Azithromycin liquid formulation

Abstract

The present disclosure is directed to liquid azithromycin formulations, methods for the preparation of the same, and uses thereof.

Description

AZITHROMYCIN LIQUID FORMULATIONCROSS REFERENCE TO RELATED APPLICATIONSThis application claims priority to U.S. Provisional Applications 63 / 564,140 filed on March 12, 2024, and 63 / 704,732, filed on October 8, 2024, which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0001] The present disclosure is directed to liquid azithromycin formulations, methods for the preparation of the same, and uses thereof.BACKGROUND

[0002] Azithromycin is an antibiotic derived from erythromycin having a wide-range antibiotic spectrum.

[0003] Azithromycin has the chemical name (2R,3S,4R,5R,8R,10R,l 1R,12S,13S,14R)- 13- [(2,6-dideoxy-3-C-methyl-3-O -methyl-a-L-ribohexopyranosyl) oxy]-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-hepta-methyl- 11- [[3,4,6-trideoxy-3-(dimethylamino)-P-D-xylo- hexopyranosyl]oxy]-l-oxa- 6-azacyclopentadecan- 15-one. Azithromycin has the following structural formula:

[0004] Azithromycin has a high bacteriostatic action in relation to a wide spectrum of pathogenic bacteria and is used mainly for the treatment of respiratory and dermatological infections.

[0005] Azithromycin can be used to treat bacterial infections in adults and paediatric patients caused by susceptible strains such as: Chlamydophila pneumonia, Chlamydia trachomatis, Haemophilus influenzae, Haemophilus ducreyi, Legionella pneumophila, Mycoplasma hominis, Mycoplasma pneumoniae, Moraxella catarrhalis, Neisseria gonorrhoeae, Staphylococcus aureus, Streptococcus agalactiae. Streptococcus pneumoniae. Streptococcus pyogenes, and the Streptococcus mitis group

[0006] Azithromycin for injection is indicated for community-acquired pneumonia in adults and pelvic inflammatory disease caused by designated, susceptible bacteria.

[0007] Azithromycin is subject to degradation that may occur during storage. For example, azithromycin in solution is particularly susceptible to degradation if exposed to elevated temperatures and / or oxygen, which may result in the presence of unacceptable levels of impurities at the time of administration.

[0008] Currently, azithromycin for injection is available in lyophilized form. The formulation is typically stored in a glass vial.

[0009] To prepare the solution for IV infusion, the lyophilized form of azithromycin needs to be reconstituted and, if necessary, diluted prior to administration to a patient.

[0010] Thus, one of the drawbacks of the existing azithromycin formulations is that, in the case of IV administration, reconstitution and dilution steps are required prior to administration to a patient, thus increasing the risk of medication errors. Further, after initial vial closure puncture and subsequent dilution, such diluted formulation may be used only for a short period of time and any unused portion should be discarded. For instance, a current lyophilized product on the market may be stored for 24 hours below 30°C upon reconstitution or dilution or 7 days at 5°C upon dilution.

[0011] Another drawback to the current lyophilized formulations is the poor solubility of azithromycin in water.

[0012] Thus, there is a need for liquid, aqueous azithromycin formulations which would be stable for certain prolonged periods of time under defined storage conditions and that could be delivered to a patient without a need for reconstitution or dilution.SUMMARY

[0013] The present disclosure relates to liquid formulations comprising azithromycin, its pharmaceutically acceptable salts, hydrates or solvates thereof, as well as products comprising the formulations.

[0014] According to the present disclosure, both the physical and chemical stability of azithromycin are improved, and the shelf life of the liquid formulation is prolonged.

[0015] In one aspect, the liquid formulation is an aqueous formulation of azithromycin.

[0016] In one aspect, the present disclosure is directed to a clear, liquid formulation of azithromycin.

[0017] In one aspect, the pH of the formulation is from 5.0 to 7.0.

[0018] In one aspect, the aqueous formulation is a ready -to-administer formulation.

[0019] In one aspect, the ready -to-administer formulation is in a unit dosage form.

[0020] In one aspect, the concentration of azithromycin in the formulation is from 0.1 mg / ml to 10 mg / ml.

[0021] Also, according to the present disclosure, a method of producing a liquid formulation comprising azithromycin is provided.

[0022] According to the present disclosure, herein is provided a method for treatment of patients in need comprising administration of a predefined concentration of a liquid azithromycin formulation.

[0023] It is to be understood that both the foregoing description and the following further description are exemplary and explanatory only and are not restrictive of the claims.DETAILED DESCRIPTION

[0024] The present disclosure relates to a liquid formulation comprising azithromycin, its pharmaceutically acceptable salts, hydrates, or solvates thereof, as well as products comprising the formulation.

[0025] According to the present disclosure, both the physical and chemical degradation of azithromycin are slowed down, and the shelf-life of such formulation is prolonged.

[0026] In accordance with an aspect of the present disclosure, azithromycin is semisynthetic.

[0027] In one aspect, the pH of the formulation is from 5.0 to 7.0.

[0028] In one aspect, the pH of the formulation is 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.

[0029] In one aspect, the pH of the formulation is from 5.5 to 6.7.

[0030] In one aspect, the pH of the formulation is from 5.8 to 6.7.

[0031] In one aspect, the pH of the formulation is from 6.0 to 6.6. In one aspect the pH of the formulation is 6.0. In one aspect, the pH of the formulation is 6.5.

[0032] “pH” is the conventional measurement unit of hydrogen ion activity in a solution at 25°C, unless another temperature is specified.

[0033] As used herein, the term “pH” in compositions is defined as ± 0.1 of the numerical value or range in question.

[0034] In one aspect, the aqueous composition is in unit dosage form.

[0035] In an aspect, the amount of azithromycin as used herein is based on azithromycin dihydrate.

[0036] In one aspect, the concentration of azithromycin in the formulation is from 0.1 mg / ml to 50 mg / ml.

[0037] In one aspect, the concentration of azithromycin in the formulation is from 0.1 mg / ml to 20 mg / ml.

