Oral Solid Dose Formulations

Abstract

Novel pharmaceutical compositions comprising gepotidacin, such as gepotidacin mesylate dihydrate, gepotidacin mesylate anhydrate, or gepotidacin anhydrate, are disclosed. The present invention also provides methods of making pharmaceutical compositions comprising gepotidacin, and methods of using such pharmaceutical compositions to treat bacterial infections.

Description

[Technical field]

[0001] STATEMENT REGARDING FEDERALLY FUNDED RESEARCH This invention was made with United States Government support under Contract No. HDTRA1-07-9-0002 awarded by the Defense Threat Reduction Agency. The United States Government may have certain rights in this invention. [Background technology]

[0002] (2R)-2-({4-[(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (hereafter referred to as "gepotidacin") selectively inhibits bacterial DNA gyrase and topoisomerase IV through a unique mechanism that is not currently exploited in any approved human therapeutic agent.

[0003] International Patent Publication WO2008 / 128942 describes a series of compounds that can be used as antibacterial agents, including gepotidacin. The mono-HCl salt of gepotidacin was prepared in Example 39 of WO2008 / 128942, which is incorporated herein by reference in its entirety. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO2008 / 128942 Summary of the Invention

[0005] The present application relates to novel pharmaceutical compositions comprising crystalline forms of gepotidacin. Gepotidacin has the structure of formula (I).

[0006] [ka]

[0007] The present invention provides novel pharmaceutical compositions comprising gepotidacin, e.g., crystalline forms of gepotidacin, e.g., gepotidacin mesylate dihydrate, gepotidacin mesylate anhydrate, and gepotidacin anhydrate. The present invention also provides methods of making pharmaceutical compositions comprising gepotidacin, e.g., crystalline forms of gepotidacin, and methods of treating bacterial infections using pharmaceutical compositions comprising gepotidacin. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 shows the X-ray powder diffraction pattern of gepotidacin mesylate dihydrate (Form 1). [Diagram 2] FIG. 1 shows the Raman spectrum of gepotidacin mesylate dihydrate (Form 1). [Diagram 3] FIG. 1 shows a differential scanning calorimetry trace of gepotidacin mesylate dihydrate (Form 1). [Figure 4] FIG. 1 shows a thermogravimetric analysis trace of gepotidacin mesylate dihydrate (Form 1). [Diagram 5] FIG. 1 shows the X-ray powder diffraction pattern of gepotidacin anhydrate. [Figure 6] FIG. 1 shows the Raman spectrum of gepotidacin anhydrate. [Figure 7] FIG. 1 shows differential scanning calorimetry trace of gepotidacin anhydrate. [Figure 8] FIG. 1 shows a thermogravimetric analysis trace of gepotidacin anhydrate. [Figure 9] FIG. 1 shows the X-ray powder diffraction pattern of gepotidacin mesylate dihydrate (Form 1). [Figure 10] FIG. 1 shows the X-ray powder diffraction pattern of gepotidacin anhydrate. [Figure 11] FIG. 1 illustrates a method for preparing a tablet containing gepotidacin mesylate dihydrate. [Figure 12] FIG. 1 shows the tabletability profiles of Formulation E (circles) and Formulation F (squares). [Figure 13]FIG. 1 shows a comparison of disintegration time as a function of tensile strength for tablets of Formulation E (circles) and Formulation F (squares). [Figure 14] FIG. 1 shows the X-ray powder diffraction pattern of gepotidacin mesylate anhydrate. [Figure 15] FIG. 1 shows the X-ray powder diffraction pattern of gepotidacin mesylate anhydrate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present application is directed to pharmaceutical compositions comprising gepotidacin. In some embodiments, the gepotidacin in the composition is crystalline gepotidacin, such as gepotidacin mesylate dihydrate (Form 1), gepotidacin mesylate anhydrate, or gepotidacin anhydrate (free base).

[0010] International Patent Application Publication WO2021 / 219637 describes certain crystalline forms of gepotidacin, including gepotidacin mesylate dihydrate, gepotidacin mesylate anhydrate, gepotidacin mesylate monohydrate, and gepotidacin anhydrate (free base).

[0011] In some embodiments, a pharmaceutical composition of the invention comprises crystalline gepotidacin.

[0012] Thus, in one embodiment, the present invention provides a pharmaceutical composition comprising a crystalline form of gepotidacin and one or more pharma- ceutically acceptable excipients, wherein the crystalline form is gepotidacin mesylate dihydrate, gepotidacin mesylate anhydrate, or gepotidacin anhydrate, and the pharmaceutical composition comprises about 45% to 75% by weight of gepotidacin (measured as the free base).

[0013] In one embodiment, the present invention provides a pharmaceutical composition comprising a crystalline form of gepotidacin and one or more pharma- ceutically acceptable excipients, wherein the crystalline form is gepotidacin mesylate dihydrate or gepotidacin anhydrate, and the pharmaceutical composition comprises about 45% to 75% by weight of gepotidacin (measured as the free base).

[0014] 1. Gepotidacin Mesylate Dihydrate (Form 1) In some embodiments, the crystalline form of gepotidacin in the pharmaceutical composition is gepotidacin mesylate dihydrate (i.e., Form 1). Gepotidacin mesylate dihydrate may be represented by the following structure:

[0015] [ka]

[0016] In one embodiment, gepotidacin mesylate dihydrate is CuK α The compound is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 diffraction angles selected from the group consisting of about 9.0, 11.5, 13.4, 14.3, 14.9, 15.5, 17.6, 18.6, and 20.7°2θ when measured using a Cu K line. As used herein, when the term "about" precedes a list of numbers, the term applies to each of the listed numbers. In one embodiment, gepotidacin mesylate dihydrate is α In one embodiment, the gepotidacin mesylate dihydrate is characterized by an XRPD pattern comprising at least three diffraction angles selected from the group consisting of about 13.4, 15.5, 17.6, and 18.6 degrees 2θ, as measured using a Cu K α In one embodiment, gepotidacin mesylate dihydrate is characterized by an XRPD pattern comprising four diffraction angles of about 13.4, 15.5, 17.6, and 18.6 degrees 2θ, as measured using a Cu K α It is characterized by an XRPD pattern including three diffraction angles, as measured using the ray at about 13.4, 17.6, and 18.6 degrees 2θ.

[0017] In one embodiment, gepotidacin mesylate dihydrate is characterized by an XRPD pattern substantially in accordance with FIG. 1. In one embodiment, gepotidacin mesylate dihydrate is characterized by an XRPD pattern substantially in accordance with FIG.

[0018] In one embodiment, gepotidacin mesylate dihydrate has a molecular weight of about 1154, 1269, 1306, 1518, 1584, 1637 and 1676 cm -1 at least three, at least four, at least five, at least six, or at least seven peaks at locations selected from the group consisting of peaks at and at. In one embodiment, gepotidacin mesylate dihydrate is characterized by a Raman spectrum substantially in accordance with FIG.

[0019] In a further embodiment, gepotidacin mesylate dihydrate is characterized by a differential scanning calorimetry trace substantially in accordance with FIG. 3 and / or a thermogravimetric analysis trace substantially in accordance with FIG.

[0020] In another embodiment, gepotidacin mesylate dihydrate has the following unit cell parameters: a=6.9255(5)Å, b=15.4500(12)Å, c=25.7918(19)Å, α=β=γ=90°, V=2759.7(4)Å 3 , Z'=1, space group P212121, Molecules / unit cell 4, Density (calculated value) 1.398g / cm 3 , where Z' is the number of molecules per asymmetric unit. The samples were characterized by single crystal XRD, which yielded:

[0021] 2. Gepotidacin anhydrous In some embodiments, the crystalline form of gepotidacin in the pharmaceutical composition is gepotidacin anhydrate (i.e., the free base). In one embodiment, gepotidacin anhydrate is Cu K αIn one embodiment, the gepotidacin anhydrate is characterized by an XRPD pattern comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 diffraction angles selected from the group consisting of about 8.8, 10.8, 11.7, 12.8, 13.2, 14.4, 16.3, 19.9, 20.8, and 25.0, as measured using a Cu K line. α In one embodiment, the gepotidacin anhydrate is characterized by an XRPD pattern comprising at least three diffraction angles selected from the group consisting of about 8.8, 13.2, 14.4, and 20.8, as measured using a Cu K α In one embodiment, gepotidacin anhydrate is characterized by an XRPD pattern including four diffraction angles of about 8.8, 13.2, 14.4, and 20.8 as measured using a Cu K α It is characterized by an XRPD pattern including three diffraction angles of about 8.8, 13.2, and 14.4 as measured using the XRPD line.

[0022] In one embodiment, gepotidacin anhydrate is characterized by an XRPD pattern substantially in accordance with FIG. 5. In one embodiment, gepotidacin anhydrate is characterized by an XRPD pattern substantially in accordance with FIG.

[0023] In one embodiment, gepotidacin anhydrate has isomers at about 1099, 1143, 1289, 1344, 1476, 1516, 1612, and 1687 cm -1 at least three, at least four, at least five, at least six, at least seven, or at least eight peaks at positions selected from the group consisting of: ...

