New prescription

Abstract

An oral formulation of granules of an active ingredient such as gepotidacin or a pharmaceutically acceptable salt thereof that rapidly disperses in water, or an oral formulation comprising such granules. Such granules provide an oral suspension with good mouthfeel and palatability. This oral suspension is particularly useful for pediatric patient populations or patient populations with difficulty swallowing.

Description

Technical Field

[0001] The present disclosure relates to a free-flowing oral granule preparation of a pharmaceutical that can be rapidly dispersed in water.

Background Art

[0002] While most adult patients can swallow normal tablets and capsules, there are also patients who have difficulty swallowing, especially for particularly large tablets. Pediatric patients, especially those under 8 years old, frequently experience this problem. The same is true for elderly patients and patients with certain conditions that affect swallowing (for example, neurological patients, patients using a nasogastric tube, and patients with certain conditions such as head and neck cancer).

[0003] Another type of preparation known in the art includes suspensions, dispersible granules or powders, dispersible tablets, and orally disintegrating tablets. Dispersible granules, powders, or tablets form a suspension that can be drunk by the patient by dispersing in water (or possibly other suitable media such as milk or juice).

[0004] Therefore, granules that can be rapidly dispersed in water and can produce a suspension that is easy to drink and has a good taste are highly desirable.

[0005] (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 (hereinafter referred to as "gepotidacin" in this specification) is an antibiotic under development that selectively inhibits bacterial DNA gyrase and topoisomerase IV by a unique and novel mechanism. International Patent Application Publication No. WO2008 / 128942 describes a series of compounds that can be used as antibacterial agents and contain gepotidacin. There is a need to develop alternative oral pharmaceutical formulations such as gepotidacin that can produce a suspension with a good taste for pediatric patients or patients with difficulty swallowing.

Summary of the Invention

[0006] In one aspect, an oral preparation comprising granules is provided, wherein the granules comprise: a. Up to about 60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b. About 15 - 75% (w / w) of a soluble filler, and c. About 20 - 60% (w / w) of microcrystalline cellulose, and d. About 2 - 5% (w / w) of a binder, and e. About 1.5 - 15% (w / w) of a disintegrant, and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL.

[0007] In another aspect, the present invention provides an oral preparation comprising granules, wherein the granules comprise: a) Up to 60% (w / w) of one or more active ingredients, and b) 15 - 75% (w / w) of a soluble filler, and c) 20 - 60% (w / w) of microcrystalline cellulose, and d) 2 - 5% (w / w) of a binder, and e) 1.5 - 15% (w / w) of a disintegrant, and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL.

Mode for Carrying Out the Invention

[0008] Ideally, particulate or powdered dosage forms, such as those contained in bottles, sachets, stick packs, etc., should be free-flowing in order to ensure content uniformity and to enable measurement of the total dose and / or retrieval from the container. In addition, the particulate or powder should disperse rapidly in liquid for patient convenience. Another important consideration is the palatability of the pharmaceutical product, particularly in pediatric patient populations. This depends in part on the taste of the drug in question, but also in part on the texture (i.e., "mouthfeel") of the suspension formed.

[0009] Gepotidacin is difficult to formulate because it is prone to compaction, cohesive, has poor flowability, and is bitter tasting. Gepotidacin has a high per unit dose requirement; for example, the tablets currently used in Phase 3 gepotidacin clinical trials contain 750 mg of gepotidacin measured as the free base, and the recommended clinical oral dose of gepotidacin for the treatment of urinary tract infection (UTI) is 1,500 mg twice daily (NCT04020341 and NCT04187144), and for the treatment of infections caused by Neisseria gonorrhoeae (e.g., uncomplicated gonorrhea or urogenital gonorrhea) is 3,000 mg twice daily (NCT04010539).

[0010] Such high daily doses require highly drug-loaded oral solid dosage forms, which pose an additional challenge, particularly for pediatric patient populations or patients with difficulty swallowing. There is a strong desire for formulations that overcome these problems and produce an orally administered suspension with good palatability.

[0011] Definition One of ordinary skill in the art will understand that the term "oral dosage form of particulates" as used herein refers to any oral pharmaceutical dosage form of a mixture of solids comminuted to a finely divided physical state, including powders and granules.

[0012] The term "oral preparation comprising granules" refers to an oral pharmaceutical dosage form comprising granules. These granules may be mixed with excipients outside the granules such as sweeteners, flavors, and / or lubricants to form the final oral pharmaceutical dosage form (for example, contained in a stick pack).

[0013] The statement "the granules have a diameter of 250 microns or less (≦250)" means that the granules have a d50 of 250 microns or less. The term d50 has its conventional meaning and can be measured by established techniques including sedimentation field flow fractionation, photon correlation spectroscopy, laser diffraction, or disc centrifugation. d50 may be related to the volume distribution of the particles, in which case the statement "the granules have a diameter of 250 microns or less" refers to a situation where at least 50% of the granule volume is 250 microns or less in diameter. By techniques based on either volume distribution or weight distribution, typically an average particle size of generally the same value is obtained.

[0014] In the context of the present disclosure, the term "soluble filler" refers to a polyol or sugar that exhibits solubility in water of 200 mg / mL or more at 25°C.

[0015] In the context of the present disclosure, the term "disintegrant" refers to an excipient that swells the granules and promotes disintegration.

[0016] In the context of the present disclosure, the term "binder" refers to a water-soluble polymer (for example, soluble in water at 100 mg / mL or more) that facilitates wet granulation. Typically, the polymer has a molecular weight in the range of 500 Da to 2 MDa and an apparent viscosity in the range of 3 to 15 mPa·s when in a 2% aqueous solution at 20°C.

[0017] The term "lubricant" is a term in the art. In one embodiment, a lubricant refers to an excipient for reducing friction between granules. The terms "approximate", "approximately", or "about" as used herein in connection with a numerical value have the meaning as having the ordinary meaning in the context of the numerical value. If necessary, the words "approximate", "approximately", or "about" may be replaced by that numerical value ±5%. When any of these terms is written before a list of numerical values as used herein, the above terms apply to each of the recited numerical values.

[0018] Unless otherwise indicated, weight percentages are calculated using the weight of the active ingredient (e.g., gepotidacin free base, gepotidacin mesylate anhydride, or gepotidacin mesylate dihydrate) relative to the weight of the granules.

[0019] The granule compressibility index or Carr's index is measured using the bulk density and tapped density tests described in USP <1174>. As recognized by those skilled in the art, Carr's index is used as an indicator of the compressibility of granules or powders. The term "FFc" means the flow function of the granules and is also measured by the shear cell technique described in USP <1174>. Both techniques are used to characterize the flow properties of the granules.

[0020] Embodiment The present disclosure provides an oral formulation comprising granules, the granules comprising a) one or more active ingredients up to about 60% (w / w), and b) a soluble filler of about 15 - 75% (w / w), and c) microcrystalline cellulose of about 20 - 60% (w / w), and d) a binder of about 2 - 5% (w / w), and e) a disintegrant of about 1.5 - 15% (w / w), wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and The above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0021] As will be understood by those skilled in the art, the granule excipients can be added to the granules without affecting the characteristics of the granules of the present disclosure. Accordingly, the present disclosure encompasses both oral formulations of the granules and oral formulations comprising the granules of the present disclosure in addition to other excipients.

[0022] Accordingly, in one embodiment, the oral formulation further comprises one or more excipients. In one embodiment, the oral formulation further comprises one or more excipients selected from flavoring agents, taste-correcting agents, and lubricants.

[0023] In one embodiment, an oral formulation of the granules is provided, the granules comprising a) one or more active ingredients up to about 60% (w / w), and b) a soluble filler of about 15 - 75% (w / w), and c) microcrystalline cellulose of about 20 - 60% (w / w), and d) a binder of about 2 - 5% (w / w), and e) a disintegrant of about 1.5 - 15% (w / w), and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0024] The granules of the present disclosure or oral formulations comprising the granules are particularly suitable for active ingredients typically administered to pediatric patients (in particular, patients under 6 years old, under 8 years old, or under 12 years old), elderly patients, and patients with certain conditions affecting swallowing (e.g., neurological patients, patients using a nasogastric tube, and patients with certain conditions such as head and neck cancer).

[0025] The granules of the present disclosure or the oral preparation comprising the granules are rapidly dispersed in water. The dispersion time can be measured using an amount of granules corresponding to 1 unit dose of the active ingredient (e.g., 500 mg equivalent of gepotidacin free base, or 750 mg equivalent of gepotidacin free base) dispersed in 15 mL of water by gently swirling in a 60 mL dosing cup. As shown in the examples, the granules of the present disclosure exhibit complete dispersion in water in less than 3 minutes. In one embodiment, about 1,100 mg to about 1,800 mg of the granules of the present disclosure are completely dispersed in 15 mL of water at room temperature within 3 minutes by gently swirling in a 60 mL dosing cup. In one embodiment, about 1,100 mg of the granules of the present disclosure are completely dispersed in 15 mL of water at room temperature within 3 minutes by gently swirling in a 60 mL dosing cup. In one embodiment, about 1,800 mg of the granules of the present disclosure are completely dispersed in 15 mL of water at room temperature within 3 minutes by gently swirling in a 60 mL dosing cup. In one embodiment, about 1,000 mg of the granules of the present disclosure are completely dispersed in 15 mL of water at room temperature within 3 minutes by gently swirling in a 60 mL dosing cup. In one embodiment, about 1,500 mg of the granules of the present disclosure are completely dispersed in 15 mL of water at room temperature within 3 minutes by gently swirling in a 60 mL dosing cup.

