Micafungin formulations

Abstract

The present disclosure is related to micafungin formulations, particularly stable aqueous pharmaceutical compositions comprising micafungin. The disclosure also describes the process for making such compositions and use of such compositions for treatment of a patient in need thereof.

Description

MICAFUNGIN FORMULATIONSCROSS-REFERENCE TO RELATED APPLICATIONSThis application claims priority to U.S. Provisional Application 63 / 624,418 filed on January 24, 2024, which is incorporated herein by reference in its entirety.FIELD OF THE DISCLOSURE

[0001] The present disclosure is related to micafungin formulations, particularly stable aqueous pharmaceutical formulations comprising micafungin. Also described are the process for making such formulations and use of such formulations for treatment of a patient in need thereof. Such formulations provide good stability.BACKGROUND

[0002] Micafungin is the active pharmaceutical ingredient in MYC AMINE®. According to the FDA label, the chemical structure of micafungin sodium is represented by formula (I):

[0003] Micafungin is also known as Pneumocandin AO, l -[(47?,57?)-4,5-dihydroxy- / V2-[4- [5-[4-(pentyloxy)phenyl]-3-isoxazolyl]benzoyl]-L-omithine]-4-[(4S)-4-hydroxy-4-[4-hydroxy-3- (sulfooxy)phenyl]-L-threonine], Micafungin sodium is furthermore known as FK-463. The assigned Registry No's by Chemical Abstracts are 235114-32-6 for micafungin and 208538-73-2 for micafungin sodium.

[0004] Micafungin is an echinocandin which inhibits 1,3- -D-glucan synthase and thus leads to fungal cell lysis. Micafungin is thus useful as an antifungal agent in the treatment of infections caused by strains of e.g., Aspergillus, Cryptococcus, Candida, Mucor, Actinomyces, Histoplasma, Dermatophyte, Malassezia, and Fusarium. Micafungin is the active ingredient in the approved drugs MYCAMINE ® and MICAFUNGIN IN SODIUM CHLORIDE INJECTION which are used in the treatment and prophylaxis of infections caused by Candida species.

[0005] A significant disadvantage of the MYCAMINE ® product is that it is provided as a lyophilized product which must be reconstituted as a 10 mg / mL (50 mg vial) or 20 mg / mL (100 mg vial) concentrate in either isotonic saline (0.9 wt. %) or isotonic dextrose (5 wt. %). The reconstituted product is then diluted in a second preparation step, typically to a concentration of 0.5-4 mg / mL in a 100 mL container. The diluted product should be protected from light and may be stored for up to 24 hours at 25° C. Thus, the prescribing information teaches that MYCAMINE® should only be stored for a maximum of 24 hours after compounding for infusion.

[0006] The MICAFUNGIN IN SODIUM CHLORIDE INJECTION product is provided in 50 mg, 100 mg and 150 mg bags. A significant disadvantage of the MICAFUNGIN IN SODIUM CHLORIDE INJECTION products is that they are not stable for more than 30 days at room temperature.

[0007] What is needed are stable liquid formulations of micafungin that do not need reconstitution and / or dilution prior to administration and are stable over a long period of time at room temperature.BRIEF SUMMARY

[0008] It has been found that the liquid formulations of micafungin described herein possess surprisingly improved stability. In particular, it has been found certain liquidformulations that are stable for a certain period of time at room temperature and / or at elevated temperatures. Specifically, the present disclosure relates to aqueous solutions comprising micafungin and hydroxypropyl-P-cyclodextrin.

[0009] The aqueous solution according to the present disclosure may further comprise at least one excipient.

[0010] It has been found that these aqueous solutions of micafungin will have low degradation of micafungin, particularly at low pH.

[0011] It has been found that these aqueous solutions of micafungin have good chemical and physical stability including color stability for a certain period of time at room temperature.

[0012] The above-described and other features will be appreciated and understood by those skilled in the art from the following detailed description and appended claims.DETAILED DESCRIPTION

[0013] As used herein, the terms “pharmaceutical composition”, “pharmaceutical formulation”, “composition” and “formulation” are used interchangeably.

[0014] By the term “aqueous solution” is understood any solution in which water is present at or above 50% v / v, such as, e.g., a solution comprising from about 50% v / v to about 100% v / v water. Accordingly, aqueous solutions include solutions comprising about 50% v / v or more, about 60% v / v or more, about 70% v / v or more, about 75% v / v or more, about 80% v / v or more, about 85% v / v or more, about 90% v / v or more, about 95% v / v or more, or about 100% v / v water.