[0024] In a further embodiment, gepotidacin anhydrate is characterized by a differential scanning calorimetry trace substantially in accordance with FIG. 7 and / or a thermogravimetric analysis trace substantially in accordance with FIG.

[0025] In another embodiment, gepotidacin anhydrate has the following unit cell parameters: a=8.44022(16) Å, b=6.42442(12) Å, c=20.2774(5) Å, α=γ=90°, β=96.778(2)°, V=1091.83(4) Å 3 , Z'=1, space group P21, Drug molecule / unit cell 2, Density (calculated value) 1.364g / cm 3 , where Z' is the number of drug molecules per asymmetric unit. The samples were characterized by single crystal XRD, which yielded:

[0026] Gepotidacin Mesylate Anhydrous In some embodiments, the crystalline form of gepotidacin is gepotidacin mesylate anhydrate. In one embodiment, gepotidacin mesylate anhydrate is Cu K α In one embodiment, the gepotidacin mesylate anhydrate is characterized by an XRPD pattern comprising at least three, at least four, at least five, at least six, or at least seven diffraction angles selected from the group consisting of about 7.1, 9.7, 12.1, 14.2, 15.2, 17.3, and 20.2, as measured using a Cu K line. α In one embodiment, the gepotidacin mesylate anhydrate is characterized by an XRPD pattern comprising at least three diffraction angles selected from the group consisting of about 7.1, 9.7, 15.2, and 17.3, as measured using a Cu K α In one embodiment, the gepotidacin mesylate anhydrate is characterized by an XRPD pattern comprising four diffraction angles of about 7.1, 9.7, 15.2, and 17.3 as measured using a Cu K α It is characterized by an XRPD pattern including three diffraction angles of about 9.7, 15.2, and 17.3 as measured using a line.

[0027] In one embodiment, gepotidacin mesylate anhydrate is characterized by an XRPD pattern substantially in accordance with Figure 14. In one embodiment, gepotidacin mesylate anhydrate is characterized by an XRPD pattern substantially in accordance with Figure 15.

[0028] In still further embodiments, as will be appreciated by one of skill in the art, a particular gepotidacin polymorph is characterized by any combination of two or more sets of analytical data characterizing the foregoing embodiments. For example, in one embodiment, gepotidacin mesylate dihydrate is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure 1 or Figure 9, a Raman spectrum substantially in accordance with Figure 2, a differential scanning calorimetry trace substantially in accordance with Figure 3, and a thermogravimetric analysis trace substantially in accordance with Figure 4.

[0029] In another embodiment, gepotidacin mesylate dihydrate is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure 1 and a Raman spectrum substantially in accordance with Figure 2. In another embodiment, gepotidacin mesylate dihydrate is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure 1 and a differential scanning calorimetry trace substantially in accordance with Figure 3. In another embodiment, gepotidacin mesylate dihydrate is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure 1 and a thermogravimetric analysis trace substantially in accordance with Figure 4.

[0030] An XRPD pattern should be understood to include diffraction angles (expressed in degrees 2θ) "about" values ​​specified herein when the XRPD pattern includes diffraction angles within ±0.2 degrees 2θ of the specified value. Furthermore, it is well known and understood by those skilled in the art that the instrumentation utilized, humidity, temperature, powder crystal orientation, and other parameters involved in obtaining an X-ray powder diffraction (XRPD) pattern can cause some variation in the appearance, intensity, and position of lines in a diffraction pattern. The term "XRPD" is used interchangeably herein with the term "PXRD."

[0031] An X-ray powder diffraction pattern that is "substantially consistent" with the X-ray powder diffraction patterns of Figures 1, 5, 9, or 10 provided herein is an XRPD pattern that would be considered by one of skill in the art to represent a compound having the same crystalline form as the compound that gave rise to the XRPD pattern of Figure 1, 5, 9, or 10. That is, the XRPD pattern may be identical to the XRPD pattern of Figure 1, 5, 9, or 10, or may be somewhat different therefrom. Such an XRPD pattern may not necessarily exhibit each of the lines of any one of the diffraction patterns presented herein, and / or may exhibit slight variations in the appearance, intensity, or shifts in position of said lines resulting from differences in the conditions involved in obtaining the data. One of skill in the art can determine whether a sample of a crystalline compound has the same or a different morphology as disclosed herein by comparison of their XRPD patterns. For example, one of ordinary skill in the art can overlay the XRPD pattern of a sample containing gepotidacin with Figure 1 and, using expertise and knowledge in the art, readily determine whether the XRPD pattern of the sample substantially matches the XRPD pattern of gepotidacin mesylate dihydrate (Form 1). If the XRPD pattern substantially matches Figure 1, the sample form can be readily and accurately identified as having the same morphology as Form 1.

[0032] The present application provides a high drug load oral solid formulation comprising gepotidacin. In some embodiments, the present application provides a high drug load oral solid formulation comprising a crystalline form of gepotidacin. The proposed clinical oral dose of gepotidacin is 1500 mg twice daily for the treatment of urinary tract infections (UTI) and 3000 mg twice daily for the treatment of infections caused by Neisseria gonorrhoeae (e.g., uncomplicated gonorrhea or urogenital gonorrhea). Such high daily doses require high drug load oral solid formulations. High drug load means less amount of excipients at reasonable tablet weight, which results in a drug product that is more sensitive to drug substance variability over its life cycle, including variability in disintegration / dissolution behavior, compression properties, and flow behavior, with less excipients to compensate for variability in drug substance properties.

[0033] In some embodiments, the high-load formulation of the present application is a tablet. In some embodiments, the high-load formulation of the present application is a capsule. In some embodiments, gepotidacin in the high-load tablet formulation is present in an amount of about 45%, 50%, 55%, 60%, 65%, 70%, or 75% by weight (measured as free base), or a range between any two preceding values. In some embodiments, gepotidacin is present in the range of about 45%-75% by weight, about 45%-70% by weight, about 45%-65% by weight, about 45%-60% by weight, about 50%-75% by weight, about 50%-70% by weight, about 50%-65% by weight, about 50%-60% by weight, or about 50%-55% by weight. As used herein, when the term "about" precedes a list of numbers, the term applies to each of the listed numbers.

[0034] Unless otherwise indicated, weight percentages are calculated using the weight of the active ingredient (i.e., gepotidacin free base, gepotidacin mesylate anhydrate, or gepotidacin mesylate dihydrate) relative to the weight of the composition (i.e., tablet). For example, for a 1400 mg tablet containing about 971 mg of gepotidacin mesylate dihydrate, the weight percentage of gepotidacin mesylate dihydrate is about 69.4% and the weight percentage of gepotidacin (measured as the free base) is about 53.6%.

[0035] In one aspect, the high-load formulation comprises gepotidacin mesylate dihydrate, wherein the gepotidacin mesylate dihydrate is present in an amount of about 60%, 65%, 70%, 75%, 80%, 85%, or 90% by weight, or a range between any two preceding values. In some embodiments, the gepotidacin mesylate dihydrate is present in a range of about 60%-90%, about 60%-80%, about 65%-85%, about 65%-75% by weight. In some embodiments, the gepotidacin mesylate dihydrate is present in an amount of about 70% by weight.

[0036] In another embodiment, the high-load formulation comprises gepotidacin anhydrate, wherein the gepotidacin anhydrate is present in an amount of about 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% by weight, or a range between any two preceding values. In some embodiments, the gepotidacin anhydrate is present in a range of about 50%-85% by weight, about 50%-80% by weight, about 50%-75% by weight, about 50%-70% by weight, about 50%-65% by weight, about 55%-70% by weight, about 55%-65% by weight, or about 60%-65% by weight. In some embodiments, the gepotidacin anhydrate is present in an amount of about 63% by weight.

[0037] In one aspect, the high-load formulation comprises gepotidacin mesylate anhydrate, wherein the gepotidacin mesylate anhydrate is in an amount of about 60%, 65%, 70%, 75%, 80%, 85%, or 90% by weight, or a range between any two preceding values. In some embodiments, the gepotidacin mesylate anhydrate is present in a range of about 60%-90%, about 60%-80%, about 65%-85%, or about 65%-75% by weight. In some embodiments, the gepotidacin mesylate anhydrate is present in an amount of about 70% by weight.

[0038] In one embodiment, the highly loaded formulation comprises gepotidacin mesylate dihydrate, a diluent, a disintegrant, and a glidant. In another embodiment, the highly loaded formulation comprises gepotidacin mesylate dihydrate, a diluent, a disintegrant, a glidant, and a lubricant.

[0039] In one embodiment, the high load formulation comprises gepotidacin anhydrate, a diluent, and a disintegrant. In another embodiment, the high load formulation comprises gepotidacin anhydrate, a diluent, a disintegrant, and a lubricant.

[0040] In one embodiment, the high load formulation comprises gepotidacin mesylate anhydrous, a diluent, and a disintegrant. In another embodiment, the high load formulation comprises gepotidacin mesylate anhydrous, a diluent, a disintegrant, and a lubricant.

