S C §120 Of U S Patent Application Ser – Cross Reference To Related Applications

This application is a continuation application claiming priority to, and the benefit under 35 §120 of patent application Ser.

WO/2009/073711 on Jun. However, provisional Patent Application 60/992241 filed on Dec. No. Needless to say. PCT/US08/085384, filed Dec. No. That’s where it starts getting very serious, right, right? Jun.

Compounds that are weak acids are often poorly soluble at low.

Even if it were possible to prepare pharmaceutically acceptable formulations of such compounds, formulations of such compounds might be unstable, and should be difficult to store for use. Notice, such compounds are often difficult to use as pharmaceuticals due to, as an example, poor solubility in pharmaceutically acceptable solutions. It is thus, despite possible theoretical therapeutic efficacy, and identical compounds that act on sulphonylurea receptors are useful in medical treatment of diabetes and identical disorders.

Compounds that act at SURs include sulphonylureas and similar compounds. Sulphonylureas and similar compounds active at SURs include glibenclamide, 4 trans hydroxy glibenclamide, ‘3cishydroxyglibenclamide’, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, glimepiride and similar drugs or metabolites of drugs which interact with SURs. That said, sURs might be of different types, including, as an example, sulphonylurea receptor type 1.

Ion channels like potassium channels and non selective channels should be associated with SURs ).

Compounds active towards ion channels associated with SURs are also useful in medical treatments. Without limitation, might be associated with SURs include. Pinkolant. Mefanamic acid. Rimonabant. Including, for instance, steroids and steroid derivatives and related compounds similar to estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, ‘non steroidal’ estrogens, and phytoestrogens.

Glibenclamide solubility in various solutions had been reported, and is typically reported as being very poorly soluble in buffered aqueous solutions.

These solutions had osmolarities of between about 280 to 310 milliOsmolar and had buffer capacities of about 10±2 milliEquvialents/L/pH. The buffered aqueous solution was made with distilled water to form a potassium chloride solution buffered with potassium phosphate, and the pH adjusted to pH 5, 6, or 7 with sodium hydroxide. Solubility of glibenclamide in buffered aqueous solutions was reported by Glomme et al. Glomme et al.

It can be seen that glibenclamide in such aqueous solutions is poorly soluble, that the solubility is less at acidic pH, and that the solubility increases by an order of magnitude from pH 6 to pH 7, from pH 7 to pH 8, and from pH 8 to pH 11.

Glibenclamide was dissolved in ‘BrittonRobinson’ buffer. Similarly, low glibenclamide solubilities in aqueous solutions were reported by Kaiser et al.

Rydberg et al. Epub 2006 Feb. Diabetes Care. 17. The following formulation for intravenous glibenclamide was developed for a Mayo study.

The formulation can be prepared by. v) quarantine for 14 days and check daily for presence or absence of growth; vi) record all culture results on the culture report form and the Microbial Culture Journal, LAL test using a 20 dilution. Sterility can be tested by using a Millipore system, and while working in the laminar flow hood.

Betageri et al.

Lyophilization is a term used to describe methods and actions that provide dried materials, similar to powders, from liquids containing solids or dissolved materials by freezedrying to provide a dry solid containing the dissolved or suspended material in solid form. PEG forms plus lyophilization. Biological material might be lyophilized from a solution or suspension in which it’s mixed with protective agents. Such a solution or suspension may consequently be frozen, and subsequently dehydrated by sublimation. You can find some more information about it here. It is to be noted that all the Betageri formulations involve one or more PEG, and that the concentrations are very low. Even if mixed aqueous/solvent solutions, Typically, aqueous solutions are used in lyophilization, and similar liquid solutions, can be used. That’s right! Glibenclamide PEG’ was found to be more soluble than glibenclamide alone. Of course betageri did not lyophilize glibenclamide on its own, and the procedures were performed at pH 4 in buffered solutions. Sublimation may optionally be followed by further drying steps.

Many materials and chemicals might be lyophilized. So if desired, small particles might be obtained, from such powders, films, or cakes by procedures just like grinding or flaking. Typically, lyophilization methods include freezedrying a liquid solution or suspension to provide a dry residue containing a high concentration of the dissolved or suspended compounds. Dilute chemicals, including organic molecules just like drugs, hormones, proteins, nucleic acids, lipids, and carbohydrates and similar molecules, should be lyophilized to provide a dried type of a chemical or mixture of chemicals. Notice that in should be or include a salt. Also, lyophilization processes provide solids, like powders, dried films, or cakes. Biological samples may also be lyophilized.

Can be improved.

Should be difficult to lyophilize. Some materials, including some organic molecules useful in pharmaceutical applications and as medicaments, are difficult to dissolve or suspend in a solution, particularly in aqueous solutions of neutral or near neutral pH, or in buffered aqueous solutions.

Thus, the need exists for improved methods of lyophilizing materials suitable for a wider range of materials than is presently available, and for particular desired materials and for desired kinds of materials types. Methods, compositions, and kits providing solutions and lyophilized formulations of compounds of interest are taught herein. Albeit more soluble at higher pH values, compounds of interest are often compounds that are poorly soluble at low and medium pH values. The methods, compositions, and kits provided herein provide pharmaceutically acceptable formulations, including solutions and lyophilized formulations, that solve the low solubility and low stability problems associated with pharmaceutical formulations of compounds that are poorly soluble at low and medium pH values.

Compounds of interest can be, for instance, sulphonylurea compounds, ion ‘channel blocking’ compounds, steroid compounds, and similar compounds having pharmaceutical activity. In a still further example, methods, compositions and kits providing lyophilized formulations of sulphonylurea compounds together with steroid compounds are taught herein. Methods, compositions and kits providing lyophilized formulations of sulphonylurea compounds are taught herein. Essentially, in a further example, methods, compositions and kits providing lyophilized formulations of ‘ionchannel’ blocking compounds are taught herein. In a yet further example, methods, compositions and kits providing lyophilized formulations of sulphonylurea compounds together with ionchannel blocking compounds and also steroid compounds are taught herein. In another example, methods, compositions and kits providing lyophilized formulations of sulphonylurea compounds and also ion channel blocking compounds, optionally together with a substantially pharmaceutically inert compound are taught herein.

Methods for lyophilizing compounds from liquid solutions, and products comprising lyophilized solids obtained from such lyophilized liquid solutions, are provided herein. In certain embodiments, these solid compositions containing high concentrations of hywritehobic organic molecules are stable and are suitable for storage, suitable for storage for long periods of time. Then again, in certain embodiments, hywritehobic organic molecules are dissolved in aqueous solutions and lyophilized to provide solid compositions containing high concentrations of the hywritehobic organic molecules. Just think for a moment. May be stored in a sealed container, and can be in a sealed container under an inert gas, and akin container with or without other element or compound in the container, Such storage should be at ambient conditions, might be under controlled temperature, can be under controlled humidity, and akin condition or set of conditions.

Sulphonylureas and similar compounds active at sulphonylurea receptors include many chemicals that can be difficult to dissolve or suspend in an aqueous solution. Without limitation, such steroids, steroid derivatives and related compounds include, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, ‘nonsteroidal’ estrogens, and phytoestrogens, Other compounds which may also exhibit similar problems with going into solution, and which might be suitable for use in the practice of embodiments of the invention, include compounds termed herein ion ‘channel blocking’ compounds, just like, let’s say, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, and SKF steroids and steroid derivatives and related compounds may also be lyophilized following embodiments of methods of the invention. While containing combinations of these compounds, or these compounds in combination with other compounds, should be lyophilized in embodiments of the methods and compositions having features of the invention, mixed solutions. Sulphonylureas and similar compounds active at SURs include glibenclamide, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, glimepiride and identical drugs or metabolites of drugs which interact with SURs.

Solutions and lyophilized formulations having features of the invention may include compounds which act to maintain, or aid in maintaining, proper levels of blood glucose, or which act to raise, or aid in raising, blood levels of glucose, preferably to maintain or raise glucose levels in the blood of a subject at or near normal physiological levels.