[0015] “Parenteral administration” includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, intrastemal injections, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing, wetting, suspending agents and / or solubilizing agents.

[0016] The term “ready -to-administer” is synonymous with “ready -to-infuse” or “ready - to-inject” and is not to be read as the term "ready-to-use” aqueous solution.

[0017] The term “ready-to-use” includes aqueous preconcentrates which require a single step of dilution with an aqueous diluent fluid such as water for injection or saline beforeadministration. The term “ready -to-administer” is also distinguished from lyophilized products that require two steps before administration to a patient: a first step of reconstitution to form a preconcentrate and then a second step where the preconcentrate is subjected to dilution with an aqueous infusion fluid and then is administered. The “ready-to-administer” parenteral dosage form according to the present disclosure avoids the inconvenience of reconstituting or diluting a concentrated parenteral formulation into infusion diluents prior to infusion, as well as eliminates the risk of any potential calculation or dilution error as well as risks of microbiological contamination during handling.

[0018] In one aspect, the aqueous micafungin formulation may be packed in a container. The container may be a vial or a bag. In an aspect, the container is a single unit dose container.

[0019] The aqueous micafungin formulations described herein may be a ready -to-use or a ready-to-administer solution that may be packed in a flexible plastic container or in a glass vial or a glass or plastic bottle.

[0020] As used herein, the term “flexible plastic container” means flexible polymeric infusion bags or other polymeric containers. Exemplary flexible plastic containers are made of polyolefins, such as polyethylene, polypropylene, copolymers and derivatives thereof, with or without other additives.

[0021] Typically, the compounds of the present disclosure are administered in an amount effective to treat a condition as described herein. The compounds of the present disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds required to treat the progress of the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.

[0022] The term “therapeutically effective amount” as used herein refers to that quantity of a compound or pharmaceutically composition that is sufficient to result in a desired activity upon administration to a subject in need thereof. An “effective amount” means the amount of a compound or pharmaceutical composition according to the present disclosure that, when administered to a patient for treating an infection or disease is sufficient to effect such treatment. The “effective amount” will vary depending on the active ingredient, the state of infection, disease or condition to be treated and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated.

[0023] The term “stability”, “chemical stability” or “stable” means that the product, composition or formulation exhibits an acceptable amount of micafungin being present, or not more than a certain amount of micafungin has degraded after a certain period of time. Accordingly, in a stable product, solution or formulation, unacceptable degradation of the active agent is avoided.

[0024] Accordingly, “stability” may be defined by the increase of total or individual impurities generated after a certain period of time. The increase of total or individual impurities generated after a certain period of time is calculated by subtracting the content of impurity or impurities at start from their content at a certain time point. The content of impurities may be expressed as a percentage, for example as a peak-area percentage of a HPLC chromatogram or calculated according to standard solution.

[0025] In addition to chemical stability, the physical stability of the composition may be monitored. Physical stability is defined as the appearance of the formulation and includes visual inspection of precipitation, clarity, and color of the solution.

[0026] Color can be determined by visual inspection in accordance with USP <630> and USP <631> or spectrophotometrically by using the L*a*b* color space method and calculating the AE in accordance with USP <1061 >.

[0027] In liquid ready -to-administer pharmaceutical products it is important to have formulations without any visible particles or precipitation.

[0028] As used herein, micafungin may be added in the formulation in the form of a salt. A non-limiting list of salts of micafungin includes the sodium salt, the potassium salt, the diisopropylethylamine (DIPEA) salt, and the like.

[0029] As used herein, amounts of micafungin are expressed as micafungin sodium. As understood in the art, micafungin sodium in water at the concentrations described herein is expected to completely dissociate to provide micafungin- and Na+.

[0030] One micafungin impurity identified in the stability studies is called the epimer impurity. The production of the epimer impurity from micafungin is illustrated in Scheme 1.Scheme 1 : Production of micafungin epimer impurity.

[0031] The epimer impurity was not identified in Zhu et al. (S. Zhu, X. Meng, X. Su, Y. Lou, Z. Sun, “Development and Validation of a Stability -Indicating High Performance Liquid Chromatographic (HPLC) Method for the Determination of Related Substances of Micafungin Sodium in Drug Substances”, International Journal of Molecular Sciences, 14 (2013) 21202- 21214; doi:10.3390 / ijmsl41121202). The epimer impurity corresponds to impurity 3 in US Patent Publication 2019 / 0151241.

