WO2024233925A1

WO2024233925A1 - Stable micafungin compositions

Info

Publication number: WO2024233925A1
Application number: PCT/US2024/028851
Authority: WO
Inventors: Jan Jezek; David GERRING; Jorge PINTO
Original assignee: Hikma Pharmaceuticals USA Inc
Current assignee: Hikma Pharmaceuticals USA Inc
Priority date: 2023-05-11
Filing date: 2024-05-10
Publication date: 2024-11-14
Anticipated expiration: 2025-11-11

Abstract

A stable liquid composition suitable for intravenous administration that includes micafungin or a pharmaceutically acceptable salt thereof. The formulation includes a net zero charge tonicity modifier, a basic amino acid, and an optional antioxidant in an aqueous solution that has a pH of 4 to 6.5. The liquid composition is a stable formulation that is supplied as a ready to administer, or ready-to-use or ready-to-dilute product in a container.

Description

Stable Micafungin Compositions

Field

[001] The invention relates to stable liquid compositions containing micafungin as an active ingredient and, in particular, ready-to-administer or ready-to-dilute liquid compositions containing micafungin, a net zero charge tonicity modifier and an amino acid that are stable when stored for extended periods in a pharmaceutically acceptable container.

Background

[002] Micafungin is an echinochandin antifungal medication listed in the World Health Organization's List of Essential Medicines. Micafungin is used for treatment and prevention of invasive fungal infections including candidemia, abscesses and esophageal candidiasis. Its mode of action involves inhibiting the production of beta-1, 3-glucan, an essential component of fungal cell walls that is not found in mammals. Micafungin typically exists in the form of a sodium salt, which has a molecular weight of 1292.25 Da.

[003] Micafungin is administered intravenously. There are a number of micafungin products for intravenous use that are presented as a powder for injection. These products require reconstitution followed by dilution into an infusion bag or other container and, therefore, can be inconvenient to use. One commercial micafungin product, Mycamine®, as well as generic alternatives, is formulated as a single-use vial that contains 50 mg or 100 mg micafungin sodium, 200 mg lactose, with citric acid and/or sodium hydroxide (used for pH adjustment). The product must be reconstituted and further diluted, for example both with 0.9% saline or 5% dextrose, prior to use. The reconstituted products are not intended to be stable for long-term storage before use.

[004] There remains a need for a ready-to-administer or ready-to-dilute compositions of micafungin that offer long-term storage stability without the need for reconstitution. The present invention provides stable liquid compositions of micafungin or salts thereof that do not require reconstitution. Presentation of micafungin as a stable liquid composition filled directly in infusion bags, IV bottles or IV infusion glass vials will circumvent the need for aseptic reconstitution and subsequent dilution into the IV bags, resulting, among other benefits, in greater convenience for the healthcare professional and a lower probability of dosing errors. Summary

[005] Described herein are stable liquid compositions of micafungin or salts thereof. In a first aspect, there is disclosed a liquid composition in a container, the composition includes micafungin or a pharmaceutically acceptable salt thereof present at a concentration of 0.1 to 5 mg/mL as the sole pharmaceutically active agent; a tonicity modifier, for example, with net zero charge present at a concentration of 1 to 500 mM, 25 to 65 mg/mL or 1 to 10 mg/mL; and a basic amino acid, and the liquid composition has a pH of 4 to 6.5. In one example of the aspect, the liquid composition is stable, and the liquid composition contains 10% or less or 5% or less total impurities wherein the total impurities are all of the micafungin impurities present in the composition, as measured by reverse-phase liquid chromatography (RP- HPLC), after 3 or 6 months of storage in the container at 25 °C or 2-8 °C.

[006] In an example of aspect 1, the composition is an aqueous composition and includes water for injection, for example, water present at more than 90% of the weight of the liquid composition.

[007] In another example of aspect 1, the liquid composition contains less than 8%, less than 7%, less than 5%, or less than 3% of total impurities as by total weight of the micafungin or pharmaceutically acceptable salt thereof in the liquid composition after 3 or 6 months of storage in the container at 25 °C or 2-8 °C.

[008] In another example of aspect 1, the tonicity modifier is present at a concentration of 100 to 300 mM , 35 to 60 mg/mL, or 1 to 10 mg/mL, and is selected from the group consisting of polyols (e.g., dextrose), neutral amino acids, sodium chloride, and a combination thereof.

[009] In another example of aspect 1, the polyol is selected from the group consisting of glucose (i.e., dextrose), sucrose, trehalose, mannitol, and combinations thereof.

[0010] In another example of aspect 1, the neutral amino acid is selected from the group consisting of proline, glycine, and a combination thereof.

[0011] In another example of aspect 1, the basic amino acid is present at a concentration of 10 to 50 mM and is selected from the group consisting of histidine, arginine, and a combination thereof. The basic amino acid is different than the neutral amino acid if present in the composition.

[0012] In another example of aspect 1, the composition further includes one or more antioxidants. [0013] In another example of aspect 1, the antioxidant is methionine or an enantiomer thereof and present at a concentration of 1 to 50 mM, for instance, 10 to 30 mM, or 1 to 10 mg/mL, for instance, 2.5 to 7.5 mg/mL or 2 to 4 mg/mL.

[0014] In another example of aspect 1, the pH of the composition is in the range of 4.5 to 5.5 or 5.0 to 5.5. In another example, the pH of the composition is in the range of 4.8 to 5.2. [0015] In another example of aspect 1, the composition further includes one or more buffers to maintain a pH range, for example, 4.5 to 6.5. The one or more buffers is in the concentration range of 1 to 50 mM, for instance, 5 to 20 mM.

[0016] In another example of aspect 1, the composition further includes a non-ionic surfactant, for example, present in a concentration of 0.1 to 10 mg/mL, for example, 0.1 to 0.5 mg/mL. The non-ionic surfactant is selected from the group consisting of polysorbates, alkyl ethers of polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, alkylphenyl ethers of polyethylene glycol, and combinations thereof.

[0017] In another example of aspect 1, the liquid composition is a ready -to-administer formulation. The ready -to-administer term indicates that the composition does not require or is not subjected to a dilution step prior to administration. A ready -to-administer formulation may also be referred to as a ready -to-use formulation.

[0018] In another example of aspect 1, the container is a vial, an IV or infusion bag, or an IV or infusion bottle.

[0019] In another example of aspect 1, the composition has a micafungin or a pharmaceutically acceptable salt thereof purity of 90% or more, 92% or more, 94% or more, 95% or more, 98% or more, 99% or more, or 99.5% or more, as measured by RP-HPLC, after 3, 6 or 12 months of storage in the container at 2-8 °C or 25 °C. The micafungin purity is measured as 100 minus the total impurities after 6 months of storage in the container at 2-8 °C, wherein the total impurities are all of the micafungin impurities in the composition. In some examples, the total impurities in the composition is less than 5%, less than 3%, or less than 1%, as measured by RP-HPLC, after 3, 6 or 12 months of storage in the container at 2-8 °C or 25 °C. In other examples, the composition retains at least 98%, at least 99% or at least 99.5% of its initial micafungin concentration after 3, 6 months or 12 months of storage in a container at 2-8° C or 25 °C.

[0020] In a second aspect, there is disclosed a ready -to-dilute liquid composition in a container, the composition includes micafungin or a pharmaceutically acceptable salt thereof present at a concentration of 10 to 20 mg/mL as the sole pharmaceutically active agent; a tonicity modifier with net zero charge present at a concentration of 100 to 300 mM or 1 to 10 mg/mL; and a basic amino acid zero charge present at a concentration of 5 to 30 mM, and the liquid composition has a pH of 4 to 6.5. In one example of the aspect, the liquid composition has 10% or less total impurities as measured by RP-HPLC, after 3 or 6 months of storage in the container at 25 °C or 2-8 °C. The ready-to-dilute term indicates that the composition requires or is subjected to a dilution step prior to administration.