[0041] Suitable diluents (i.e., fillers) include lactose, sucrose, dextrose, mannitol, sorbitol, starches (e.g., corn starch, potato starch, and pregelatinized starch), cellulose and its derivatives (e.g., microcrystalline cellulose), calcium sulfate, and calcium hydrogen phosphate. In one embodiment, the diluent is selected from the group consisting of microcrystalline cellulose, lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose, calcium sulfate, calcium hydrogen phosphate, and combinations thereof. In one embodiment, the diluent is microcrystalline cellulose. In one embodiment, the diluent is present in an amount of about 20% to 25% by weight of the composition.

[0042] Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, croscarmellose sodium, alginic acid, sodium alginate, and sodium carboxymethylcellulose. In one embodiment, the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose, croscarmellose sodium, alginic acid, sodium alginate, sodium carboxymethylcellulose, and combinations thereof. In one embodiment, the disintegrant is croscarmellose sodium. In one embodiment, the disintegrant is present in an amount of about 4% to 10% by weight of the composition.

[0043] Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, and talc. In one embodiment, the lubricant is selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and combinations thereof. In one embodiment, the lubricant is magnesium stearate. In one embodiment, the lubricant is present in an amount of about 0.5% to 5%, or 0.5% to 2% by weight of the composition.

[0044] Glidants include colloidal silicon dioxide (i.e., silica). Certain lubricants can be used as glidants, such as talc, magnesium stearate, stearic acid, and sodium stearyl fumarate. In one embodiment, the glidant is selected from the group consisting of colloidal silicon dioxide, magnesium stearate, and combinations thereof. In one embodiment, the glidant is colloidal silicon dioxide. In one embodiment, the glidant is present in an amount of about 0.5% to 2% by weight of the composition.

[0045] 1) Preparation of gepotidacin mesilate dihydrate In some embodiments, the pharmaceutical compositions disclosed herein include about 65% to 75% by weight of gepotidacin mesylate dihydrate; about 20% to 25% by weight of a diluent; About 4% to 10% by weight of a disintegrant, and About 0.5% to 2% by weight of a glidant Includes.

[0046] In one embodiment, the pharmaceutical composition disclosed herein comprises: about 65% to 75% by weight of gepotidacin mesylate dihydrate; about 20% to 25% by weight of microcrystalline cellulose; About 4% to 10% by weight of croscarmellose sodium, and Approximately 0.5% to 2% by weight of colloidal silicon dioxide Includes.

[0047] In some embodiments, the pharmaceutical composition further comprises about 0.5% to 5% by weight of a lubricant, or about 0.5% to 2% by weight of a lubricant, such as magnesium stearate.

[0048] In some embodiments, the pharmaceutical composition comprises: about 70% by weight of gepotidacin mesylate dihydrate, about 22% by weight of diluent; about 6% by weight of a disintegrant, and About 1% by weight of a glidant Includes.

[0049] In some embodiments, the pharmaceutical composition comprises: about 70% by weight of gepotidacin mesylate dihydrate, about 22% by weight of microcrystalline cellulose; About 6% by weight of croscarmellose sodium, and Approximately 1% by weight colloidal silicon dioxide Includes.

[0050] In some embodiments, the pharmaceutical composition comprises: about 70% by weight of gepotidacin mesylate dihydrate, about 22% by weight of diluent; about 6% by weight of a disintegrant, and About 0.5% by weight of a glidant Includes.

[0051] In some embodiments, the pharmaceutical composition comprises: about 70% by weight of gepotidacin mesylate dihydrate, about 22% by weight of microcrystalline cellulose; About 6% by weight of croscarmellose sodium, and Approximately 0.5% by weight colloidal silicon dioxide Includes.

[0052] In some embodiments, the pharmaceutical composition comprises: about 70% by weight of gepotidacin mesylate dihydrate, about 22% by weight of diluent; about 6% by weight of a disintegrant; about 1% by weight of a glidant, and Approximately 1.4% by weight of lubricant Includes.

[0053] In some embodiments, the pharmaceutical composition comprises: about 70% by weight of gepotidacin mesylate dihydrate, about 22% by weight of microcrystalline cellulose; about 6% by weight of croscarmellose sodium, About 1% by weight of colloidal silicon dioxide, and Approximately 1.4% by weight of magnesium stearate Includes.

[0054] In some embodiments, the pharmaceutical composition comprises: about 70% by weight of gepotidacin mesylate dihydrate, about 22% by weight of diluent; about 6% by weight of a disintegrant; about 0.5% by weight of a glidant, and Approximately 1.9% by weight of lubricant Includes.

[0055] In some embodiments, the pharmaceutical composition comprises: about 70% by weight of gepotidacin mesylate dihydrate, about 22% by weight of microcrystalline cellulose; about 6% by weight of croscarmellose sodium, About 0.5% by weight of colloidal silicon dioxide, and Approximately 1.9% by weight of magnesium stearate Includes.

[0056] In some embodiments, the pharmaceutical composition comprises: Gepotidacin mesylate dihydrate approximately 971 mg, Microcrystalline cellulose, approximately 311 mg Croscarmellose sodium approximately 84 mg, Approximately 14 mg of colloidal silicon dioxide, and Magnesium stearate approx. 19.5mg Includes.

[0057] In some embodiments, the pharmaceutical composition comprises: Gepotidacin mesylate dihydrate approximately 971 mg, Microcrystalline cellulose, approximately 311 mg Croscarmellose sodium approximately 84 mg, Approximately 7 mg of colloidal silicon dioxide, and Magnesium stearate approx. 26.5mg Includes.

[0058] In another aspect, the pharmaceutical composition comprises about 60% to 80% by weight of gepotidacin mesylate dihydrate, an intragranular excipient, and an extragranular excipient. In some embodiments, the intragranular excipient is about 4% to 8% by weight of a diluent; About 1% to 5% by weight of a disintegrant, and About 0.1% to 1% by weight of a glidant Includes.

[0059] In some embodiments, the intragranular excipient is: about 4% to 8% by weight of microcrystalline cellulose; About 1% to 5% by weight of croscarmellose sodium, and Approximately 0.1% to 1% by weight of colloidal silicon dioxide Includes.

[0060] In some embodiments, the extragranular excipient is: about 10% to 20% by weight of a diluent; About 1% to 5% by weight of a disintegrant, and About 0.1% to 1% by weight of a glidant Includes.

[0061] In some embodiments, the extragranular excipient is: about 10% to 20% by weight of microcrystalline cellulose; About 1% to 5% by weight of croscarmellose sodium, and Approximately 0.1% to 1% by weight of colloidal silicon dioxide Includes.

[0062] In some embodiments, the extragranular excipient is: about 10% to 20% by weight of a diluent, and About 1% to 5% by weight of a disintegrant Includes.

[0063] In some embodiments, the extragranular excipient is: about 10% to 20% by weight of microcrystalline cellulose, and Approximately 1% to 5% by weight of croscarmellose sodium Includes.

[0064] In some embodiments, the intragranular excipient further comprises about 0.1% to 3% by weight of a lubricant, and the extragranular excipient further comprises about 0.1% to 3% by weight of a lubricant. Each excipient of the intragranular excipient and the extragranular excipient may be independently selected. For example, the diluent of the intragranular excipient may be the same as or different from the diluent of the extragranular excipient.

[0065] In some embodiments, the pharmaceutical composition comprises: Approximately 65% ​​to 75% by weight of gepotidacin mesylate dihydrate Including, Intragranular excipients are: about 5% to 7% by weight of a diluent; about 2% to 4% by weight of a disintegrant; about 0.4% to 0.6% by weight of a glidant, and Approximately 0.2% to 0.6% by weight of a lubricant Including, Extragranular excipients are: about 14% to 18% by weight of a diluent; about 2% to 4% by weight of a disintegrant; about 0.4% to 0.6% by weight of a glidant, and Approximately 0.5% to 1.5% by weight of a lubricant Includes.

[0066] In some embodiments, the pharmaceutical composition comprises: Approximately 65% ​​to 75% by weight of gepotidacin mesylate dihydrate Including, Intragranular excipients are: about 5% to 7% by weight of microcrystalline cellulose; about 2% to 4% by weight of croscarmellose sodium, About 0.4% to 0.6% by weight of colloidal silicon dioxide, and Approximately 0.2% to 0.6% by weight of magnesium stearate Including, Extragranular excipients are: about 14% to 18% by weight of microcrystalline cellulose; about 2% to 4% by weight of croscarmellose sodium, About 0.4% to 0.6% by weight of colloidal silicon dioxide, and Approximately 0.5% to 1.5% by weight of magnesium stearate Includes.

[0067] In some embodiments, the pharmaceutical composition comprises: Approximately 70% by weight of gepotidacin mesylate dihydrate Including, Intragranular excipients are: about 6% by weight of a diluent; about 3% by weight of a disintegrant; about 0.5% by weight of a glidant, and Approximately 0.4% by weight of lubricant Including, Extragranular excipients are: about 16% by weight of a diluent; about 3% by weight of a disintegrant; about 0.5% by weight of a glidant, and Approximately 1% by weight of lubricant Includes.

[0068] In some embodiments, the pharmaceutical composition comprises: Approximately 70% by weight of gepotidacin mesylate dihydrate Including, Intragranular excipients are: about 6% by weight of a diluent; about 3% by weight of a disintegrant; about 0.5% by weight of a glidant, and Approximately 0.4% by weight of lubricant Including, Extragranular excipients are: about 16% by weight of a diluent; about 3% by weight of a disintegrant, and Approximately 1.5% by weight of lubricant Includes.