[0032] Another micafungin impurity is the open ring impurity. The open ring impurity corresponds to Impurity 2 in Zhou et al. and Impurity 1 in US Patent Publication 2019 / 0151241. The production of the open ring impurity from micafungin is illustrated in Scheme 2.Scheme 2. Production of open ring impurity

[0033] The sulfate ester impurity is formed by hydrolysis under acidic conditions. The sulfate ester impurity corresponds to Impurity 6 in Zhou and Impurity 4 in US Patent Publication2019 / 0151241 . The production of the sulfate ester impurity from micafungin is illustrated in Scheme 3.Scheme 3. Production of sulfate ester impurity

[0034] The stability studies in the Examples herein have identified micafungin impurities, specifically micafungin impurities that form at low pH. It was found that at low pH, such as below 5.0, the primary degradation pathway of micafungin is acidic hydrolysis to produce an epimer impurity shown in Scheme 1.

[0035] Thus, described herein are aqueous micafungin formulations comprising hydroxypropyl-P-cyclodextrin that are stabilized at low pH such as below pH 5.0, particularly ready to administer micafungin formulations.

[0036] In an aspect, the increase of epimer impurity in micafungin formulation described herein is less than 1.5 area% as measured by HPLC after 1 month at 25°C. In an aspect, the increase of epimer impurity is less than 1.5. 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3 or 0.2 area% as measured by HPLC.

[0037] In an aspect, the increase of epimer impurity in micafungin formulation described herein is less than 2.0 area% as measured by HPLC after 7 days at 40°C. In an aspect, the increase of epimer impurity is less than 2.0, 1.9, 1.8, 1.7, 1.6, 1.5. 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4 or 0.3 area% as measured by HPLC.

[0038] In an aspect, the increase of epimer impurity in micafungin formulations described herein, is less than 4.0 area% as measured by HPLC after 14 days at 40°C. In an aspect, the increase of epimer impurity is less than 4.0, 3.5, 3.0, 2.5, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5. 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6 or 0.5 area% as measured by HPLC. In an aspect, the increase of epimer impurity is less than 2.5 area% as measured by HPLC.

[0039] In an aspect, the increase of total impurities in micafungin formulations described herein, is less than 2.5 area% as measured by HPLC after 1 month at 25°C. In an aspect, the increase of total impurities is less than 2.5, 2.0, 0.9, 1.8, 1.7, 1.6, 1.5. 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, or 0.7 area% as measured by HPLC.

[0040] In an aspect, the increase of total impurities in micafungin formulations described herein is less than 6.0 area % as measured by HPLC, after 7 days at 40°C. In an aspect, the increase of total impurities is less than 6.0, 6.5, 5.0, 4.5, 4.0, 3.9, 3.8, 3.7, 3.6 or 3.5area% as measured by HPLC.

[0041] In an aspect, the increase of total impurities in micafungin formulations described herein is less than 9.0 area % as measured by HPLC after 14 days at 40°C. In an aspect, the increase of total impurities is less than 9.0, 8.5, 8.0 or 7.5 area% as measured by HPLC.

[0042] In an aspect, the increase of sulfate ester impurity in micafungin formulations described herein is less than 0.30 area% as measured by HPLC after 1 month at 25°C. In an aspect, the increase of sulfate ester impurity is less than 0.30,0.29, 0.28, 0.27, 0.26, 0.25, 0.24, 0.23, 0.22, 0.21, 0.20 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11 or 0.10 area% as measured by HPLC.

[0043] In an aspect, the increase of sulfate ester impurity in micafungin formulations described herein is less than 1.0 area% as measured by HPLC, after 7 days at 40°C. In an aspect, the increase of sulfate ester impurity is less than 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3 or 0.2 area% as measured by HPLC.

[0044] In an aspect, the increase of sulfate ester impurity in micafungin formulations described herein is less than 1.0 area% as measured by HPLC after 14 days at 40°C. In an aspect, the increase of sulfate ester impurity is less than 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3 or 0.25 area% as measured by HPLC.

[0045] In an aspect, the aqueous micafungin formulation described herein has a pH of 3.0 to 5.0, such as 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8. 3.9. 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.75, 4.8, 4.9 or 5.0. In an aspect the pH is 3.0 to 4.0. In another aspect the pH is 3.5 to 5.0. In another aspect the pH is 3.8 to 5.0. In another aspect the pH is 4.0 to 5.0. In another aspect the pH is 4.5 to 5.0. In an aspect the pH is 4.0 to 4.5. In an aspect the pH is 4.0. In an aspect the pH is 4.7.