[0038] In one aspect, the concentration of azithromycin in the formulation is from 1 mg / ml to 10 mg / ml.

[0039] In one aspect, the concentration of azithromycin in the formulation is from 1 mg / ml to 2 mg / ml.

[0040] In one aspect, the concentration of azithromycin in the formulation is 2 mg / ml.

[0041] In one aspect, the concentration of azithromycin in the formulation is 1 mg / ml.

[0042] In one aspect, azithromycin is in the form of a salt.

[0043] In one aspect, azithromycin is in the form of a solvate or hydrate. In one aspect, azithromycin may be selected from the ethanol solvate, the propanol solvate, or a hydrate.

[0044] In one aspect, azithromycin is in the form of azithromycin dihydrate.

[0045] In one aspect, azithromycin is in the form of azithromycin monohydrate.

[0046] In one aspect, the liquid formulation is an aqueous formulation of azithromycin.

[0047] By the term “aqueous composition”, “aqueous solution” or “aqueous” is understood any composition in which the solvent is water (e.g., distilled water, deionized water, water for injection, sterile water for injection, or bacteriostatic water for injection). Accordingly, aqueous compositions include compositions comprising water in a concentration of at least 80% v / v, at least 85% v / v, at least 90% v / v, at least 93% v / v, at least 94% v / v, at least 95% v / v, at least 96%, v / v at least 97% v / v, at least 98% v / v, or at least 99% v / v.

[0048] In one aspect, the aqueous composition of azithromycin comprises 90% v / v or more water.

[0049] In an aspect, the pharmaceutical formulation may comprise water or standard diluents for parenteral use, such as, but not limited to, sodium chloride for injection, dextrose injection solution, or other suitable diluents.

[0050] According to the present disclosure, the aqueous formulation of azithromycin is stable for a certain period of time.

[0051] The term “stable” means that the compositions meet one or more of the following criteria:(i) The composition exhibits an acceptable amount of active ingredient degraded after a certain time period compared to the amount of azithromycin present at the beginning of the time period; and / or(ii) the composition exhibits an acceptable amount of total and / or individual impurities being formed after a certain time period; and / or(iii) the composition retains a desirable appearance such as clarity, color, and contains no visible particles (e.g., particle free, agglomerate free, or precipitate free composition) over a time period.

[0052] Visual inspection for visible particles may be performed as follows: the container under inspection is gently swirled and inverted, ensuring that no air bubbles are produced, andinspected during certain period (approximately 5 to 20 sec) with the naked eye and / or under a magnifier. Visual inspection for a change of color may be performed as follows: the container is inspected by eye and a color is assigned to the composition. Color may also be determined spectrophotometrically by using the L*a*b* color space method and calculating the AE in accordance with USP <1061>.

[0053] Azithromycin and its impurities may be analyzed, for example, by liquid chromatography using different detectors, e.g., high pressure liquid chromatography (HPLC), ultra high pressure liquid chromatrography (UHPLC) with diode array detection (DAD), mass spectrometry (MS), or an amperometric electrochemical detector. In one aspect, azithromycin and its impurities may be analyzed by methods such as described in the USP Azithromycin Monograph.

[0054] By the term “impurity” as used herein is meant a degradation impurity of the active pharmaceutical ingredient (e.g., azithromycin) in the pharmaceutical formulation.

[0055] In one aspect, the compositions are stable for at least 7 days, at least 14 days, at least 21 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, a least 5 months, at least 6 months, at least 9 months, or at least 12 months, when stored at room temperature.

[0056] By the term “room temperature” as used herein, it means a temperature from 20 to 25°C.

[0057] In an aspect, the present disclosure provides a clear, precipitate free aqueous composition. In one aspect, the compositions are clear for at least 7 days, at least 14 days, at least 21 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, or at least 12 months, when stored at room temperature, or an elevated temperature such as 30°C, 40°C or 60°C.

[0058] In one aspect, an aqueous composition according to the present disclosure is stable at 2-8°C for a certain time period.

[0059] In one aspect, the compositions are stable for at least 7 days, at least 14 days, at least 21 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, or at least 12 months, when stored at 2-8°C.

[0060] Formulations according to the present disclosure showed surprising stability for a reasonable period of time, when stored at 30°C. In one aspect, the compositions are stable for at least 7 days, at least 14 days, at least 21 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months, when stored at 30°C.

[0061] Formulations according to the present disclosure showed surprising stability for a reasonable period of time, when stored at 40°C. In one aspect, the compositions are stable for at least 7 days, at least 14 days, at least 21 days, or at least 1 month, when stored at 40°C.

[0062] Formulations according to the present disclosure showed surprising stability for a reasonable period of time, when stored at 60°C. In one aspect, the compositions are stable for at least 7 days, or at least 14 days, when stored at 60°C.

[0063] In a specific aspect, “stable” is defined as no more than a 10%, 15%, 20%, 25 or 30% of drop of azithromycin assay in the pharmaceutical formulation, analyzed by liquid chromatography.

[0064] In a specific aspect, “stable” is defined as no more than a 10% of drop of azithromycin assay in the pharmaceutical formulation after storing the formulation at room temperature, analyzed by liquid chromatography.

[0065] For example, a stable composition can be one which has not more than a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25 or 30% drop of azithromycin assay after a predetermined time period analyzed by liquid chromatography.

[0066] In an aspect, a stable composition can be one which has not more than an 8% drop of azithromycin assay after a predetermined period at a particular temperature, such as after 1 month under room temperature as analyzed by UHPLC.

[0067] In an aspect, a stable or stabilized formulation can be one which has not more than a 4% azithromycin assay drop after 1 month under room temperature as analyzed by UHPLC.

[0068] In an aspect, a stable or stabilized formulation can be one which has not more than a 3% azithromycin assay drop after 1 month under room temperature as analyzed by UHPLC.

[0069] In an aspect, a stable or stabilized formulation can be one which has not more than a 5% azithromycin assay drop after 3 months under room temperature as analyzed by UHPLC.