[0069] In some embodiments, the pharmaceutical composition comprises: Approximately 70% by weight of gepotidacin mesylate dihydrate Including, Intragranular excipients are: about 6% by weight of microcrystalline cellulose; about 3% by weight of croscarmellose sodium, About 0.5% by weight of colloidal silicon dioxide, and Approximately 0.4% by weight of magnesium stearate Including, Extragranular excipients are: about 16% by weight of microcrystalline cellulose; about 3% by weight of croscarmellose sodium, About 0.5% by weight of colloidal silicon dioxide, and Approximately 1% by weight of magnesium stearate Includes.

[0070] In some embodiments, the pharmaceutical composition comprises: Approximately 70% by weight of gepotidacin mesylate dihydrate Including, Intragranular excipients are: about 6% by weight of microcrystalline cellulose; about 3% by weight of croscarmellose sodium, About 0.5% by weight of colloidal silicon dioxide, and Approximately 0.4% by weight of magnesium stearate Including, Extragranular excipients are: about 16% by weight of microcrystalline cellulose; About 3% by weight of croscarmellose sodium, and Approximately 1.5% by weight of magnesium stearate Includes.

[0071] In some embodiments, the pharmaceutical composition comprises: Gepotidacin mesilate dihydrate approx. 971mg Including, Intragranular excipients are: Microcrystalline cellulose approximately 84.5 mg, Croscarmellose sodium approximately 42 mg, Approximately 7 mg of colloidal silicon dioxide, and Magnesium stearate approx. 5.5mg Including, Extragranular excipients are: Microcrystalline cellulose approx. 227 mg, Croscarmellose sodium approximately 42 mg, Approximately 7 mg of colloidal silicon dioxide, and Magnesium stearate approx. 14mg Includes.

[0072] In some embodiments, the pharmaceutical composition comprises: Gepotidacin mesilate dihydrate approx. 971mg Including, Intragranular excipients are: Microcrystalline cellulose approximately 84.5 mg, Croscarmellose sodium approximately 42 mg, Approximately 7 mg of colloidal silicon dioxide, and Magnesium stearate approx. 5.5mg Including, Extragranular excipients are: Microcrystalline cellulose approx. 227 mg, Approximately 42 mg of croscarmellose sodium, and Magnesium stearate approx. 21mg Includes.

[0073] 2) Preparation of gepotidacin anhydride In some embodiments, the pharmaceutical compositions disclosed herein include about 60% to 65% by weight of gepotidacin anhydrate; about 25% to 35% by weight of a diluent, and About 4% to 8% by weight of a disintegrant Includes.

[0074] In some embodiments, the pharmaceutical composition further comprises about 0.5% to 5% by weight of a lubricant.

[0075] In some embodiments, the pharmaceutical composition comprises: about 63% by weight of gepotidacin anhydrate, about 31% by weight of a diluent, and Approximately 5% by weight of disintegrant Includes.

[0076] In some embodiments, the pharmaceutical composition comprises: about 63% by weight of gepotidacin anhydrate, about 31% by weight of diluent; about 5% by weight of a disintegrant, and Approximately 1% by weight of lubricant Includes.

[0077] In some embodiments, the pharmaceutical composition comprises: Gepotidacin anhydrous approximately 750mg, Microcrystalline cellulose approx. 375 mg, Approximately 64 mg of croscarmellose sodium, and Magnesium stearate approx. 11mg Includes.

[0078] In some embodiments, the pharmaceutical composition comprises about 55% to 70% by weight of gepotidacin anhydrate, an intragranular excipient, and an extragranular excipient. about 10% to 15% by weight of a diluent, and About 1% to 5% by weight of a disintegrant Includes.

[0079] In some embodiments, the extragranular excipient is: about 15% to 20% by weight of a diluent, and About 1% to 5% by weight of a disintegrant Includes.

[0080] In some embodiments, the intragranular excipients further comprise between about 0.1% and 3% by weight of a lubricant, and the extragranular excipients further comprise between about 0.1% and 3% by weight of a lubricant.

[0081] In some embodiments, the pharmaceutical composition comprises: About 60% to 65% by weight of gepotidacin anhydrate Including, Intragranular excipients are: about 11% to 15% by weight of a diluent; About 1% to 4% by weight of a disintegrant, and Approximately 0.2% to 0.6% by weight of a lubricant Including, Extragranular excipients are: about 16% to 20% by weight of a diluent; About 2% to 4% by weight of a disintegrant, and Approximately 0.3% to 0.7% by weight of a lubricant Includes.

[0082] In some embodiments, the pharmaceutical composition comprises: Approximately 63% by weight of gepotidacin anhydrate Including, Intragranular excipients are: about 13% by weight of a diluent; about 2.3% by weight of a disintegrant, and Approximately 0.4% by weight of lubricant Including, Extragranular excipients are: about 18% by weight of a diluent; about 3% by weight of a disintegrant, and Approximately 0.5% by weight of lubricant Includes.

[0083] In some embodiments, the pharmaceutical composition comprises: Gepotidacin anhydrous approx. 750mg Including, Intragranular excipients are: Microcrystalline cellulose approx. 155 mg, Approximately 28 mg of croscarmellose sodium, and Magnesium stearate approx. 4.7mg Including, Extragranular excipients are: Microcrystalline cellulose approx. 221 mg, Approximately 36 mg of croscarmellose sodium, and Magnesium stearate approx. 6mg Includes.

[0084] In some embodiments, the pharmaceutical compositions disclosed herein are tablets, hi some embodiments, the tablets are film coated.

[0085] 3) Preparation of gepotidacin mesylate anhydrous In some embodiments, the pharmaceutical compositions disclosed herein include about 65% to 75% by weight of gepotidacin mesylate anhydrous; about 20% to 25% by weight of a diluent; About 4% to 10% by weight of a disintegrant, and About 0.5% to 2% by weight of a glidant Includes.

[0086] In one embodiment, the pharmaceutical composition disclosed herein comprises: about 65% to 75% by weight of gepotidacin mesylate anhydrous; about 20% to 25% by weight of microcrystalline cellulose; About 4% to 10% by weight of croscarmellose sodium, and Approximately 0.5% to 2% by weight of colloidal silicon dioxide Includes.

[0087] 3. Methods of Use and Treatment The present application provides a method for treating a bacterial infection in a human in need thereof, comprising administering to the human a pharmaceutical composition comprising an effective amount of gepotidacin. Bacterial infections can be caused by a wide range of organisms, including both gram-negative and gram-positive organisms, and infections include, but are not limited to, upper and / or lower respiratory tract infections, skin and soft tissue infections, urinary tract infections, and gonorrhea. In some embodiments, the infection is a urinary tract infection. In some embodiments, the infection is gonorrhea. Methods for treating bacterial infections by using gepotidacin are disclosed in WO2008 / 128942, WO2016 / 027249, and WO2020 / 201833, all of which are incorporated herein by reference in their entirety.

[0088] In some embodiments, the infection is a urinary tract infection caused by Escherichia coli (E. coli), Staphylococcus saprophyticus, Citrobacter koseri, or Klebsiella pneumoniae (K. pneumoniae). In some embodiments, the infection is a urinary tract infection caused by E. coli. In another embodiment, the infection is gonorrhea caused by Neisseria gonorrhoeae.

[0089] As used herein, the term "treatment" refers to alleviating the specified condition, relieving or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the recurrence of the condition in a previously affected or diagnosed patient or subject.

[0090] As used herein, the term "effective amount" refers to an amount of a drug or agent that elicits the biological or medical response of a tissue, system, animal, or human as desired, for example, by a researcher or clinician. Unless otherwise specified, the amount of drug or agent refers to the amount of the free base compound and not the amount of the corresponding pharma- ceutically acceptable salt.

[0091] In one embodiment, the present application provides a method of treating a urinary tract infection (UTI), comprising administering a therapeutically effective amount of a pharmaceutical composition disclosed herein in a human subject in need thereof, wherein gepotidacin is administered at 1500 mg twice daily, 6-12 hours apart.

[0092] In particular, the pharmaceutical compositions of the present application are presented as unit doses and are preferably administered 1 to 5 times daily, for example, once or twice daily to achieve the desired effect. In one embodiment, gepotidacin is administered for any of 3, 4, 5, 6, or 7 consecutive days. In one embodiment, in any aspect of the present application, gepotidacin is administered for 5 consecutive days.

[0093] In another embodiment, the present application provides a method of treating infection caused by Neisseria gonorrhoeae, comprising administering a therapeutically effective amount of a pharmaceutical composition disclosed herein in a human subject in need thereof, wherein gepotidacin is administered in two doses of 3000 mg each, 6-12 hours apart.

[0094] In another embodiment, the present application provides a method of treating gonorrhea, comprising administering a pharmaceutical composition disclosed herein in a therapeutically effective amount in a human subject in need thereof, wherein gepotidacin is administered in two doses of 3000 mg each, 6-12 hours apart.

[0095] The invention is exemplified by the following clauses.