[0021] In an example of aspect 2, the container is a glass vial.

[0022] In another example of aspect 2, the liquid composition contains less than 8%, less than 7%, less than 5%, or less than 3% of total impurities by total weight of the micafungin or pharmaceutically acceptable salt thereof in the liquid composition, as measured by RP- HPLC, after 6 months of storage in the container at 25 °C or 2-8 °C.

[0023] In another example of aspect 2, the tonicity modifier is selected from the group consisting of polyols and neutral amino acids.

[0024] In another example of aspect 2, the polyol is selected from the group consisting of glucose, sucrose, trehalose, mannitol, and combinations thereof.

[0025] In another example of aspect 2, the neutral amino acid is selected from the group consisting of proline, glycine, and a combination thereof.

[0026] In another example of aspect 2, the composition further includes methionine or an enantiomer thereof present at a concentration of 1 to 50 mM or 1 to 10 mg/mL.

[0027] In another example of aspect 2, the composition is aqueous and further includes a buffer.

[0028] In another example of aspect 2, the composition further includes water present at more than 90% of the weight of the liquid composition.

[0029] In another example of aspect 2, the pH of the composition is in the range of 4.5 to 5.5 or 5.0 to 5.5.

[0030] In another example of aspect 2, the composition has a purity of micafungin or a pharmaceutically acceptable salt thereof of 90% or more, 92% or more, 94% or more, 95% or more, 98% or more, 99% or more, or 99.5% or more, as measured by RP-HPLC, after 3, 6 or 12 months of storage in the container at 2-8 °C. The micafungin purity is measured as 100 minus the total impurities after 3 or 6 months of storage in the container at 2-8 °C or 25 °C, wherein the total impurities are all of the micafungin impurities in the composition. In some examples, the total impurities in the composition is less than 5%, less than 3%, or less than 1%, as measured by RP-HPLC, after 3, 6 or 12 months of storage in the container at 2-8 °C. In other examples, the composition retains at least 98%, at least 99% or at least 99.5% of its initial micafungin concentration after 3, 6 months or 12 months of storage in a container at 2- 8° C or 25 °C.

[0031] In a third aspect, there is disclosed a liquid composition in a container, the composition includes micafungin or a pharmaceutically acceptable salt thereof present at a concentration of 0.1 to 5 mg/mL as the sole pharmaceutically active agent; a sodium chloride tonicity modifier present at a concentration of 1 to 10 mg/mL, 5 to 10 mg/mL or 7.5 mg/mL; and a basic amino acid, an optional antioxidant, and the liquid composition has a pH of 4 to 6.5. In one example of the aspect, the liquid composition is stable, and the liquid composition contains 10% or less or 5% or less total impurities wherein the total impurities are all of the micafungin impurities present in the composition, as measured by reverse-phase liquid chromatography (RP-HPLC), after 3 or 6 months of storage in the container at 25 °C or 2-8 °C.

[0032] Any one of the above aspects (or examples of those aspects) may be provided alone or in combination with any one or more of the examples of that aspect discussed above; e.g., the first aspect may be provided alone or in combination with any one or more of the examples of the first aspect discussed above; and the second aspect may be provided alone or in combination with any one or more of the examples of the second aspect discussed above; and so-forth.

[0033] Additional features and advantages will be set forth in the detailed description which follows, and in part will be readily apparent to those skilled in the art from that description or recognized by practicing the embodiments as described herein, including the detailed description which follows, and the claims. It is to be understood that both the foregoing general description and the following detailed description are merely exemplary, and are intended to provide an overview or framework to understanding the nature and character of the claims.

Detailed Description

[0034] Herein, when a range such as 5-25 (or 5 to 25) is given, this means preferably at least or more than 5 and, separately and independently, preferably not more or less than 25. In an example, such a range defines independently 5 or more, and separately and independently, 25 or less. Moreover, all ranges disclosed herein are to be understood to encompass any and all values and sub-ranges between the stated values. [0035] The present disclosure is directed to stable liquid aqueous compositions as a medical and pharmaceutical preparation. The compositions include micafungin or a pharmaceutically acceptable salt thereof, a tonicity modifier with net zero charge, a basic amino acid and water for injection (WFI). The compositions can further include an antioxidant, and optionally a buffer and/or a non-ionic surfactant. The compositions have a pH in the range of, for example, 3.5 to 7.0, 4.0 to 6.5, or 4.5 to 5.5, desirably around 5.0. The compositions are stable when stored in the container they are filled in and pH drift outside of the range is minimized.

[0036] Administration of the compositions may be performed by subcutaneous injection, intramuscular injection, percutaneous injection, intradermal injection or intravenous injection by means of a device. In certain embodiments the compositions are administered intravenously. The compositions of micafungin are ready -to-administer or ready-to-dilute formulations and can be used without the need for reconstitution or, in the case of the ready- to-administer compositions, without additional ingredient mixing or dilution prior to administration. The ready -to-administer compositions are sterile, liquid formulations that do not require mixing before use, for example, with another active ingredient or buffer, such that the formulations can be directly administered. Alternately, the ready-to-dilute compositions are sterile, liquid formulations that do require mixing before use, for example, with another active ingredient or buffer or further diluted with an acceptable carrier liquid if present as a concentrated solution. For example, a ready-to-administer composition can include the required active ingredient concentration and suitable volume in the container it is filled in such as a syringe, vial, ampule, injector, IV bag or bottle. The ready-to-dilute composition can be stored in a suitable container, for example an IV bag, syringe, pre-filled syringe or a vial, and be ready for dilution with a carrier liquid such as water for injection, saline solution, or a glucose solution. Diluents, if used, can include, for instance, fluids suitable for parenteral administration such as water for injection or isotonic sodium chloride (saline) or glucose solutions or a combination of sodium chloride and glucose solutions.

[0037] The compositions of the present invention are pharmaceutical compositions for use in therapy, for instance, treatment of invasive fungal infections including candidemia, abscesses and esophageal candidiasis. The compositions can be administered for known indications that include treatment of candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses, with or without meningoencephalitis and/or ocular dissemination, for instance, by injection and intravenous administration. The compositions are also suitable for treatment of esophageal candidiasis, and prophylaxis of Candida infections in HSCT recipients. The formulations of the present disclosure are suitable for administration, for example, to a mammal. Preferably, the mammal is a human. The human can be an adult or a pediatric patient, for instance, 4 months of age or older.

[0038] The aqueous micafungin liquid compositions of the present disclosure are stable or exhibit stability (e.g., active agent assay, impurity profile) when stored at low temperature, room temperature or elevated temperature over a period of time. Storage of the compositions that have been diluted and/or reconstituted in a sealed container can result in stability concerns, which includes formulation properties that may be affected by storage conditions, for example, active ingredient strength or concentration, impurities (e.g., individual components and total), visual appearance characteristics (e.g., color, clarity, cloudy, haze, precipitates, etc.) and pH range that can trigger concentration loss and impurity formation. Storage conditions that may affect stability can include, for example, storage temperature, humidity (e.g., relative), and storage time.

[0039] In one or more embodiments the stability of a micafungin composition can be measured over time after an initial time point measured at or shortly after preparation of the composition. The initial measurements representing the initial micafungin impurities present and initial micafungin concentration in the composition are taken within 24 hours of the filling of the composition into a pharmaceutically acceptable container (e.g., a vial) that is sealed and used for storage. Herein, these can be labeled as measurements at T(0).