[0046] In an aspect, formulation includes O.lmg / ml to 20 mg / ml of micafungin. The formulations include O.lmg / ml to 20 mg / ml micafungin sodium, such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8. 1.9. 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.2, 3.4, 3.5, 3.6, 3.8, 4.0, 4.5, 5.0. 5.5, 6.0, 6.5, 7.0, 8.0. 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0. 17.0, 18.0, 19.0 or 20.0 mg / ml. micafungin. In an aspect, the formulations include 0.2mg / ml to 2.0 mg / ml micafungin sodium.

[0047] The formulations include a buffer to maintain the pH between 3.0 and 5.0. Exemplary buffers include citrate, acetate, phosphate, potassium phthalate, gluconate, and tartrate buffers and the mixture thereof.

[0048] In an aspect, the buffer is sodium acetate.

[0049] In an aspect, the buffer is present at a concentration of 1 mM to 25 mM. In an aspect, the buffer is present at a concentration of 1 mM to 20 mM. In another aspect the buffer is present at 10 mM to 25 mM. In another aspect the buffer is present at 15 mM to 25 mM. In another aspect the buffer is present at 5 mM to 15 mM. In another aspect the buffer is present at 5 mM to 10 mM. In another aspect the buffer is present at 5 mM, 6 mM, 7 mM, 8 mM, 9 mM or 10 mM.

[0050] In an aspect, the micafungin formulations comprise one or more osmolality adjusting agents. Exemplary osmolality adjusting agents include but are not limited to sodium chloride, Dextrose 5% , combination of sodium chloride and dextrose, or other osmolality agents.

[0051] In an aspect, the osmolality adjusting agent is dextrose.

[0052] In an aspect, the osmolality agent is sodium chloride.

[0053] In an aspect, the micafungin formulations have an osmolality less than 600 mOsmol / kg.

[0054] In an aspect, the micafungin formulations have an osmolality in the range of 240 to 360 mOsmol / kg.

[0055] In an aspect, the concentration of an osmolality adjusting agent in the product is in the amount to provide an iso-osmotic ready -to-administer or ready-to-use product.

[0056] In an aspect, the micafungin formulations have an osmolality within the physiological osmolality of blood. According to the literature, and as used herein, the physiological osmolality of blood is in the range of 270 to 340 mOsmol / kg.

[0057] In an aspect, the concentration of an osmolality adjusting agent in the micafungin formulation should be in the amount to achieve an osmolality of the product within the targeted range of 270 to 340 mOsmol / kg.

[0058] In an aspect, the concentration of an osmolality adjusting agent in the micafungin formulation should be in the amount to achieve an osmolality of the product within the targeted range of 240 to 360 mOsmol / kg.

[0059] In an aspect, the micafungin formulations are both iso-osmotic and have an osmolality similar the physiological osmolality of blood as described above.

[0060] In an aspect, the formulation comprises hydroxypropyl-beta-cyclodextrin.

[0061] In an aspect the amount of hydroxypropyl-beta-cyclodextrin is 10:1 to 0.1 :1 molar ratio to micafungin. In an aspect the molar ratio of hydroxypropyl-beta-cyclodextrin to micafungin is 10: 1, 9: 1, 8: 1, 7: 1, 6:1, 5: 1, 4: 1, 3: 1, 2:1, 1: 1, 0.9: 1, 0.8: 1, 0.7:1, 0.6: 1, 0.5: 1, 0.4:1, 0.3: 1, 0.2 : 1 or 0.1 :1. In an aspect the amount of hydroxypropyl-beta-cyclodextrin is 5:1 to 0.1: 1 molar ratio to micafungin.

[0062] In an aspect, the formulation comprises sodium benzoate and / or methylparaben. In an aspect the formulation comprises sodium benzoate. In an aspect the formulation comprises methylparaben.

[0063] In an aspect, the aqueous micafungin formulation comprises micafungin, hydroxypropyl-beta-cyclodextrin and a buffer, wherein the formulation has pH from 3.0 to 5.0.

[0064] In an aspect, the aqueous micafungin formulation comprises micafungin, hydroxypropyl-beta-cyclodextrin and sodium acetate, the formulation has pH from 3.0 to 5.0.

[0065] In an aspect, the aqueous micafungin formulation comprises micafungin, hydroxypropyl-beta-cyclodextrin, a buffer and an osmolality adjusting agent, wherein the formulation has pH from 3.0 to 5.0.

