Gipodamycin formulations

Abstract

The present invention provides oral formulations of particles of an active pharmaceutical ingredient, such as gepodasine or a pharmaceutically acceptable salt thereof, which are rapidly dispersed in water, or oral formulations comprising particles of an active pharmaceutical ingredient. The particles form palatable oral suspensions in solution, taste good, and are particularly useful for pediatric or difficult-to-swallow patient populations.

Description

Technical Field

[0001] The present disclosure relates to free-flowing oral granular formulations of drugs that are capable of rapidly dispersing in water. Background Art

[0002] While most adult patients are able to swallow conventional tablets and capsules, a subset of patients have difficulty doing so, particularly with larger tablets. Pediatric patients, particularly those under 8 years of age, often experience problems, as do elderly patients and patients with certain conditions that affect swallowing, such as neurological patients, patients with nasogastric tubes, and patients with special conditions such as head and neck cancer.

[0003] Alternative formulation types known in the art include suspensions, dispersible granules or powders, dispersible tablets and orodispersible tablets. Dispersible granules, powders or tablets are dispersed in water (or potentially, other suitable vehicles such as milk or juice) to form a suspension that can be drunk by the patient.

[0004] Therefore, particles that can be dispersed rapidly in water and produce a palatable suspension with an acceptable mouthfeel 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") is an antibiotic under development that selectively inhibits bacterial DNA gyrase and topoisomerase IV through a unique and novel mechanism. International Patent Application Publication No. WO 2008 / 128942 describes a series of compounds useful as antibacterial agents, including gepotidacin. There is a need to develop alternative formulations of oral drugs (such as gepotidacin) that can produce a palatable suspension for pediatric or difficult-to-swallow patient populations. Summary of the invention

[0006] In one aspect, an oral formulation is provided comprising particles comprising

[0007] a. up to about 60% (w / w) of gepodaxin or a pharmaceutically acceptable salt thereof;

[0008] b. about 15-75% (w / w) of a soluble filler;

[0009] c. about 20-60% (w / w) microcrystalline cellulose;

[0010] d. about 2-5% (w / w) of a binder; and

[0011] e. about 1.5-15% (w / w) of a disintegrant;

[0012] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0013] The diameter of the particles is ≤250 microns and the density is 0.4-0.6 g / mL.

[0014] In another aspect, the present invention provides an oral formulation comprising particles comprising

[0015] a) up to 60% (w / w) of one or more active pharmaceutical ingredients;

[0016] b) 15-75% (w / w) of a soluble filler;

[0017] c) 20-60% (w / w) microcrystalline cellulose;

[0018] d) 2-5% (w / w) of a binder; and

[0019] e) 1.5-15% (w / w) of a disintegrant;

[0020] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0021] The diameter of the particles is ≤250 microns and the density is 0.4-0.6 g / mL. DETAILED DESCRIPTION OF THE INVENTION

[0023] Ideally, dispersible granules or powders in bottles, sachets, stick packs, etc. should be free-flowing to ensure uniformity of the contents and to enable full dose measurement and / or recovery from the container. In addition, the granules or powders should disperse rapidly in the liquid for patient convenience. Another important consideration, particularly for the pediatric population, is the palatability of the drug. While this depends in part on the taste of the drug in question, it also depends in part on the texture (i.e., "mouth feel") of the suspension formed.

[0024] Gepodacin tends to solidify, is sticky, has poor flowability and tastes bitter, which makes its formulation challenging. It has a high unit dose requirement; for example, the tablets currently used in the Phase 3 gepodacin clinical trial contain 750 mg of gepodacin measured as the free base, and the recommended clinical oral dose of gepodacin is 1500 mg twice daily for the treatment of urinary tract infections (UTI) (NCT04020341 and NCT04187144) and 3000 mg twice daily for the treatment of infections caused by Neisseria gonorrhoeae (e.g., uncomplicated gonorrhea or urogenital gonorrhea) (NCT04010539).