[0070] In an aspect, a stable or stabilized formulation can be one which has not more than a 10% azithromycin assay drop after 7 days when stored at 40°C, as analyzed by UHPLC.

[0071] In an aspect, a stable or stabilized formulation can be one which has not more than an 8% azithromycin assay drop after 7 days when stored at 40°C, as analyzed by UHPLC.

[0072] In an aspect, a stable or stabilized formulation can be one which has not more than a 30% azithromycin assay drop after 7 days when stored at 60°C, as analyzed by UHPLC.

[0073] In an aspect, a stable or stabilized formulation can be one which has not more than a 20% azithromycin assay drop after 7 days when stored at 60°C, as analyzed by UHPLC.

[0074] In an aspect, the term “stable” is defined as not more than a 10% increase of total impurities in the formulation after a predetermined time.

[0075] In an aspect, the term “stable” is defined as not more than an 8% increase of total impurities in the formulation after a predetermined time.

[0076] In an aspect, a stable formulation comprises no more than a 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% increase of total impurities under room temperature conditions after a predetermined time.

[0077] In an aspect, a stable formulation can be one that has not more than a 4% increase of total impurity formation after 1 month under room temperature conditions and as analyzed by UHPLC.

[0078] In an aspect, a stable formulation can be one that has not more than a 3% increase of total impurity formation after 1 month under room temperature conditions and as analyzed by UHPLC.

[0079] As used herein, in the case where more than one impurity of the individual active pharmaceutical ingredient can be formed over time, “stable” may be defined as no more than a 5% increase of each individual impurity formation after a predetermined time, analyzed by liquid chromatography.

[0080] In an aspect, where more than one impurity of the individual active pharmaceutical ingredient can be formed over time, a stable composition can be one that has not more than a 1%, 2%, 3%, 4%, or 5% increase of the individual impurity formation after a predetermined time as analyzed by liquid chromatography.

[0081] By the terms “pharmaceutical composition” or “pharmaceutically acceptable composition” as used herein, is meant any composition suitable and intended for in vivo use, for example administration to a patient or a subject. As used herein, the terms “patient” and “subject”are interchangeable and refer to any human or animal individual who is receiving a composition as described herein.

[0082] As used herein, the terms “pharmaceutical composition”, “pharmaceutically acceptable composition”, “pharmaceutical formulation”, “composition” and “formulation” are used interchangeably.

[0083] In an aspect, an aqueous formulation of azithromycin comprises at least one N- acetylated amino acid. In some aspects, the N-acetylated amino acid may be in the L configuration, while in some other aspect it may be in the D configuration. In an aspect, the N- acetylated amino acid may be a non-chiral N-acetylated amino acid, such as N-acetylglycine.

[0084] In an aspect, the aqueous formulation of azithromycin comprises at least one N- acetyl-D-amino acid.

[0085] In an aspect, aqueous formulation of azithromycin comprises at least one N-acetyl- L-amino acid.

[0086] N-acetyl-D-amino acids are compounds represented by the following structure:wherein R is a side chain of an a-amino acid.

[0087] The a-amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, valine, and ornithine.

[0088] N-acetyl-L-amino acids are compounds represented by the following structure:wherein R is a side chain of an a-amino acid.

[0089] The term “N-acetyl-L-amino acids” is also meant to cover any salt thereof, especially pharmaceutically acceptable salts.

[0090] In one aspect, the N-acetyl-L-amino acid is selected from N-acetyl-L-alanine, N- acetyl-L-arginine, N-acetyl-L-asparagine, N-acetyl-L-aspartic acid, N-acetyl-L-cysteine, N-acetyl- L-glutamic acid, N-acetyl-L-glutamine, N-acetyl-L-histidine, N-acetyl-L-isoleucine, N-acetyl-L- leucine, N-acetyl-L-lysine, N-acetyl-L-methionine, N-acetyl-L-phenylalanine, N-acetyl-L- proline, N-acetyl-L-serine, N-acetyl-L -threonine ,N-acetyl-L-tyrosine, N-acetyl-L-tryptophan, N- acetyl-L-valine, N-acetyl-L-ornithine, and combinations thereof.

[0091] The term “N-acetyl-D-amino acids” is also meant to cover any salt thereof, especially pharmaceutically acceptable salts.

[0092] In one aspect the N-acetyl-D-amino acid is selected from N-acetyl-D-alanine, N- acetyl-D-arginine, N-acetyl-D-asparagine, N-acetyl-D-aspartic acid, N-acetyl-D-cysteine, N- acetyl-D-glutamic acid, N-acetyl-D-glutamine, N-acetyl-D-histidine, N-acetyl-D-isoleucine, N- acetyl-D-leucine, N-acetyl-D-lysine, N-acetyl-D-methionine, N-acetyl-D-phenylalanine, N-acetyl- D-proline, N-acetyl-D-serine, N-acetyl-D-threonine, N-acetyl-D-tyrosine, N-acetyl-D-tryptophan, N-acetyl-D-valine, N-acetyl-D-ornithine, and combinations thereof.

[0093] In one aspect, the N-acetyl-D-amino acid is N-acetyl-D-alanine (NADA).

[0094] In one aspect, the N-acetyl-L-amino acid is N-acetyl-L-histidine (NALH).

[0095] In one aspect, the N-acetyl-L-amino acid is N-acetyl-L -valine (NALV).

[0096] In one aspect, the N-acetylated amino acid is N-acetyl-glycine (NAG).

[0097] In an aspect, the formulation comprises at least two N-acetylated amino acids.

[0098] In an aspect, the formulation comprises at least two N-acetyl-D-amino acids. In an aspect, the formulation comprises at least two N-acetyl-L-amino acids. In an aspect, the formulation comprises at least one N-acetyl-D-amino acid and at least one N-acetyl-L-amino acid.

[0099] In one aspect, the formulation comprises azithromycin, at least one N-acetylated amino acid, water, and optionally a pH adjusting agent to adjust the pH, wherein the pH of the composition is from 5.0 to 7.0.