[0040] In one or more embodiments, stability can be measured by, for example, the amount of total impurities present in the compositions where the amount of total impurities includes the sum of all individual micafungin impurities present in the composition determined at a specified period of time at specified storage conditions (e.g., temperature, humidity) in a container. Total impurities may include micafungin impurities present in the initially prepared compositions (“initial impurities”) (the initial impurities may be the result of micafungin impurities present in the active pharmaceutical ingredient). Total impurities may also include any degradation impurities of micafungin formed after initial preparation of the compositions (i.e., micafungin impurities formed after T(0)). In one or more embodiments, a liquid micafungin composition includes a formulation that has 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or 0.8% or less total impurities in the formulation after storage for a certain period of time (e.g., 1 month, 2 months, 3 months, 6 months, 12 months) under refrigerated conditions (e.g., 2-8 °C), room temperature conditions (e.g., 25 °C) or accelerated conditions (e.g., 40 °C) . In certain embodiments the relative humidity may be in the range of 40 to 75%, for instance, 60%.

[0041] Using the total impurities, the micafungin purity in the composition after a specified storage period can be calculated as 100 minus the total impurities. In one or more embodiments, liquid micafungin compositions can have a micafungin purity of 90% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 99.5% or more after storage (e.g., 1 month, 2 months, 3 months, 6 months, 12 months) under refrigerated conditions (e.g., 2-8 °C), under room temperature conditions (e.g., 25 °C) or accelerated conditions (e.g., 40 °C). In certain embodiments the relative humidity may be in the range of 40 to 75%. The concentration of micafungin in the liquid composition can be measured by RP-HPLC as known in the art.

[0042] Alternatively, in one or more embodiments, stability can be measured by, for example, the amount of micafungin impurities that are formed following preparation of the compositions determined after a specified period of time at specified storage conditions (e.g., temperature, humidity) in a container (“total formed impurities”). The amount of total formed impurities can be calculated by taking the total impurities present in the composition at a specified time and subtracting the initial impurities present in the composition measured at T(0). Total formed impurities may include degradation products that are formed after initial preparation of the micafungin compositions. Total formed impurities can be present in the liquid micafungin composition in an amount of 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or 0.8% or less after storage in a container (e.g., 1 month, 2 months, 3 months, 6 months, 12 months) under refrigerated conditions (e.g., 2-8 °C), room temperature conditions (e.g., 25 °C) or accelerated conditions (e.g., 40 °C).

[0043] In other examples, stability of a micafungin composition can be measured by, for example, the amount of an individual micafungin impurity formed following preparation of the compositions determined after a specified period of time at specified storage conditions (e.g., temperature, humidity) in a container . The stable micafungin composition can include a formulation that contains 6%, or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or 0.5% or less of a single individual formed impurity (e.g., a degradation impurity), which amount is measurable at a point in time after storage under specified storage conditions (e.g., 2-8 °C, 25 °C, 40 °C) for about 1, about 2, about 3, about 6, about 9 or about 12 or more months. The individual impurities are measured by RP-HPLC relative to the total weight of the micafungin or pharmaceutically acceptable salt thereof in the liquid composition. [0044] In one or more embodiments, a liquid micafungin composition includes a formulation that is stable for about 3 months or more, about 6 months or more, or about 12 months or more when stored in a container at a temperature of about 2-8 °C, 25 ° or 40 °C. In one or more embodiments, a liquid micafungin composition includes a formulation that is stable for about 6 months or more, or about 12 months or more when stored at about room temperature (i.e. 25 °C) or a low temperature 2-8 °C.

[0045] The compositions of the present disclosure contain, as the active ingredient, micafungin or any pharmaceutically acceptable salt thereof. In some embodiments, the compositions preferably contain micafungin or any pharmaceutically acceptable salt thereof as the sole active ingredient characterized in that no other active ingredients are present or detectable in the composition. In one example, the composition contains micafungin or micafungin sodium. The micafungin or salt thereof can be present in the composition, for example a ready -to-administer composition, at a concentration of 0.1 mg/mL (milligrams/milliliter) or more, 0.5 mg/mL or more, 1 mg/mL or more, 1.5 mg/mL or more or 2 mg/mL, or 5 mg/mL or less, 2.5 mg/mL or less, 2 mg/mL or less. In some embodiments, the ready -to-administer liquid compositions contain a concentration of 1 mg/mL, 1.5 mg/mL, or 2 mg/mL of micafungin or a pharmaceutically acceptable salt thereof. In one or more embodiments, the liquid micafungin compositions contain 1 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 150 mg, 160 mg, 180 mg, or 200 mg of micafungin or a pharmaceutically acceptable salt thereof per storage container (e.g., polymeric IV bag or IV bottle). A desirable presentation of a stable liquid micafungin composition is a 1 mg/mL product formulated either in a polymeric infusion bag or bottle. The product will be ready -to- administer by intravenous administration without a further dilution.

[0046] In other embodiments, the composition contains micafungin or micafungin sodium present in the composition, for example a ready -to-dilute composition, at a concentration of 5 mg/mL (milligrams/milliliter) or more, 10 mg/mL or more, 15 mg/mL or more, 20 mg/mL or more or 25 mg/mL or more, or 50 mg/mL or less, 45 mg/mL or less or 30 mg/mL or less. In some embodiments, the ready -to-dilute liquid compositions contain a concentration of 10 mg/mL, 15 mg/mL, or 20 mg/mL of micafungin or a pharmaceutically acceptable salt thereof. In one or more embodiments, the liquid micafungin compositions contain 1 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 150 mg, 160 mg, 180 mg, or 200 mg of micafungin or a pharmaceutically acceptable salt thereof per storage container (e.g., glass vial). A desirable presentation of a stable liquid micafungin composition is a 10 or 20 mg/mL product formulated in a glass vial. The product will be ready to dilute with an acceptable liquid (e.g., isotonic saline or isotonic glucose solution) to a required concentration, for example, 0.5 to 10 mg/mL, 1 to 5 mg/mL, or 1 or 2 mg/mL, for subsequent intravenous administration.

[0047] In one or more embodiments, the composition or formulation volume (e.g., amount of liquid in a storage container) is about 1 mL or more, about 2.5 mL or more, about 5 mL or more, about 10 mL or more, about 15 mL or more, about 20 mL or more, about 25 mL or more, about 30 mL or more, or about 40 mL or more. In one or more embodiments, the formulation volume is about 200 mL or less, about 175 mL or less, about 150 mL or less, about 125 mL or less, about 120 mL or less, or about 110 mL or less. For example, the formulation volume can be about 1 mL to about 200 mL, about 5 mL to about 150 mL, about 10 mL to about 100 mL, or about 25 mL, 50 mL, 75 mL, 100 mL or 150 mL. Appropriatesized containers for storing formulation volumes can be determined by one of ordinary skill in the art to achieve a desirable concentration and administration amount of micafungin, for example, 50, 100 or 150 mg of micafungin.

[0048] The compositions for administration can be stored in or supplied in any suitable container. For example, the compositions of the invention may suitably be packaged for injection, particularly for intravenous infusion or intravenous injection. The container may contain a single dose of micafungin or a plurality of doses of the composition as described herein. The composition can be in a container that includes, but is not limited to, a vial (e.g., single or multidose vials), ampoule, IV bottle, IV bag or syringe (e.g., pre-filled syringe or component of an auto-injector). The container can be made of any suitable material, for instance, glass, plastic or polymer, or rubber, although glass is preferred for vials and a polymeric material is preferred for an IV bag or IV bottle. Prior to filling the composition in a container, the container can be sterile and has been subjected to a sterilization process prior to filing with the sterile compositions of the invention.