[0066] The pH of the formulation may be adjusted in any suitable manner. The pH may be adjusted with one or more pH adjusting agents, which may be selected from mineral acids, organic acids, weak and strong bases, and salts and derivatives thereof. pH adjusting agents simply allow one to achieve a desired pH, but do not generally act to stabilize the pH or prevent changes in pH. pH adjusting agents can be distinguished from buffering agents which can help to achieve a desired pH, but also provide pH stability. For example, if an acid or base is added to a buffered solution, the pH of the solution will be resistant to change. Examples of pH-adjustingagents include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, succinic acid, lactic acid, citric acid, phenolic acid, sodium hydroxide, ammonium hydroxide, sodium bicarbonate, and the like, and combinations thereof.

[0067] In an aspect, the composition also includes an excipient. Exemplary excipients include amino acids, amino acid derivatives, chelating agents, inorganic salts, sugars, polyols and surfactants. In an aspect the compositions include combinations of the stabilizing agents listed above. The excipients can be in molar ratios of 20:1 to 0.5:1 excipient to Micafungin sodium.

[0068] In an aspect the amount of the excipient is 20: 1 to 0.5: 1 molar ratio to micafungin, such as 20:1, 19: 1, 18: 1, 17:1, 16:1, 15:1, 14:1, 13:1, 12: 1, 11: 1, 10:1, 9:1, 8: 1, 7:1, 6:1, 5:1, 4:1, 3: 1, 2:1, 1:1 or 0.5:1 molar ratio.

[0069] In an aspect, the formulations described herein are intended to be administered via injection or infusion, for example intravenously.

[0070] In an aspect, the present disclosure provides a method of treating a human subject in need thereof by administering a formulation disclosed herein comprising an effective dose of micafungin to the human subject in need thereof.

[0071] In an aspect, the present disclosure provides a method of treating a human subject in need thereof by administering a ready -to-administer formulation disclosed herein comprising an effective dose of micafungin formulation to the human subject in need thereof intravenously.

[0072] In an aspect, the invention provides a method of anti-fungal treatment in a human subject in need thereof, the method comprising: intravenously administering to the human subject a pharmaceutical composition disclosed herein that comprises from 0.1 mg / ml to 20mg / ml of micafungin or a pharmaceutically acceptable salt thereof.

[0073] The invention is further illustrated by the following non-limiting examples.ExamplesExperimental methods

[0074] Aqueous micafungin formulations were prepared containing 0.5 to 2.0 mg / ml micafungin sodium, 20 mM sodium acetate in water. The pH was adjusted to pH 3 to 4.6 with hydrochloric acid. Hydroxypropyl-P-cyclodextrin were included in the formulations in an amount to give a molar ratio of 5:1 of hydro xypropyl-P-cyclodextrin to micafungin sodium.

[0075] After preparation, the initial time point content of the active pharmaceutical ingredient and impurities were determined by high performance liquid chromatography (HPLC) and afterwards containers were loaded into stability chambers at different storage conditions, 40°C, 30°C and 25°C.

[0076] In order to determine the stability of the active pharmaceutical ingredient in formulations according to the present disclosure, containers were taken from stability chambers at various time points, such as 7 days, 14 days, 28 days, 1 month, 2 months, 3 months, 6 months etc. and analyzed by HPLC.