[0026] Accordingly, in one embodiment, there is provided an oral preparation of granules or an oral preparation comprising granules, the granules comprising a) one or more active ingredients up to about 60% (w / w); and b) a soluble filler of about 15 - 75% (w / w); and c) microcrystalline cellulose of about 20 - 60% (w / w); and d) a binder of about 2 - 5% (w / w); and e) a disintegrant of about 1.5 - 15% (w / w), wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and The above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL, and one unit dose of the above-mentioned granules can be completely dispersed in 15 mL of water within 3 minutes by gently swirling in a 60 mL dosing cup.

[0027] In one embodiment, an oral formulation of granules or an oral formulation comprising the granules is provided, and the granules a) one or more active ingredients in an amount of about 0.1 to 60% (w / w), and b) a soluble filler in an amount of about 15 to 75% (w / w), and c) microcrystalline cellulose in an amount of about 20 to 60% (w / w), and d) a binder in an amount of about 2 to 5% (w / w), and e) a disintegrant in an amount of about 1.5 to 15% (w / w), and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL, and one unit dose of the above-mentioned granules can be completely dispersed in 15 mL of water within 3 minutes by gently swirling in a 60 mL dosing cup.

[0028] In one embodiment, an oral formulation of granules or an oral formulation comprising the granules is provided, and the granules a) 0.1 to 60% (w / w) of one or more active ingredients, and b) 15 to 75% (w / w) of a soluble filler, and c) 20 to 60% (w / w) of microcrystalline cellulose, and d) 2 to 5% (w / w) of a binder, and e) 1.5 to 15% (w / w) of a disintegrant, and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL, and one unit dose of the above-mentioned granules can be completely dispersed in 15 mL of water within 3 minutes by gently swirling in a 60 mL dosing cup.

[0029] As shown in the examples, the granules of the present disclosure are completely dispersed in water in less than 3 minutes. In one embodiment, 1 unit dose of the granules of the present disclosure is completely dispersed in water in less than 2 minutes. In one embodiment, 1 unit dose of the granules of the present disclosure is completely dispersed in water in less than 1 minute. In one embodiment, 1 dose of granules comprising 500 mg of API is completely dispersed in 15 mL of water within 3 minutes by gently swirling in a 60 mL dosing cup. In one embodiment, a dose of granules comprising 750 mg of API is dispersed in 15 mL of water within 3 minutes by gently swirling in a 60 mL dosing cup.

[0030] Also, the granules of the present disclosure may be compressed into tablets. In that case, the degree of dispersion is measured by dispersing 1 to 4 tablets (core weight 150 mg or less) in 5 mL of water or 5 to 8 tablets in 10 mL of water and gently swirling for 1 to 3 minutes in a 30 mL dosing cup.

[0031] The granules of the present disclosure or an oral formulation comprising the granules have good mouthfeel and palatability. The mouthfeel can be measured by standard techniques. For example, the amount of insoluble solids (such as microcrystalline cellulose) in the granules may be used as an index of mouthfeel, or the Pharmacopeia fineness of dispersion test may be used.

[0032] The free-flowability of the granules or an oral formulation comprising the granules ensures weight uniformity, and thus the uniformity of the contents, and enables the measurement of the total dose and / or the recovery from the container in which they are stored. The free-flowability of the granules of the present disclosure can be characterized by a Carr's index value of 30% or less and an FFc value of 10 or more. Thus, in one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, the granules comprising a) one or more active ingredients up to about 60% (w / w), and b) a soluble filler of about 15 - 75% (w / w), and c) microcrystalline cellulose of about 20 - 60% (w / w), d) about 2 to 5% (w / w) of a binder, and e) about 1.5 to 15% (w / w) of a disintegrant, and comprises wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL, a Carr's index value of 30% or less, and an FFc value of 10 or more.

[0033] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, the granules comprising a) about 0.1 to 60% (w / w) of one or more active ingredients, and b) about 15 to 75% (w / w) of a soluble filler, and c) about 20 to 60% (w / w) of microcrystalline cellulose, and d) about 2 to 5% (w / w) of a binder, and e) about 1.5 to 15% (w / w) of a disintegrant, and comprises wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL, a Carr's index value of 30% or less, and an FFc value of 10 or more.

[0034] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, the granules comprising a) 0.1 to 60% (w / w) of one or more active ingredients, and b) 15 to 75% (w / w) of a soluble filler, and c) 20 to 60% (w / w) of microcrystalline cellulose, and d) 2 to 5% (w / w) of a binder, and e) 1.5 to 15% (w / w) of a disintegrant, and comprises wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL, a Carr's index value of 30% or less, and an FFc value of 10 or more.

[0035] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, wherein the granules comprise: a) one or more active ingredients of up to about 60% (w / w); and b) a soluble filler of about 15 - 75% (w / w); and c) microcrystalline cellulose of about 20 - 60% (w / w); and d) a binder of about 2 - 5% (w / w); and e) a disintegrant of about 1.5 - 15% (w / w), and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL, a Carr's index value of 30% or less and an FFc value of 10 or more, and one unit dose of the granules can be dispersed in 15 mL of water within 3 minutes by gently swirling in a 60 mL dosing cup.

[0036] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, wherein the granules comprise: a) one or more active ingredients of about 0.1 - 60% (w / w); and b) a soluble filler of about 15 - 75% (w / w); and c) microcrystalline cellulose of about 20 - 60% (w / w); and d) a binder of about 2 - 5% (w / w); and e) a disintegrant of about 1.5 - 15% (w / w), and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL, a Carr's index value of 30% or less and an FFc value of 10 or more, and one unit dose of the granules can be dispersed in 15 mL of water within 3 minutes by gently swirling in a 60 mL dosing cup.

[0037] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, wherein the granules comprise: a) 0.1 to 60% (w / w) of one or more active ingredients, and b) 15 to 75% (w / w) of a soluble filler, and c) 20 to 60% (w / w) of microcrystalline cellulose, and d) 2 to 5% (w / w) of a binder, and e) 1.5 to 15% (w / w) of a disintegrant, and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the above granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL, a Carr's index value of 30% or less and an FFc value of 10 or more, and one unit dose of the above granules is dispersed in 15 mL of water within 3 minutes by gently swirling in a 60 mL dosing cup.

[0038] The suspension formed by the dispersion of the granules of the present disclosure or an oral preparation comprising the granules has fluidity and flows freely.

[0039] To achieve this desirable combination of properties, the inventors have identified several important parameters essential for rapid dispersion and palatability. This work is described in the examples.

[0040] The diameter and density of the granules are important parameters for rapid dispersion. The diameter of the granules defines the distance required for water to penetrate to the "core" of the granules. Example 1 shows that granules with a median diameter of 250 microns or less disperse within 1 minute. The density of the granules reflects the degree of pores and flow channels within the granules. Also, the presence of pores and flow channels to allow water to rapidly enter the granules affects the dispersion time. Example 1 shows that a granule density of 0.4 to 0.6 g / mL allows rapid uptake of water into the granules, thereby causing granule disintegration and release of the active ingredient. In one embodiment, the granules of the present disclosure have a granule density of about 0.45 to 0.60 g / mL.

[0041] The size and density of the granules are mainly controlled by the parameters of the granulation process (e.g., the amount of water added for granulation, the spraying rate, and the wet massing time), and the granules of a large size (e.g., over 500 microns) will then become of a smaller size in the subsequent dry milling stage. The size and density of the granules are also controlled by the grades and levels of excipients (binders, as well as soluble and insoluble fillers).

[0042] Example 1 also shows that the granules with a size of 250 microns or less in diameter are rapidly dispersed in water. In one embodiment, the granules of the present disclosure have a granule size of about 60 microns to about 250 microns. In one embodiment, the granules of the present disclosure have a granule size of about 80 microns to about 250 microns. Thus, in one embodiment, an oral formulation comprising the granules is provided, and the granules are f) up to about 60% (w / w) of one or more active ingredients, and g) about 15 - 75% (w / w) of a soluble filler, and h) about 20 - 60% (w / w) of microcrystalline cellulose, and i) about 2 - 5% (w / w) of a binder, and j) about 1.5 - 15% (w / w) of a disintegrant, and wherein the ratio of microcrystalline cellulose to the above binder is 5:1 or more, and the above granules have a diameter of about 80 to about 250 microns or less and a density of 0.4 - 0.6 g / mL.

[0043] In another embodiment, an oral formulation of the granules is provided, and the granules are f) up to about 60% (w / w) of one or more active ingredients, and g) about 15 - 75% (w / w) of a soluble filler, and h) about 20 - 60% (w / w) of microcrystalline cellulose, and i) about 2 - 5% (w / w) of a binder, and j) about 1.5 - 15% (w / w) of a disintegrant, and wherein the ratio of microcrystalline cellulose to the above binder is 5:1 or more, and The above-mentioned granules have a diameter of about 80 to about 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0044] From the above, it is clear that the physical structure of the granules affects the dispersion rate. Furthermore, as will be described later, the composition of the granules also affects the dispersion rate.