[0049] Containers are sealed as typical in the industry, for example, with the use of a lid, cap, closure, stopper and the like. The containers also can be coated or treated with one or more components to reduce degradation and reaction with ingredients of the compositions and prevent pH drift. For example, a container surface in contact with the composition can be coated with silicone. In another example, a vial with a treated inner surface for storing the composition can be used. Optionally, to shield the composition from exposure to light, a container can optionally be opaque or tinted with a color, and preferably stored in a box for transport or shelving. For instance, amber- or flint-colored vials are suitable containers. [0050] The micafungin compositions of the invention further include a tonicity modifier, which may be uncharged or has a net zero charge. The tonicity modifier is included in the micafungin compositions at a concentration of, for example, 1 to 10 mg/mL, 2 to 8 mg/mL, or 2.5 to 7.5 mg/mL. In another example, the tonicity modifier is included in the micafungin compositions at a concentration of 25 to 65 mg/mL, 30 to 60 mg/mL, 35 to 55 mg/mL, or 40, 42, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55 mg/mL. In one or more embodiments, the tonicity modifier can have a stabilizing effect on the micafungin compositions. Examples of net zero charged tonicity modifiers include sugars (such as glucose, sucrose, trehalose and lactose), sugar alcohols (such as mannitol and sorbitol), other polyols (such as glycerol and 1,2-propanediol) and polyethylene glycols (such as PEG300 and PEG400). In one embodiment, the net zero charge tonicity modifier is selected from the group consisting of glycerol, 1,2-propanediol, mannitol, sorbitol, glucose, sucrose, trehalose, lactose, PEG300 and PEG400. The net zero charge tonicity modifier is included in the micafungin compositions at a concentration of 1 to 500 mM, for example 50 to 400 mM, 100 to 350 mM, 100 to 300 mM, 200 to 300 mM, or 150 to 250 mM. In one embodiment, the micafungin composition includes glucose or sucrose present in a concentration range of 100 to 300 mM. Individual examples of the sugars, sugar alcohols and other polyols can be present in the liquid compositions as the sole tonicity modifier, in combination with one another as a group of tonicity modifiers, or in combination with a neutral amino acid tonicity modifier.

[0051] In other embodiments, the net zero charge tonicity modifier can be a neutral amino acid. Examples of a neutral amino acid include glycine, alanine, glutamine, asparagine and proline. In one embodiment, the neutral amino acid as the net zero charge tonicity modifier is selected from the group consisting of glycine (e.g., L-glycine), proline (e.g., L-proline) and a combination thereof. The neutral amino acid can be included in the micafungin compositions at a concentration of 1 to 500 mM, for example 50 to 400 mM, 100 to 350 mM, 100 to 300 mM, 200 to 300 mM, or 150 to 250 mM. In one embodiment, the micafungin composition includes proline present in a concentration range of 100 to 300 mM. Individual neutral amino acids can be the sole tonicity modifier present in the micafungin composition, or optionally can be present in combination with one another or with a net zero charge tonicity modifier selected from the group of sugars, sugar alcohols and other polyols noted above.

[0052] In another embodiment, the tonicity modifier may be sodium chloride, which can be the sole tonicity modifier in the composition. The sodium chloride tonicity modifier included in the micafungin compositions is at a concentration of 1 to 15 mg/mL, 2 to 12 mg/mL, 2.5 to 10 mg/mL, or 5, 6, 7, 7.5, 8 or 9 mg/mL. [0053] The compositions further include a basic amino acid or a salt thereof. At the pH of the compositions, for instance, 4 to 6.5, the basic amino acids will include a negatively charged counter-ion. In one or more embodiments, the basic amino acid is not a buffer at the given pH of the composition.

[0054] Examples of a basic amino acid include arginine, lysine, histidine, and combinations thereof. The basic amino acid or combination of basic amino acids can be included in the micafungin compositions at a concentration of 1 to 50 mM, for example 5 to 40 mM, 10 to 35 mM, 10 to 30 mM, 15 to 25 mM, or 10, 15 or 20 mM. In another example, the basic amino acid or combination of basic amino acids included in the micafungin compositions is at a concentration of 1 to 10 mg/mL, 1 to 8 mg/mL, 2 to 6 mg/mL, or 2.5, 2.8, 2.9, 3, 3.1, 3.2 or 3.5 mg/mL. Individual basic amino acids can be the sole basic amino acid present in the micafungin composition, or optionally can be present in combination with one another, for example, a combination of histidine and arginine. In one embodiment, the micafungin composition includes two basic amino acids. The two basic amino acids can be present in concentrations in the composition, for example, each in the range of 5 to 20 mM. For instance, the composition can include histidine present in the range of 5 to 20 mM and arginine present in the range of 5 to 20 mM. In some examples, the two basic amino acids can be present in the composition at the same concentration, such as 20 mM.

[0055] The compositions can further include an optional antioxidant. Examples of an antioxidant include methionine, glutathione, ascorbate, butylated hydroquinone, lactate, nicotinamide, nicotinate, tryptophan, phenylalanine, tyrosine and combinations thereof. In certain embodiments the antioxidant is selected from methionine, glutathione, ascorbate and butylated hydroquinone. The antioxidant is present in the composition at a concentration of 1 to 50 mM, for example 5 to 40 mM, 10 to 35 mM, 10 to 30 mM, 15 to 25 mM, or 10, 15 or 20 mM. In another example, the antioxidant included in the micafungin compositions is at a concentration of 1 to 10 mg/mL, 1 to 8 mg/mL, 2 to 6 mg/mL, or 2.5, 2.8, 2.9, 3, 3.1, 3.2 or 3.5 mg/mL. In one embodiment, the micafungin composition includes methionine or an enantiomer thereof as the sole antioxidant, for example, in a concentration range of 10 to 30 mM. The presence of an antioxidant may improve the chemical and/or physical stability of micafungin, for example by eliminating free radicals that may play a part in some of the degradation pathways.

[0056] The micafungin compositions can optionally include one or more non-ionic surfactants, for instance, polysorbates, alkyl ethers of polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, alkylphenyl ethers of polyethylene glycol, and combinations thereof. Examples of non-ionic surfactants include polysorbates (fatty acid esters of ethoxylated sorbitan), such as polysorbate 20 or polysorbate 80. Polysorbate 20 is a mono ester formed from lauric acid and polyoxyethylene (20) sorbitan in which the number 20 indicates the number of oxyethylene groups in the molecule. Polysorbate 80 is a mono ester formed from oleic acid and polyoxyethylene (20) sorbitan in which the number 20 indicates the number of oxyethylene groups in the molecule. Polysorbate 20 is known under a range of brand names including in particular Tween 20, and also Alkest TW 20. Polysorbate 80 is known under a range of brand names including in particular Tween 80, and also Alkest TW 80. Other suitable polysorbates include polysorbate 40 and polysorbate 60.

[0057] Another example class of non-ionic surfactants is alkyl ethers of polyethylene glycol, especially those known under a brand name Brij . Examples of non-ionic surfactants can further include block copolymers of polyethylene glycol and polypropylene glycol, also known as poloxamers, in particular pol oxamer 188, pol oxamer 407, pol oxamer 171 and poloxamer 185. Poloxamers are also known under brand names Pluronics or Koliphors. For example, poloxamer 188 is marketed as Pluronic F-68. Another example class of non-ionic surfactants include alkylphenyl ethers of polyethylene glycol, for instance, 4-(l, 1,3,3- tetramethylbutyl)phenyl-poly ethylene glycol, also known under a brand name Triton X-100. [0058] The non-ionic surfactant, either as a sole surfactant or combination of surfactants, can be present in the composition at a concentration of 0.1 to 10 mg/mL, for example 0.25 to 5 mg/mL, 0.5 to 2.5 mg/mL, 0.1 to 1 mg/ml, 1 to 2 mg/mL, or 0.1, 0.2, 0.3, 0.4 or 0.5 mg/mL. In one embodiment, the micafungin composition includes a non-ionic surfactant as the sole surfactant, for example, in a concentration range of 0.1 to 1 mg/mL.