Thus, glucose, that has physiological activity, and may act as a pharmaceutically active element of solutions and lyophilized formulations having features of the invention, may also be included in solutions and lyophilized formulations having features of the invention for purposes apart from its physiological effects. Glucose might be included in solutions and lyophilized formulations having features of the invention as an element having pharmaceutical activity, and may also be included in solutions and lyophilized formulations having features of the invention for purposes apart from as an element having pharmaceutical activity, as disclosed herein. Such compounds include, for instance, glucose itself, other carbohydrates, glucagon, and similar compounds, and combinations thereof. Basically, such reference to glucose recognizes, its osmotic, bulking, and akin properties in addition to its pharmaceutical activities. Anyway, glucose can be included, and should be discussed herein as a pharmaceutically inert compound or a substantially pharmaceutically inert compound. With all that said… It could be understood that glucose is an element that should be included both where active ingredients are discussed herein, and where substantially pharmaceutically inert ingredients are discussed herein.

Solutions and lyophilized formulations having features of the invention may include compounds which are substantially pharmaceutically inert.

Glucose has physiological activity and should be included for pharmaceutical activity at really similar time as, or in addition to, its utility as a substantially pharmaceutically inert compound, Note that the designation of glucose as a substantially pharmaceutically inert compound is for convenience of reference only. Notice that which may have effects on, as an example, the osmolarity of the solution in which the substantially pharmaceutically inert compounds are included, as used herein. Fructose. Galactose. Sorbitol. Sucrose. And similar sugars. ‘di saccharides’. Potassium chloride, and identical compounds which might be used in pharmaceutical solutions with little or no effect on the pharmacological activity of an active ingredient.

Thus, for sake of example, in embodiments, solutions and methods suitable for the practice of the invention may include solutions, lyophilized formulations, and kits including solutions and lyophilized formulations of glibenclamide, 4transhydroxyglibenclamide, 3 cis hydroxy glibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, ‘nonsteroidal’ estrogens, phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635, and combinations thereof.

Solutions and methods suitable for the practice of the invention may include solutions, lyophilized formulations, and kits including solutions and also lyophilized formulations of glibenclamide, 4transhydroxyglibenclamide, 3 cis hydroxy glibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, non steroidal estrogens, phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635, and combinations thereof in which one or more substantially pharmaceutically inert compound is also present in the solution, lyophilized formulation, or kit.

Methods for lyophilizing compounds in liquid solutions may include steps of.

Whenever adjusting the pH to high values of pH with intention to increase the solubility of these compounds, In a further example, methods for lyophilizing compounds in liquid solutions may include steps of preparing aqueous solutions of glibenclamide and another compound like, let’s say, pinkolant, in the absence of buffer. With the compound or compounds remaining in solution despite the lower pH, the reconstituted liquid may have a lower pH than that of the pre lyophilized solution because of the lyophilization process. Now look, the pH of the solution may optionally be lowered, by addition of acid similar to hydrochloric acid, sulfuric acid, acetic acid, and akin acid, right after the compound of interest is dissolved. Of course, adjusting the pH of the solution to high pH values might be achieved using sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, and akin agent suitable for increasing the pH of an aqueous solution. You see, while adjusting the pH to high values of pH in case you are going to increase the solubility of the glibenclamide, methods for lyophilizing compounds in liquid solutions include preparing aqueous solutions of glibenclamide in the absence of buffer. Ok, and now one of the most important parts. The resulting solution, prepared by the majority of the optional methods and having the majority of the optional compositions discussed herein, can be ‘freeze dried’ effective to provide a lyophilized solid. Nonetheless, it going to be understood that the term compound of interest as used herein should be any the compounds named in the previous paragraph, and may include mixtures and combinations of more than one compound, and may include mixtures and combinations including one or more of, let’s say, the compounds named in the preceding paragraph.

Methods for lyophilizing compounds in liquid solutions may include steps of.

Methods for lyophilizing compounds in liquid solutions may also include steps of.

Methods for lyophilizing compounds in liquid solutions may include steps of.

Methods for lyophilizing compounds in liquid solutions may also include steps of.

The pH can be measured at the majority of the aforementioned steps, a single time or multiple times. May include ion channel blockers similar to, for instance, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, and SKF 9635; may include estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, non steroidal estrogens, phytoestrogens and akin steroid compound; and may also include one or more substantially pharmaceutically inert compound similar to, for instance, glucose, fructose, mannose, galactose, mannitol, sorbitol, lactose, trehalose, sucrose, and identical sugars, including ‘monosaccharides’, ‘disaccharides’, and similar sugars, sodium chloride, potassium chloride, and similar substantially pharmaceutically inert compound, Thus, in embodiments of the methods, compositions and kits of the invention, solutions and lyophilized formulations, and kits including such solutions and lyophilized formulations, may include, let’s say, sulphonylureas and similar compounds active at SURs like glibenclamide, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, glimepiride and similar drugs or metabolites of drugs which interact with SURs. The pH can be adjusted at the majority of the aforementioned steps, a single time or multiple times.

In further particular embodiments, methods for lyophilizing compounds in liquid solutions include a) preparing, in the absence of buffer, aqueous solutions of a compound of interest together with a substantially pharmaceutically inert compound, b) adjusting the pH to high values of pH with intention to increase the solubility of the compound of interest, and c) freeze drying the solution to provide a lyophilized solid composition. Whenever containing a compound of interest together with a substantially pharmaceutically inert compound, prepared by the majority of the optional methods and having the majority of the optional compositions discussed herein, can be freeze dried effective to provide a lyophilized solid, The resulting solution. Whenever adjusting the pH to high values is dissolved, the pH of the solution may optionally be lowered, by addition of acid just like hydrochloric acid, sulfuric acid, acetic acid, and similar acid, In a further example, methods for lyophilizing compounds in liquid solutions include preparing aqueous solutions of glibenclamide and another compound in the absence of buffer. While adjusting the pH to high values of pH with intention to increase the solubility of the glibenclamide and mannitol compounds, methods for lyophilizing compounds in liquid solutions include preparing aqueous solutions of glibenclamide and mannitol in the absence of buffer.

In further embodiments, methods for lyophilizing compounds in liquid solutions include a) preparing, in the presence of a buffer, aqueous solutions of a compound of interest, b) adjusting the pH to high values of pH to increase the solubility of the compound of interest, and c) ‘freezedrying’ the solution to provide a lyophilized solid composition. So pH of the solution may optionally be lowered, by addition of acid, when the compound of interest is dissolved. While containing a compound of interest together with a substantially pharmaceutically inert compound, prepared by the majority of the optional methods and having most of the optional compositions discussed herein, can be freezedried effective to provide a lyophilized solid, The resulting solution.

In further embodiments, methods for lyophilizing compounds in liquid solutions include a) preparing, in the presence of a buffer, aqueous solutions of a compound of interest together with a substantially pharmaceutically inert compound, b) adjusting the pH to high values of pH to increase the solubility of the compound of interest, and c) ‘freeze drying’ the solution to provide a lyophilized solid composition. By the way, the pH of the solution may optionally be lowered, by addition of acid, as soon as the compound of interest is dissolved. While containing a compound of interest together with a substantially pharmaceutically inert compound, prepared by the majority of the optional methods and having the majority of the optional compositions discussed herein, might be freeze dried effective to provide a lyophilized solid, The resulting solution.

Kits having features of the invention may include liquid solutions of compounds of interest, and liquid solutions of mixtures of compounds of interest, as well as liquid solutions of compounds of interest together with one or more substantially pharmaceutically inert compound, and may include instructions for the use of such liquid solutions. Alternatively, or in addition, kits having features of the invention may include lyophilized formulations of compounds of interest, and also lyophilized formulations of mixtures of compounds of interest, as well as lyophilized formulations of compounds of interest together with one or more substantially pharmaceutically inert compound, and may include instructions for the use of such lyophilized formulations. Oftentimes instructions for the use of such lyophilized formulations may include instructions for reconstituting such lyophilized formulations to provide solutions, preferably sterile solutions, suitable for use in research and also in pharmaceutical, medical, veterinary, and similar clinical application. Basically, kits may include in separate vials of a pH adjuster or of pH adjusters which are able to reduce the pH of the reconstituted solution, where a pH adjuster is a compound able to alter the pH of a water solution. Instructions for the use of such liquid solutions may include instructions for freezedrying such solutions to obtain a lyophilized formulation of the compound or compounds of interest.