[0045] Granule composition The granules of the present disclosure comprise one or more active pharmaceutical ingredients (「API」) at a maximum of 60% (w / w). In one embodiment, the granules of the oral formulation of the present disclosure contain one, two, or three different APIs. In one embodiment, the granules of the oral formulation of the present disclosure contain one or two different APIs. In one embodiment, the granules of the oral formulation of the present disclosure contain two different APIs. In one embodiment, the granules of the oral formulation of the present disclosure contain only one kind of API.

[0046] Those skilled in the art will readily understand that the granules of the present disclosure disperse rapidly. Thus, it is clear that the physical properties of the API, particularly its solubility, do not affect the dispersion time. The examples demonstrate that three very different APIs, namely daprodustat [(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine), cabotegravir ((3R,6S)-N-[(2,4-difluorophenyl)methyl]-10-hydroxy-6-methyl-8,11-dioxo-4-oxa-1,7-diazatricyclo[7.4.0.03,7]tridec-9,12-dien-12-carboxamide), and gepotidacin, can be successfully formulated. These APIs have a wide range of solubilities from almost insoluble to very soluble (daprodustat 0.074 mg / mL, cabotegravir 2.9 mg / mL, gepotidacin 175 mg / mL, all in water at 25 °C). Thus, the examples surprisingly show that diverse APIs can be formulated into the granules of the present disclosure, and these exhibit rapid dispersion regardless of their solubility in water.

[0047] Thus, in one embodiment, the granules of the present disclosure comprise from about 0.1 to 60% (w / w) of an active ingredient. In one embodiment, the granules of the present disclosure comprise from about 0.1 to 1% (w / w) of an active ingredient. In one embodiment, the granules of the present disclosure comprise from about 2 to 9% (w / w) of an active ingredient. In one embodiment, the granules of the present disclosure comprise from about 40 to 60% (w / w) of an active ingredient. In one embodiment, the granules of the present disclosure comprise from about 45 to 60% (w / w) of an active ingredient. In one embodiment, the granules of the present disclosure comprise from about 50 to 60% (w / w) of an active ingredient. In one embodiment, the granules of the present disclosure comprise from about 55 to 60% (w / w) of an active ingredient.

[0048] In one embodiment, the active ingredient in the granules of the present disclosure is gepotidacin or a pharmaceutically acceptable salt thereof. In another embodiment, the active ingredient in the granules of the present disclosure is daprodustat or a pharmaceutically acceptable salt thereof. In another embodiment, the active ingredient in the granules of the present disclosure is cabotegravir or a pharmaceutically acceptable salt thereof.

[0049] The granules of the present disclosure may be prepared by any suitable method such as direct tableting, dry granulation, or wet granulation. In one embodiment, a wet granulation process is employed.

[0050] Those skilled in the art will understand that wet granulation can be used to form the granules of the present disclosure. Wet granulation is complex compared to other formulation technologies (e.g., direct tableting and dry granulation) and is usually only carried out when other technologies are not suitable. Thus, in one embodiment, the API in the oral formulation of the present disclosure is an API that is not suitable for formulation by direct tableting or dry granulation using a low shear blending process.

[0051] Generally, wet granulation is particularly suitable in situations where the drug load is low. This is because this technique ensures that the active pharmaceutical ingredient is uniformly dispersed and fixed in the granules. In addition, granules made by wet granulation are usually materials with better flowability than ungranulated powders (used in direct tableting) or roller-compressed granules. Granules with better flowability also contribute to the uniformity of the contents to ensure better weight control during further processing into tablets, stick packs, sachets, or bottles. Thus, the present disclosure also provides a method for manufacturing the granules of the present disclosure by wet granulation. Granules made by wet granulation also further mask the taste by reducing the surface area of the drug in contact with the taste buds.

[0052] WO2016 / 12058 discloses a dispersible tablet of vedacurine fumarate, in which silicified microcrystalline cellulose is used within the granules. However, the use of silicified microcrystalline cellulose within the granules is considered to interfere with the wet granulation process and limit the control of this process necessary to obtain granules of appropriate size and density. In fact, in WO2016 / 12058, it should be noted that the granulation process was a complex process involving a separate binder fraction consisting of a binder and a wetting agent and an "intra-granular" fraction consisting of an active ingredient, silicified microcrystalline cellulose, a disintegrant, and a glidant. When silicified microcrystalline cellulose and the glidant are omitted from the granules, the wet granulation becomes much simpler. Thus, in one embodiment, the granules of the oral formulation of the present disclosure do not contain silicified microcrystalline cellulose (SMCC) or a glidant.

[0053] In Example 2 below, it is shown that the fastest dispersion time was observed when the intra-granular microcrystalline cellulose was 20-60% (w / w), and it was also observed that this improved the robustness of the granulation process. Granules having 20-30% (w / w) microcrystalline cellulose have the best mouthfeel and palatability. Thus, in one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, the granules comprising 20-30% (w / w) microcrystalline cellulose. Further, in a specific embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, the granules comprising about 20% (w / w) microcrystalline cellulose.

[0054] A number of different grades of microcrystalline cellulose are available. One of ordinary skill in the art will understand that the selected grade should exhibit good compressibility and mouthfeel. Mouthfeel depends in part on the particle size. A size of 125 microns or less is desirable, and a size of 50 microns or less is ideal. Avicel PH101 and Ceolus KG-1000 are suitable grades. Ceolus KG-1000 is a premium grade of microcrystalline cellulose and has improved mouthfeel. In one embodiment, the MCC used in the granule formulations of the present disclosure is 50 microns or less in size.

[0055] In addition to containing the active ingredient and microcrystalline cellulose, the granules must further contain a binder. The binder may be a natural polymer such as a polysaccharide, polypeptide, or derivative thereof, or a synthetic polymer such as a polyalkylene oxide (e.g., PEG), polyacrylate, polyvinylpyrrolidone. Mixed polymers such as block copolymers and glycopeptides may also be used. In one embodiment, the binder may be selected from the group consisting of hydroxypropylmethylcellulose, povidone, maltodextrin, or starch 1500. In another embodiment, the binder may be selected from the group consisting of hydroxypropylmethylcellulose (HPMC, also known as hypromellose) and povidone.

[0056] In one embodiment, the binder is hydroxypropylmethylcellulose containing hydroxypropyl groups and methoxy groups sufficient to be water-soluble. HPMC having a methoxy substitution degree of about 19.0 to about 30.0 and a hydroxypropoxy molar substitution of about 4.0 to about 12.0 is generally water-soluble. The methoxy substitution degree refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. The hydroxypropyl molar substitution refers to the average number of moles of propylene oxide reacted with each anhydroglucose unit of the cellulose molecule. Preferred HPMC is hypromellose 2910·3 mPa·s or hypromellose 2910·5 mPa·s, particularly hypromellose 2910·3 mPa·s. Hydroxypropylmethylcellulose is the United States common name for hypromellose (see Martindale, The Extra Pharmacopoeia, 29th edition, page 1435). In the four-digit number "2910", the first two digits represent the approximate proportion of methoxyl groups, and the third and fourth digits represent the approximate percentage composition of hydroxypropoxyl groups. 3 mPa·s or 5 mPa·s is a value indicating the apparent viscosity of a 2% aqueous solution at 20°C. In one embodiment, the hydroxypropylmethylcellulose binder is hypromellose 2910·3 mPa·s (i.e., Pharmacoat® 603).

[0057] Example 3 shows that the ratio of microcrystalline cellulose to binder should be 5:1 or more in granules that are rapidly dispersed. In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, the granules comprising microcrystalline cellulose and a binder selected from HPMC or povidone in a ratio of 5:1 or more. In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, the granules comprising microcrystalline cellulose and HPMC in a ratio of 5:1 or more. In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, the granules comprising microcrystalline cellulose and a binder in a ratio of about 5:1 to 10:1. In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, the granules comprising microcrystalline cellulose and a binder in a ratio of about 5:1. In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, the granules comprising microcrystalline cellulose and a binder in a ratio of about 10:1.

[0058] The granules further contain about 15 - 75% (w / w) of a soluble filler. In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, the granules comprising microcrystalline cellulose, a binder, one or more soluble fillers, and one or more disintegrants, but no further class of excipients.

[0059] Granules comprising about 15 to 75% (w / w) of a soluble filler (e.g., mannitol) have high mechanical strength (low level of fine powder) for downstream processes (e.g., tableting, filling into bottles or sachets / stick packs). Suitable soluble fillers are polyols such as mannitol, sorbitol, maltitol, xylitol, erythritol, isomalt, lactitol, and low molecular weight dextrin, and saccharides such as lactose (including anhydrous lactose and lactose monohydrate), fructose, sucrose, dextrose, and maltose. In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, and the granules comprise mannitol. Mannitol is more preferred than lactose because it provides better tolerance especially in the pediatric population. However, it will be understood that the active ingredient may limit the soluble filler selected due to incompatibility.

[0060] By using a soluble filler in the granules, the total amount of insoluble solids in the granules is kept low and the mouthfeel is improved. Example 4 shows that 17 to 75% (w / w) of a soluble filler (e.g., mannitol) has high mechanical strength (low level of fine powder) for downstream processes. As will be understood, large variations in the soluble filler level are allowed, and thus large variations in the active ingredient level in the granules that can be compensated for by changing the soluble filler level are also allowed. In one embodiment, the soluble filler is mannitol.