[0077] HPLC ASSAY AND IMPURITIES METHOD:Phosphate buffer: 0.96 g of sodium dihydrogen phosphate and 5.6 g of sodium perchlorate monohydrate in 1000 mL of HPLC grade water, adjust pH to 3.0Mobile phase A: phosphate buffer and acetonitrile (60 / 40)Mobile phase B: AcetonitrileDetector: UV 210nmColumn: (EC)-C18, 4.6 x 150 mm; 2.7 mColumn temperature: 45°CInjection volume: 5 pLGradient timetable:Diluent: Methanol: water (40 / 60)Prepare Standard Solution of micafungin sodium to obtain final concentration of about 0.5mg of micafungin standard per mL; diluted with diluent.Samples are diluted to concentration 0.5 mg / mL with highly purified water.CalculationsCalculate micafungin assay in micafungin drug product sample using external standard method and chromatograms obtained at 210 nm.Assay CalculationsCalculate response factor for each injection of Standard solution using the following formula:Calculate average response factor at 210 nm, <RFSTD>, using all injections of Standard solutions.AreasTD : The area of the micafungin peak in standard solution at 210 nmVSTD : Volume of standard solution (mL)WSTD : Mass of micafungin Na working standard in standard solution (mg)PSTD : Potency of micafungin Na working standard corrected for water content(% / 100)RFSTD : Response factor of micafungin peak in standard solution at 210 nm < FSTD> : Average response factor of micafungin peak in standard solutionCalculate Assay of micafungin in drug product expressed in mg / ml and % of LC (label claim) using the following formulas: 100where:Areasample : The area of the micafungin peak in the sample solution at 210 nmD : Dilution factor for sample preparation<RFSTD> : Average response factor of micafungin peak in standard solutionLC : Label claim (0.5)Calculation for Related substancesThe content of the individual related substances (impurities) is given as Area % of the total area. Peaks < 0.05 % are to be omitted.Example 1:Table 1 shows the increase in total impurities, epimer impurity and sulphate ester impurity at 40°C, at 7 days and at 14 days at pH 4.0. The formulations include hydroxypropyl-beta- cyclodextrin (HPBCD) in a molar ratio of 5 : 1 (HPBCD : micafungin). 20mM of Sodium Acetate is included in all formulations in Table 1.Table 1:Table 2 shows the increase in total impurities, epimer impurity and sulphate ester impurity at 25°C, at 1 month and at 2 months at pH 4.0. The formulations include hydroxypropyl-beta- cyclodextrin (HPBCD) in a molar ratio of 5: 1 (HPBCD : micafungin). 20mM of Sodium Acetate is included in all formulations in Table 2.Table 2:Table 3 shows the increase in total impurities, epimer impurity and sulphate ester impurity at 25 °C after 3 and 6 months at pH 4.7. The formulations include hydroxypropyl-beta- cyclodextrin (HPBCD) in a molar ratio of 5:1(HPBCD: micafungin). 20mM of Sodium Acetate is included in all formulations in Table 3.Table 3:Table 4 shows the increase in total impurities, epimer impurity and sulphate ester impurity at 40°C, at 7 days and 14 days and at 25 °C 90 and 180 days at pH 4.0. The formulations include hydroxypropyl-beta- cyclodextrin (HPBCD) in a molar ratio of 5:1 (HPBCD : micafungin) and optionally a tonicity agent. 20mM of Sodium Acetate is included in all formulations in Table 4.Table 4:

[0078] The use of the terms “a” and “an” and “the” and similar referents (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms first, second etc. as used herein are not meant to denote any particular ordering, but simply for convenience to denote a plurality of, for example, layers. The terms “comprising”, “having”, “including”, and “containing” are to be construed as open-ended terms (i.e. , meaning “including, but not limited to”) unless otherwise noted. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention as used herein.

[0079] While the invention has been described with reference to an exemplary embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation ormaterial to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Any combination of the abovedescribed elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

What is claimed is:

1. An aqueous micafungin formulation comprising hydroxypropyl-P-cyclodextrin (HPBCD).

2. The aqueous micafungin formulation according to claim 1, wherein a molar ratio of the micafungin to HPBCD is from 1 :0.1 to 1 : 10.

3. The aqueous micafungin formulation according to claims 1 and 2, wherein the pH of the formulation is from 3.0 to 5.0.

4. The aqueous micafungin formulation according to claims 1 and 2, wherein the pH of the formulation is from 3.8 to 5.0.

5. The aqueous micafungin formulation according to any one of claims 1 to 4, wherein the formulation comprises a buffer.

6. The aqueous micafungin formulation according to claim 5, wherein the buffer may be citrate, acetate, phosphate, potassium phthalate, gluconate, tartrate buffer or a mixture thereof.

7. The aqueous micafungin formulation according to claim 6, wherein the buffer is an acetate buffer.

8. The aqueous micafungin formulation according to claims 5 to 7, wherein the buffer is in concentration of from ImM to 25mM.

9. The aqueous micafungin formulation according to any one of claims 1 to 8, wherein the formulation comprises one or more osmolality adjusting agents.

10. The aqueous micafungin formulation according to claim 9, wherein the osmolality agent may be selected from sodium chloride, dextrose, or combination thereof.

11. The aqueous micafungin formulation according to any one of claims 1 to 10, wherein the formulation comprises sodium benzoate and / or methylparaben.

12. The aqueous micafungin formulation according to claims 1 to 11, wherein the formulation comprises of 0.1 mg / ml to 20 mg / ml of micafungin.

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