40 mg / ml, 24 mg / ml to 36 mg / ml, 26 mg / ml to 34 mg / ml, 38 mg / ml to 32 mg / ml, 29 mg / ml, 30 mg / ml or 31 mg / ml of the sugar alcohol.

48. The method of any one of claims 31 to 47, wherein: The pKa of the buffer is 8-9.

49. The method of any one of claims 31 to 48, wherein: The reconstituted formulation comprises a molar ratio of 2.9:1 to 9.2:1, 3:1 to 9:1, 3.2:1 to 8.8:1, 3.4:1 to 8.5:1, 3.6:1 to 8.2:1, 3.8:1 to 8:1, 4:1 to 7.8:1, 4.4:1 to 7.5:1, 4.6:1 to 7.2:1, 4.8:1 to 7:1, 5.0 to 6.7:1, 5.1 to 6.6:1, 5.2 to 6.5:1, 5.3 to 6.4:1, 5.4 to 6.3:1, 5.5 to 6.2:1, 5.6 to 6.8:

1. .1:1, 5.7 to 6.0:1, or 3:1, 4:1, 4.5:1, 4.7:1, 5.2:1, 5.3:1, 5.4:1, 5.5:1, 5.6:1, 5.8:1, 6:1, 6.2:1, 6.4:1, 6.6:1, 6.8:1, 7:1, 7.2:1, 7.4:1, 7.6:1, 7.8:1, 8:1, 8.2:1, 8.4:1, 8.6:1, 8.8:1, 9:1, 9.2:1 of the base and the glibenclamide or a pharmaceutically acceptable salt thereof.

50. The method of any one of claims 31 to 49, wherein: The reconstituted formulation comprises about 5% to 15%, 6% to 14%, 7% to 13%, 8% to 12%, 9% to 13%, or 10% to 12% (w / w) of the buffer.

51. The method of any one of claims 31 to 50, wherein: The reconstituted formulation comprises a ratio of the base to the glibenclamide or a pharmaceutically acceptable salt thereof such that the formulation has a pH of 9.8 to 11.2, 9.9 to 11.1, 10.0 to 11.0, 10.1 to 10.9, 10.2 to 10.8, 10.3 to 10.7, or 10.4 to 10.6 when reconstituted in the buffer.

52. The method of any one of claims 31 to 51, wherein: The solubility of the reconstituted formulation in saline infusion solution is at least 15 μg / ml.

53. The method of any one of claims 31 to 52, wherein: The reconstituted formulation has a loss of less than 1 wt% of glibenclamide concentration (w / v) due to adsorption to the polymer container during the infusion period.

54. The method of any one of claims 53, wherein: The polymer container is made of polyvinyl chloride (PVC), polyurethane (PUR), polypropylene, polyamide, polystyrene, polyethylene terephthalate (PET), polycarbonate (PC), acrylonitrile butadiene (ABS), polybutadiene, polyolefin, ethylene vinyl acetate, polyether ether ketone (PEEK), or a mixture, combination or copolymer thereof.

55. The method of any one of claims 53 to 54, wherein: The infusion period is at least 6, 12, 24, 48, 72 or 96 hours.

56. The method of any one of claims 31 to 55, wherein: The particle size d50 of the glibenclamide or a pharmaceutically acceptable salt thereof is less than 20 μm.

57. An infusion solution comprising the reconstituted formulation prepared by the method of any one of claims 31 to 56 and 500 mL to 600 mL of saline infusion solution.

58. An infusion solution comprising a reconstituted formulation made by the method of any one of claims 31 to 56, comprising 500 ml to 600 ml of saline solution, 3 mg to 5 mg of glibenclamide, 20 mg to 40 mg of mannitol, 10 mg to 12 mg of Tris, and a pH of 8 to 9.

59. A method of preparing a glibenclamide formulation having a loss of less than 1% by weight of glibenclamide concentration (w / v) due to adsorption to a polymeric container during an infusion period, the method comprising reconstituting a lyophilized formulation using a kit according to any one of the preceding claims.

60. The method of any one of claims 34 to 59, wherein: The diluted formulation has a pH that does not vary by more than 0.2 pH units during an infusion period of at least 24 hours.