[0061] Various grades of mannitol are available. As an example, Pearlitol 160C produces larger and more flowable granules compared to Pearlitol 50C.

[0062] A person skilled in the art would understand that the total amount of mannitol in the daily dose (note that multiple unit doses can be dispersed in the medium) should be within the recommended daily dose limit of 50 mg / kg / day (WHO Food additive series Toxicological monograph. 616. Mannitol (WHO Food Additives Series 21)(inchem.org)).

[0063] Example 5 shows that tablets made from granules containing 1.5 - 15% disintegrant disperse in less than 2 minutes. Any suitable disintegrant may be used in the granules. Suitable disintegrants include cross-linked polyvinylpyrrolidone, modified cellulose gums such as croscarmellose sodium (e.g., Ac-di-Sol), sodium starch glycolate, sodium carboxymethylcellulose, sodium dodecyl sulfate, processed corn starch, microcrystalline cellulose, magnesium aluminum silicate, alginic acid, alginates, powdered cellulose, crospovidone (such as Polyplasdone XL). Other possible disintegrants include xanthan gum, gellan gum, and soy polysaccharides. The optimal amount of disintegrant varies depending on which extragranular disintegrant is selected and can be readily determined by a person skilled in the art. The disintegrant swells the granules and promotes dispersion.

[0064] In one embodiment, the disintegrant is selected from croscarmellose sodium, crospovidone, and sodium starch glycolate. In one embodiment, the disintegrant is selected from croscarmellose sodium, crospovidone XL-10, and sodium starch glycolate. In one embodiment, the disintegrant is croscarmellose sodium. In a more specific embodiment, the disintegrant is croscarmellose sodium and is used in an amount of about 1.5 to 3% (w / w) in the granules. In one embodiment, the disintegrant is crospovidone. In a more specific embodiment, the disintegrant is crospovidone and is used in an amount of about 5 to 15% (w / w) in the granules. In one embodiment, the disintegrant is crospovidone XL. In a specific embodiment where the disintegrant is crospovidone, a high-quality grade of crospovidone (such as Polyplasdone XL-10) may be used. In one embodiment, the disintegrant is sodium starch glycolate. In a more specific embodiment, the disintegrant is sodium starch glycolate and is used in an amount of about 3 to 5% (w / w) in the granules. It will be understood that the active ingredient may affect the selection of the disintegrant based on incompatibility.

[0065] The granules of the present disclosure may be blended with a sweetening agent (which may also be referred to as a flavoring agent or flavor enhancer) to mask the taste and improve patient acceptability and medication compliance. Whether a separate sweetening agent is required depends on factors such as the taste of the active drug. Taste acceptability is important, especially for once-daily long-term administration in the pediatric population. Thus, although a separate sweetening agent may be required to be mixed with the granules of the present disclosure, it should be noted that some of the excipients that can be used as soluble intra-granular fillers are saccharides and may also have a favorable effect on palatability. Suitable sweetening agents include saccharides and artificial sweeteners. Five artificial sweeteners (sucralose, aspartame, neotame, acesulfame potassium, and saccharin) are approved by the FDA for pediatric use. In one embodiment, the sweetening agent is sucralose or neotame. In a further specific embodiment, the sweetening agent is neotame or sucralose and is used at 1-3% (w / w) of the oral formulation of the present disclosure. In the case of extremely bitter drugs, sucralose can also be used in combination with acesulfame potassium or neotame, or replaced with neotame alone, which is about 20 times sweeter than sucralose. In one embodiment, a sweetening agent such as neotame is used together with a flavoring agent in the oral formulation.

[0066] In one embodiment, the granules of the present disclosure do not contain any lubricant. In one embodiment, the granules of the present disclosure do not contain any surfactant.

[0067] One aspect of the present disclosure is a process for preparing the granules of the present disclosure. The granules may be prepared by any suitable method such as direct tableting, dry granulation, or wet granulation. In one embodiment, a wet granulation process is employed.

[0068] The granules of the present disclosure may also be further processed to form tablets by compression. The density of the granules of the present disclosure is not significantly affected by compression for forming tablets and remains within the range of 0.4 - 0.6 g / mL.

[0069] The present disclosure provides an oral formulation of granules or an oral formulation comprising granules, wherein the granules comprise a) one or more active ingredients at up to about 60% (w / w), and b) a soluble filler at about 15 - 75% (w / w), and c) microcrystalline cellulose at about 20 - 60% (w / w), and d) HPMC at about 2 - 5% (w / w), and e) a disintegrant at about 1.5 - 15% (w / w), and wherein the ratio of microcrystalline cellulose to HPMC is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL.

[0070] The present disclosure provides an oral formulation of granules or an oral formulation comprising granules, wherein the granules comprise a) one or more active ingredients at up to about 60% (w / w), and b) mannitol at about 15 - 75% (w / w), and c) microcrystalline cellulose at about 20 - 60% (w / w), and d) a binder at about 2 - 5% (w / w), and e) a disintegrant at about 1.5 - 15% (w / w), and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL.

[0071] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, wherein the granules comprise a) one or more active ingredients at up to about 60% (w / w), and b) mannitol at about 15 - 75% (w / w), and c) microcrystalline cellulose at about 20 - 60% (w / w), and d) HPMC at about 2 - 5% (w / w), and e) a disintegrant selected from sodium croscarmellose, sodium starch glycolate, or crospovidone at about 1.5 - 15% (w / w), and Here, the ratio of microcrystalline cellulose to HPMC is 5:1 or more, and the above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0072] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, wherein the granules a) about 0.1 to 60% (w / w) of one or more active ingredients, and b) about 15 to 75% (w / w) of mannitol, and c) about 20 to 60% (w / w) of microcrystalline cellulose, and d) about 2 to 5% (w / w) of HPMC, and e) about 1.5 to 15% (w / w) of a disintegrant selected from sodium croscarmellose, sodium starch glycolate, or crospovidone, and here, the ratio of microcrystalline cellulose to HPMC is 5:1 or more, and the above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0073] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, wherein the granules a) up to about 60% (w / w) of one or more active ingredients, and b) about 15 to 75% (w / w) of mannitol, and c) about 20 to 30% (w / w) of microcrystalline cellulose, and d) about 2 to 5% (w / w) of HPMC, and e) about 1.5 to 15% (w / w) of a disintegrant selected from sodium croscarmellose, sodium starch glycolate, or crospovidone, and here, the ratio of microcrystalline cellulose to HPMC is 5:1 or more, and the above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0074] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, wherein the granules comprise a) one or more active ingredients in an amount of about 0.1 to 60% (w / w); and b) mannitol in an amount of about 15 to 75% (w / w); and c) microcrystalline cellulose in an amount of about 20 to 30% (w / w); and d) HPMC in an amount of about 2 to 5% (w / w); and e) a disintegrant selected from croscarmellose sodium, sodium starch glycolate, or crospovidone in an amount of about 1.5 to 15% (w / w), wherein the ratio of microcrystalline cellulose to HPMC is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0075] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, wherein the granules comprise a) one or more active ingredients in a maximum amount of about 60% (w / w); and b) mannitol in an amount of about 15 to 75% (w / w); and c) microcrystalline cellulose in an amount of about 20 to 30% (w / w); and d) HPMC in an amount of about 2 to 5% (w / w); and e) a disintegrant selected from croscarmellose sodium, sodium starch glycolate, or crospovidone in an amount of about 1.5 to 15% (w / w), wherein the ratio of microcrystalline cellulose to HPMC is about 5:1 to 10:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0076] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, wherein the granules comprise a) one or more active ingredients in an amount of about 0.1 to 60% (w / w); and b) mannitol in an amount of about 15 to 75% (w / w); and c) about 20 to 30% (w / w) of microcrystalline cellulose, and d) about 2 to 5% (w / w) of HPMC, and e) about 1.5 to 15% (w / w) of a disintegrant selected from sodium croscarmellose, sodium starch glycolate, or crospovidone, and comprises, wherein the ratio of microcrystalline cellulose to HPMC is about 5:1 to 10:1 or more, and the above granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0077] In one embodiment, any of the above formulations of the present disclosure further comprises about 1 to 3% (w / w) of a sweetener.

[0078] In one embodiment, the granules of the present disclosure are presented in a single-use stick pack or sachet. In another embodiment, the granules of the present disclosure are presented in a single-use or multi-use bottle or container. Accordingly, the present disclosure provides a container such as a stick pack, sachet, bottle, or other container containing the granules of the present disclosure. The granules of the present disclosure are preferably taken by dissolving in water.

[0079] In one embodiment, an oral formulation of the granules or an oral formulation comprising the granules is provided, the granules are in a single-use or multi-use bottle or container, and the granules are a) up to about 60% (w / w) of one or more active ingredients, and b) about 15 to 75% (w / w) of a soluble filler, and c) about 20 to 60% (w / w) of microcrystalline cellulose, and d) about 2 to 5% (w / w) of a binder, and e) about 1.5 to 15% (w / w) of a disintegrant, and comprises, wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the above granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL, a Carr's index value of 30% or less and an FFc value of 10 or more.

[0080] In one embodiment, an oral formulation of granules or an oral formulation comprising granules is provided, the granules are in a single-use container, and the granules a) one or more active ingredients up to about 60% (w / w); and b) a soluble filler of about 15 - 75% (w / w); and c) microcrystalline cellulose of about 20 - 60% (w / w); and d) a binder of about 2 - 5% (w / w); and e) a disintegrant of about 1.5 - 15% (w / w), and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and wherein the granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL, a Carr's index value of 30% or less, and an FFc value of 10 or more.