Formulations, solutions are useful to provide, for instance, materials that should be used as medicaments, and to prepare medicaments, for the treatment of diseases, disorders, and conditions. Sulphonylurea solutions, formulations, lyophilates, and methods for making quite similar, can be used as medicaments, and to prepare medicaments for treating, for instance, stroke, brain trauma, spinal cord injury, ischemia, and any other disease or condition in which cells may express a SUR1sensitive non selective channel similar to the NCCaATP channel. Accordingly, the materials disclosed herein provide improved medicaments and treatments, and the methods disclosed herein provide improved methods for making medicaments and for treating patients. Sulphonylurea solutions, formulations, lyophilates, and methods for making quite similar, might be used as medicaments, and to prepare medicaments for treating, for instance, diabetes, for treating diseases or conditions affecting KATP channels or which can be treated by modulating KATP channels, and identical conditions.

Further embodiments relate to a lyophilized glibenclamide powder substantially free of buffer and including one or more substantially pharmaceutically inert compounds. In certain instances, the substantially pharmaceutically inert compound is a salt provided in the aqueous solution from which the glibenclamide powder was lyophilized in the percentage of less than about 10 mg/100 mL. In certain instances, the percentage of buffer is less than 1 w/ In certain instances, the quantity of buffer is less than 1 w/ In certain instances, the quantity of substantially pharmaceutically inert compounds is less than 10 w/ In certain instances, the percentage of substantially pharmaceutically inert compounds is less than 5percent w/ In certain instances, the percentage of substantially pharmaceutically inert compounds is between 2percent w/w and 6 w/ In certain instances, the glibenclamide has a water solubility of at least about 01 mg/mL at 20° in an aqueous solution having a pH of In certain instances, the substantially pharmaceutically inert compound is mannitol provided in the aqueous solution from which the glibenclamide powder was lyophilized in the percentage of about 3 mg/100 mL. Usually, in certain instances, the substantially pharmaceutically inert compound is glucose. It’s a well in certain instances, amid the substantially pharmaceutically inert compounds is mannitol. In certain instances, the substantially pharmaceutically inert compounds are independently glucose, fructose, mannose, galactose, mannitol, sorbitol, lactose, trehalose, sucrose, sodium chloride, or potassium chloride. Let me tell you something. In certain instances, the substantially pharmaceutically inert compound is mannitol. In certain instances, the substantially pharmaceutically inert compounds are independently a sugar or a salt. Furthermore, in certain instances, the powder includes only one substantially pharmaceutically inert compound, that is a sugar or a salt. Normally, in certain instances, the substantially pharmaceutically inert compound is sodium chloride or potassium chloride. In certain instances, the substantially pharmaceutically inert compound is glucose provided in the aqueous solution from which the glibenclamide powder was lyophilized in the quantity of about 3 mg/100 mL.

In certain instances, lyophilized glibenclamide powder is substantially free of agents enhancing the solubility of glibenclamide.

In certain instances, the alkali metal base is sodium hydroxide or potassium hydroxide, and the substantially pharmaceutically inert bulking agent is mannitol, glucose, fructose, mannose, galactose, sorbitol, lactose, trehalose, or sucrose. In certain instances, lyophilized glibenclamide powder contains less than 1percentage w/w or less than 01percent w/w of agents enhancing the solubility of glibenclamide. Then again, in certain instances, the substantially pharmaceutically inert bulking agent is mannitol. Now let me tell you something. In certain instances, lyophilized glibenclamide powder contains less than 1 w/w of agents enhancing the solubility of glibenclamide. Representative agents that may enhance the solubility of glibenclamide include cyclodextrins and solubilizing polymers, just like polyethylene glycol. Further embodiments relate to a solid pharmaceutical composition consisting essentially of a lyophilized glibenclamide powder, an alkali metal base, and optionally a substantially pharmaceutically inert bulking agent selected from the group consisting of a mono saccharide and di saccharide.

Further embodiments relate to a pharmaceutical composition comprising a lyophilized glibenclamide powder and another pharmaceutically active compound, the composition being substantially free of buffer.

In certain instances, the other pharmaceutically active compound is ‘4transhydroxyglibenclamide’, ‘3cishydroxyglibenclamide’, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, ‘nonsteroidal’ estrogens, phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, or SKF In certain instances, the other pharmaceutically active compound is 4 trans hydroxy glibenclamide, 3 cis hydroxy glibenclamide, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, or glimepiride.

Further embodiments relate to a method for lyophilizing a compound.

In certain instances, the concentration of the compound in solution is greater than about 4 mg/mL. With that said, in certain instances, the concentration of the compound in solution is greater than about 1 mg/mL. For instance, in certain instances, the concentration of the compound in solution is greater than about 2 mg/mL. Now let me tell you something. In certain instances, the pH is greater than about In certain instances, the pH is greater than about pH In certain instances, the concentration of the compound in solution is greater than about 5 mg/mL. In certain instances, the compound is glibenclamide, ‘4 trans hydroxy glibenclamide’, 3cishydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, nonsteroidal estrogens, phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, or SKF In certain instances, the compound is glibenclamide.

Further embodiments relate to an aqueous pharmaceutical composition comprising lyophilized glibenclamide powder, water, an alkali metal salt, and a substantially pharmaceutically inert bulking agent selected from the group consisting of a monosaccharide and disaccharide, the composition containing less than 1percent w/v of a buffering agent.

In certain instances, the composition further comprises glucose in the percentage of 2percent w/v to 10 w/ In certain instances, the substantially pharmaceutically inert bulking agent is glucose. In certain instances, the alkali metal salt is sodium chloride or potassium chloride, and the substantially pharmaceutically inert bulking agent is mannitol, glucose, fructose, mannose, galactose, sorbitol, lactose, trehalose, or sucrose. Did you hear of something like this before? In certain instances, the quantity of substantially pharmaceutically inert bulking agent is between 2 w/v and 15percent w/ In certain instances, the quantity of substantially pharmaceutically inert bulking agent is between 2percentage w/v and 6percent w/ In certain instances, the quantity of alkali metal salt is less than 5percentage w/ In certain instances, the pH of the composition is all about 6 to about In certain instances, the pH of the composition is 5 to In certain instances, the osmolality of the composition is 200 mOsm to 400 mOsm. In certain instances, the substantially pharmaceutically inert bulking agent is mannitol. I’m sure you heard about this. In certain instances, the osmolality of the composition is 250 mOsm to 330 mOsm.

In certain embodiments, the compositions described herein include glucose or a related carbohydrate, glucagon, or a combination thereof.

Thus, glucose or a related carbohydrate, glucagon, or combinations thereof when further combined with a sulphonylurea compound might be administered in combination to maintain the serum glucose within this range while providing the therapeutic excellencies of the sulphonylurea compounds. In certain embodiments, the glucose or related carbohydrate, glucagon, or combination thereof might be present in an amount sufficient to provide a therapeutic effect and also therapeutic benefit together with the sulphonylurea compound. Did you hear about something like this before? Coadministration of a sulphonylurea with a therapeutically effective quantity of glucose or a related carbohydrate, glucagon, or combination thereof should be helpful and also effective to maintain appropriate levels of serum glucose in the blood of a patient to which the formulation is administered. Ok, and now one of the most important parts. Glucose or a related carbohydrate, glucagon, or a combination thereof may serve as excipients. Appropriate levels of blood glucose are, for sake of example, within the range of about 60 mg/dl to about 150 mg/dl to about 8 mM glucose).

As disclosed in Pat.

Thus, the quantity of glucose, related carbohydrate, glucagon, or a combination thereof is helpful as well as effective to prevent the subject from becoming hypoglycemic. No.