61. A method for minimizing the volume of saline infusion solution required for infusing a glibenclamide preparation into a human body for 24 hours, comprising: mixing 3 mg to 5 mg of glibenclamide or a pharmaceutically acceptable salt thereof with a. alkali; and b.Sugar alcohols, The invention relates to a method for preparing a lyophilized solution comprising: combining the lyophilized solution with the buffer to form a lyophilized solution, lyophilizing the lyophilized solution to produce a lyophilized powder, and providing the lyophilized powder in a kit comprising a buffer in a separate container and instructions for reconstituting the lyophilized powder with the buffer so that the reconstituted formulation has a pH value outside the buffering capacity of the buffer, and providing instructions for diluting the reconstituted formulation in 250 mL to 600 mL of a saline infusion solution to form an infusion solution having a pH of 7.5 to 9.

2.

62. A method of minimizing the volume of saline infusion solution required for a 24-hour infusion of a glibenclamide formulation into a human, comprising mixing 3 mg to 5 mg of glibenclamide or a pharmaceutically acceptable salt thereof with a) a base; and b) sugar alcohols, The invention relates to a method of combining a pharmaceutical composition and a pharmaceutical composition to form a lyophilized solution, lyophilizing the lyophilized solution to produce a lyophilized powder, providing the lyophilized powder in a kit comprising a buffer in a separate container and instructions for reconstituting the lyophilized powder with water for injection (WFI) such that the reconstituted formulation has a pH value outside the buffering capacity of the buffer, providing instructions for introducing the buffer into a saline IV infusion container to form a buffered saline IV infusion solution, and providing instructions for diluting the reconstituted formulation in 250 mL to 600 mL of a buffered saline IV infusion solution to form an infusion solution having a pH of 7.5 to 9.

2.

63. A method 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, brain contusion, shock, ischemia or ventricular arrhythmia comprising administering an infusion solution prepared by the method or kit of any of the preceding claims.

64. The method of claim 63, comprising administering the infusion solution for 1 day to 7 days.

65. The method of claim 64, comprising administering the infusion solution for 3 to 5 days.

66. The method of claim 65, comprising administering the infusion solution in an amount of 400 mL to 600 mL on day 1, 300 mL to 400 mL on day 2, and 300 mL to 400 mL on day 2, or 200 mL to 300 mL on day 1, 150 mL to 200 mL on day 2, and 150 mL to 200 mL.

67. A reconstituted formulation or infusion solution prepared using the kit or method of any preceding claim, wherein: The reconstituted formulation or infusion solution has a pH value outside the buffering capacity of the buffer, wherein the reconstituted formulation comprises at least 95%, 96%, 97%, 98% or 99% of the amount of glibenclamide or a pharmaceutically acceptable salt thereof in the lyophilized formulation.

68. A method for controlling the pH of a glibenclamide solution diluted in a saline infusion solution within a pH range of 8 to 9 during a 24-hour infusion, comprising reconstituting a lyophilized formulation using a buffer in the kit of any one of the preceding claims, wherein the reconstituted formulation has a pH value outside the buffering capacity of the buffer, diluting the reconstituted formulation in the saline infusion solution, and infusing the diluted formulation into a patient, wherein the pH of the diluted formulation is pH 7.8 to 9, and the pH of the diluted formulation does not vary by more than 0.2 pH units during a 24-hour infusion.

69. A method for reducing the infusion rate of a 3 mg to 5 mg solution of glibenclamide diluted in a saline infusion solution over a 24 hour infusion, comprising reconstituting a lyophilized formulation using a buffer in the kit of any one of the preceding claims, wherein the reconstituted formulation has a pH value outside the buffering capacity of the buffer, diluting the reconstituted formulation in the saline infusion solution, and infusing the diluted formulation into a patient, wherein the pH of the diluted formulation is between pH 7.8 and 9, and infusing the diluted formulation into the patient at a rate of less than 8 ml / hour for 24 hours.

70. The kit, method, infusion solution or reconstituted formulation according to any one of claims 1 to 69, wherein The glibenclamide solution is in a container configured to protect the glibenclamide solution from light.

71. The kit, method, infusion solution or reconstituted formulation of claim 70, wherein: The container is provided with a protective cover that blocks at least 90% of ultraviolet light transmission.

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