[0081] In one embodiment, an oral formulation of granules or an oral formulation comprising granules is provided, the granules are in a single-use container, and the granules a) one or more active ingredients up to about 60% (w / w); and b) a soluble filler of about 15 - 75% (w / w); and c) microcrystalline cellulose of about 20 - 60% (w / w); and d) a binder of about 2 - 5% (w / w); and e) a disintegrant of about 1.5 - 15% (w / w), and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL, and one unit dose of the granules is completely dispersed in 15 mL of water within 3 minutes by gently swirling in a 60 mL dosing cup.

[0082] Gepotidacin, Cabotegravir, and Daprodustat Granules In one embodiment, the granules of the present disclosure comprise gepotidacin or a pharmaceutically acceptable salt thereof.

[0083] International Patent Application Publication No. WO2021 / 219637 (incorporated herein by reference in its entirety) describes certain crystalline forms of gepotidacin including gepotidacin mesylate dihydrate, gepotidacin mesylate anhydrate, gepotidacin mesylate monohydrate, and gepotidacin anhydrate (free base).

[0084] As described above, gepotidacin is cohesive or sticky, has poor fluidity, and is bitter. For this reason, formulation, particularly formulation for patients with difficulty swallowing (e.g., pediatric patients), is difficult. These difficult properties of gepotidacin are overcome by the oral formulations of the present disclosure that are surprisingly free-flowing and dispersible in water despite the inherent properties of gepotidacin.

[0085] In one embodiment, the granules of the present disclosure comprise gepotidacin mesylate dihydrate, gepotidacin mesylate anhydrate, and / or gepotidacin anhydrate.

[0086] In one embodiment, the granules of the present disclosure comprise gepotidacin mesylate dihydrate.

[0087] In one embodiment, the granules of the present disclosure comprise about 40 - 60% (w / w) gepotidacin or a pharmaceutically acceptable salt thereof. In one embodiment, the granules of the present disclosure comprise about 45 - 60% (w / w) gepotidacin or a pharmaceutically acceptable salt thereof. In one embodiment, the granules of the present disclosure comprise about 50 - 60% (w / w) gepotidacin or a pharmaceutically acceptable salt thereof. In one embodiment, the granules of the present disclosure comprise about 55 - 60% (w / w) gepotidacin or a pharmaceutically acceptable salt thereof. In one embodiment, the granules of the present disclosure comprise about 60% (w / w) gepotidacin or a pharmaceutically acceptable salt thereof. In one embodiment, the granules of the present disclosure comprise about 55, 56, 57, 58, 59, or 60% (w / w) gepotidacin or a pharmaceutically acceptable salt thereof.

[0088] In one embodiment, the granules of the present disclosure comprise about 40 to 60% (w / w) of gepotidacin mesylate gepotidacin dihydrate. In one embodiment, the granules of the present disclosure comprise about 45 to 60% (w / w) of gepotidacin mesylate dihydrate. In one embodiment, the granules of the present disclosure comprise about 50 to 60% (w / w) of gepotidacin mesylate dihydrate. In one embodiment, the granules of the present disclosure comprise about 55 to 60% (w / w) of gepotidacin mesylate gepotidacin dihydrate. In one embodiment, the granules of the present disclosure comprise about 55, 56, 57, 58, 59, or 60% (w / w) of gepotidacin mesylate dihydrate. In one embodiment, the granules of the present disclosure comprise about 60% (w / w) of gepotidacin mesylate dihydrate.

[0089] Thus, in one embodiment, the present disclosure provides an oral formulation of the granules or an oral formulation comprising the granules, wherein the granules a) up to about 60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15 to 75% (w / w) of a soluble filler, and c) about 20 to 60% (w / w) of microcrystalline cellulose, and d) about 2 to 5% (w / w) of a binder, and e) about 1.5 to 15% (w / w) of a disintegrant, and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0090] In one embodiment, an oral formulation of the granules or an oral formulation comprising the granules is provided, wherein the granules a) up to about 60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15 to 75% (w / w) of a soluble filler, and c) about 20 to 60% (w / w) of microcrystalline cellulose, and d) about 2 to 5% (w / w) of a binder, and e) about 1.5 to 15% (w / w) of a disintegrant, and wherein Here, the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the above-mentioned granules have a diameter of about 80 to about 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0091] In one embodiment, the granules comprise about 40-60% (w / w) gepotidacin or a pharmaceutically acceptable salt thereof. In one embodiment, the granules comprise about 45-60% (w / w) gepotidacin or a pharmaceutically acceptable salt thereof. In one embodiment, the granules comprise about 50-60% (w / w) gepotidacin or a pharmaceutically acceptable salt thereof. In one embodiment, the granules comprise about 55-60% (w / w) gepotidacin or a pharmaceutically acceptable salt thereof.

[0092] In one embodiment, the soluble filler is mannitol.

[0093] In one embodiment, the binder is HPMC.

[0094] In one embodiment, the disintegrant is selected from croscarmellose sodium, sodium starch glycolate, or crospovidone. In one embodiment, the disintegrant is croscarmellose sodium.

[0095] In one embodiment, the ratio of microcrystalline cellulose to HPMC is about 5:1 to 10:1.

[0096] Thus, in one embodiment, the present disclosure provides an oral formulation of the granules or an oral formulation comprising the granules, wherein the granules a) up to about 60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15-75% (w / w) of mannitol, and c) about 20-60% (w / w) of microcrystalline cellulose, and d) about 2-5% (w / w) of the binder, and e) about 1.5-15% (w / w) of the disintegrant, and Here, the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0097] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, and the granules a) up to about 60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15 to 75% (w / w) of a soluble filler, and c) about 20 to 60% (w / w) of microcrystalline cellulose, and d) about 2 to 5% (w / w) of HPMC, and e) about 1.5 to 15% (w / w) of a disintegrant, and here, the ratio of microcrystalline cellulose to HPMC is 5:1 or more, and the above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0098] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, and the granules a) up to about 60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15 to 75% (w / w) of a soluble filler, and c) about 20 to 60% (w / w) of microcrystalline cellulose, and d) about 2 to 5% (w / w) of a binder, and e) about 1.5 to 15% (w / w) of a disintegrant, and here, the ratio of microcrystalline cellulose to the binder is about 5:1 to 10:1 or more, and the above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0099] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising the granules, and the granules a) up to about 60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15 to 75% (w / w) of a soluble filler, and c) about 20 to 30% (w / w) of microcrystalline cellulose, and d) about 2 to 5% (w / w) of a binder, and e) about 1.5 to 15% (w / w) of a disintegrant, and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0100] In one embodiment, the present disclosure provides an oral formulation of the granules or an oral formulation comprising the granules, and the granules a) about 50 to 60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15 to 75% (w / w) of a soluble filler, and c) about 20 to 60% (w / w) of microcrystalline cellulose, and d) about 2 to 5% (w / w) of a binder, and e) about 1.5 to 15% (w / w) of a disintegrant, and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0101] In one embodiment, the present disclosure provides an oral formulation of the granules or an oral formulation comprising the granules, and the granules a) about 50 to 60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15 to 26.5% (w / w) of a soluble filler, and c) about 20 to 31.5% (w / w) of microcrystalline cellulose, and d) about 2 to 5% (w / w) of a binder, and e) about 1.5 to 15% (w / w) of a disintegrant, and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0102] In one embodiment, the present disclosure provides an oral formulation of gepotidacin granules, and this oral formulation comprises a) about 50-60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15-26.5% (w / w) of mannitol, and c) about 20-31.5% (w / w) of microcrystalline cellulose, and d) about 2-5% (w / w) of HPMC, and e) about 1.5-3% (w / w) of croscarmellose sodium, and wherein the ratio of microcrystalline cellulose to HPMC is 5:1 or more, and the above granules have a diameter of 250 microns or less and a density of 0.4-0.6 g / mL.

[0103] In one embodiment, the present disclosure provides an oral formulation of gepotidacin granules, and this oral formulation comprises a) about 50-60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15-26.5% (w / w) of mannitol, and c) about 20-31.5% (w / w) of microcrystalline cellulose, and d) about 2-5% (w / w) of HPMC, and e) about 1.5-3% (w / w) of croscarmellose sodium, and wherein the ratio of microcrystalline cellulose to HPMC is about 5:1 to 10:1 or more, and the above granules have a diameter of 250 microns or less and a density of 0.4-0.6 g / mL.

[0104] In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, and the granules comprise a) about 55-60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15-21.5% (w / w) of a soluble filler, and c) about 20-26.5% (w / w) of microcrystalline cellulose, and d) about 2 to 5% (w / w) of a binder, and e) about 1.5 to 15% (w / w) of a disintegrant, and comprises, wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0105] In one embodiment, the oral formulation of gepotidacin of the present disclosure further comprises a sweetening agent. In one embodiment, the sweetening agent is added at about 1 to 3% (w / w) of the oral formulation. In one embodiment, the sweetening agent is added after the granules of the present disclosure are formed (i.e., outside the granules) and blended with the granules. In one embodiment, neotame is added to and blended with the gepotidacin granules of the present disclosure (i.e., outside the granules). In one embodiment, neotame is added at about 1% (w / w).