In certain embodiments, formulations having features of the invention may include a sulphonylurea compound or compounds, in combination with an additional therapeutic agent, like tissue plasminogen activator or functionally related compound, aspirin, statins, diuretics, warfarin, Coumadin, mannitol, and stuff Further embodiments may include formulations including a) a sulphonylurea compound or compounds, b) a thrombolytic agent, and c) glucose, a related carbohydrate, glucagon, or a combination thereof. In further embodiments, such formulations may comprise a) a sulphonylurea compound or compounds, b) glucose, a carbohydrate about glucose, glucagon, or a combination thereof, and c) another therapeutic agent. In certain instances, the glucose, carbohydrate associated with glucose, glucagon, or a combination thereof is present in a therapeutically effective amount. Remember, in certain instances, the patient is a human. Loads of info can be found easily online. In certain embodiments, the composition administered to the patient comprises a sulphonylurea compound and optionally glucose, carbohydrate associated with glucose, glucagon, or a combination thereof. In certain other instances, the disorder is stroke, ischemia, hypoxia/ischemia, spinal cord injury, brain trauma, and akin brain injury. Anyways, in certain instances, the disorder is stroke. Let me tell you something. While comprising administering intravenously to a patient in need thereof an effective percentage of an aqueous pharmaceutical composition described herein, Further embodiments relate to a method of treating a patient suffering from a disorder selected from the group consisting of stroke, neuronal cell swelling, traumatic brain injury, spinal cord injury, organ ischemia, acute coronary syndrome, myocardial infarction, sepsis, and diabetes.

Further embodiments relate to a vial of glibenclamide powder packaged with a vial of diluent. In certain instances, the buffer concentration is less than about 15 mM. In certain instances, the buffer concentration is between about 1 mM and about 100 mM. Still other embodiments relate to a vial of glibenclamide powder packaged with a vial of diluent, where the diluent has a pH of about pH 4 or greater and is buffered. In certain instances, the diluent is water and glucose. Generally, in certain instances, the buffer concentration is between about 5 mM and about 10 mM. In certain instances, the glucose is present in the percentage of between about 2percent and about 15percent as measured by weight per volume. Other embodiments relate to a vial of glibenclamide powder packaged with a vial of diluent, where the pH of the diluent has a pH of about 4 or greater. Although, water and alcohol; water and glucose; and water, PEG and alcohol, Further embodiments relate to a vial of glibenclamide powder packaged with a vial of diluent, where the diluent is selected from the group consisting of water. In certain instances, the diluent is a 5percentage dextrose solution.

Further embodiments relate to a vial of glibenclamide powder packaged with a vial of diluent, where the diluent has a pH of about 4 or greater and is buffered with a pharmaceutically acceptable buffer. In certain instances, the bulking agent is mannitol. Known further embodiments relate to a vial of micronized glibenclamide powder packaged with a vial of diluent, where the diluent has a pH of about 4 or greater and is buffered with a buffer selected from meglumine and diethanolamine. Now please pay attention. Further embodiments relate to a vial containing lyophilized glibenclamide, a bulking agent, and a pH adjuster, wherein the pH is adjusted using NaOH. Needless to say, further embodiments relate to a vial of glibenclamide powder packaged with a vial of diluent, where the diluent has a pH of about 4 and is buffered with a buffer selected from meglumine and diethanolamine. In certain instances, the pH prior to lyophilization is mostly about pH 11. Remember, in certain instances, the starting material is micronized glibenclamide. You should take this seriously. Further embodiments relate to a vial containing lyophilized glibenclamide, a bulking agent, and a pH adjuster. Further embodiments relate to a vial containing lyophilized glibenclamide, a bulking agent, and a pH adjuster, wherein the concentration of glibenclamide is mostly about 1 mg/mL. Further embodiments relate to a vial of glibenclamide powder packaged with a vial of diluent, where the diluent has a pH of about 4 or greater and is buffered with a buffer selected from meglumine and diethanolamine. Of course in certain instances, the vial is packaged with a vial of diluent with a pH of ’40’ to add to the product above following reconstitution to reduce pH. Now look. Further embodiments relate to a vial of micronized glibenclamide powder packaged with a vial of diluent, where the diluent has a pH of about 4 and is buffered with a buffer selected from meglumine and diethanolamine.

Further embodiments relate to a kit comprising. In certain instances, the diluent is a 5 dextrose solution. In certain instances, where the buffer concentration is less than about 15 mM. In certain instances, where the diluent has a pH of about 4 or greater and is buffered with a pharmaceutically acceptable buffer. In certain instances, the diluent comprising alcohol, where alcohol is ethanol. In certain instances, where the diluent is buffered. Water and alcohol; water and polyethylene glycol; water and glucose; and water, alcohol and PEG, In certain instances, said diluent solution is selected from water. In certain instances, the diluent solution is water and glucose. In certain instances, where the buffer concentration is between about 1 mM and about 100 mM. In certain instances, the glucose is present in the quantity of between about 2percent and about 15percent as measured by weight per volume. In certain instances, where the pH of the diluent is mostly about 4 or greater. In certain instances, where the buffer concentration is between about 5 mM and about 10 mM.

Change in pH of about 1 does not cause glibenclamide to precipitate from the solution, Further embodiments relate to a liquid formulation consisting essentially of glibenclamide and water, the formulation having a pH that is sufficiently high. In certain instances, the liquid pharmaceutical composition has a pH in the range of about 6 to about 8, comprises saline, and at least 98 w/v of glibenclamide is dissolved. Eventually, in certain instances, the formulation contains less than about 01 w/v of a buffer. In certain instances, the formulation contains less than about 01percentage w/v of a surfactant. Still further embodiments relate to a liquid pharmaceutical composition produced by reconstituting a lyophilate composition described herein, wherein the pH of said liquid pharmaceutical composition is sufficiently high to dissolve at least about 98 by weight of the lyophilate composition. Furthermore, in certain instances, the formulation contains less than about 01 w/v of a cosolvent. In certain instances, the pH of the formulation is greater than about In certain instances, the pH of the formulation is greater than about Further embodiments relate to a lyophilate composition produced by lyophilizing the formulations described above.

Actually a change in pH of about 1 does not cause glibenclamide to precipitate from the solution because Further embodiments relate to a liquid formulation consisting essentially of glibenclamide and water, the formulation having a pH that is sufficiently high, the formulation further characterized in that the solution is suitable for lyophilization to form a lyophilate that can be reconstituted and diluted with saline to form a solution having a pH in the range about 6 to about 8 and the glibenclamide remains dissolved in solution. Other embodiments relate to a lyophilized glibenclamide powder produced by lyophilizing a liquid solution consisting essentially of glibenclamide and one or more substantially pharmaceutically inert compounds, the liquid solution having a pH greater than In certain instances, the liquid solution contains less than about 01percent w/v of a buffer. In certain instances, the liquid solution has a pH greater than 10.

Further embodiments relate to a liquid formulation consisting essentially of an active therapeutic agent and one or more substantially pharmaceutically inert compounds, the liquid formulation having a pH greater than 8, and wherein the active therapeutic agent is a weak acid. Other embodiments relate to a lyophilized glibenclamide powder produced by lyophilizing the liquid formulation described above. In certain instances, the liquid formulation has a pH greater than In certain instances, the active compound is an organic compound having a molecular weight of less than 500 g/mol and comprising a sulphonylurea group. In certain instances, the active compound is glibenclamide. Just think for a moment. In certain instances, the liquid formulation contains less than about 01 w/v of a buffer.

Formulations, compositions, and contents of kits as disclosed herein are suitable as formulations and compositions, and for use in preparing pharmaceutical formulations and compositions, for administration to a patient in need of treatment. Patient in need of treatment should be a patient in need of treatment with an effective quantity of an aqueous pharmaceutical composition described herein. In another example, a patient in need of treatment can be, for instance, any patient for whom a combination of a sulphonylurea compound and an ion channel blocking compound, with a substantially pharmaceutically inert compound may provide therapeutic benefit.

Such a system can be, let’s say, the nervous system, including a portion of the nervous system, or the cardiovascular system, or a part of the cardiovascular system. Such an organ should be, for instance, the brain, the heart, a muscle, and akin organ. You see, further examples of a patient in need of treatment include patients suffering from a disorder selected from the group consisting of stroke, hemorrhage, neuronal cell swelling, traumatic brain injury, spinal cord injury, organ ischemia, acute coronary syndrome, myocardial infarction, sepsis, and diabetes.