[0100] In one aspect, the formulation consists essentially of azithromycin, at least one N- acetylated amino acid, water, and optionally a pH adjusting agent to adjust the pH, wherein the pH of the composition is from 5.0 to 7.0.

[0101] In one aspect, the formulation consists of azithromycin, at least one N-acetylated amino acid, water, optionally a buffer, and optionally a pH adjusting agent to adjust the pH, wherein the pH of the composition is from 5.0 to 7.0.

[0102] In one aspect, the concentration of at least one N-acetylated amino acid in the formulation is from 0.1 mg / ml to 15 mg / ml.

[0103] In one aspect, the concentration of at least one N-acetyl-D-amino acid in the formulation is from 0.1 mg / ml to 15 mg / ml.

[0104] In one aspect, the concentration of at least one N-acetyl-L-amino acid in the formulation is from 0.1 mg / ml to 15 mg / ml.

[0105] In one aspect, the concentration of N-acetyl-D-alanine in the formulation is from 0.1 mg / ml to 15 mg / ml.

[0106] In one aspect, the concentration of at the least one N-acetylated amino acid in the formulation is 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1 mg / ml, 1.1 mg / ml. 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, 2 mg / ml, 2.5 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, or 15 mg / ml.

[0107] In one aspect, the concentration of at least one N-acetylated amino acid in the formulation is from 0.1 mg / ml to 2 mg / ml.

[0108] In one aspect, the molar ratio of azithromycin to the at least one N-acetylated amino acid is from 1 :0.5 to 1 :25.

[0109] In one aspect, the molar ratio of azithromycin to the at least one N-acetylated amino acid is 1 :0.5, 1 :1, 1 :2, 1 :3, 1 :4, 1 :5; 1 :6, 1 :7, 1 :8, 1:9, 1 :10, 1 : 15, 1 :20, or 1 :25.

[0110] In one aspect, the molar ratio of azithromycin to the at least one N-acetylated amino acid is from 1 : 1 to 1 :5.

[0111] In one aspect, the molar ratio of azithromycin to the at least one N-acetylated amino acid is from 1 :2 to 1 :5.

[0112] In one aspect, the molar ratio of azithromycin to the total amount of N-acetylated amino acid is from 1 :2 to 1 :30.

[0113] In one aspect, the molar ratio of azithromycin to the total amount of N-acetylated amino acid is 1 :2, 1 :3, 1 :4, 1 :5; 1:6, 1 :7, 1 :8, 1 :9, 1 : 10, 1 : 15, 1:20, 1 :25, or 1 :30.

[0114] In one aspect, the molar ratio of azithromycin to the total amount of N-acetylated amino acid is from 1: 1 to 1 :5.

[0115] In one aspect, the molar ratio of azithromycin to the total amount of N-acetylated amino acid is from 1 :2 to 1 :5.

[0116] In one aspect, the composition comprises at least one amino acid or its pharmaceutically acceptable salt. As used herein an amino acid is not an N-acetylated amino acid, preferably an unmodified amino acid. In one aspect, the composition comprises at least two amino acids or pharmaceutically acceptable salt thereof.

[0117] In one aspect, the amino acid is alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, valine, ornithine, or a pharmaceutically acceptable salt thereof.

[0118] In one aspect, an amino acid may be in the L configuration, while in another aspect an amino acid may be in the D configuration. In an aspect, the amino acid may be a non-chiral amino acid, such as glycine.

[0119] In an aspect, the aqueous formulation of azithromycin comprises at least one D- amino acid.

[0120] In an aspect, aqueous formulation of azithromycin comprises at least one L-amino acid.

[0121] In one aspect, the composition comprises histidine or its pharmaceutically acceptable salt.

[0122] In one aspect, the composition comprises aspartic acid or its pharmaceutically acceptable salt.

[0123] In one aspect, the concentration of the at least one amino acid in the formulation is from 0.1 mg / ml to 5 mg / ml.

[0124] In one aspect, the concentration of the at least one amino acid in the formulation is 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, or 5 mg / ml.

[0125] In one aspect, the concentration of the at least one amino acid in the formulation is from 0.1 mg / ml to 2 mg / ml.

[0126] In one aspect, the concentration of the at least one amino acid in the formulation is from 0.5 mg / ml to 2 mg / ml.

[0127] In one aspect, the concentration of the at least one amino acid in the formulation is from 0.1 mg / ml to 1 mg / ml.

[0128] In one aspect, an aqueous formulation of azithromycin comprises at least one N- acetylated amino acid and at least one amino acid, e.g., an unmodified amino acid, as described above. In a specific aspect, the at least one N-acetylated amino acid comprises NADA, NALH, NALV, NAG, or a combination thereof. In an aspect, the at least one unmodified amino acid comprises L-histidine, L-aspartic acid, or a combination thereof.

[0129] In an aspect, the molar ratio of N-acetylated amino acid to unmodified amino acid is 0.5:1 to 6: 1, specifically, 1 :1 to 4: 1.

[0130] In one aspect, the formulation comprises azithromycin, at least one amino acid, water, and optionally a pH adjusting agent to adjust the pH, wherein the pH of the composition is from 5.0 to 7.0.

[0131] In one aspect, the formulation consists essentially of azithromycin, at least one amino acid, water, and optionally a pH adjusting agent to adjust the pH, wherein the pH of the composition is from 5.0 to 7.0.

[0132] In one aspect, the formulation consists of azithromycin, at least one amino acid, water, optionally a buffer and optionally a pH adjusting agent to adjust the pH, wherein the pH of the composition is from 5.0 to 7.0.

[0133] In one aspect, the formulation comprises azithromycin, at least one N-acetylated amino acid, at least one amino acid, water, and optionally a pH adjusting agent to adjust the pH, wherein the pH of the composition is from 5.0 to 7.0.

[0134] In one aspect, the formulation consists essentially of azithromycin, at least one N- acetylated amino acid, at least one amino acid, water, and optionally a pH adjusting agent to adjust the pH, wherein the pH of the composition is from 5.0 to 7.0.