[0059] The pH of the compositions, prior to filling and sealing in a container, can be adjusted with conventional methods, for example, with a pH adjuster. The compositions can be free of a pH adjuster or optionally include one or more pH adjusters, for example, a single pH adjuster or a combination of two pH adjusters. The pH adjuster can serve to aid in adjusting the pH of the aqueous compositions. The pH adjuster is used in an amount to adjust the aqueous composition to a pH of 3.5 to 7, for example, a pH of 4 to 6.5, 4 to 6, or 4.5 to 5.5, and preferably 5 to 5.5, or about 5. An acid or a base is used depending on the desired pH of the composition. When the composition is to be adjusted to a lower pH, an acidic pH adjuster, such as hydrochloric acid, sulfuric acid, nitric acid or acetic acid, can be used. Hydrochloric acid is preferably used. When the composition needs to be adjusted to a higher pH, a basic pH adjuster, such as sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, or magnesium hydroxide, can be used. Sodium hydroxide is preferably used. Such pH adjusters can be used singly or in a combination of two or more. [0060] The composition can optionally include a buffer to maintain a desired pH range. In one or more embodiments, the composition can include a single buffer. In other embodiments, the composition includes two buffers. Examples of suitable buffers include maleates, tartrates, lactates, succinates, benzoates, acetates, bicarbonates, phosphates, citrates, and combinations thereof. In one or more embodiments the buffer is sodium succinate, sodium citrate, or sodium L-lactate. In one embodiment, the micafungin composition includes sodium acetate as the sole buffer, for example, in a concentration range of 5 to 20 mM. The buffer, either a single buffer or more than one, is present in the composition at a concentration of 1 to 50 mM, for example 5 to 40 mM, 10 to 35 mM, 10 to 30 mM, 15 to 25 mM, or 5, 10, 15 or 20 mM.

[0061] The composition can include water present at more than, for example, 80%, 85%, or 90% of the weight of the liquid composition.

[0062] The liquid compositions, as stored in a sealed container, can have a suitable pH in the range of 3.5 to 7, 4 to 6.5, 4 to 6 or 4.5 to 5.5, preferably 5.0 to 5.5. In an example, the composition can have a pH of 3.5 or more, 4.0 or more, 4.5 or more, 4.6 or more, 4.7 or more, 4.8 or more, 4.9 or more, or about 5.0 or more. In another example, the composition can have a pH of 6.0 or less, 5.5 or less, 5.4 or less, 5.3 or less, 5.2 or less, or 5.1 or less. In one or more embodiments, the composition can have a pH of about 5.0.

[0063] The liquid micafungin compositions can be free of the presence of other known components, for example, a chelating agent (e.g., EDTA) or preservatives such that no chelating agent or preservative is present or detectable in the composition.

[0064] The compositions disclosed herein are useful for the treatments mentioned and are expected to have good physical and chemical stability as described herein.

[0065] In order to demonstrate the practice of the present invention, the following examples have been prepared and tested. The examples should not, however, be viewed as limiting the scope of the invention. The claims will serve to define the invention.

[0066] EXAMPLES

Example 1

[0067] This example demonstrates the stability of exemplary aqueous compositions including micafungin. The pH of seven compositions was varied in a pH range of 3.0 to 10.0 to investigate whether pH resulted in better stability of micafungin. The components of each aqueous composition is listed below in Table 1. Each composition included 1 mg/mL of micafungin, 300 mM glucose and 1 mM of buffer suitable for the pH (citrate, acetate, phosphate, glycine). The compositions were filled aseptically into Type 1 glass vials (2R Fiolax Clear, Schott) stoppered with a rubber stopper (13 mm fluorotech injection stopper, 4023/50 Westar RS, Adelphi) with air headspace.

[0068] Each composition was stored in the container that it was filled in at 40° C for 4 weeks. The stability of each composition was tested after filling, T(0), and then after 4 weeks of storage, T(4wks). Stability testing included measuring micafungin concentration using reverse phase high performance liquid chromatography (RP-HPLC) using a Dionex Ultimate 3000 with variable wavelength detector (VWD-3400RS) and with a Poroshell 120, Cl 8, 150 mm x 4.6 mm, 2.7 pm column. Mobile phase A (60% Methanol, 1.27 mg/mL sodium dihydrogen and 6.4 mg/mL sodium perchlorate monohydrate pH 3.0 in HPLC water) and Mobile Phase B (30% Acetonitrile, 21% Methanol and 1.27 mg/mL sodium dihydrogen and 6.4 mg/mL sodium perchlorate monohydrate pH 3.0 in HPLC water) were used in gradient elution. Injection volume was 5 pl and flow rate was 0.5 mL/min, with 270 nm UV detection and column temperature at 35°C. The RP-HPLC method was used for determination of (a) % individual micafungin-related impurities, (b) % total impurities and (c) micafungin purity (%). For each individual impurity the following equation was used:

Peak area of Concentration of Micafungin impurity in sample

% Impurity = x sodium in standard x RRF x 100 Peak area of Concentration of Micafungin

Micafungin in standard sodium in sample where

Peak area of impurity in sample: RP-HPLC peak area of the specific impurity in the Micafungin test sample in mAUxmin

Peak area of Micafungin in standard: RP-HPLC peak area of the main peak in the Micafungin standard solution in mAUxmin

Concentration of Micafungin sodium in sample: Concentration of Micafungin in the Micafungin in test sample (mg/mL)

Concentration of Micafungin sodium in standard: Concentration of Micafungin in the Micafungin standard solution (mg/mL) RRF: Relative responsive factor

% Total impurities are determined as a sum of all individual micafungin impurities.

Micafungin purity (%) is determined as 100 - %Total impurities.

[0069] The results of the testing are shown in Table 2 below.

[0070] Table 1

[0071] Table 2

[0072] As evidenced in Table 2, the testing results show a pH range of 4.0 to 6.0, and particularly 5.0-5.5, resulted in the best stability of the compositions of micafungin with the degradation rate accelerating above and below the range of 4.0 to 6.0.

Example 2

[0073] The stability of a micafungin composition (test sample 9) was compared to a reconstituted presentation of a commercial lyophilized product, Mycamine® (test sample 8). The commercial product was reconstituted in 0.9% aqueous saline solution and the test sample 9 composition included glucose as a tonicity modifier. The pH of both compositions was 6.0. The components of each aqueous composition are listed below in Table 3. Both compositions were filled aseptically into Type 1 glass vials (2R Fiolax Clear, Schott) stoppered with a rubber stopper (13 mm fluorotech injection stopper, 4023/50 Westar RS, Adelphi) with air headspace.

[0074] Each composition was stored in the container that it was filled in at 40 °C for 4 weeks. The stability of each composition was tested after filling, T(0), and then after 4 weeks of storage, T(4wks). Stability testing included measuring micafungin concentration using RP-HPLC as specified in Example 1. The results of the testing are shown in Table 4 below. [0075] Table 3

[0076] Table 4

[0077] As evidenced in Table 4, the stability of micafungin in the presence of glucose as a tonicity modifier was significantly better as compared to the reconstituted form of the commercial product in saline after storage at 40 °C for 4 weeks. Example 3

[0078] The stability of micafungin-containing compositions was compared in the presence of a range of charged and uncharged (net zero charge) tonicity modifiers. The pH of the compositions was held constant at 5.5. A net zero charge tonicity modifier, mannitol, a neutral amino acid (glycine) and two different salts (sodium chloride and sodium sulfate) were evaluated. Sodium acetate was used as a buffer to control pH. The components of each aqueous composition are listed below in Table 5. The compositions were filled aseptically into Type 1 glass vials (2R Fiolax Clear, Schott) stoppered with a rubber stopper (13 mm fluorotech injection stopper, 4023/50 Westar RS, Adelphi) with air headspace. Each composition was stored in the container that it was filled in at 40 °C for 4 weeks. The stability of each composition was tested after filling, T(0), and then after 4 weeks of storage, T(4wks). Stability testing included measuring micafungin concentration using RP-HPLC as specified in Example 1. The results of the testing are shown in Table 6 below.