[0096] 1. A pharmaceutical composition comprising gepotidacin and one or more pharma- ceutically acceptable excipients, the pharmaceutical composition comprising about 45% to 75% by weight of gepotidacin (measured as the free base).

[0097] 1a. A pharmaceutical composition comprising a crystalline form of gepotidacin and one or more pharma- ceutical acceptable excipients, wherein the crystalline form is gepotidacin mesylate dihydrate or gepotidacin anhydrate, and the pharmaceutical composition comprises about 45% to 75% by weight of gepotidacin (measured as the free base).

[0098] 2. The pharmaceutical composition according to clause 1, wherein gepotidacin is in a crystalline form.

[0099] 3. The pharmaceutical composition according to clause 2, wherein the crystalline form is gepotidacin mesylate dihydrate, gepotidacin mesylate anhydrate or gepotidacin anhydrate.

[0100] 4. The pharmaceutical composition according to clause 1a or 3, wherein the crystalline form is gepotidacin mesylate dihydrate.

[0101] 5. Gepotidacin mesylate dihydrate is a phosphate ion exchange inhibitor. α 5. The pharmaceutical composition of claim 4, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three or at least four diffraction angles selected from the group consisting of about 9.0, 11.5, 13.4, 14.3, 14.9, 15.5, 17.6, 18.6, and 20.7°2θ, as measured using a ray.

[0102] 6. The pharmaceutical composition described in clause 4, wherein the gepotidacin mesylate dihydrate is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure 1.

[0103] 7. A pharmaceutical composition according to any one of clauses 4 to 6, comprising about 60% to 90% by weight of gepotidacin mesylate dihydrate.

[0104] 8. The pharmaceutical composition according to any one of clauses 4 to 7, wherein the pharmaceutical composition comprises about 60% to 80% by weight of gepotidacin mesylate dihydrate, and the one or more excipients comprise a diluent, a disintegrant, and a glidant.

[0105] 9. About 65% to 75% by weight of gepotidacin mesylate dihydrate, about 20% to 25% by weight of a diluent; About 4% to 10% by weight of a disintegrant, and About 0.5% to 2% by weight of a glidant 9. The pharmaceutical composition according to clause 8, comprising:

[0106] 10. The diluent is selected from the group consisting of microcrystalline cellulose, lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose, calcium sulfate, calcium hydrogen phosphate, and combinations thereof; the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose, croscarmellose sodium, alginic acid, sodium alginate, sodium carboxymethylcellulose, and combinations thereof; The glidant is selected from the group consisting of colloidal silicon dioxide, magnesium stearate, and combinations thereof; 10. A pharmaceutical composition according to clause 8 or 9.

[0107] 11. The pharmaceutical composition of any one of clauses 7 to 10, wherein the one or more excipients further comprise a lubricant.

[0108] 12. The pharmaceutical composition according to clause 11, wherein the lubricant is selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and combinations thereof.

[0109] 13. The pharmaceutical composition of clause 11 or 12, wherein the lubricant comprises about 0.5% to 5% by weight.

[0110] 13. About 70% by weight of gepotidacin mesylate dihydrate; about 22% by weight of diluent; about 6% by weight of a disintegrant, and About 1% by weight of a glidant 10. The pharmaceutical composition according to clause 9, comprising:

[0111] 14. About 70% by weight of gepotidacin mesylate dihydrate, about 22% by weight of diluent; about 6% by weight of a disintegrant; about 1% by weight of a glidant, and Approximately 1.4% by weight of lubricant 10. The pharmaceutical composition according to clause 9, comprising:

[0112] 15. About 70% by weight of gepotidacin mesylate dihydrate, about 22% by weight of diluent; about 6% by weight of a disintegrant; about 0.5% by weight of a glidant, and Approximately 1.9% by weight of lubricant 10. The pharmaceutical composition according to clause 9, comprising:

[0113] 16. The pharmaceutical composition comprises about 60% to 80% by weight of gepotidacin mesylate dihydrate, an intragranular excipient, and an extragranular excipient; The intragranular excipient is about 4% to 8% by weight of a diluent; About 1% to 5% by weight of a disintegrant, and About 0.1% to 1% by weight of a glidant Including, The extragranular excipient is about 10% to 20% by weight of a diluent, and About 1% to 5% by weight of a disintegrant 8. The pharmaceutical composition according to any one of clauses 4 to 7, comprising:

[0114] 17. The pharmaceutical composition of clause 16, wherein the extragranular excipient further comprises about 0.1% to 1% by weight of a glidant.

[0115] 18. Each of said diluents is independently selected from the group consisting of microcrystalline cellulose, lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose, calcium sulfate, calcium hydrogen phosphate, and combinations thereof; each of the disintegrants is independently selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose, croscarmellose sodium, alginic acid, sodium alginate, sodium carboxymethylcellulose, and combinations thereof; The pharmaceutical composition of claim 16 or 17, wherein each of said glidants is independently selected from the group consisting of colloidal silicon dioxide, magnesium stearate, and combinations thereof.

[0116] 19. The pharmaceutical composition of any one of clauses 16 to 18, wherein the intragranular excipients further comprise from about 0.1% to 3% by weight of a lubricant and the extragranular excipients further comprise from about 0.1% to 3% by weight of a lubricant.

[0117] 20. The pharmaceutical composition of clause 19, wherein each of the lubricants is independently selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and combinations thereof.

[0118] 21. A pharmaceutical composition comprising about 65% to 75% by weight of gepotidacin mesylate dihydrate, The intragranular excipient is about 5% to 7% by weight of a diluent; about 2% to 4% by weight of a disintegrant; about 0.4% to 0.6% by weight of a glidant, and Approximately 0.2% to 0.6% by weight of a lubricant Including, The extragranular excipient is about 14% to 18% by weight of a diluent; about 2% to 4% by weight of a disintegrant; about 0.4% to 0.6% by weight of a glidant, and Approximately 0.5% to 1.5% by weight of a lubricant 21. The pharmaceutical composition according to any one of clauses 16 to 20, comprising:

[0119] 22. A pharmaceutical composition comprising about 70% by weight of gepotidacin mesylate dihydrate, The intragranular excipient is about 6% by weight of a diluent; about 3% by weight of a disintegrant; about 0.5% by weight of a glidant, and Approximately 0.4% by weight of lubricant Including, The extragranular excipient is about 16% by weight of a diluent; about 3% by weight of a disintegrant; about 0.5% by weight of a glidant, and Approximately 1% by weight of lubricant 22. The pharmaceutical composition according to clause 21, comprising:

[0120] 23. The pharmaceutical composition according to clause 1a or 3, wherein the crystalline form is gepotidacin anhydrate.

[0121] 24. Gepotidacin anhydride is reacted with Cu K α 24. The pharmaceutical composition of claim 23, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three or at least four diffraction angles selected from the group consisting of about 8.8, 10.8, 11.7, 12.8, 13.2, 14.4, 16.3, 19.9, 20.8, and 25.0°2θ, as measured using a 350 nm X-ray diffraction line.

[0122] 25. The pharmaceutical composition described in clause 23, wherein gepotidacin anhydrate is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure 4.

[0123] 26. A pharmaceutical composition according to any one of clauses 23 to 25, comprising about 50% to 75% by weight of gepotidacin anhydrate.

[0124] 27. The pharmaceutical composition according to any one of clauses 23 to 26, wherein the pharmaceutical composition comprises about 55% to 70% by weight of gepotidacin anhydrate, and the one or more excipients comprise a diluent and a disintegrant.

[0125] 28. The pharmaceutical composition according to clause 26, wherein the one or more excipients further comprise a lubricant.

[0126] 29. The diluent is selected from the group consisting of microcrystalline cellulose, lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose, calcium sulfate, calcium hydrogen phosphate, and combinations thereof; 28. The pharmaceutical composition of clause 27, wherein the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose, croscarmellose sodium, alginic acid, sodium alginate, sodium carboxymethylcellulose, and combinations thereof.

[0127] 30. The pharmaceutical composition of any one of clauses 23 to 29, wherein the one or more excipients further comprise a lubricant selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and combinations thereof.

[0128] 31. About 60% to 65% by weight of gepotidacin anhydrate; about 25% to 35% by weight of a diluent, and About 4% to 8% by weight of a disintegrant 31. The pharmaceutical composition according to any one of clauses 27 to 30, comprising:

[0129] 32. The pharmaceutical composition of any one of clauses 27 to 31, wherein the one or more excipients further comprise about 0.5% to 5% by weight of a lubricant.