[0135] In one aspect, the formulation consists of azithromycin, at least one N-acetylated amino acid, at least one amino acid, water, optionally a buffer and optionally a pH adjusting agent to adjust the pH, wherein the pH of the composition is from 5.0 to 7.0.

[0136] In one aspect, the aqueous compositions of azithromycin comprise at least one antioxidant. An “antioxidant” is a pharmaceutical additive that can be added to an aqueous composition to prevent oxidation of the pharmaceutically active agent or an inactive component of the composition.

[0137] In one aspect, the aqueous compositions of azithromycin comprise at least one buffer. In one aspect, buffers are selected from buffers having at least one ionizable group having a pKa from 4 to 8 and wherein the pKa is within 1 unit from the pH of the aqueous formulation. For example, buffer may be a citrate, phosphate, or succinate buffer.

[0138] In an aspect, the aqueous composition does not comprise a buffer.

[0139] In one aspect, the composition is an isosmotic composition. It is to be understood that the term “isosmotic” in accordance with the present disclosure means having similar osmolality to the physiologic osmolality of blood.

[0140] In one aspect, the composition has osmolality from 150 to 900 mOsm / kg.

[0141] In one aspect, the composition has osmolality from 240 to 600 mOsm / kg.

[0142] Typically, the compositions have an osmolality from 250 to 350 mOsm / kg.

[0143] In one aspect, the composition is both isotonic and has an osmolality similar to the physiological osmolality of blood as described above.

[0144] In one aspect, the aqueous composition further comprises one or more osmolality adjusting agents. Exemplary osmolality adjusting agents for use in compositions include but are not limited to sodium chloride, mannitol, sorbitol and dextrose. In an aspect, the osmolality adjusting agent may be mannitol. In an aspect, the osmolality adjusting agent may be dextrose.

[0145] The pH of the solutions 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 thereof. Examples of pH adjusting agents 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. In an aspect, the pH adjusting agents may include hydrochloric acid and / or sodium hydroxide.

[0146] In one aspect, liquid formulation comprising azithromycin comprises a one-phase solvent system. In one aspect, one-phase solvent system may comprise micelles.

[0147] In one aspect, the liquid formulation comprising azithromycin comprises micelles. By the term “micelles” herein means supramolecular assembly of surfactant amphipathic lipid molecules dispersed in a liquid.

[0148] Micelles are composed of hydrophobic and hydrophilic components. Micelles’ surfactant molecules may be aggregated either by cationic, anionic, zwitterionic or non-ionic groups. Micelles may be formed from, but not limited to, a fatty acid, a salt of a fatty acid, phospholipids, or other similar molecules.

[0149] In one aspect, a one-phase solvent system may comprise a pharmaceutically acceptable salt of a bile acid, a triglyceride, and a lecithin.

[0150] In one aspect, the formulation is a ready -to-administer formulation.

[0151] A “ready -to-administer” composition is herein used synonymously with “ready-to- infuse” or “ready -to-inject” and is not to be read as the term “ready-to-use” aqueous solution. A “ready -to-administer” composition is suitable for administration directly to the patient and does not require any dilution steps.

[0152] 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 before administration.

[0153] The term “ready -to-administer” is also distinguished from lyophilized products that require two steps, 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. A “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 toinfusion, as well as eliminates the risk of any potential calculation or dilution error as well as risks of microbiological contamination during handling.

[0154] The aqueous azithromycin formulation described herein may be a ready -to-use or a ready -to-administer solution that may be packed in a flexible plastic container or it may be packed in a vial or a bottle,

[0155] Ready-to-administer or ready-to use formulations according to the present disclosure may be used for treatment of a bacterial infection by administering azithromycin to a subject in need thereof.

[0156] This disclosure also provides a process for manufacturing the disclosed pharmaceutical formulations. In various embodiments, the process may comprise the steps of dissolving azithromycin and predefined excipients in water or predefined solvent and filling a container with the formulation. If necessary, the pH is adjusted to achieve the desired pH range.

[0157] In one aspect, the process of manufacturing an aqueous formulation of azithromycin comprises dissolving at least one N-acetylated amino acid in an aqueous solution, such as water, and adding azithromycin into the solution. If necessary, the pH of the solution may be adjusted to the predetermined pH using a pH adjusting agent.

[0158] In another aspect, an aqueous formulation in accordance with the present disclosure may be manufactured by any process known to the person skilled in the art.

[0159] In one aspect, the aqueous formulation of azithromycin is packaged into a suitable container. The container may be a vial, a bottle, an ampule, a syringe, or a bag. In one aspect, the container is a single unit dose container. In one aspect, the container is a single unit dose plastic bag. In one aspect, the container is a single unit dosage container for IV administration.

[0160] In one aspect, the volume of the container is from 1 ml to 1000 ml.

[0161] In one aspect, the volume of the container is from 50 ml to 1000 ml.

[0162] In one aspect, the volume of the container is from 100 ml to 1000 ml.

[0163] In one aspect, the volume of the container is 1 ml, 5ml, 10ml, 50 ml, 100 ml, 200 ml, 250 ml, 300 ml, 400ml, 500 ml, 600 ml, 700 ml, 800 ml, 900 ml, or 1000 ml.

[0164] In one aspect, the volume of the container is 250 ml.

[0165] In an aspect, the formulation is stored in a plastic container. In an aspect, the formulation is packaged in a flexible plastic bag. In one aspect, formulation is packaged in aplastic container produced by blow-fill-seal technology. In one aspect, the material of the container is PVC free. In one aspect, the formulation is not in contact with the PVC material of the container.

[0166] In one aspect, the plastic material may be a polyolefin, such as polyethylene (PE), polypropylene (PP), ethylene vinyl acetate (EVA), ethylene vinyl alcohol (EVOH), a polyolefin comprising SiOx (silicon oxide), a polyolefin / styrene-block copolymer and derivatives thereof with or without other additives, and combinations, in particular blends, composites or laminates, of at least two of said polymeric materials.

[0167] In an aspect, the container is a single layer or multilayer container.