[0025] Such high daily doses would require oral solid dosage forms with high drug loads, which presents further challenges, especially for pediatric or difficult-to-swallow patient populations. A formulation that overcomes these issues to produce a palatable oral suspension with a good mouthfeel is highly desirable.

[0026] definition

[0027] It will be understood by those skilled in the art that the term "granular oral formulation" as used herein refers to any oral pharmaceutical dosage form of a solid mixture reduced to a finely divided physical state, and includes powders and granules.

[0028] The term "oral formulation comprising granules" refers to an oral pharmaceutical dosage form comprising granules, wherein the granules may be mixed with extragranular excipients (eg sweeteners, flavoring agents and / or lubricants) to form a final oral pharmaceutical dosage form (eg contained in a stick pack).

[0029] "Particle diameter ≤ 250 microns" means that the d50 of the particles is ≤ 250 microns. The term d50 has its conventional meaning and can be measured by well-established techniques, including sedimentation field flow fractionation, photon correlation spectroscopy, laser diffraction, or disk centrifugation. The d50 may be related to the volume distribution of the particles, and in this case, the phrase "particle diameter ≤ 250 microns" means that at least 50% of the volume of the particles have a diameter of ≤ 250 microns. Techniques based on volume or weight distribution will generally produce approximately the same average particle size value.

[0030] In the context of the present disclosure, the term "soluble filler" refers to a polyol or a sugar that exhibits a solubility in water at 25°C of greater than or equal to 200 mg / ml.

[0031] In the context of the present disclosure, the term "disintegrant" refers to an excipient that causes swelling of granules and promotes disintegration.

[0032] In the context of the present disclosure, the term "binder" refers to a water-soluble polymer (e.g., a solubility in water greater than or equal to 100 mg / mL) that facilitates wet granulation. Typically, the molecular weight of the polymer is in the range of 500 Da to 2 MDa, and the apparent viscosity is in the range of 3 to 15 mPa·s when in a 2% aqueous solution at 20°C.

[0033] The term "lubricant" is a technical term. In one embodiment, it refers to an excipient used to reduce interparticle friction. The terms "approximately," "about," or "about" as used herein in conjunction with numerical values ​​are intended to have their usual meaning in the numerical context. Where necessary, the words "approximately," "about," or "about" may be replaced by numerical values ​​+ / - 5%. As used herein, when any of these terms precedes a list of numbers, the term applies to each of the numbers listed.

[0034] Unless otherwise indicated, weight percentages are calculated by using the weight of the active ingredient (eg, gepodacin free base, gepodacin mesylate anhydrate, or gepodacin mesylate dihydrate) relative to the weight of the granules.

[0035] The particle compressibility index or Carr index is a USP <1174> The Carr Index is measured by the Bulk and Tap Density Tests described in USP. As will be appreciated by those skilled in the art, the Carr Index is used as an indicator of the compressibility of a granule or powder. The term "FFc" refers to the Flow Function of a Particle and is also measured by the USP. <1174> Both techniques are used to characterize the flow properties of particles.

[0036] Implementation

[0037] The present disclosure provides an oral formulation comprising particles comprising

[0038] a) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0039] b) about 15-75% (w / w) of a soluble filler;

[0040] c) about 20-60% (w / w) microcrystalline cellulose;

[0041] d) about 2-5% (w / w) of a binder; and

[0042] e) about 1.5-15% (w / w) of a disintegrant;

[0043] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0044] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0045] As will be appreciated by the skilled artisan, extragranular excipients may be added to the granules without affecting the properties of the granules of the present disclosure.Thus, the present disclosure encompasses oral formulations of the granules, as well as oral formulations comprising the granules of the present disclosure and other excipients.

[0046] Thus 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 masking agents and lubricants.