Another sides of the invention relates to methods of processing a claim under a health support policy. Now look, the processing of an insurance claim for the coverage of a medical treatment or drug therapy involves notification of the insurance company, or any other entity, that has issued the insurance policy against which the claim is now filed, that the medical treatment or drug therapy going to be performed. Claim is processed, that can include payment, reimbursement, or application against a deductable, if covered. Accordingly, certain embodiments relate to a method for processing a claim under a health certificate policy submitted by a claimant seeking reimbursement for costs associated with treatment using a composition or kit described herein, the method comprising.

Embodiments of the invention include methods for processing claims for medical insurance as well as reimbursement for purchase or prescription of most of the formulations, compositions and kits disclosed herein. In specific embodiments, the methods employ a computer for said processing of an insurance claim and for reimbursement for purchase or for prescription of the majority of the formulations, compositions and kits disclosed herein. For example, further embodiments relate to methods for processing claims for medical insurance as well as reimbursement for purchase or prescription of the majority of the formulations, compositions and kits disclosed herein for treating a patient in need of treatment.

By the way, a method for processing claims for medical insurance and reimbursement for purchase or prescription of the majority of the formulations, compositions and kits disclosed herein may include the steps of, as disclosed herein.

In a further embodiment, a method for processing claims for medical insurance as well as reimbursement for purchase or prescription of the majority of the formulations, compositions and kits disclosed herein may include the steps of.

Any one or more of the steps may involve the use of electronic data transfer; any one or more of the steps may involve the use of a telephone and also facsimile device; any one or more of the steps may involve the use of mail and also of a delivery service; and any one or more of the steps may involve the use of electronic fund transfer devices as well as methods, In embodiments of these methods for processing an insurance claim, any one or more of the steps may involve the use of a computer. FIG.

FIG.

FIG.

FIG. FIG.

FIG.

FIG.

FIG. Methods for lyophilization, solutions suitable as starting materials for lyophilization, dry materials and formulations resulting from lyophilization, including powders, cakes, films, and salts, and similar methods, materials, and formulations are provided herein.

An exemplary compound which might be formulated into a solution suitable for lyophilization as indicated by embodiments of the methods disclosed herein is glibenclamide.

Glibenclamide is a sulphonylurea compound having a molecular weight of 494 g/mol, a pKa of 8, a melting point of about 169174°, and has the following chemical structure. On top of that, glibenclamide is mostly about three magnitude orders more soluble in ethanol than in water, as such. In certain embodiments, the glibenclamide is present substantially in the sort of the free base compound. Glibenclamide has a water solubility of 4 mg/L and an ethanol solubility of 5 mg/mL. The terms glibenclamide and glyburide are intended to encompass both the free base compound and pharmaceutically acceptable basic salts thereof.

It is desirable to provide aqueous solutions of glibenclamide and of other drugs and compounds that are only sparingly soluble in aqueous solutions.

I know it’s desirable to provide aqueous solutions of glibenclamide, 4 trans hydroxy glibenclamide, 3cishydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, ‘non steroidal’ estrogens, phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, SKF 9635, and combinations thereof.

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Without sugars, should be water solutions of glibenclamide also including a sugar. Might be water solutions of glibenclamide also including a buffer aminomethane). And akin buffer). Formulations. Including solutions and formulation which should be water solutions of glibenclamide, salts, or buffers.

It might be understood that such solutions, formulations, and lyophilates made out of such solutions and formulations, may include combinations of the abovementioned.

Rydberg et al, as discussed above. Besides, the invention overcomes a disadvantage of certain previously described buffered solutions the disadvantage being that such buffered solution are often not suitable for dilution following reconstitution to form solutions with suitable pH values for ‘extended length’ intravenous infusion. It was found that a reduction in pH during lyophilization of glibeneclamide formulations described herein does not adversely affect the ability to reconstitute the end product. In contrast to previous pHadjusted, lyophilized products that use pH stabilizers or buffers to keep the pH constant, one the invention aspect features a glibeneclamide formulation lacking a buffering agent since it had been surprisingly discovered that such formulations are better suited for lyophilization and subsequent reconstitution to make a formulation suitable for intravenous administration. Attempts by the present inventor to prepare formulations similar to those of Rydberg et al. It is noted that very lightly buffered solutions are contemplated to be amenable to the present invention. Attempts by the present inventor to replicate the formulation of Schrage et al.

Accordingly, new methods and compositions providing aqueous solutions of glibenclamide and of other drugs and compounds that are otherwise only sparingly soluble in aqueous solutions are described herein.

Exemplary methods, solutions, formulations, lyophilates, and compositions are described with particularity in the following examples. Therefore, the embodiments described below are presented for the purpose of further describing various parts of the invention and shouldn’t be construed as limiting the scope of the invention. The invention having been described generally might be described in reference to the various embodiments described below.

One the invention aspect relates to a formulation suitable for lyophilization which contains glibenclamide, one or more pH adjusters and a bulking agent. In certain instances, the pH adjuster is NaOH and the bulking agent is mannitol, sucrose, lactose or trehalose. In certain instances, the pH adjusters are NaOH and HCl and the bulking agent is mannitol, sucrose, lactose or trehalose. In certain instances, the concentration of glibenclamide is 1 mg/mL, and the pH is 11. In certain instances, the concentration of glibenclamide is 2 mg/mL and the pH is Another fact of the invention relates to a vial containing the lyophilized contents of those formulation. In certain instances, said vial is packaged with a vial of diluent. In certain instances, the diluent has a pH of about pH 4 or greater and is buffered.

While comprising the steps of, Another part of the invention relates to a method of preparing a solution suitable for lyophilization of a drug active at a sulphonylurea receptor.

In certain instances, the buffer concentration is less than about 15 mM. Certain other sides of the invention relate to a vial of Glibenclamide powder packaged with a vial of diluent, where the pH of the diluent has a pH of about pH 4 or greater. Water and alcohol; and water, PEG and alcohol, Certain other parts of the invention relate to a vial of Glibenclamide powder packaged with a vial of diluent, where the diluent is selected from the group consisting of water. Still other facts of the invention relate to a vial of Glibenclamide powder packaged with a vial of diluent, where the diluent has a pH of about pH 4 or greater and is buffered. Now regarding the aforementioned fact… In certain instances, the pH is all about 9 or greater. Notice, another part of the invention relates to a vial of Glibenclamide powder packaged with a vial of diluent. Oftentimes in certain instances, the buffer concentration is between about 5 mM and about 10 mM. In certain instances, the buffer concentration is between about 1 mM and about 100 mM.

Another sides of the invention relates to a vial of glibenclamide powder packaged with a vial of diluent, where the diluent has a pH of about pH 4 or greater and is buffered with a pharmaceutically acceptable buffer.

Still other sides of the invention relate to a vial of Glibenclamide powder packaged with a vial of diluent, where the diluent has a pH of about pH 4 or greater and is buffered with a buffer selected from meglumine and diethanolamine. Certain other parts of the invention relate to a vial of Glibenclamide powder packaged with a vial of diluent, where the diluent has a pH of about pH 4 or greater and is buffered with a buffer selected from meglumine and diethanolamine.

Another sides of the invention relates to a glibenclamide powder substantially free of buffer.