[0168] In one aspect, the container may, optionally, be overwrapped with an overwrap. In one aspect, the overwrap may comprise a gas-barrier and / or a light barrier material.

[0169] In one aspect, the overwrap may comprise aluminum or SiOx (silicon oxide).

[0170] In one aspect, the overwrap is made of aluminum.

[0171] In an aspect, the overwrap completely covers the container.

[0172] In one aspect, the space between a container and an overwrap is filled with an inert gas or any other suitable gas. In one aspect, the space between a container and an overwrap is filled with nitrogen (N2), argon, or any combination thereof.

[0173] In one aspect, a vacuum is applied to the space between a container and an overwrap.

[0174] In one aspect, the space between a container and an overwrap comprises an oxygen scavenger.

[0175] In one aspect, the container is overwrapped with an overwrap and the space between the container and the overwrap comprises an oxygen scavenger.

[0176] In one aspect, the container and / or the overwrap has a water vapor transmission rate (WVTR) 3.0 g / m2x day, in particular < 3.0 g / m2x day. In one aspect, the container and / or the overwrap has a WVTR from 3 g / m2x day to 0 g / m2x day, from 2 g / m2x day to 0 g / m2x day, from 1 g / m2x day to 0 g / m2x day. In one aspect, the container and / or the overwrap has a water vapor transmission rate less than 1 g / m2x day.

[0177] The “water vapor transmission rate”, also abbreviated as “WVTR”, as used herein may be determined by ASTM Fl 249 or ISO 15106.

[0178] In one aspect, the container and / or the overwrap has an oxygen transmission rate (OTR) 5 cm3 / (m2xdxbar) or less. In one aspect, the container and / or the overwrap has an OTR of 3 cm3 / (m2xdxbar, 2 cm3 / (m2xdxbar, 1 cm3 / (m2xdxbar), 0.1 cm3 / (m2xdxbar) or less. In one aspect, the container and / or the overwrap has an OTR of less than 1 cm3 / (m2xdxbar). The OTR, as used according to the present invention may be determined by ASTM F1927 or ISO 15105.

[0179] In one aspect, there is provided a dosage form comprising: a container containing a ready -to-administer azithromycin composition according to the present disclosure, wherein the concentration of azithromycin is in a range from 0.1 mg / ml to 50 mg / ml.

[0180] In one aspect, there is provided a dosage form for intravenous administration comprising, consisting essentially of, or consisting of: a container containing a ready -to-administer azithromycin composition according to the present disclosure, wherein the concentration of azithromycin is in a range from 0.1 mg / ml to 5 mg / ml.

[0181] In one aspect, there is provided a dosage form for intravenous administration comprising:- a container containing from 50 ml to 500 ml of a ready -to-administer composition, the ready -to-administer composition comprising, consisting essentially of, or consisting of azithromycin or a pharmaceutically acceptable salt, hydrate, or solvate thereof at a concentration in a range from 0.1 mg / ml to 5 mg / ml, a pH adjusting agent, and water, the solution having a pH in a range from 5.0 to 7.0.

[0182] In one aspect, there is provided a dosage form for intravenous administration comprising, consisting essentially of, or consisting of:-a container containing a ready-to-administer composition, the ready-to-administer composition comprising, consisting essentially of, or consisting of azithromycin or a pharmaceutically acceptable salt, hydrate, or solvate thereof at a concentration in a range from 0.1 mg / ml to 5 mg / ml, a pH adjusting agent, and water, the solution having a pH in a range from 5.0 to 7.0,- wherein the composition is stable for 7 days at 40°C.

[0183] In one aspect, there is provided a method of producing a product comprising a ready-to-administer azithromycin formulation, wherein the method comprises:- providing a ready-to-administer azithromycin formulation at an azithromycin concentration in a range from 0.1 mg / ml to 50 mg / ml, and placing such formulation into the container.

[0184] In one aspect, there is provided a method of producing a product comprising a ready-to-administer azithromycin formulation, wherein the method comprises:- providing a ready-to-administer azithromycin formulation at an azithromycin concentration in a range from 1 mg / ml to 2 mg / ml, and placing such formulation into the container.

[0185] In one aspect, there is provided a dosage form for intravenous administration comprising, consisting essentially of, or consisting of: a container containing a ready-to-administer composition, the ready-to-administer composition comprising, consisting essentially of, or consisting of azithromycin or a pharmaceutically acceptable salt, hydrate, or solvate thereof at a concentration in a range from 0.1 mg / ml to 5 mg / ml, and an overwrap surrounding said container, wherein the space between the container and the overwrap comprise an oxygen scavenger.

[0186] In one aspect, there is provided a dosage form for intravenous administration comprising, consisting essentially of, or consisting of:- a container containing from 50 ml to 500 ml of a ready-to-administer composition, the ready-to-administer composition comprising, consisting essentially of, or consisting of azithromycin or a pharmaceutically acceptable salt, hydrate, or solvate thereof at a concentration in a range from 0.1 mg / ml to 5 mg / ml, a pH adjusting agent, and water for injection, the solution having a pH in a range from 5.0 to 7.0, and- an overwrap surrounding said container, wherein the space between the container and the overwrap comprise an oxygen scavenger.

[0187] In one aspect, there is provided a dosage form for intravenous administration comprising, consisting essentially of, or consisting of:-a container containing from 50 ml to 500 ml of a ready -to-administer composition, the ready-to-administer composition comprising, consisting essentially of, or consisting of azithromycin or a pharmaceutically acceptable salt, hydrate, or solvate thereof at a concentration in a range from 0.1 mg / ml to 5 mg / ml, a pH adjusting agent, and water for injection, the solution having a pH in a range from 5.0 to 7.0, and- an overwrap surrounding said container and wherein the space between the container and the overwrap comprises an oxygen scavenger,- wherein the composition is stable for 14 days at 25°C.

[0188] In one aspect, there is provided a method of producing a product comprising a ready-to-administer azithromycin formulation, wherein the method comprises:- providing a ready-to-administer azithromycin formulation wherein the azithromycin concentration is in a range from 0.1 mg / ml to 10 mg / ml and placing such formulation into the container, and-overwrapping the container with an overwrap in such a manner that an oxygen scavenger is placed in the space between the container and the overwrap before the overwrap completely covers the container.