[0079] Table 5

[0080] Table 6

[0081] The data in Table 6 evidences that micafungin stability is higher in the composition containing a net zero charge tonicity modifier or neutral amino acid as compared with the use of either salt. A tonicity modifier with zero net charge is a preferred component of the micafungin compositions.

Example 4

[0082] The impact of methionine antioxidant on the stability of micafungin was investigated by adding 300 mM glucose as a net zero charge tonicity modifier at a pH of 5.5. The components of each aqueous composition are shown below in Table 7. The compositions were filled aseptically into Type 1 glass vials (2R Fiolax Clear, Schott) stoppered with a rubber stopper (13 mm fluorotech injection stopper, 4023/50 Westar RS, Adelphi) with air headspace.

[0083] Each composition was stored in the container that it was filled in at 40 °C for 4 weeks. The stability of each composition was tested after filling, T(0), and then after 4 weeks of storage, T(4wks). Stability testing included measuring micafungin concentration using RP-HPLC as specified in Example 1. The results of the testing are shown in Table 8 below.

[0084] Table 7

[0085] Table 8

[0086] The data from Table 8 evidences that the presence of methionine with a net zero charge tonicity modifier improved the stability of micafungin in storage conditions at 40° C for 4 weeks as compared to no methionine being present.

[0087] The presence of methionine in a micafungin composition was further investigated. The amount of methionine was varied between 5 mM and 20 mM in a composition with glycine as the tonicity modifier. The components of each aqueous composition are shown below in Table 9. The compositions were filled as specified in Example 1. Each composition was stored in the container that it was filled in at 40 °C for 4 weeks. The stability of each composition was tested after filling, T(0), and then after 4 weeks of storage, T(4wks). The below T(4wks) total impurity measurements include the total impurities measured at T(0). Stability testing included measuring the concentration of micafungin impurities, for instance, of impurity A and H using RP-HPLC as specified in Example 1. For this Example, and used herein, impurity A is sodium 5-((lS,2S,3S)-4-(((2S,3R)-5-amino-l-((2S,4S)-2-carbamoyl-3- hydroxy-4-methylpyrroli din- l-yl)-3-hydroxy-l,5-di oxopentan-2 -yl)amino)-3-((2S,4R)-l- ((2S,3R)-2-((4S)-4,5-dihydroxy-l-(4-(5-(4-(pentyloxy)phenyl)isoxazol-3- yl)benzoyl)pyrrolidine-2-carboxamido)-3-hydroxybutanoyl)-4-hydroxypyrrolidine-2- carboxamido)-l,2-dihydroxy-4-oxobutyl)-2-hydroxyphenyl sulfate (C56H70N9O23S : Na) and impurity H is Sodium 5- [( 1 S,2S)-2-{(2R,6S,9S, 11R, 12S, 14aS, 15 S, 16S,20S,23 S,25aS)-20- [(R)-3 -amino 1 -hydroxy-3 -oxopropyl]-2, 11,12, 15 -tetrahydroxy-6- [(R)- 1 -hydroxy ethyl]- 16- methyl 5,8,14,19,22,25-hexaoxo-9-(4-{5-[4-(pentyloxy)phenyl]isoxazol-3- yl }benzamido)tetracosahydro- lH-dipyrrolo[2, 1 -c : 2' , 1 ' -

1] [ 1 ,4,7, 10, 13 , 16]hexaazacyclohenicosin-23 -y 1 } - 1 ,2-dihydroxyethyl]-2-hydroxyphenyl sulfate (C56H70N9O23S : Na).

[0088] The results of the testing are shown in Table 10 below.

[0089] Table 9

[0090] Table 10

[0091] As evidenced in Table 10, the amount of impurity A, impurity H and total impurities was less when using 20 mM of methionine in the micafungin composition as compared to 5 mM of methionine after storage of the compositions at 40 °C for 4 weeks. Thus, an increase in the concentration of methionine improved the stability and impurity formation in a micafungin composition.

Example 5

[0092] The impact of the presence basic amino acids in combination with a tonicity modifier having a zero net charge and methionine in a 1 mg/mL micafungin concentration composition was investigated. The components of the aqueous compositions having a 1 mg/mL micafungin concentration are shown below in Table 11. Three different tonicity modifiers, glycine, proline and glucose were used. The compositions in Table 11 all had a pH of 5.0 and contained the same amount of sodium acetate buffer. The compositions were filled as specified in Example 1.

[0093] Each composition of Table 11 was stored in the container that it was filled in at 25 °C for 26 weeks. The stability of each composition was tested after filling, T(0), and then after 6 months of storage, T(6 mon). The below T(6 mon) total impurity measurements include the total impurities measured at T(0). Stability testing included measuring the concentration of impurity A and H as described above using RP-HPLC as specified in Example 1. The results of the testing are shown in Table 12 below.

[0094] Table 11

[0095] Table 12

[0096] The data from Table 12 evidences that the presence of arginine, a basic amino acid, improves the stability of micafungin as compared to the micafungin-containing compositions devoid of a basic amino acid. The test sample compositions 23 and 24 resulted in the lowest level of total impurities and contained glucose as the tonicity modifier.

[0097] Another investigation measured the impact that arginine, histidine and a mixture of arginine and histidine had on compositions prepared using glucose as the tonicity modifier, methionine as the antioxidant, and micafungin in a 1 mg/mL concentration. The components of the aqueous compositions having a 1 mg/mL micafungin concentration are shown below in Table 13. The compositions in Table 13 all had a pH of 5.0 and contained 10 mM sodium acetate buffer. The compositions were filled as specified in Example 1.

[0098] Each composition of Table 13 was stored in the container that it was filled in at 40 °C for 8 weeks. The stability of each composition was tested after filling, T(0), and then after 8 weeks of storage, T(8wks). Stability testing included measuring the concentration of impurity A and H as described above using RP-HPLC as specified in Example 1. The results of the testing are shown in Table 14 below.

[0099] Table 13

[00100] Table 14

[00101] The data of Table 14 evidences that the presence of one or more basic amino acids can improve the stability micafungin and reduce the total amount of impurities formed in a micafungin composition further containing a net zero charge tonicity modifier and an antioxidant. The greatest reduction in total formed impurities and formation of impurity A resulted from the use of 20 mM histidine as well as a combination of 20 mM of arginine and 10 mM histidine.

[00102] Another investigation was conducted that measured the impact of histidine and a mixture of arginine and histidine in combination with either glucose or proline as the tonicity modifier, and methionine as an antioxidant in a 1 mg/mL micafungin concentration composition. The components of the aqueous compositions having a 1 mg/mL micafungin concentration are shown below in Table 15. The compositions in Table 15 all had a pH of 5.0 and contained 10 mM sodium acetate buffer. The compositions were filled aseptically into Technoflex polypropylene 100 mM IV bags (Technoflex IX01001T009.029 D). Each bag was placed in an aluminum protection overwrap (Technoflex R924-PF-002).

[00103] Each composition of Table 15 was stored in the container that it was filled in at 25 °C for 26 weeks. The stability of each composition was tested after filling, T(0), and then after 6 months of storage, T(6 mon). The below T(6 mon) total impurity measurements include the total impurities measured at T(0). Stability testing included measuring the concentration of impurity A and H as described above using RP-HPLC as specified in Example 1. The results of the testing are shown in Table 16 below.