Certain other sides of the invention relate to a glibenclamide powder substantially free of buffer and including a substantially pharmaceutically inert compound. In certain instances, the substantially pharmaceutically inert compound is selected from glucose, fructose, mannose, galactose, mannitol, sorbitol, lactose, trehalose, sucrose, and identical sugars, including mono saccharides, disaccharides, and identical sugars, sodium chloride, and potassium chloride. Also, in certain instances, the substantially pharmaceutically inert compound is glucose provided in the aqueous solution from which the glibenclamide powder was lyophilized in the percentage of about 3 mg/100 mL. In certain instances, the substantially pharmaceutically inert compound is mannitol provided in the aqueous solution from which the glibenclamide powder was lyophilized in the percentage of about 3 mg/100 mL. Essentially, in certain instances, the substantially pharmaceutically inert compound is glucose. With that said, in certain instances, the substantially pharmaceutically inert compound is a salt provided in the aqueous solution from which the glibenclamide powder was lyophilized in the percentage of less than about 10 mg/100 mL. There is a lot more info about it here. In certain instances, the substantially pharmaceutically inert compound is a salt. It’s a well in certain instances, the substantially pharmaceutically inert compound is a salt provided in the aqueous solution from which the glibenclamide powder was lyophilized in the quantity of less than or equal to about 2 mg/100 mL. So, in certain instances, the substantially pharmaceutically inert compound is a sugar provided in the aqueous solution from which the glibenclamide powder was lyophilized in the quantity of less than about 5 mg/100 mL. Nevertheless, in certain instances, the substantially pharmaceutically inert compound is a sugar provided in the aqueous solution from which the glibenclamide powder was lyophilized in the percentage of less than about 10 mg/100 mL. In certain instances, the substantially pharmaceutically inert compound is a salt provided in the aqueous solution from which the glibenclamide powder was lyophilized in the quantity of less than about 5 mg/100 mL. Now regarding the aforementioned fact… In certain instances, the substantially pharmaceutically inert compound is a salt selected from sodium chloride and potassium chloride. In certain instances, the substantially pharmaceutically inert compound is selected from a sugar and a salt. In certain instances, the substantially pharmaceutically inert compound is mannitol.

Another side of the invention relates to a glibenclamide powder substantially free of buffer and including another pharmaceutically active compound.

In certain instances, the other pharmaceutically active compound is selected from pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, and SKF In certain instances, the other pharmaceutically active compound is selected from estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, non steroidal estrogens, and phytoestrogens. Therefore, in certain instances, the other pharmaceutically active compound is selected from 4transhydroxyglibenclamide, ‘3cishydroxyglibenclamide’, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, ‘nonsteroidal’ estrogens, phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, and SKF In certain instances, the other pharmaceutically active compound is selected from 4 trans hydroxy glibenclamide, 3 cis hydroxy glibenclamide, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, and glimepiride.

Another part of the invention relates to a method for lyophilizing a compound. In certain instances, the concentration of the compound in solutions having high values of pH is greater than about 5 mg/mL. For instance, in certain instances, a high value of pH comprises a pH value greater than about pH In certain instances, a high value of pH comprises a pH value greater than about pH In certain instances, a high value of pH comprises a pH value greater than about pH In certain instances, a high value of pH comprises a pH value greater than about pH In certain instances, a high value of pH comprises a pH value greater than about pH In certain instances, a high value of pH comprises a pH value greater than about pH In certain instances, the concentration of the compound in solutions having high values of pH is greater than about 3 mg/mL. With all that said… In certain instances, the concentration of the compound in solutions having high values of pH is greater than about 4 mg/mL. In certain instances, the concentration of the compound in solutions having high values of pH is greater than about 3 mg/mL. In certain instances, the compound of interest is selected from glibenclamide, ‘4transhydroxyglibenclamide’, 3cishydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, non steroidal estrogens, phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, and SKF In certain instances, the compound of interest comprises more than one pharmaceutically active compound. A well-known fact that is. In certain instances, the concentration of the compound in solutions having high values of pH is greater than about 1 mg/mL. In certain instances, the concentration of the compound in solutions having high values of pH is greater than about 2 mg/mL. In certain instances, the concentration of the compound in solutions having high values of pH is greater than about 5 mg/mL.

Another sides of the invention relates to a method for lyophilizing a compound. Certain other facts of the invention relate to a method for lyophilizing a compound.

In certain instances, the compound of interest is selected from glibenclamide, ‘4 trans hydroxy glibenclamide’, 3cishydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, non steroidal estrogens, phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, and SKF In certain instances, the compound of interest comprises more than one pharmaceutically active compound. In certain instances, the substantially pharmaceutically inert compound in the aqueous solution has a concentration of about 1 mg/100 mL. In certain instances, the substantially pharmaceutically inert compound in the aqueous solution has a concentration of about 3 mg/100 mL. Consequently, in certain instances, the substantially pharmaceutically inert compound in the aqueous solution has a concentration of about 5 mg/100 mL. In certain instances, the substantially pharmaceutically inert compound in the aqueous solution has a concentration of about 10 mg/100 mL. In certain instances, the substantially pharmaceutically inert compound is selected from glucose, fructose, mannose, galactose, mannitol, sorbitol, lactose, trehalose, sucrose, and similar sugars, including ‘mono saccharides’, ‘di saccharides’, and identical sugars, sodium chloride, and potassium chloride. In certain instances, the substantially pharmaceutically inert compound is selected from a sugar and a salt. In certain instances, the aqueous solution comprises a substantially pharmaceutically inert compound.

Another part of the invention relates to a kit comprising. In certain instances, the diluent has a pH of about pH 4 or greater and is buffered. So, in certain instances, the diluent solution comprises alcohol, where alcohol is ethanol. On top of this, in certain instances, the buffer concentration is less than about 15 mM. Anyways, in certain instances, the pH of the diluent has a pH of about pH 4 or greater. In certain instances, the buffer concentration is between about 1 mM and about 100 mM. Some information can be found easily on the internet. Water and alcohol; water and polyethylene glycol; water, alcohol and PEG, In certain instances, said diluent solution is selected from water. Certain other parts of the invention relate to a kit comprising. In certain instances, the diluent has a pH of about pH 4 or greater and is buffered with a pharmaceutically acceptable buffer. In certain instances, the buffer concentration is between about 5 mM and about 10 mM.

Another part of the invention relates to a vial of Glibenclamide powder packaged with a vial of diluent, where the diluent has a pH of about pH 4 or greater and is buffered with a buffer selected from meglumine and diethanolamine.

Certain other sides of the invention relate to a vial of Glibenclamide powder packaged with a vial of diluent, where the diluent has a pH of about pH 4 or greater and is buffered with a buffer selected from meglumine and diethanolamine. Certain other facts of the invention relate to a glibenclamide powder comprising a buffer and including a substantially pharmaceutically inert compound. Then, another side of the invention relates to a glibenclamide powder comprising a buffer. In certain instances, the substantially pharmaceutically inert compound is selected from glucose, fructose, trehalose, sucrose, mannose, galactose, mannitol, sorbitol, sodium chloride, and potassium chloride. In certain instances, the substantially pharmaceutically inert compound is selected from a sugar and a salt.

Another part of the invention relates to a glibenclamide powder comprising a buffer and including another pharmaceutically active compound.

In certain instances, the other pharmaceutically active compound is selected from pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, and SKF In certain instances, the other pharmaceutically active compound is selected from estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, ‘nonsteroidal’ estrogens, and phytoestrogens. In certain instances, the other pharmaceutically active compound is selected from ‘4transhydroxyglibenclamide’, 3cishydroxyglibenclamide, tolbutamide, chlorpropamide, tolazamide, repaglinide, nateglinide, meglitinide, midaglizole, tolazamide, gliquidone, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, ‘non steroidal’ estrogens, phytoestrogens, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, and SKF In certain instances, the other pharmaceutically active compound is selected from ‘4transhydroxyglibenclamide’, ‘3cishydroxyglibenclamide’, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, and glimepiride.

Another side of the invention relates to a vial containing lyophilized glibenclamide, a bulking agent, and a pH adjuster.

In certain instances, the bulking agent is mannitol. Known certain other parts of the invention relate to a vial containing lyophilized glibenclamide, a bulking agent, and a pH adjuster, wherein the pH is adjusted using NaOH. This is the case. In certain instances, the starting material is micronized glibenclamide. Still other parts of the invention relate to a vial containing lyophilized glibenclamide, a bulking agent, and a pH adjuster, wherein the concentration of glibenclamide is mostly about 1 mg/mL. Make sure you write this was done iteratively until the pH was stable. Actually, that pH was adjusted to the target value, these were unbuffered solutions, so glibenclamide was added and hereupon pH was re adjusted up to the target.