[0106] That is, in one embodiment, an oral formulation comprising granules and an extra-granular portion is provided. The granules are as defined herein. The extra-granular portion may include a sweetening agent and / or a flavoring agent. Here, the sweetening agent is selected from the group consisting of sucralose, aspartame, neotame, acesulfame potassium, and saccharin. In one embodiment, the sweetening agent is sucralose or neotame. In a more specific embodiment, the sweetening agent is neotame or sucralose and is present in an amount of about 1 to 3% (w / w) of the total oral formulation (granules and extra-granular portion). In one embodiment, the flavoring agent is present in an amount of about 2 to 3% (w / w) of the total oral formulation.

[0107] In one embodiment, the extra-granular portion may further include a lubricant. In one embodiment, the lubricant is present in an amount of 0.5 to 3% (w / w) of the total oral formulation. In one embodiment, the lubricant is present in an amount of 0.5 to 1.5% (w / w) of the total oral formulation.

[0108] Suitable lubricants are pharmaceutically acceptable lubricants such as magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, etc. The selection of the lubricant must take into account incompatibility with the active ingredient. In one embodiment, the lubricant is magnesium stearate (e.g., LIGAMED). In a more specific embodiment, the lubricant is magnesium stearate and is used at a level of 1% (w / w) of the total oral formulation.

[0109] In one embodiment, the present disclosure provides an oral formulation of gepotidacin granules or an oral formulation comprising gepotidacin granules, wherein the granules a) about 50 - 60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15 - 75% (w / w) of mannitol, and c) about 20 - 31.5% (w / w) of microcrystalline cellulose, and d) about 2 - 5% (w / w) of HPMC, and e) about 1.5 - 3% (w / w) of croscarmellose sodium, and wherein the ratio of microcrystalline cellulose to HPMC is 5:1 or more, and the above granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL, and optionally, the above granules are blended with about 1 - 3% (w / w) of a sweetener.

[0110] In one embodiment, the present disclosure provides an oral formulation of gepotidacin granules or an oral formulation comprising gepotidacin granules, wherein the granules a) about 50 - 60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15 - 26.5% (w / w) of mannitol, and c) about 20 - 31.5% (w / w) of microcrystalline cellulose, and d) about 2 - 5% (w / w) of HPMC, and e) about 1.5 - 3% (w / w) of croscarmellose sodium, Here, the ratio of microcrystalline cellulose to HPMC is 5:1 or more, and the above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL, and, optionally, the above-mentioned granules are blended with about 1 - 3% (w / w) of a sweetening agent.

[0111] In one embodiment, the present disclosure provides an oral formulation comprising gepotidacin granules, the granules comprising a) about 50 - 60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15 - 26.5% (w / w) of mannitol, and c) about 20 - 31.5% (w / w) of microcrystalline cellulose, and d) about 2 - 5% (w / w) of HPMC, and e) about 1.5 - 3% (w / w) of croscarmellose sodium, and here, the ratio of microcrystalline cellulose to HPMC is 5:1 or more, and the above-mentioned granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL, and, optionally, the above-mentioned granules are blended with about 1 - 3% (w / w) of a sweetening agent.

[0112] In another embodiment, the present disclosure provides an oral formulation comprising gepotidacin granules, the granules comprising a) about 50 - 60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof, and b) about 15 - 26.5% (w / w) of mannitol, and c) about 20 - 31.5% (w / w) of microcrystalline cellulose, and d) about 2 - 5% (w / w) of HPMC, and e) about 1.5 - 3% (w / w) of croscarmellose sodium, and here, the ratio of microcrystalline cellulose to HPMC is 5:1 or more, and the above-mentioned granules have a diameter of about 80 - about 250 microns or less and a density of 0.4 - 0.6 g / mL, And, optionally, the granules are blended with about 1-3% (w / w) sweetener.

[0113] In an embodiment, the present disclosure provides an oral formulation of gepotidacin granules, wherein a unit dose of granules comprising 500 mg or 750 mg of gepotidacin (measured as the free base) completely disperses in 15 mL of water within 3 minutes by gently swirling in a 60 mL dosing cup.

[0114] In one embodiment, the oral formulation of gepotidacin or a pharmaceutically acceptable salt thereof according to the present disclosure is presented in a single-use stick pack or sachet. Accordingly, the present disclosure provides a single-use stick pack or sachet containing the granules of the present disclosure comprising gepotidacin or a pharmaceutically acceptable salt thereof. In one embodiment, the stick pack or sachet contains a dose of gepotidacin (measured as the free base) of 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg.

[0115] In one embodiment, the stick pack or sachet contains a unit dose of gepotidacin (measured as the free base) of 325 mg, 500 mg, 650 mg, or 750 mg. In one embodiment, the stick pack or sachet contains a unit dose of gepotidacin (measured as the free base) of 500 mg or 750 mg.

[0116] The present disclosure also provides a bottle or container containing the granules of the present disclosure comprising gepotidacin or a pharmaceutically acceptable salt thereof. Accordingly, in another embodiment, the oral formulation of gepotidacin or a pharmaceutically acceptable salt thereof is in a single-use bottle or container containing 1,500 mg of gepotidacin (measured as the free base).

[0117] In one embodiment, the granules of the present disclosure contain daprodustat or a pharmaceutically acceptable salt thereof. Daprodustat is the USAN, INN, and JAN name of the compound N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine (the IUPAC name of this compound is N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine). Daprodustat is a HIF prolyl hydroxylase inhibitor and has been developed for the treatment of anemia associated with chronic kidney disease in patients on dialysis and in patients not on dialysis. Anemia associated with chronic kidney disease rarely occurs in children including 3-month-old infants. As described above, dialysis patients need to limit their dietary intake. Therefore, for daprodustat, a dispersible oral formulation (e.g., granules or tablets) that can be rapidly dispersed in a very small amount to produce a palatable suspension is highly desirable. Accordingly, in one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, the granules comprising daprodustat or a pharmaceutically acceptable salt thereof. Here, the unit dose of the granules is dispersed in 5 mL of water by gently swirling in a 30 mL dosing cup for 1 to 3 minutes. The unit dose of granules may be in the form of a tablet.

[0118] Daprodustat exhibits keto / enol tautomerism. All tautomers of daprodustat (including mixtures thereof) are intended to be encompassed within the scope of the present disclosure.

[0119] Accordingly, in one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, the granules comprising a) up to about 60% (w / w) of daprodustat or a pharmaceutically acceptable salt thereof, and b) about 15 - 75% (w / w) of a soluble filler, and c) about 20 - 60% (w / w) of microcrystalline cellulose, and d) about 2 - 5% (w / w) of a binder, and e) about 1.5 to 15% (w / w) of a disintegrant, and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the above granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0120] In one embodiment, the granules of the present disclosure comprise cabotegravir or a pharmaceutically acceptable salt thereof, such as sodium cabotegravir. Thus, in one embodiment, the present disclosure provides an oral formulation of the granules or an oral formulation comprising the granules, the granules comprising a) up to about 60% (w / w) of cabotegravir or a pharmaceutically acceptable salt thereof, and b) about 15 to 75% (w / w) of a soluble filler, and c) about 20 to 60% (w / w) of microcrystalline cellulose, and d) about 2 to 5% (w / w) of a binder, and e) about 1.5 to 15% (w / w) of a disintegrant, and wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the above granules have a diameter of 250 microns or less and a density of 0.4 to 0.6 g / mL.

[0121] In one embodiment, the present disclosure provides an oral formulation of the following granules:

[0122]

Table A

[0123] Medical Use The present disclosure provides an oral formulation of the present disclosure for use in therapy.

[0124] The present application provides a method for treating a bacterial infection, comprising administering to a human subject in need of treatment for a bacterial infection an oral formulation of the present disclosure comprising gepotidacin or a pharmaceutically acceptable salt thereof. The bacterial infection can be caused by a wide range of organisms including both Gram-negative and Gram-positive organisms, and the 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 with gepotidacin are disclosed in WO2008 / 128942, WO2016 / 027249, and WO2020 / 201833, all of which are incorporated herein by reference in their entirety.

[0125] 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.

[0126] Accordingly, the present disclosure provides an oral formulation of the present disclosure comprising gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of bacterial infections in a human subject. In one embodiment, the infection is uUTI or gonorrhea. The present disclosure also provides the use of gepotidacin or a pharmaceutically acceptable salt thereof in the manufacture of an oral formulation of the present disclosure for use in the treatment of bacterial infections in a human subject. In one embodiment, the infection is uUTI or gonorrhea. In another embodiment, the present disclosure provides a method for treating it in a human subject in need of treatment for a bacterial infection, the method comprising administering to the human granules of the present disclosure comprising gepotidacin or a pharmaceutically acceptable salt thereof.

[0127] In certain embodiments, the human subject is a pediatric patient under 18 years of age. In one embodiment, the human subject is a pediatric patient under 12 years of age. In one embodiment, the human subject is a pediatric patient under 6 years of age. In one embodiment, the human subject is a pediatric patient between 6 and 12 years of age. In one embodiment, the human subject is a pediatric patient between 3 months and 12 years of age. In another embodiment, the human subject is a pediatric patient under 8 years of age. In a more particular embodiment, the human subject is a pediatric patient from 3 months to 8 years of age.

[0128] In one embodiment, the human subject is a pediatric, adolescent, or adult female.