[0130] 33. About 63% by weight of gepotidacin anhydrate; about 31% by weight of a diluent, and Approximately 5% by weight of disintegrant 32. The pharmaceutical composition according to clause 31, comprising:

[0131] 34. Gepotidacin anhydrate, about 63% by weight; about 31% by weight of diluent; about 5% by weight of a disintegrant, and Approximately 1% by weight of lubricant 32. The pharmaceutical composition according to clause 31, comprising:

[0132] 35. Gepotidacin anhydrous, approximately 750 mg, Microcrystalline cellulose approx. 375 mg, Approximately 64 mg of croscarmellose sodium, and Magnesium stearate approx. 11mg 28. The pharmaceutical composition according to clause 27, comprising:

[0133] 36. A pharmaceutical composition comprising about 55% to 70% by weight of gepotidacin anhydrate, an intragranular excipient, and an extragranular excipient; The intragranular excipient is about 10% to 15% by weight of a diluent, and About 1% to 5% by weight of a disintegrant Including, The extragranular excipient is about 15% to 20% by weight of a diluent, and About 1% to 5% by weight of a disintegrant 31. The pharmaceutical composition according to any one of clauses 26 to 30, comprising:

[0134] 37. Each of said diluents is selected from the group consisting of microcrystalline cellulose, lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose, calcium sulfate, calcium hydrogen phosphate, and combinations thereof; 37. The pharmaceutical composition of claim 36, wherein each of said disintegrants is selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose, croscarmellose sodium, alginic acid, sodium alginate, sodium carboxymethylcellulose, and combinations thereof.

[0135] 38. The pharmaceutical composition of clause 36 or 37, wherein the intragranular excipients further comprise about 0.1% to 3% by weight of a lubricant, and the extragranular excipients further comprise about 0.1% to 3% by weight of a lubricant.

[0136] 39. The pharmaceutical composition of clause 38, wherein each of the lubricants is independently selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and combinations thereof.

[0137] 40. A composition comprising about 60% to 65% by weight of gepotidacin anhydrate, The intragranular excipient is about 11% to 15% by weight of a diluent; About 1% to 4% by weight of a disintegrant, and Approximately 0.2% to 0.6% by weight of a lubricant Including, The extragranular excipient is about 16% to 20% by weight of a diluent; About 2% to 4% by weight of a disintegrant, and Approximately 0.3% to 0.7% by weight of a lubricant 40. The pharmaceutical composition according to any one of clauses 36 to 39, comprising:

[0138] 41. A pharmaceutical composition comprising about 63% by weight of gepotidacin anhydrate; The intragranular excipient is about 13% by weight of a diluent; about 2.3% by weight of a disintegrant, and Approximately 0.4% by weight of lubricant Including, The extragranular excipient is about 18% by weight of a diluent; about 3% by weight of a disintegrant, and Approximately 0.5% by weight of lubricant 41. The pharmaceutical composition according to clause 40, comprising:

[0139] 42. Contains approximately 750 mg of gepotidacin anhydrate; The intragranular excipient is Microcrystalline cellulose approx. 155 mg, Approximately 28 mg of croscarmellose sodium, and Magnesium stearate approx. 4.7mg Including, The extragranular excipient is Microcrystalline cellulose approx. 221 mg, Approximately 36 mg of croscarmellose sodium, and Magnesium stearate approx. 6mg 37. The pharmaceutical composition according to clause 36, comprising:

[0140] 43. A pharmaceutical composition according to any one of clauses 1 to 42, in the form of a tablet.

[0141] 44. The pharmaceutical composition according to clause 43, wherein the tablet is film-coated.

[0142] 45. A method for treating a bacterial infection in a human in need thereof, comprising administering to the human a pharmaceutical composition described in any one of clauses 1 to 44.

[0143] 46. ​​The method according to clause 45, wherein the bacterial infection is an uncomplicated urinary tract infection or a gonococcal infection.

[0144] 47. The method according to clause 45, wherein the bacterial infection is an uncomplicated urinary tract infection and the pharmaceutical composition is administered at a dose of 1500 mg of gepotidacin (measured as the free base) twice daily for 5 days.

[0145] 48. The method according to clause 45, wherein the bacterial infection is an infection caused by Neisseria gonorrhoeae and the pharmaceutical composition is administered at a dose of 3000 mg of gepotidacin (measured as the free base), followed by a second dose of 3000 mg 10 to 12 hours later.

[0146] 49. A pharmaceutical composition according to any one of clauses 1 to 42 for use in therapy.

[0147] 50. A pharmaceutical composition according to any one of clauses 1 to 42 for use in treating uncomplicated urinary tract infections or infections caused by gonococcal bacteria.

[0148] The examples presented below are illustrative of the present invention and are not intended to limit the scope of the invention in any manner. EXAMPLES

[0149] experiment The following examples illustrate the present invention. These examples are not intended to limit the scope of the present invention, but are intended to provide guidance to those skilled in the art for preparing and using the compounds, compositions, and methods of the present invention. Although specific embodiments of the present invention are described, those skilled in the art will understand that various changes and modifications may be made without departing from the spirit and scope of the present invention. Unless otherwise specified, reagents are commercially available or prepared according to literature procedures.

[0150] [Example 1] Gepotidacin Mesylate Dihydrate (Form 1) Example 1a - Preparation method 1 Acetone (5 ml) was added to gepotidacin (294.14 mg). To the slurry was added methanesulfonic acid (3 M aqueous solution, 1 eq.) over a period of 60 minutes. The slurry was heated to 50° C. for 3 hours, slowly cooled to 20° C., left stirring at 20° C. for 5 hours and further cooled to 5° C. The slurry was stirred at 5° C. overnight. The crystalline solid was filtered under vacuum, washed with acetone and dried in a vacuum oven at 60° C. to give crystalline gepotidacin mesylate dihydrate (Form 1) in 72.9% yield.

[0151] Example 1b - Preparation method 2 Gepotidacin (32.00 kg) and methanesulfonic acid (7.00 kg, 1.02 eq) were heated to 74-80 °C in 304 L of 2-propanol and 16.1 kg of water. The solution was filtered into a crystallization vessel and cooled to 59-63 °C. Form 1 dihydrate (0.318 kg) suspended in 5% v / v aqueous 2-propanol (1.194 kg of 2-propanol and 0.080 L of water) was added and the mixture was aged at 58-64 °C for 2 hours. The mixture was cooled to 15-25 °C and the resulting slurry was wet milled. The slurry was heated to 55-61 °C and cooled to 15-25 °C. Gepotidacin mesylate dihydrate was isolated by filtration, washed twice with 5% v / v aqueous 2-propanol (2×106 L 2-propanol and 2×5.6 kg water) and dried under vacuum at about 40° C. to obtain gepotidacin mesylate dihydrate (Form 1) (38.505 kg) as a crystalline solid.

[0152] Example 1c - XRPD The X-ray powder diffraction (XRPD) pattern of gepotidacin mesylate dihydrate (Form 1) is shown in FIG. 1 and a summary of the diffraction angles and d-spacings is given in Table 1 below. XRPD analysis was carried out on a PANalytical X'Pert Pro diffractometer on a Si zero background wafer. The acquisition conditions were Cu K αline, generator voltage 45 kV, generator current: 40 mA, step size 0.03° 2θ.

[0153] [Table 1] TIFF2024506013000004.tif93152

[0154] The XRPD pattern of another sample of gepotidacin mesylate dihydrate (Form 1) is shown in FIG. 9 (see Table 2). XRPD analysis was performed on a PANalytical Empyrean diffractometer on a Si zero background wafer. Acquisition conditions were Cu K α line, generator voltage 45 kV, generator current: 40 mA, step size 0.03° 2θ.

[0155] [Table 2] TIFF2024506013000006.tif94136

[0156] Example 1d - Raman Spectrum Raman spectra of gepotidacin mesylate dihydrate (Form 1) were recorded on a Nicolet NXR9650 or Thermo Electron NXR 960 spectrometer with excitation from a Nd:YVO4 laser (λ=1064 nm) at 4 cm -1 The Raman spectrum of gepotidacin mesylate dihydrate (Form 1) is shown in Figure 2 and shows major peaks at 455, 492, 558, 525, 590, 628, 667, 752, 775, 823, 940, 993, 1037, 1109, 1154, 1216, 1269, 1306, 1346, 1392, 1424, 1472, 1518, 1584, 1637, 1676, 2929, 3005 and 3046 cm. -1 is observed.

[0157] Example 1e -DSC DSC of gepotidacin mesylate dihydrate (Form 1) was performed using a TA Instruments Q2000 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under 40 mL / min N2 purge. DSC thermograms of samples were obtained in crimped Al pans at 15°C / min. The DSC thermogram of Form 1 exhibits a broad endotherm followed by a sharp endotherm with an onset temperature of about 129°C, followed by an endotherm with an onset temperature of about 195°C (Figure 3). One skilled in the art will recognize that the onset temperature of the endotherm may vary depending on the experimental conditions.

[0158] Example 1f - TGA Thermogravimetric analysis (TGA) thermograms of gepotidacin mesylate dihydrate (Form 1) were recorded on a TA Instruments Q50 thermogravimetric analyzer under 60 mL / min N2 flow and a heating rate of 10 °C / min. The TGA thermogram of gepotidacin mesylate dihydrate (Form 1) exhibits a loss of approximately 6% (2.0 eq) from 30 to 130 °C (Figure 4).

[0159] [Example 1g] - Single crystal structure Single crystals of gepotidacin mesylate dihydrate were prepared by slow cooling from a water / 2-propanol solution of gepotidacin mesylate.