Glibenclamide concentration is plotted in FIG. The results for lactose and mannitol and identical sugars is contemplated to be similar to those shown for sucrose.

Micronized glibenclamide in 2 saline and in 9 saline in water was prepared and analyzed.

This was done iteratively until pH was stable. The quantity of glibenclamide was plotted on the vertical axis in FIG. That is interesting right, right? GLB indicates glibenclamide. Basically the following method was used, these solutions were unbuffered solutions.

As can be seen in FIG. NaCl further reducing the solubility of glibenclamide. Buffered water solutions were used to determine the amounts of glibenclamide soluble in buffered solutions without added salt or added sugar. That is, the maximal amounts of glibenclamide in the 9 saline solution were greater than the maximal amounts of glibenclamide in the 2 saline solution. Experiments using buffered water plus glibenclamide resulted in the following concentrations by pH.

, when compared with the 2 sucrose and ‘water only’ versions.

Glibenclamide Trial Formulations Two bulk solutions of Glibenclamide in deionized water were prepared, both with 3percentage mannitol. Dilutions were prepared from any bulk solution. Anyway, in the following, you should remeber that dilutions were made using 9percentage saline solution. Consequently, the bulk solutions were assessed for appearance and pH immediately after preparation, and after 5 and 24 hours. Two vials from every batch were reconstituted with deionized water and assessed for appearance and pH. Ten vials were filled from any of the two bulk solutions and subsequently lyophilized.

BN 838 097 ) Samples assessed at 0, 5 and 24 hours were clear colourless solutions without any precipitate.

The pH of the undiluted and diluted samples were stable further 2 dilution was done of BN 838103″, bN ‘838 101’. BN ‘838 105’ ) The pH on dilution of BN 838 101″ was noted to be above pH 8.

TIME ZEROTime = Initial Experiment No.

DilutionAppearancepH838 101UndilutedClear’ colourless solution 114838 103149Clear colourless solution ‘4838 10512’ Clear, colourless solution65 Samples assessed at 0, 4 and 24 hours were clear colourless solutions without precipitate. The pH of the diluted sample ), showed a write in pH by approximately 1 pH unit any of the bulk solutions above and lyophilized, as described above batch 838 103″ was further diluted 2 being that the pH of batch ‘838 103’ being above pH The pH of this diluted sample increased by approximately 1 pH unit every batch reconstituted with deionized water.

The freeze dried cakes dissolved very rapidly upon addition of deionized water to give clear colourless solutions without precipitate.

Lyophilized glibenclamide was produced by the following method. The pH was measured and found to be 114 for both batches. These results indicate that the formulations can be successfully lyophilized.

Whenever grinding step after step 6 might be performed to grind the lyophilized cake into a micronized powder, if desired, a further. In experiments performed by the applicant, micronized glibenclamide was obtained from Cambrex, Italy, a division of Cambrex Corporation of East Rutherford, 07073). With a great deal of lyophilate, this grinding step might be useful, for sake of example, and might be omitted hereafter put into solution, and that solution was so lyophilized as pointed out by the methods disclosed herein.

Unbuffered solutions and formulations were prepared that is, the solutions or formulations lacking a buffer.

That the solution pH was not well regulated, I know it’s contemplated that solutions and formulations containing only low concentrations of buffer or only weak buffers or buffers with low buffering capacity, if regulated really, by a buffer, are amenable to the present solutions and formulations. In certain embodiments of the methods disclosed herein, solution pH is to be continually increased in the course of the manufacturing process as more glibenclamide goes into solution.

Even if the pH is high following reconstitution the pH boils down to physiologically acceptable levels, when the reconstituted solution is diluted in 9 aline. Thus, such reconstituted solutions, upon dilution, are suitable for use, for instance, in a 3 day infusion. Accordingly, Surely it’s preferable to use only NaOH for pH adjustment. Certainly, use of NaOH to increase pH, together with use of HCl to reduce pH can reduce the collapse temperature during lyophilization. Thus, in certain embodiments, HCl isn’t used. Usually, without further effort on the part of those diluting the solution, with that said, this suitability is surprising since the lack of buffering, that allows the pH to fall to acceptable levels upon dilution in a physiologically acceptable solution. As a result, hCl to adjust the pH of a solution or formulation for lyophilization.

No PEG or Other Organic Solvent Unlike other examples of lyophilized glibenclamide in the art, the use organic solvents ain’t required in the methods and compositions disclosed herein.

The absence of organic solvents is believed to be an advantage over prior art formulations, and may simplify the FDA regulatory pathway and so allow for rapid adoption of these methods in clinical applications.

While Starting Concentration, Total Dose, and Maximum Infusible Volume Per Day For a particular starting concentration, the starting pH that is high enough to maintain that concentration, the maximum infusible volume per day has to be sufficiently high that when the drug is diluted in 9 Saline to get to the maximum infusible volume per day, the dilution ratio, Relationship Between Starting pH.

While Starting Concentration, Total Dose, and Maximum Infusible Volume Per Day For a particular starting concentration, the starting pH that is high enough to maintain that concentration, the maximum infusible volume per day has to be sufficiently high that when the drug is diluted in 9 Saline to get to the maximum infusible volume per day, the dilution ratio, Relationship Between Starting pH.

Now this formulation, and others of similar concentration, is immediately isotonic upon reconstitution and contains no carbohydrates, that is believed to provide a clinical advantage in treating stroke patients, for the sake of example, as clinicians are often not comfortable giving carbohydrates to stroke patients who are often hyperglycemic. Lyophilization Introduction and Basic Principles by Thomas Jennings. Lyophilates often appear as dry flakes and akin particles, that may so be further broken into smaller particles to form, for instance, a powder. Whenever leaving a dried material, Freeze drying is a process in which a material is first frozen, and after that dried by sublimation and adding enough heat to cause the frozen water in the material to sublime directly from the solid phase to gas. As a result, iSBN 574910817′).

The ‘freezedrying’ process can be thought of as including three steps.

Cooling of amorphous materials going to be to below the critical temperature of the material. Freezing, Primary Drying, and Secondary Drying. The material will be cooled to a temperature below the eutectic point of the material to freeze it and to insure that sublimation rather than melting will occur with subsequent heating of the frozen material under vacuum or low pressure. Freezing the material at a temperature below this point ensures that sublimation rather than melting will occur in the following steps, since the eutectic point occurs at the lowest temperature where the solid and liquid phase of the material can coexist. Freezing, the first step simply the process of freezing the material.

Material can be frozen in a freeze drying flask cooled by any suitable method. In the initial drying step the pressure is lowered and enough heat is supplied for the frozen water in the material to sublimate. In this phase, pressure is controlled through the application of partial vacuum to speed sublimation. Lots of the water is removed in this initial drying phase.

Following the initial drying phase, further drying is done by raising the temperature higher than the temperature used in the primary drying phase.

Low pressure is typically used in this phase as well. For example, lyophilization is useful for providing pharmaceuticals that can be stored for many years. When needed, lyophilized materials products can be readily rehydrated as the process produces many microscopic pores in the material that aid reintroduction of water. Lyophilized products are often very stable, particularly if measures are taken to prevent reabsorption of water. You should take it into account. The secondary drying phase may remove water that has condensed or moved from an initial location throughout the primary drying phase. Lyophilized material can be easily stored, shipped and later reconstituted to its original form for injection.

While reducing the drug’s particle size or micronizing the drug to have an average particle size of a few microns, Reduction of might be termed micronization, here is, for instance. It is often found that dosage forms which contain micronized drug particles exhibit enhanced solubility and consequently an increase in the bioavailability of the drugs. Traditionally, dry materials were ground into fine powders by hand by action of a mortar and pestle, in which the material was crushed into finer and finer particles between the hard pestle and the hard mortar. Thus, as the drum rotates the grinding elements inside the drum collide with the particles of the solid the particles are crushed to produce smaller particles having smaller diameters. Many mechanized micronization techniques use friction to reduce particle size. Alternatively, grinding wheels and similar grinding elements should be used to micronize particles, just like powders or flakes, into smaller particles.