[0189] In one aspect, there is provided a method of producing a product comprising a ready-to-administer azithromycin formulation, wherein the method comprises:- providing a ready-to-administer azithromycin formulation wherein the azithromycin is in concentration in a range from 1 mg / ml to 2 mg / ml and placing such formulation into the container, and- overwrapping the container with an overwrap in such a manner that an oxygen scavenger is placed in the space between the container and the overwrap before the overwrap completely covers the container.

[0190] The formulation disclosed herein may be sterilized by known means. In one aspect, the formulation disclosed herein may be sterilized by sterile filtration.

[0191] In one aspect, the present disclosure provides a method to increase the solubility of azithromycin in an aqueous formulation.

[0192] In an aspect, the formulations described herein may be administered orally, parenterally, for example via an intravenous route, or via an ophthalmic route of administration.

[0193] According to the present disclosure, herein is provided a method for treatment of patients in need thereof comprising administration of a predefined concentration of azithromycin directly from the container, without the need for reconstitution and / or dilution.

[0194] In one aspect, the present disclosure provides a method of treating humans by administering a suitable dose of azithromycin by an intravenous route.

[0195] In one aspect, present disclosure provides a method of treating humans by administering a ready-to-administer effective dose of azithromycin formulation to a human by an IV administration.

[0196] In one aspect, the disclosure provides a method of treating bacterial infections in humans caused by susceptible strains such as: Chlamydophila pneumonia, Chlamydia trachomatis, Haemophilus influenzae, Haemophilus ducreyi, Legionella pneumophila, Mycoplasma hominis, Mycoplasma pneumoniae, Moraxella catarrhalis, Neisseria gonorrhoeae, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, or Streptococcus mitis group with an effective dose of an azithromycin formulation in accordance with this disclosure.

[0197] In one aspect, the present disclosure provides a method of treating humans with an effective dose of azithromycin, the method comprising administering to the human a liquid pharmaceutical composition disclosed herein from the unit dosage form, wherein the unit dosage form comprises from 0.1 to 50 mg / ml of azithromycin or a pharmaceutically acceptable salt or solvate thereof.

[0198] In one aspect, the present disclosure provides a method of treating humans with an effective dose of azithromycin, the method comprising intravenously administering to the human a ready-to-administer pharmaceutical composition disclosed herein from the unit dosage form, wherein the unit dosage form comprises from 1 to 2 mg / ml of azithromycin or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0199] In one aspect, the present disclosure provides a method of treating humans with an effective dose of azithromycin, the method comprising: intravenously administering to the human a ready-to-administer azithromycin composition as disclosed herein directly from the unit dosage form, wherein the unit dosage form comprises 2 mg / ml of azithromycin or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0200] In one aspect, the present disclosure provides a method of treating a bacterial infection in a human, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.1 mg / mL to about 0.5 mg / mL of azithromycin or a pharmaceutically -acceptable salt, hydrate, or solvate thereof; b) storing the pharmaceutical composition at 2-8°C for at least 1 month; and c) intravenously administering the pharmaceutical composition to the human.

[0201] In one aspect, the present disclosure provides a method of treating a bacterial infection in a human, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in an unit dosage form for intravenous administration : i) from about 0.1 mg / mL to about 0.5 mg / mL of azithromycin or a pharmaceutically-acceptable salt, hydrate, or solvate thereof; b) storing the pharmaceutical composition at 2-8°C for at least 1 month; and c) intravenously administering the pharmaceutical composition to the human, wherein the pharmaceutical composition exhibits less than about 5 percent azithromycin degradation after storage at 2-8 °C for at least 1 month.

[0202] In one aspect, the present disclosure provides a method of treating a bacterial infection in a human, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from about 0.1 mg / mL to about 0.5 mg / mL of azithromycin or a pharmaceutically-acceptable salt, hydrate, or solvate thereof; b) storing the pharmaceutical composition at 2-8 °C for at least 1 month; and c) intravenously administering the pharmaceutical composition to the human, wherein the pharmaceutical composition is particle-free after storage at 2-8 °C, for at least 1 month.

[0203] In one aspect, the present disclosure provides a method of treating a bacterial infection in a human, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from 0.1 mg / mL to 0.5 mg / mL of azithromycin or a pharmaceutically-acceptable salt, hydrate or solvate thereof; b) storing the pharmaceutical composition at room temperature for at least 1 month; and c) intravenously administering the pharmaceutical composition to the human.

[0204] In one aspect, the present disclosure provides a method of treating a bacterial infection in a human, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising, in an unit dosage form for intravenous administration : i)from 0.1 mg / mL to 0.5 mg / mL of azithromycin or a pharmaceutically-acceptable salt, hydrate, or solvate thereof; b) storing the pharmaceutical composition at room temperature for 1 month; and c) intravenously administering the pharmaceutical composition to the human, wherein the pharmaceutical composition exhibits less than 5% of azithromycin assay drop after 1 month storage at room temperature.

[0205] In one aspect, the present disclosure provides a method of treating a bacterial infection in a human, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from 0.1 mg / mL to 0.5 mg / mL of azithromycin or a pharmaceutically-acceptable salt, hydrate, or solvate thereof; b) storing the pharmaceutical composition at room temperature for at least 14 days; and c) intravenously administering the pharmaceutical composition to the human.

[0206] In one aspect, the present disclosure provides a method of treating a bacterial infection in a human, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from 0.1 mg / mL to 0.5 mg / mL of azithromycin or a pharmaceutically-acceptable salt, hydrate, or solvate thereof; b) storing the pharmaceutical composition at room temperature for at least 14 days; and c) intravenously administering the pharmaceutical composition to the human, wherein the pharmaceutical composition exhibits less than 3 % of azithromycin assay drop after storage at room temperature for at least 14 days.