[0129] As used herein, the term "treatment" refers to alleviating a designated condition, removing or reducing one or more symptoms of a condition, slowing or removing the progression of a condition, and preventing or delaying the recurrence of a condition in a patient or subject previously afflicted with or diagnosed with the condition.

[0130] As used herein, the term "effective amount" means an amount of a drug or agent that elicits a biological or medical response in a tissue, system, animal, or human subject, for example, as determined by a researcher or clinician.

[0131] In one embodiment, the present application provides a method for treating urinary tract infection (UTI), comprising administering to a human subject in need thereof a therapeutically effective amount of the granules of the present disclosure, wherein gepotidacin is administered at 500 mg, 750 mg, or 1500 mg, twice a day, at 6- to 12-hour intervals, depending on the age group and / or body weight.

[0132] In one embodiment, the present application provides a method for treating urinary tract infection (UTI), comprising administering to a human subject in need thereof a therapeutically effective amount of the gepotidacin granules of the present disclosure, wherein the subject has a body weight of 10-20 kg, and the gepotidacin granules are administered at 500 mg, twice a day, at 6-12 hour intervals for 2 days, 3 days, 4 days, or 5 days. In one embodiment, the present application provides a method for treating urinary tract infection (UTI), comprising administering to a human subject in need thereof a therapeutically effective amount of the gepotidacin granules of the present disclosure, wherein the subject has a body weight of 10-20 kg, and the gepotidacin granules are administered at 500 mg, twice a day, at 6-12 hour intervals for 5 days.

[0133] In one embodiment, the present application provides a method for treating urinary tract infection (UTI), comprising administering to a human subject in need thereof a therapeutically effective amount of the gepotidacin granules of the present disclosure, wherein the subject has a body weight of 20-40 kg, and the gepotidacin granules are administered at 750 mg, twice a day, at 6-12 hour intervals for 2 days, 3 days, 4 days, or 5 days. In one embodiment, the present application provides a method for treating urinary tract infection (UTI), comprising administering to a human subject in need thereof a therapeutically effective amount of the gepotidacin granules of the present disclosure, wherein the subject has a body weight of 20-40 kg, and the gepotidacin granules are administered at 750 mg, twice a day, at 6-12 hour intervals for 5 days. In one embodiment, the present application provides a method for treating urinary tract infection (UTI), comprising administering to a human subject in need thereof a therapeutically effective amount of the gepotidacin granules of the present disclosure, wherein the subject has a body weight of 40 kg or more, and the gepotidacin granules are administered at 1,500 mg, twice a day, at 6-12 hour intervals for 2 days, 3 days, 4 days, or 5 days. In one embodiment, the present application provides a method for treating urinary tract infection (UTI), comprising administering to a human subject in need thereof a therapeutically effective amount of the gepotidacin granules of the present disclosure, wherein the subject has a body weight of 40 kg or more, and the gepotidacin granules are administered at 1,500 mg, twice a day, at 6-12 hour intervals for 5 days.

[0134] In one embodiment, the present application provides a method of treating urinary tract infection (UTI), which comprises administering to a human subject in need thereof a therapeutically effective amount of the gepotidacin granules of the present disclosure, wherein the subject is 2 to 6 years old, and the gepotidacin granules are administered at 500 mg, twice a day, at 6- to 12-hour intervals for 2, 3, 4, or 5 days. In one embodiment, the present application provides a method of treating urinary tract infection (UTI), which comprises administering to a human subject in need thereof a therapeutically effective amount of the gepotidacin granules of the present disclosure, wherein the subject is 2 to 6 years old, and the gepotidacin granules are administered at 500 mg, twice a day, at 6- to 12-hour intervals for 5 days.

[0135] In one embodiment, the present application provides a method of treating urinary tract infection (UTI), which comprises administering to a human subject in need thereof a therapeutically effective amount of the gepotidacin granules of the present disclosure, wherein the subject is 6 to 12 years old, and the gepotidacin granules are administered at 750 mg, twice a day, at 6- to 12-hour intervals for 2, 3, 4, or 5 days. In one embodiment, the present application provides a method of treating urinary tract infection (UTI), which comprises administering to a human subject in need thereof a therapeutically effective amount of the gepotidacin granules of the present disclosure, wherein the subject is 6 to 12 years old, and the gepotidacin granules are administered at 750 mg, twice a day, at 6- to 12-hour intervals for 5 days.

[0136] In one embodiment, the present application provides a method for treating urinary tract infection (UTI), which comprises administering to a human subject in need thereof gepotidacin granules of the present disclosure in a therapeutically effective amount, wherein the subject is 12 years of age or older, and the gepotidacin granules are administered at 1,500 mg twice a day at intervals of 6 to 12 hours for 2 days, 3 days, 4 days, or 5 days. In one embodiment, the present application provides a method for treating urinary tract infection (UTI), which comprises administering to a human subject in need thereof gepotidacin granules of the present disclosure in a therapeutically effective amount, wherein the subject is 12 years of age or older, and the gepotidacin granules are administered at 500 mg twice a day at intervals of 6 to 12 hours for 5 days.

[0137] In one embodiment, in any of the above-described methods for treating UTI of the present disclosure, the twice-daily dosing is performed at approximately 12-hour intervals. In one embodiment, the UTI is a simple UTI. In particular, the granules of the present application are presented as unit doses and are preferably administered 1 to 5 times a day, for example, once or twice a day to achieve the desired effect.

[0138] In one embodiment, the gepotidacin granules of the present disclosure are administered twice a day. In one embodiment, gepotidacin is administered on any of 2, 3, 4, 5, 6, or 7 consecutive schedules. In one embodiment, in any aspect of the present application, gepotidacin is administered on a 5-day consecutive schedule.

[0139] In another embodiment, the present application provides a method for treating an infection caused by Neisseria gonorrhoeae, which comprises administering to a human subject in need thereof gepotidacin granules disclosed herein in a therapeutically effective amount, wherein the gepotidacin granules are administered twice, each at 3,000 mg, at intervals of 6 to 12 hours. In one embodiment, the gepotidacin granules are administered twice, each at 3,000 mg, at intervals of 10 to 12 hours.

[0140] The granules of daprodustat may be used for treatment, more specifically for the treatment of anemia. In certain embodiments, the granules of daprodustat of the present disclosure may be used for the treatment of anemia associated with chronic kidney disease (also known as renal anemia). In yet another embodiment, the present disclosure provides the use of daprodustat or a pharmaceutically acceptable salt thereof in the manufacture of the daprodustat granules of the present disclosure for use in the treatment of anemia caused by chronic kidney disease. In another embodiment, the present disclosure provides a method of treating a subject in need of treatment for anemia caused by chronic kidney disease, the method comprising administering to the subject the daprodustat granules of the present disclosure.

[0141] Manufacture One aspect of the present disclosure is a process for preparing the granules of the present disclosure. The granules may be prepared by any suitable method such as direct tableting, dry granulation, or wet granulation. In one embodiment, a wet granulation process is employed. In wet granulation, the granules may be prepared by contacting or mixing the relevant components with a medium which may be aqueous or non-aqueous or a combination thereof. In one embodiment, the medium is water (in an appropriate amount), more specifically purified water (in an appropriate amount). Such a wet granulation process is, in one embodiment, a batch high-shear granulation process. By using a batch high-shear wet granulation process, the granule size is better controlled and the fines level is lower compared to top-spray granulation or dry granulation (i.e., roller compaction).

[0142] As shown in Example 4, the use of a soluble filler in the granules improves wet granulation, and granules comprising 15 - 75% (w / w) of a soluble filler (e.g., mannitol) have high mechanical strength (low fines level) for downstream processes.

[0143] By using a batch high-shear wet granulation process, the granule properties (flow properties, control of particle size distribution, fines level) are improved, and the palatability of the granules is improved by reducing the drug surface area in contact with the taste buds.

[0144] The following are examples of embodiments:

[0145] 1. An oral formulation of granules, comprising: a) one or more active ingredients at up to about 60% (w / w); and b) a soluble filler at about 15 - 75% (w / w); and c) microcrystalline cellulose at about 20 - 60% (w / w); and d) a binder at about 2 - 5% (w / w); and e) a disintegrant at about 1.5 - 15% (w / w), wherein the ratio of microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL. Oral formulation of granules.

[0146] 2. The oral formulation according to clause 1, wherein the granules have a Carr's index value of 30% or less and an FFc value of 10 or more.

[0147] 3. The oral formulation according to any one of clauses 1 or 2, wherein one unit dose of the granules is completely dispersed in 15 mL of water within 3 minutes by gently swirling in a 60 mL dosing cup.

[0148] 4. The oral formulation according to any one of clauses 1 - 3, wherein the binder is HPMC or povidone.

[0149] 5. The oral formulation according to any one of clauses 1 - 4, wherein the ratio of the microcrystalline cellulose to the binder is about 5:1 - 10:1.

[0150] 6. The oral formulation according to any one of clauses 1 - 5, wherein the soluble filler is mannitol.

[0151] 7. The oral formulation according to any one of clauses 1 - 6, wherein the disintegrant is selected from croscarmellose sodium, crospovidone, and sodium starch glycolate.

[0152] 8. An oral preparation according to any one of clauses 1 to 7, wherein the active ingredient is gepotidacin or a pharmaceutically acceptable salt thereof.