[00104] Table 15

[00105] Table 16

[00106] As can be seen from Table 16, the amount of impurity A, impurity H and total impurities was the highest with the compositions containing no histidine or arginine after storage at 25 °C for 6 months in a container as compared to compositions containing histidine or a mixture of arginine and histidine. The inclusion of histidine, 20 mM, resulted in improved reduction of impurity A, impurity H and total impurities, and the combination of histidine and arginine resulted in even greater improvement in the reduction of impurity A, impurity H and total impurities. Histidine had a greater impact in reducing impurity A, impurity H and total impurities when in combination with glucose as the tonicity modifier as compared to proline.

[00107] As further shown in Table 16, the inclusion of 20 mM of histidine in test samples 32 and 36 shows that total impurity formation can be less than 7% whether glucose or proline is used as the tonicity modifier. The combination of 20 mM of histidine and 20 mM of arginine, as evidenced in test sample 37, shows that total impurity formation can be less than 7% when used in combination with proline as the tonicity modifier and methionine. The combination of 20 mM of histidine and 20 mM of arginine, as evidenced in test sample 33, shows that total impurity formation can be less than 3% when used in combination with glucose as the tonicity modifier and methionine. The testing results also evidence that the compositions can retain 92% or more, 93% or more, 94% or more, 95% or more, 96% or more or 97% or more of the initial concentration of the micafungin or a pharmaceutically acceptable salt thereof after 6 months of storage in the container at 25 °C.

Example 6

[00108] A long-term stability trial was set up at 2-8° C using micafungin (1 mg/mL) compositions comprising acetate buffer, methionine, glucose, and a basic amino acid. The components of the aqueous compositions having a 1 mg/mL micafungin concentration are shown below in Table 17. The compositions were filled aseptically into Technoflex polypropylene IV bags and each bag was placed in an aluminum protection overwrap . [00109] Each composition of Table 17 was stored in the container that it was filled in at 2- 8° C for 52 weeks. The stability of each composition was tested after filling, T(0), and then after specified time-points up to 52 weeks of storage. Stability testing included measuring % total impurities using RP-HPLC as specified in Example 1. The results of the testing are shown in Table 18 below.

[00110] Table 17

[00111] Table 18

[00112] As seen in Table 18, the micafungin compositions, 38 and 39, have a total impurity content of less than 1% after 1 month, 3 months, 6 months and 12 months when stored in a container at 2-8° C. For composition 38, the initial micafungin purity was 99.51% at T(0) (100 — 0.49) and the micafungin purity was 99.56% at 1 month, 99.44% at 3 months, 99.38% at 6 months, and 99.29% at 6 months of storage in a container at 2-8° C. Thus, the micafungin composition 38 retained at least 99.8% of its initial micafungin concentration after 6 months or 12 months of storage in a container at 2-8° C.

[00113] For composition 39, the initial micafungin purity was 99.51% at T(0) (100 — 0.49) and the micafungin purity was 99.54% at 1 month, 99.40% at 3 months, 99.35% at 6 months, and 99.30% at 6 months of storage in a container at 2-8° C. Thus, the micafungin composition 38 retained at least 99.8% of its initial micafungin concentration after 6 months or 12 months of storage in a container at 2-8° C.

Example 7

[00114] Listed below are prophetic examples of aqueous micafungin compositions as additional embodiments.

[00115] Composition A

[00116] Composition B

[00117] Composition C

[00118] Composition D

[00119] Composition E

[00120] Composition F

[00121] Composition G

[00122] Composition H

[00123] Composition I

[00124] Composition J

Example 8

[00125] A long-term stability trial was set up at 2-8° C and 25° C / 60% relative humidity (RH) using 1 mg/mL micafungin. The components of the aqueous compositions having micafungin are shown below in Table 19 and pH was adjusted to a range of 4.5 to 5.5, and preferably 5.0 to 5.2. The compositions were filled into 50 mL type 1 glass vials and each vial was stoppered and sealed.

[00126] The composition of Table 19 was stored in the glass vial that it was filled in at 2-8° C for 3 months, protected from light, and 25° C / 60% RH for 3 months. The stability of the composition was tested after filling, T(0), and then after specified time-points up to 3 months of storage. Stability testing included measuring % total impurities using RP-HPLC as specified in Example 1. The results of the testing are shown in Table 20 below. Herein, <LOQ means below limit of quantification. For this Example, and used herein, impurity D is pneumocandin A0, l-[(4R,5R)-4,5-dihydroxy-N2-[4-[5-[4-(pentyloxy)phenyl]-3- isoxazolyl]benzoyl]-L-ornithine]-4-[(4S)-4-hydroxy-4-(3,4-dihydroxyphenyl)-L-threonine]. [00127] Table 19

[00128] Table 20

[00129] Other testing evidenced the composition exhibited the following properties. At filling, time zero T(0), the composition, 50 mL vial, was measured to have a micafungin open ring analog amount of 0.14%, 0.15% after 3 months of storage at 2-8° C, and 1.0% after 3 months of storage at 25° C / 60% RH. Further, at T(0), the composition, 50 mL vial, was measured to have a micafungin epimer amount of 0.05%, 0.06% after 3 months of storage at 2-8° C, and 0.37% after 3 months of storage at 25° C / 60% RH. In addition, the impurity at RRT 1.04 at T(0) of the composition, 50 mL vial, was measured as 0.06%, 0.11% after 3 months of storage at 2-8° C, and 0.88% after 3 months of storage at 25° C / 60% RH.

Example 9

[00130] A long-term stability trial was set up at 2-8° C and 25° C / 60% relative humidity (RH) using 1 mg/mL micafungin. The components of the aqueous compositions having micafungin are shown below in Table 21 and pH was adjusted to a range of 4.5 to 5.5, and preferably 5.0 to 5.2. The compositions were filled into 50 mL and 100 mL flint glass vials and each vial was stoppered and sealed

[00131] The composition of Table 21 was stored in the glass vial that it was filled in at 2-8° C for 3 months, protected from light, and 25° C / 60% RH for 3 months. The stability of the composition was tested after filling, T(0), and then after specified time-points up to 3 months of storage. Stability testing included measuring % total impurities using RP-HPLC as specified in Example 1. The results of the testing are shown in Table 22 below.

[00132] Table 21

[00133] Table 22

[00134] Other testing evidenced the composition exhibited the following properties. At filling, time zero T(0), the composition, 50 mL vial, was measured to have a micafungin open ring analog amount of <LOQ, 0.1% after 3 months of storage at 2-8° C, and 1.6% after 3 months of storage at 25° C / 60% RH. Further, at T(0), the composition, 50 mL vial, was measured to have a micafungin epimer amount of 0.06%, 0.09% after 3 months of storage at 2-8° C, and 0.3% after 3 months of storage at 25° C / 60% RH. In addition, the impurity at RRT 1.04 at T(0) of the composition, 50 mL vial, was measured as <LOQ, 0.15% after 3 months of storage at 2-8° C, and 1.15% after 3 months of storage at 25° C / 60% RH.

Example 10

[00135] A long-term stability trial was set up at 2-8° C and 25° C / 60% relative humidity (RH) using 1 mg/mL micafungin. The components of the aqueous compositions having micafungin are shown below in Tables 23 and 24, and pH was adjusted to a range of 4.5 to 5.5, and preferably 5.0 to 5.2. The compositions were filled into 50 mL and 100 mL type 1 glass vials and each vial was stoppered and sealed. The examples herein, and filling techniques in general, can be set up for aseptic filling depending on a facility capability.

[00136] The compositions of Tables 23 and 24, compositions 40 and 41, were stored in the glass vial that it was filled in at 2-8° C for 3 months, protected from light, and 25° C / 60% RH for 3 months. The stability of the composition was tested after filling, T(0), and then after specified time-points up to 3 months of storage. Stability testing included measuring % total impurities using RP-HPLC as specified in Example 1. The results of the testing are shown in Table 25 below.