[0160] Single crystal data were collected on a Bruker D8 Venture system using an Incotec microfocus 3.0 CuKα Source. Data collection and unit cell indexing were performed with the APEX3 v2017.3-0 suite (Bruker AXS Inc., 2017), and processing of the measured intensity data was carried out with the SAINT V8.38A software package (Bruker AXS Inc., 2017). The structure was solved by direct methods using the SHELXT-2018 / 2 software package (Sheldrick, 2018). The derived atomic parameters (coordinates and temperature factors) were refined by full-matrix least-squares in SHELXL-2018 / 3 (Sheldrick, 2018). Hydrogens were introduced at ideal positions, which were freely refined, except for positions at heteroatoms.

[0161] Single crystal X-ray data was measured at low temperature (-123 °C). The single crystal had the following unit cell parameters: a = 6.9255(5) Å, b = 15.4500(12) Å, c = 25.7918(19) Å, α = β = γ = 90°, V=2759.7(4)Å 3 , Z'=1, space group P212121, Molecules / unit cell 4, Density (calculated value) 1.398g / cm 3 , where Z' is the number of molecules per asymmetric unit. The structure was confirmed as the mesylate dihydrate having the formula:

[0162] Example 1h - Solubility The solubility of gepotidacin mesylate dihydrate (Form 1) was determined in simulated gastric fluid pH 1.6 (SGF), fasted simulated intestinal fluid pH 6.5 (FaSSIF) and fed simulated intestinal fluid pH 6.5 (FeSSIF) at ambient room temperature (20-25° C.), see Table 3 below.

[0163] [Table 3]

[0164] [Example 2] Gepotidacin anhydrous Example 2a - Preparation method 1 Gepotidacin (52 g) and 1-propanol (440 mL) were heated to 90° C. 40 mL of 1-propanol was added to the clear solution and the combined contents were reheated to 90° C. The clear solution was cooled to 76° C. and left to stir for 1 hour. The slurry was cooled to 0° C. and left to stir overnight. The slurry was filtered, washed with chilled 1-propanol and dried under vacuum at 50° C. for approximately 6 hours to give gepotidacin anhydrate as a crystalline solid (47.8 g).

[0165] Example 2b - Preparation method 2 The preparation of gepotidacin anhydrate was carried out on a mass scale according to the following steps: Add n-propanol (12 volumes) to gepotidacin (1.0 equiv.) and heat the mixture to 95±3°C to achieve complete dissolution. Filter the mass at 95±3°C and wash the filter with n-propanol (0.1 volumes). Collect the filtrate and heat again to 95±3°C to ensure complete dissolution. Cool the mass to 77±2°C. Add seed slurry (1.0% w / w suspended in 2.5 volumes n-propanol) and stir at 77±2°C for at least 1 hour. Further cool the slurry mass to 0±2°C and stir for 1 hour. Filter the material and wash the cake with n-propanol (2 volumes). Dry the material under vacuum at 50±2°C.

[0166] Example 2c - XRPD The X-ray powder diffraction (XRPD) pattern of gepotidacin anhydrate is shown in FIG. 5 and a summary of the diffraction angles and d-spacings is given in Table 4 below. XRPD analysis was carried out on a PANalytical X'Pert Pro diffractometer on a Si zero background wafer. The acquisition conditions were Cu K α line, generator voltage 45 kV, generator current: 40 mA, step size 0.02° 2θ.

[0167] [Table 4] TIFF2024506013000009.tif14137

[0168] The XRPD pattern of another sample of gepotidacin anhydrate is shown in FIG. 10 (see Table 5). XRPD analysis was carried out on a PANalytical X'Pert Pro diffractometer on a Si zero background wafer. The acquisition conditions were Cu K α line, generator voltage 45 kV, generator current: 40 mA, step size 0.02° 2θ.

[0169] [Table 5] TIFF2024506013000011.tif111143

[0170] Example 2d - Raman Spectroscopy Raman spectra of gepotidacin anhydrate were recorded on a Nicolet NXR9650 or Thermo Electron NXR 960 spectrometer with excitation from a Nd:YVO4 laser (λ = 1064 nm) at 4 cm -1 The Raman spectrum of this material is shown in Figure 6, with major peaks at 453, 471, 586, 630, 656, 748, 825, 985, 1099, 1143, 1289, 1344, 1391, 1429, 1476, 1516, 1572, 1612, 1647, 1687, 2927 and 3051 cm. -1 is observed.

[0171] Example 2e -DSC DSC of gepotidacin anhydrate was performed using a TA Instruments Q2000 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under 40 mL / min N2 purge. DSC thermograms of samples were obtained at 10°C / min in crimped Al pans. The DSC thermogram of gepotidacin anhydrate exhibits a single endotherm with an onset temperature of about 196°C (Figure 7). One skilled in the art will recognize that the onset temperature of the endotherm may vary depending on the experimental conditions.

[0172] Example 2f - TGA Thermogravimetric analysis (TGA) thermograms of gepotidacin anhydrate were recorded on a TA Instruments Q50 thermogravimetric analyzer under 25 mL / min N2 flow and a heating rate of 10 °C / min. The TGA thermogram of the anhydrate exhibits a loss of approximately 0.25% from 25 to 200 °C (Figure 8).

[0173] [Example 2g] - Single crystal structure Single crystals of gepotidacin anhydrate were prepared by slow cooling with seeding from a 1-propanol solution.

[0174] Single crystal data were collected on an Oxford Diffraction Xcalibur A Nova system using a Nova X-ray CuKα Source. Data collection and unit cell indexing were performed with the CrysAlisPro 1.171.37.34i suite (Agilent Technologies, 2014), and processing of measured intensity data was also performed with the CrysAlisPro 1.171.37.34i (Agilent Technologies, 2014) software package. The structure was solved by direct methods using the SHELXT-2018 / 2 (Sheldrick, 2018) software package. The derived atomic parameters (coordinates and temperature factors) were refined by full-matrix least-squares in SHELXL-2018 / 3 (Sheldrick, 2018). Hydrogens were introduced at ideal positions, which were freely refined, except for positions at heteroatoms.

[0175] Single crystal X-ray data was measured at low temperature (-123 °C). The single crystal had the following unit cell parameters: a = 8.44022(16) Å, b = 6.42442(12) Å, c = 20.2774(5) Å, α = γ = 90°, β = 96.778(2)°, V = 1091.83(4) Å. 3 , Z'=1, space group P21, Drug molecule / unit cell 2, Density (calculated value) 1.364g / cm 3 , where Z' is the number of drug molecules per asymmetric unit. The free base anhydrate structure was identified as having the formula:

[0176] Gepotidacin anhydrous exhibits low to moderate solubility (<20 mg / mL) in common solvents and water, except dichloromethane and trifluoroethanol (>100 mg / mL).

[0177] [Example 3] Capsule formulation of gepotidacin mesilate Gepotidacin mesylate dihydrate capsules (containing 100 mg and 500 mg of gepotidacin free base) were prepared according to Table 6 and used in first time in human (FTIH) and Phase 2 clinical trials.

[0178] [Table 6]

[0179] The blended gepotidacin mesylate dihydrate was dry granulated by roller compaction and then encapsulated into size 4 (100 mg) and size 00 (500 mg) capsules. A Phase 1 single-dose oral study showed gastrointestinal irritation that was mitigated by food intake and had no effect on exposure. The capsules were stable for 24 months under all storage conditions.

[0180] [Example 4] Tablet formulation of gepotidacin mesylate An oral relative bioavailability study (RBA Study 1) was conducted to compare a tablet formulation of gepotidacin mesylate dihydrate (Formulation B) containing 750 mg of gepotidacin (measured as the free base) presented in Table 7 with a reference formulation A (500 mg capsule) presented in Table 6. Both the reference capsule formulation and the test tablet formulation utilized gepotidacin mesylate dihydrate and were manufactured using a roller compaction granulation process. Gepotidacin mesylate dihydrate was found to have poor flow properties and the composition of Formulation B was initially developed to provide a formulation process with reasonable flow performance.

[0181] At a single dose of 1500 mg, the bioavailability of Formulation B (2 × 750 mg) was found to be similar to that of Formulation A (3 × 500 mg), and rapid absorption of gepotidacin was observed from both the tablet and the reference capsule.

[0182] [Table 7]

[0183] [Example 5] Tablet formulation of gepotidacin free base. A second oral relative bioavailability study (RBA Study 2) was conducted to compare two formulations of gepotidacin tablets 750 mg presented in Table 8 with reference formulation A presented in Table 6. Both tablet formulations utilized gepotidacin free base (gepotidacin anhydrate). Formulation C was manufactured using roller compaction (RC) method and formulation D was manufactured using high shear wet granulation (HSWG) method.

[0184] [Table 8]

[0185] Blends of gepotidacin free base with AVICEL PH101 (microcrystalline cellulose), AVICEL PH105 (microcrystalline cellulose) or lactose were prepared to compare compressibility. The two blends containing microcrystalline cellulose compressed better than the blend containing lactose.

[0186] Tablets prepared by HSWG can reduce pill burden or tablet size by increasing drug loading. These tablets met manufacturability criteria. Relative bioavailability data was collected to evaluate two different tablet formulations (Formulation C and Formulation D). The free base RC and HSWG tablets were evaluated against a reference mesylate capsule (Formulation A). The AUC and Cmax of the RC tablet and the AUC of the HSWG tablet were determined to be comparable to those of the reference capsule, while the Cmax of the HSWG tablet was determined to be higher than that of the reference capsule.