[0153] 9. An oral preparation according to clause 8, wherein the granules comprise gepotidacin mesylate dihydrate.

[0154] 10. An oral preparation according to any one of clauses 1 to 9 for use in therapy.

[0155] 11. An oral preparation according to any one of clauses 8 to 9 for use in the treatment of bacterial infections in a human subject.

[0156] 12. Use of gepotidacin or a pharmaceutically acceptable salt thereof in the manufacture of an oral preparation according to any one of clauses 1 to 9 for the treatment of bacterial infections in a human subject.

[0157] 13. A method of treating a bacterial infection, the method comprising administering to a human subject in need thereof a therapeutically effective amount of an oral preparation according to any one of clauses 8 to 9.

[0158] 14. The use or method according to any one of clauses 12 to 13, wherein the human subject is a pediatric patient under 12 years of age.

[0159] 15. A method for manufacturing an oral preparation according to any one of clauses 1 to 9, wherein the granules are formed by wet granulation.

Example

[0160] Dispersion time measurement protocol: · Method 1 (granules) : According to the patient instructions, the dispersion time is measured by dispersing an amount of granules corresponding to 1 unit dose of the API (for example, corresponding to 750 mg of free gepotidacin) in 15 mL of water by gently swirling in a 60 mL dosing cup. Measure the time until a uniform fine dispersion is formed. · Method 2 (tablets): The disintegration property is measured using the USP method <701>. · Method 3 (tablets) : According to the patient instructions, the dispersibility is measured by dispersing 1 - 4 tablets in 5 mL of water and 5 - 8 tablets in 10 mL of water by gently swirling in a 30 mL dosing cup for 1 - 3 minutes. It was observed that the dispersion times measured by Method 2 and Method 3 showed a good correlation. Method 1 was used in all examples with granules. Method 2 or Method 3 was used in all examples with tablets.

[0161] Example 1 - Particle size The granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL. These granules pass the European Pharmacopoeia dispersion fineness test and form a fine and uniform dispersion by dispersing extremely rapidly in water in less than 60 seconds. Granules with a median diameter of 300 microns are too large and fail the European Pharmacopoeia dispersion fineness test.

[0162] All of the following granules have good flow properties and good content uniformity, with a Carr's index of less than 30% and an FFc value of 10 or more.

[0163]

Table 1

[0164] The composition of Formulation 4 is shown in Table 2 below.

[0165]

Table 2

[0166] As described above, the oral formulation may further contain an extra - granular part. Examples of oral formulations comprising the granules and the extra - granular part of Formulation 4 are shown in the following table.

[0167]

Table 2A

[0168] Example 2 - MCC content Table 3a shows that granules containing 20 - 60% (w / w) microcrystalline cellulose (MCC) disperse rapidly in water. Dispersion test method 1 was used. The granule median diameter of formulation 4 used in this example was 149 microns (the granule sizes of formulations 5 and 6 were not tested). Among the amounts tested, the fastest dispersion time of gepotidacin granules was observed with 20% (w / w) microcrystalline cellulose, which was also optimal for the robustness of the granulation process.

[0169]

Table 3A

[0170] Table 3b shows the rapid dispersion times of tablets made from granules containing 20 - 60% (w / w) microcrystalline cellulose (MCC). Dispersion test methods 2 and 3 were used. Although the dosage forms tested were tablets, due to the granule size, density, and composition, the granules in the tablets dispersed the tablets rapidly. Compression into tablets may make granule dispersion more difficult; however, the results show complete dispersion of the tablets in less than 2 minutes.

[0171]

Table 3B

[0172] Table 4 shows the compositions of formulations 1, 2, 3, 4, 5, 6, 8, and 9. The components within the granules shown in the table are the components of the granules. The additional tablet components of formulations 1, 2, 3, 8, and 9 are shown as "tablet formulations" in the table.

[0173]

Table 4

[0174] Example 3 - MCC Binder Ratio Table 5 shows that gepotidacin granules with an MCC: binder ratio of 5:1 to 10:1 disperse extremely rapidly in water.

[0175] [Table 5]

[0176] The compositions of Formulation 4 and Formulation 7 are shown in Table 6.

[0177] [Table 6]

[0178] Example 4 - Soluble filler Table 7 shows that granules comprising a soluble filler in addition to MCC and tablets made from such granules have a low amount of insoluble solids and thus improved mouthfeel.

[0179] Formulation 4 was tested both as granules and as tablets. The dispersion time of Formulation 4 was measured from the granules (without addition of extragranular components, before compression). The dispersion times of Tablet Formulation 1, Tablet Formulation 3, Tablet Formulation 4, and Tablet Formulation 8 were measured from tablet dosage forms with a target average tablet tensile strength of 2 MPa (±0.5 MPa). The granules in the tablets, due to their size, density, and composition, disperse the tablets rapidly even when compressed into tablets. Compression into tablets can potentially make granule dispersion more difficult; however, the results show complete dispersion in less than 2 minutes.

[0180] [Table 7]

[0181] The compositions of Formulation 1, Formulation 3, Formulation 4, and Formulation 8 are shown in Table 8. As mentioned above, Formulation 4 was tested separately both as granules consisting of only the following intra-granular constituents and as compressed tablets consisting of the following tablet formulation constituents.

[0182]

Table 8

[0183] Example 5 - Disintegrant Table 9 shows that granules containing an intra-granular disintegrant (e.g., croscarmellose sodium, sodium starch glycolate, and crospovidone XL-10) disperse in less than 3 minutes when compressed into tablets at a target average tensile strength of 2 MPa (±0.5 MPa). By using 1.5 - 3% (w / w) of croscarmellose sodium, 5 - 15% (w / w) of crospovidone XL, and 3 - 5% (w / w) of sodium starch glycolate in the granules, we successfully produced a fast-dispersing drug product (dispersing in 30 seconds). The dispersion / disintegration of the tablets was measured using Test Method 2 and Test Method 3 described above. Table 9 shows the disintegration times of tablets comprising granules containing the optimal levels of disintegrants (3% (w / w) of croscarmellose sodium, 4% (w / w) of sodium starch glycolate, and 5% (w / w) of crospovidone XL-10).

[0184]

Table 9

[0185] Table 10 shows the compositions of Formulation 1, Formulation 3, and Formulation 10.

[0186]

Table 10

[0187] Example 6 Examples of dosages for other oral granule formulations include the following:

[0188]

Table 11

[0189] Table 12 shows the weight ratios of the components of the granules comprising gepotidacin mesylate dihydrate of the present disclosure.

[0190]

Table 12

Claims

1. An oral preparation comprising granules, wherein the granules comprise: f. up to about 60% (w / w) of gepotidacin or a pharmaceutically acceptable salt thereof; g. about 15 - 75% (w / w) of a soluble filler; h. about 20 - 60% (w / w) of microcrystalline cellulose; i. about 2 - 5% (w / w) of a binder; j. about 1.5 - 15% (w / w) of a disintegrant, and wherein the ratio of the microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL. An oral preparation.

2. The oral preparation according to claim 1, wherein the granules have a Carr's index value of 30% or less and an F Fc value of 10 or more.

3. The oral preparation according to any one of claims 1 or 2, wherein one unit dose of the granules is completely dispersed in 15 mL of water within 3 minutes by gently swirling in a 60 mL dosing cup.

4. The oral preparation according to any one of claims 1 - 3, wherein the binder is HPMC or povidone.

5. The oral preparation according to any one of claims 1 - 4, wherein the ratio of the microcrystalline cellulose to the binder is about 5:1 - 10:

1.

6. The oral preparation according to any one of claims 1 - 5, wherein the soluble filler is mannitol.

7. The oral preparation according to any one of claims 1 - 6, wherein the disintegrant is selected from croscarmellose sodium, crospovidone, and sodium starch glycolate.

8. The oral preparation according to any one of claims 1 - 7, wherein the active ingredient is gepotidacin mesylate.

9. The oral preparation according to claim 8, wherein the active pharmaceutical ingredient is gepotidacin mesylate dihydrate.

10. An oral preparation comprising granules, wherein a. up to about 60% (w / w) of one or more active ingredients; b. about 15 - 75% (w / w) of a soluble filler; c. about 20 - 60% (w / w) of microcrystalline cellulose; d. about 2 - 5% (w / w) of a binder; e. about 1.5 - 15% (w / w) of a disintegrant, and wherein the ratio of the microcrystalline cellulose to the binder is 5:1 or more, and the granules have a diameter of 250 microns or less and a density of 0.4 - 0.6 g / mL. An oral preparation.

11. The oral preparation according to any one of claims 1 - 10 for use in therapy.

12. An oral preparation according to any one of claims 1 to 10 for use in pediatric patients under 12 years of age.

13. An oral preparation according to any one of claims 1 to 10 for use in the treatment of bacterial infections in human subjects.

14. Use of gepotidacin or a pharmaceutically acceptable salt thereof in the manufacture of an oral preparation according to any one of claims 1 to 10 for the treatment of bacterial infections in human subjects.

15. A method of treating a bacterial infection, the method comprising administering to a human subject in need thereof a therapeutically effective amount of an oral preparation according to any one of claims 1 to 10.

16. Use or method according to any one of claims 14 or 15, wherein the human subject is a pediatric patient under 12 years of age.

17. A method for manufacturing an oral preparation according to any one of claims 1 to 10, wherein the granules are formed by wet granulation.

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