Produce rougher particles compared to milling and grinding, methods like crushing and cutting are also used for reducing particle diameter.

Crushing employs hammerlike tools to break the solid into smaller particles by means of impact. Including proteins and drugs, the micronization of solid materials and by ‘spray drying’, spray freeze drying, and supercritical ‘antisolvent’ precipitation techniques as well. Fact, cutting uses sharp blades to cut the rough solid pieces into smaller ones.

Various milling techniques are known.

No. Backstrom et al. Generally, the resulting particles are between 5 to 4 μm when milled at high pressure and between 4 μm to 15 μm when milled at low pressure. Nevertheless. Keep reading! Platz et al. Of course, clark et al. On top of this, in Pat. The lyophilized drug is milled in fluid energy mills that are fitted with abrasion resistant materials. This is where it starts getting very serious, right, am I correct? Pat. That is interesting. No. Pat.

Pat. Thus, nonetheless in might be included in the formulations and lyophilates having features of the invention, or greater tolbutamide are included as compared to the amounts of glibenclamide discussed above. Prog, 14108 15 and so is more easily used in water solutions. Fong et al. Nonetheless, sonication is another technique employed to micronize particles. No. Tracy. Considering the above said. Micronization of core material by milling or ultrasonic probe sonication of solid drug particles in polymer solution is disclosed. About 100 times as much tolbutamide as glibenclamide is necessary if you want to have identical clinical effect as glibenclamide. No. Pat. Certainly, removing solvent from the mixture to form a hard matrix containing the drug particles in polymer; and micronizing the matrix by fragmenting the matrix below the glasstransition point of the polymer, Burke discloses a method for forming polymer/drug microparticles by forming a polymer solution/insoluble drug mixture.

Formulations may include mixtures of drugs.

Without sugars, should be water solutions of tolbutamide also including a sugar. Should be water solutions of tolbutamide also including a buffer aminomethane). And akin buffer), uch tolbutamide solutions and formulations might be water solutions of tolbutamide, salts, or buffers. Similar to the glibenclamide solutions, formulations, and lyophilates discussed above, tolbutamide solutions, formulations, and lyophilates can be prepared. Now pay attention please. It should be understood that such solutions, formulations, and lyophilates created from such solutions and formulations, may include combinations of the foregoing.

Repaglinide is another pharmaceutically active ingredient that acts on SURs and is suitable for the practice of the invention. Without sugars, can be water solutions of repaglinide also including a sugar. Can be water solutions of repaglinide also including a buffer aminomethane). And similar buffer), uch repaglinide solutions and formulations might be water solutions of repaglinide, salts, or buffers. It is similarly to the glibenclamide and tolbutamide solutions, formulations, and lyophilates discussed above, repaglinide solutions, formulations, and lyophilates might be prepared. Actually, it might be understood that such solutions, formulations, and lyophilates made out of such solutions and formulations, may include combinations of those. Accordingly, repaglinide water formulations are contemplated to be similar to glibenclamide water formulations. Repaglinide has a water solubility of 6 mg/mL at pH 9, that is a bit lower than the solubility of glibenclamide in water at this pH.

Similarly, solutions and formulations, and lyophilates created from such solutions and formulations, should be created from other drugs and pharmaceutically active compounds and ingredients. Ion channel blockers like, for instance, pinkolant, flufenamic acid, mefanamic acid, niflumic acid, rimonabant, and SKF 9635; estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, non steroidal estrogens, phytoestrogens and similar steroid compound; and akin pharmaceutically active compound, Thus, let’s say, similar solutions and formulations, and lyophilates created from such solutions and formulations, might be made of, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, glimepiride and identical drugs or metabolites of drugs which interact with SURs.

Kits might be prepared including solutions, formulations, and lyophilates having features of the invention.

Water and alcohol; water and polyethylene glycol; water, alcohol and PEG, this type of a diluent solution can be selected from water. In embodiments, the buffer concentration is between about 5 mM and about 10 mM, In embodiments, the buffer concentration can be less than about 15 mM. In embodiments, the pH of the diluent should be a pH of about pH 4 or greater. A well-known fact that is. Accordingly a diluent solution; and instructions for the use of such liquid solutions, a kit may include a liquid formulation of a compound of interest. In yet further embodiments, the diluent of the kit is buffered, and the buffer concentration is between about 1 mM and about 100 mM. Buffer can be a pharmaceutically acceptable buffer, In further embodiments, the pH of the diluent is mostly about pH 4 or greater and the diluent is buffered.

The data obtained from this study indicate that lyophilized glibenclamide has good stability over at least 3 months at the temperatures and relative humidity conditions tested. Lyophilization of this aqueous mixture removed 6 water mL per vial. Vials containing lyophilized glibenclamide powder were used in this study. Seriously. Lyophilized glibenclamide powder was obtained by lyophilization of an aqueous mixture containing 7 0 mg glibenclamide, 180 mg mannitol, and sodium hydroxide as needed to adjust the pH to 113 prior to lyophilization. Experimental procedures and results from the study are described in detail below.

The lyophilized glibenclamide powder was evaluated at the following time points for appearance, reconstitution time, p11″ after reconstitution, moisture content, quantity of glibenclamide as analyzed by HPLC, and the quantity of substances associated with glibenclamide.

Lyophilized vials were inspected visually.

Reconstitution time of duplicate samples from 2 separate vials were measured after adding 6 water mL for injection. The pH of duplicate samples from two separate vials used for the reconstitution were measured.

Assay for Amount of Glibenclamide and Assay for Substances Related to Glibenclamide.

The glibenclamide content was assayed by comparison with similarly chromatographed reference solutions. Related substances were evaluated as area with reference to the Glibenclamide peak at 230 nm. Make sure you write while eluting with an acetonitrile/water/formic acid eluent, Zorbax XDBC18, 0 vun, 150 mm×6 mm column was used, operated at 50°. Methanol was used as diluent.

Moisture Content Analyzed by Coulometric Karl Fischer. Results are reported as mg/vial. The moisture content was evaluated by dispersing the lyophilized cake in benzyl alcohol and analyzing this solution by coulometric Karl Fischer titration.

At the 3 month time point, the appearance before and after reconstitution of the lyophilized glibenclamide powder showed no change from the initial time point.

Approximately 12 14 mm in depth was observed, with some small cracks on the surface, before reconstitution a white to ‘off white’ cake. After reconstitution a clear colourless solution free from visible particles and fibres was observed. There was no significant variation in the reconstitution time across all time points and conditions. These fibres were determined to have entered during determination of the pH, the appearance 24 hours after reconstitution contained a few small fibres across all time points and conditions.

There was no significant variation in pH across all time points and conditions, and all results were within the pH range of 10411″. Assay for Amount of Glibenclamide and Assay for Substances Related to Glibenclamide.

Each vial was reconstituted with 6 methanol mL to give an expected concentration of ’78 83′ mg/mL glibenclamide. Results from the assay of glibenclamide upon storage were within the range of ’78 83′ mg/mL except for samples stored at 40° and 75 RH at the 6 week and 3 month time points,, and one sample stored 3 months at 28″° The concentration of glibenclamide in the samples upon storage at 40° and 75 RH were both 77 mg/mL the reduction in glibenclamide content is likely due to elevated temperature and relative humidity compared to other samples. Samples stored for 3 months at a temperature of 2 8″° had a glibenclamide concentration of 844 mg/mL and 762 mg/mL.

Three substances presumably about glibenclamide were identified in the course of the stability study. Notably, for samples stored at ’28’° and at 25° with 60percent RH, there were no significant changes in concentration of related substances when compared to the initial time point. This is the case. Samples stored at 40° and 75percent RH had slightly increased levels of the first substance. The third substance had a HPLC relative retention time of 41 and was present at trace levels. The second substance had a HPLC relative retention time of 33 and was present at trace levels for the 6 week time point only. The first substance had a HPLC relative retention time of 19 and produced a quantifiable peak.

Moisture Content Determined by Coulometric Karl Fischer Titration.

There was no significant variation in the moisture content across all time points and conditions. All mean results are within the range of 50 mg/vial.

The entire disclosure of every of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein. The invention should be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein.

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