[0187] Although the solubility of gepotidacin anhydrate is lower than that of gepotidacin mesylate dihydrate, gepotidacin anhydrate was found to be acceptable for development in terms of solubility, as shown by the results of RBA study 2. However, during formulation development, it was found that tablets of formulation C prepared from certain batches of gepotidacin free base drug substance had disintegration issues, which may be attributed to the synthetic route of these batches. Therefore, a new formulation of gepotidacin was further investigated to improve the robustness of the formulation.

[0188] [Example 6] Improved tablet formulation of gepotidacin mesylate. As mentioned above, gepotidacin mesylate dihydrate was found to have poor flowability. Studies were conducted to further improve the flow performance of the tableting process for gepotidacin mesylate dihydrate. For example, it was found that adding a glidant to the intragranular blend helps improve flowability. Tablets of Formulation E (see Table 9) were prepared by the method shown in Figure 11.

[0189] [Table 9]

[0190] Another tablet formulation was prepared with the addition of magnesium stearate in the extragranular blend (Table 9, Formulation F). The tableting process of Formulation F was observed to have similar flow properties as compared to that of Tablet E.

[0191] The data in Figure 12 shows the tableting profiles of Formulation E (round) and Formulation F (square). The data shows that (a) both formulations exhibit acceptable tableting profiles, and (b) additional magnesium stearate does not affect the tableting profile. Addition of magnesium stearate up to a 1.5% w / w level does not affect either tablet disintegration or dissolution. For example, Figure 13 shows a comparison of disintegration time as a function of tablet tensile strength for Formulation E (round) and Formulation F (square).

[0192] Gepotidacin was studied in adults and adolescents to evaluate oral gepotidacin mesylate 750 mg tablets (Formulation E). Data from a single dose of 1,500 mg and two doses of 3,000 mg administered 6 or 12 hours apart confirmed dose selection in Phase 3 trials for ongoing acute uncomplicated urinary tract infection (gepotidacin 1,500 mg twice daily for 5 days; NCT04020341 and NCT04187144) and genitourinary gonorrhea (two doses of gepotidacin 3,000 mg 10-12 hours apart; NCT04010539), respectively.

[0193] Plasma and urinary pharmacokinetic data were collected and analyzed for gepotidacin mesylate capsules and tablets (Formulations A and B), two gepotidacin free base tablets (Formulations C and D), and an improved gepotidacin mesylate tablet (Formulation E). Overall, similar systemic plasma and urinary exposures were observed following administration of the various tablet and capsule formulations of gepotidacin.

[0194] [Example 7] Gepotidacin Mesylate Anhydrous Example 7a - Preparation Gepotidacin mesylate dihydrate (Form 1) (894 mg) was suspended in isopropyl alcohol (IPA) (5.4 ml) and heated to 61° C. The resulting solid was analyzed in situ by Raman and as a wet slurry by XRPD.

[0195] In another preparation, a spatula (<20 mg) of gepotidacin mesylate dihydrate (Form 1) was suspended in IPA (<1.5 ml). The suspension was heated using a heat gun to dissolve most of the solids and then allowed to slowly cool to room temperature. The resulting crystals were filtered and analyzed by DSC, TGA, and XRPD. It should be noted that this form is unstable under ambient conditions and therefore the analysis obtained may not be for a phase pure anhydrous sample.

[0196] Example 7b - Single crystal structure Single crystals of gepotidacin mesylate anhydrate were prepared by slow cooling from a 2-propanol solution.

[0197] Single crystal data were collected on a Bruker D8 Venture system using an Incotec microfocus 3.0 CuKα Source. Data collection and unit cell indexing were performed with the APEX3 v2017.3-0 suite (Bruker AXS Inc., 2017), and processing of the measured intensity data was carried out with the SAINT V8.38A (Bruker AXS Inc., 2017) software package. The structure was solved by direct methods using the SHELXT-2018 / 2 (Sheldrick, 2018) software package. The derived atomic parameters (coordinates and temperature factors) were refined by full-matrix least-squares in SHELXL-2018 / 3 (Sheldrick, 2018). Hydrogens were introduced at ideal positions, which were freely refined, except for positions at heteroatoms.

[0198] Single crystal X-ray data was measured at low temperature (-123 °C). The single crystal had the following unit cell parameters: a = 12.3921(7) Å, b = 7.0262(4) Å, c = 14.6536(9) Å, α = γ = 90°, β = 95.0077(13)°, V = 1271.01(13) Å. 3 , Z'=1, space group P21, Drug molecule / unit cell 2, Density (calculated value) 1.423g / cm 3 , where Z' is the number of drug molecules per asymmetric unit. The structure was confirmed as the anhydrous mesylate salt having the formula:

[0199] It is to be understood that the present invention is not limited to the aspects or embodiments exemplified above, but is entitled to all modifications within the scope of the exemplified aspects or embodiments and the following claims.

[0200] Various references to journals, patents, and other publications cited herein contain the state of the art and are incorporated herein by reference as if set forth in their entirety.

Claims

1. A pharmaceutical composition comprising gepotidacin and one or more pharma- ceutically acceptable excipients, the pharmaceutical composition comprising about 45% to 75% by weight of gepotidacin (measured as the free base).

2. 2. The pharmaceutical composition of claim 1, wherein the gepotidacin is in a crystalline form.

3. 3. The pharmaceutical composition of claim 2, wherein the crystalline form is gepotidacin mesylate dihydrate, gepotidacin mesylate anhydrate or gepotidacin anhydrate.

4. 4. The pharmaceutical composition of claim 3, wherein the crystalline form is gepotidacin mesylate dihydrate.

5. Gepotidacin mesylate dihydrate is Cu K α 5. The pharmaceutical composition of claim 4, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three or at least four diffraction angles selected from the group consisting of about 9.0, 11.5, 13.4, 14.3, 14.9, 15.5, 17.6, 18.6, and 20.7 degrees 2θ, as measured using X-ray powder diffraction (XRPD) lines.

6. 5. The pharmaceutical composition of claim 4, wherein the gepotidacin mesylate dihydrate is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.

7. 7. The pharmaceutical composition of any one of claims 4 to 6, comprising about 60% to 90% by weight of gepotidacin mesylate dihydrate.

8. 8. The pharmaceutical composition of any one of claims 4 to 7, wherein the pharmaceutical composition comprises about 60% to 80% by weight of gepotidacin mesylate dihydrate, and the one or more excipients include a diluent, a disintegrant, and a glidant.

9. about 65% to 75% by weight of gepotidacin mesylate dihydrate; about 20% to 25% by weight of a diluent; About 4% to 10% by weight of a disintegrant, and About 0.5% to 2% by weight of a glidant 9. The pharmaceutical composition of claim 8, comprising:

10. the diluent is selected from the group consisting of microcrystalline cellulose, lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose, calcium sulfate, calcium hydrogen phosphate, and combinations thereof; the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose, croscarmellose sodium, alginic acid, sodium alginate, sodium carboxymethylcellulose, and combinations thereof; The glidant is selected from the group consisting of colloidal silicon dioxide, magnesium stearate, and combinations thereof; 10. The pharmaceutical composition according to claim 8 or 9.

11. 11. The pharmaceutical composition of any one of claims 7 to 10, wherein the one or more excipients further comprise a lubricant.

12. 12. The pharmaceutical composition of claim 11, wherein the lubricant is selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and combinations thereof.

13. 13. The pharmaceutical composition of claim 11 or 12, wherein the lubricant comprises about 0.5% to 5% by weight.

14. 4. The pharmaceutical composition of claim 3, wherein the crystalline form is gepotidacin anhydrate.

15. Gepotidacin anhydride is Cu K α 15. The pharmaceutical composition of claim 14, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three or at least four diffraction angles selected from the group consisting of about 8.8, 10.8, 11.7, 12.8, 13.2, 14.4, 16.3, 19.9, 20.8, and 25.0 degrees 2θ, as measured using X-ray powder diffraction (XRPD) angles.

16. 15. The pharmaceutical composition of claim 14, wherein gepotidacin anhydrate is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.

17. 17. The pharmaceutical composition according to any one of claims 1 to 16, in the form of a tablet.

18. A pharmaceutical composition according to any one of claims 1 to 17 for use in treating a bacterial infection.

19. 19. The pharmaceutical composition of claim 18, wherein the bacterial infection is an uncomplicated urinary tract infection or a gonococcal infection.

20. 19. The pharmaceutical composition of claim 18, wherein the bacterial infection is an uncomplicated urinary tract infection and the pharmaceutical composition is administered at a dose of 1500 mg of gepotidacin (measured as the free base) twice daily for 5 days.

21. 19. The pharmaceutical composition of claim 18, wherein the bacterial infection is an infection caused by Neisseria gonorrhoeae and the pharmaceutical composition is administered at a dose of 3000 mg of gepotidacin (measured as the free base), followed 10 to 12 hours later by a second dose of 3000 mg.

22. 18. A pharmaceutical composition according to any one of claims 1 to 17 for use in therapy.

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