[00137] Table 23 (Composition 40)

[00138] Table 24 (Composition 41; reduced dextrose)

[00139] Table 25

[00140] Other testing evidenced the compositions exhibited the following properties. At filling, time zero T(0), composition 40 (table 23), 50 mL vial, was measured to have a micafungin open ring analog amount of 0.14%, 0.13% after 3 months of storage at 2-8° C, and 0.96% after 3 months of storage at 25° C / 60% RH. Further, at T(0), composition 40 (table 23), 50 mL vial, was measured to have a micafungin epimer amount of 0.05%, 0.06% after 3 months of storage at 2-8° C, and 0.29% after 3 months of storage at 25° C / 60% RH. In addition, the impurity at RRT 1.04 at T(0) of composition 40 (table 23), 50 mL vial, was measured as <LOQ, 0.1% after 3 months of storage at 2-8° C, and 0.83% after 3 months of storage at 25° C / 60% RH.

[00141] For the other composition, testing evidenced the composition exhibited the following properties. At filling, time zero T(0), composition 41 (table 24), 50 mL vial, was measured to have a micafungin open ring analog amount of 0.13%, 0.13% after 3 months of storage at 2-8° C, and 0.93% after 3 months of storage at 25° C / 60% RH. Further, at T(0), composition 41 (table 24), 50 mL vial, was measured to have a micafungin epimer amount of 0.05%, 0.06% after 3 months of storage at 2-8° C, and 0.34% after 3 months of storage at 25° C / 60% RH. In addition, the impurity at RRT 1.04 at T(0) of composition 41 (table 24), 50 mL vial, was measured as <LOQ, 0.1% after 3 months of storage at 2-8° C, and 0.86% after 3 months of storage at 25° C / 60% RH.

Example 11

[00142] A long-term stability trial was set up at 2-8° C and 25° C / 60% relative humidity (RH) using 1 mg/mL micafungin. The components of the aqueous composition having micafungin are shown below in Table 26 and pH was adjusted to a range of 4.5 to 5.5, and preferably 5.0 to 5.2. The composition was filled into 50 cc plastic IV bag with a single twist port packed in an aluminum protective overwrap.

[00143] The composition of Table 26 was stored in the plastic IV bag that it was filled in at 2-8° C for 6 months, protected from light, and 25° C / 60% RH for 6 months. The stability of the composition was tested after filling, T(0), and then after specified time-points up to 6 months of storage. Stability testing included measuring % total impurities using RP-HPLC as specified in Example 1. The results of the testing are shown in Table 27 below.

[00144] Table 26

[00145] Table 27

[00146] Other testing evidenced the composition exhibited the following properties. At filling, time zero T(0), the composition was measured to have a micafungin open ring analog amount of 0.08%, 0.12% after 3 months of storage at 2-8° C, 0.18% after 6 months of storage at 2-8° C, and 1% after 3 months of storage at 25° C / 60% RH, 1.59% after 6 months of storage at 25° C / 60% RH Further, at T(0), the composition was measured to have a micafungin epimer amount of 0.06%, 0.06% after 3 months of storage at 2-8° C, 0.07% after 6 months of storage at 2-8° C, 0.5% after 3 months of storage at 25° C / 60% RH, and 1.08% after 6 months of storage at 25° C / 60% RH. In addition, the impurity at RRT 1.04 at T(0), was measured as <LOQ, 0.12% after 3 months of storage at 2-8° C, 0.16% after 6 months of storage at 2-8° C, 1.3% after 3 months of storage at 25° C / 60% RH, and 2.29% after 6 months of storage at 25° C / 60% RH.

[00147] Many variations and modifications may be made to the above-described embodiments of the disclosure without departing substantially from the spirit and various principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims.

Claims

Claims:

1. A liquid composition in a container, the composition comprising: a. micafungin or a pharmaceutically acceptable salt thereof present at a concentration of 0.1 to 5 mg/mL as the sole pharmaceutically active agent; b. a tonicity modifier with net zero charge present at a concentration of 1 to 500 mM; and c. a basic amino acid, wherein the liquid composition has a pH of 4 to 6.5.

2. The liquid composition of claim 1, further comprising water present at more than 80% of the weight of the liquid composition.

3. The liquid composition of claim 1, wherein the tonicity modifier is present at a concentration of 100 to 300 mM and is selected from the group consisting of polyols and neutral amino acids.

4. The liquid composition of claim 3, wherein the polyol is selected from the group consisting of glucose, sucrose, trehalose, mannitol, and combinations thereof.

5. The liquid composition of claim 3, wherein the neutral amino acid is selected from the group consisting of proline, glycine, and a combination thereof.

6. The liquid composition of claim 1, wherein the basic amino acid is present at a concentration of 10 to 50 mM and is selected from the group consisting of histidine, arginine, and a combination thereof.

7. The liquid composition of claim 1, further comprising an antioxidant.

8. The liquid composition of claim 1, wherein the antioxidant is methionine or an enantiomer thereof and present at a concentration of 1 to 50 mM.

9. The liquid composition of claim 1, wherein the pH is in the range of 4.5 to 5.5.

10. The liquid composition of claim 1, further comprising a buffer.

11. The liquid composition of claim 1, wherein the liquid composition is a ready-to- administer formulation.

12. The liquid composition of claim 1, wherein the container is a vial, an intravenous bag, or an intravenous bottle.

13. The liquid composition of claim 1, wherein the liquid composition has 10% or less total impurities as measured by RP-HPLC, after 3 months of storage in the container at 25° C and 60% relative humidity.

14. The liquid composition of claim 1, wherein the liquid composition has 5% or less total impurities as measured by RP-HPLC, after 3 months of storage in the container at 25° C and 60% relative humidity.

15. The liquid composition of claim 1, wherein the liquid composition has a micafungin or a pharmaceutically acceptable salt thereof purity of 98% or more, as measured by RP-HPLC, after 3 months of storage in the container at 2-8 °C.

16. The liquid composition of claim 1, wherein the total impurities in the liquid composition is less than 1%, as measured by RP-HPLC, after 3 months of storage in the container at 2-8 °C.

17. The liquid composition of claim 1, wherein the liquid composition retains at least 98% of its initial micafungin concentration after 3 months of storage in a container at 2-8° C.

18. A ready -to-dilute liquid composition in a container, the composition comprising: a. micafungin or a pharmaceutically acceptable salt thereof present at a concentration of 10 to 20 mg/mL as the sole pharmaceutically active agent; b. a tonicity modifier with net zero charge present at a concentration of 100 to 300 mM; and c. a basic amino acid zero charge present at a concentration of 5 to 30 mM, wherein the liquid composition has a pH of 4 to 6.5.

19. The ready -to-dilute liquid composition of claim 18, wherein the container is a glass vial.

20. The ready -to-dilute liquid composition of claim 18, wherein the tonicity modifier is selected from the group consisting of glucose, sucrose, trehalose, mannitol, and combinations thereof.

21. The ready -to-dilute liquid composition of claim 20, wherein the neutral amino acid is selected from the group consisting of proline, glycine, and a combination thereof.

22. The ready -to-dilute liquid composition of claim 18, further comprising methionine or an enantiomer thereof present at a concentration of 1 to 50 mM.

23. The ready -to-dilute liquid composition of claim 18, further comprising water present at more than 80% of the weight of the liquid composition.

24. The ready -to-dilute liquid composition of claim 18, wherein the ready -to-dilute liquid composition has 5% or less total impurities as measured by RP-HPLC, after 3 months of storage in the container at 2-8 °C or 25° C