[0207] In one aspect, the present disclosure provides a method of treating a bacterial infection in a human, the method comprising: a) providing a pharmaceutical composition for intravenous administration comprising: i) from 0.1 mg / mL to 0.5 mg / mL of azithromycin or a pharmaceutically acceptable salt, hydrate, or solvate thereof; b) storing the pharmaceutical composition at 40°C for at least 7 days; and c) intravenously administering the pharmaceutical composition to the human, wherein the pharmaceutical composition exhibits less than 4% of azithromycin assay drop after 7 days storage at 40°C .

[0208] Other objects, features and advantages will become apparent from the following detailed description and examples. It should be understood, however, that the detailed description and the examples, while indicating specific embodiments, are given by way of illustration only, and are not intended to limit the breadth or scope of the concepts in any manner.EXAMPLES

[0209] The examples in the present disclosure are intended to be illustrative and not limiting as to the general disclosure.GENERAL TECHNIQUES

[0210] All formulations presented in the examples below are prepared by providing an aqueous solution of azithromycin. If necessary, the pH was adjusted to achieve the desired pH range.

[0211] Prepared compositions were transferred into containers, such as vials, bottles, or IV bags to achieve the desirable amount of active component per container.

[0212] After preparation, an initial time point amount of azithromycin and individual impurities were analyzed by liquid chromatography, and afterwards containers were loaded into stability chambers at different storage conditions: 60°C, 40°C, 30°C, and 25°C.

[0213] 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, 21 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months etc., and analyzed.

[0214] At the beginning of visual inspection at each stability time point, the bottom of the container was checked for precipitate formation, then visual particle inspection was checked by gently swirling and inverting containers, ensuring that no air bubbles were produced. Containers were inspected for approximately 15 sec with the naked eye.ANALYTICAL METHODS

[0215] Azithromycin assay and individual impurities content were determined in accordance with the USP Azithromycin Monograph.Calculation of the assay dropAssay(tp) (%) - Value of the assay of the main peak at time point (tp) different than initial, for example: 7 days, 1 month, 2 months etc. at different storage conditions.Assay(st) (%) - Value of the assay of the main peak at initial time pointAAssay - Calculated assay drop of the main compound: (%) AAssay(%) = Assay(st) (%) - Assay(tp)(%)Calculation of total impurities and total impurity increaseThe content of total impurities is calculated as sum of content of each found individual impurity.Total impurities(tp) (%) - Value of the total impurity content at time point (tp) different than initial, for example: 7 days, 1 month, 2 months etc. at different storage conditions. Total impurities(st) (%) - Value of the total impurity content at initial time point ATotal impurities - Calculated increase of total impurities (%)ATotal impurities(%) = Total impurities(tp) (%) - Total impurities(st)(%)EXAMPLE 1

[0216] If not otherwise stated, in the below examples, azithromycin was added in the form of azithromycin dihydrate. If not otherwise stated, the amount of azithromycin in the tables below is based on azithromycin dihydrate.

[0217] Ready-to-administer formulations of azithromycin were prepared by dissolving azithromycin in a concentration of 2 mg / ml and predetermined excipients in water under predefined conditions. The contents were stirred using a magnetic stirrer. If necessary, the pH was adjusted to achieve the desired pH range. The solution was mixed to ensure homogeneity, water was added to make up the predefined volume, and the solution was filtered through a 0.2 pm filter and transferred to a glass vial.

[0218] Formulations were then stored at a predetermined temperature and stability was determined at different time points as disclosed in the Tables below.

[0219] All formulations were clear after the preparation and at measured time-points, without any visible particles.Table 1 : Stability data of azithromycin formulations at a targeted pH of 6.5. All formulations were contained in 10 ml glass vials. Stability data is shown after 7 days storage at 40°C.Table 2: Stability data of azithromycin formulations at a targeted pH of 6.5. All formulations were contained in 10 ml glass vials. Stability data is shown after 7 days storage at 60°C.Table 3: Stability data of azithromycin formulations at a targeted pH of 6.0. All formulations were contained in 10 ml glass vials. Stability data is shown after 7 days storage at 40°C.Table 4: Stability data of azithromycin formulations at a targeted pH of 6.0. All formulations were contained in 10 ml glass vials. Stability data is shown after 7 days storage at 60°C.

[0220] 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.

[0221] 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 or material 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

Claims1. A liquid azithromycin formulation comprising at least one N-acetylated amino acid.

2. The liquid azithromycin formulation according to claim 1, wherein the amino acid that is N-acetylated comprises alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, valine, ornithine, or a combination comprising 2 or more of the foregoing.

3. The liquid azithromycin formulation according to claims 1 or 2, wherein the N- acetylated amino acid is N-acetyl-alanine, N-acetyl-histidine, N-acetyl-valine, or N-acetyl- glycine.

4. The liquid azithromycin formulation according to any of claims from 1 to 3, wherein N-acetylated amino acid is N-acetyl-D-alanine, N-acetyl-L-histidine, N-acetyl-L-valine, or N-acetyl-glycine.

5. The liquid azithromycin formulation according to any of claims from 1 to 4, wherein the N-acetylated amino acid is N-acetyl-D-alanine.

6. The liquid azithromycin formulation according to any of claims from 1 to 4, wherein the N-acetylated amino acid is N-acetyl-L-histidine.

7. The liquid azithromycin formulation according to any of claims from 1 to 4, wherein the N-acetylated amino acid is N-acetyl-L-valine.

8. The liquid azithromycin formulation according to any of claims from 1 to 4, wherein the N-acetylated amino acid is N-acetyl-glycine.

9. The liquid azithromycin formulation according to any of claims from 1 to 4, wherein the pH of the formulation is from 5.0 to 7.0.

10. The liquid azithromycin formulation according to any of claims from 1 to 5, wherein the formulation is an aqueous formulation.

11. The liquid azithromycin formulation according to any of claims from 1 to 6, wherein the formulation further comprises at least one amino acid.

12. The liquid azithromycin formulation according to claim 11, where amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamic acid,glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, valine, ornithine, a pharmaceutically acceptable salt thereof, or a combination comprising two or more of the foregoing.