[0047] In one embodiment, an oral formulation of particles is provided, the particles comprising

[0048] a) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0049] b) about 15-75% (w / w) of a soluble filler;

[0050] c) about 20-60% (w / w) microcrystalline cellulose;

[0051] d) about 2-5% (w / w) of a binder; and

[0052] e) about 1.5-15% (w / w) of a disintegrant;

[0053] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0054] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0055] The particles of the present disclosure or oral formulations comprising the particles are particularly suitable for active pharmaceutical ingredients that are typically administered to pediatric patients (particularly patients under 6, 8 or 12 years of age), elderly patients and patients with certain conditions that affect swallowing (e.g., neurological patients, patients with nasogastric tubes, and patients with special conditions such as head and neck cancer).

[0056] The particles of the present disclosure or the oral formulations comprising the particles are quickly dispersed in water. The dispersion time can be measured by using a certain amount of particles (e.g., 500 mg equivalent of gepodaxine free base or 750 mg equivalent of gepodaxine free base) equivalent to a unit dose of the active pharmaceutical ingredient in 15 mL of water in a 60 mL quantitative cup using gentle swirling. As shown in the examples, the particles of the present disclosure are shown to be completely dispersed in water in less than 3 minutes. In one embodiment, about 1100 mg to 1800 mg of the particles of the present disclosure are completely dispersed in 15 mL of water in a 60 mL quantitative cup using gentle swirling at room temperature in 3 minutes or less. In one embodiment, about 1100 mg of the particles of the present disclosure are completely dispersed in 15 mL of water in a 60 mL quantitative cup using gentle swirling at room temperature in 3 minutes or less. In one embodiment, about 1800 mg of the particles of the present disclosure are completely dispersed in 15 mL of water in a 60 mL quantitative cup using gentle swirling at room temperature in 3 minutes or less. In one embodiment, about 1000 mg of the disclosed particles are completely dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling at room temperature in 3 minutes or less. In one embodiment, about 1500 mg of the disclosed particles are completely dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling at room temperature in 3 minutes or less.

[0057] Thus, in one embodiment, an oral formulation of or comprising particles is provided, the particles comprising

[0058] a) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0059] b) about 15-75% (w / w) of a soluble filler;

[0060] c) about 20-60% (w / w) microcrystalline cellulose;

[0061] d) about 2-5% (w / w) of a binder; and

[0062] e) about 1.5-15% (w / w) of a disintegrant;

[0063] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0064] The particles have a diameter of ≤250 μm, a density of 0.4–0.6 g / mL, and a unit dose of the particles is completely dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling in 3 minutes or less.

[0065] In one embodiment, an oral formulation of or comprising particles is provided, the particles comprising

[0066] a) about 0.1-60% (w / w) of one or more active pharmaceutical ingredients;

[0067] b) about 15-75% (w / w) of a soluble filler;

[0068] c) about 20-60% (w / w) microcrystalline cellulose;

[0069] d) about 2-5% (w / w) of a binder; and

[0070] e) about 1.5-15% (w / w) of a disintegrant;

[0071] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0072] The particles have a diameter of ≤250 μm, a density of 0.4–0.6 g / mL, and a unit dose of the particles is completely dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling in 3 minutes or less.

[0073] In one embodiment, an oral formulation of or comprising particles is provided, the particles comprising

[0074] a) 0.1-60% (w / w) of one or more active pharmaceutical ingredients;

[0075] b) 15-75% (w / w) of a soluble filler;

[0076] c) 20-60% (w / w) microcrystalline cellulose;

[0077] d) 2-5% (w / w) of a binder; and

[0078] e) 1.5-15% (w / w) of a disintegrant;

[0079] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0080] The particles have a diameter of ≤250 μm, a density of 0.4–0.6 g / mL, and a unit dose of the particles is completely dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling in 3 minutes or less.

[0081] As shown in the Examples, the particles of the present disclosure are completely dispersed in water in less than 3 minutes. In one embodiment, one unit dose of the particles of the present disclosure is completely dispersed in water in less than 2 minutes. In one embodiment, one unit dose of the particles of the present disclosure is completely dispersed in water in less than 1 minute. In one embodiment, a dose of particles containing 500 mg of API is completely dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling in 3 minutes or less. In one embodiment, a dose of particles containing 750 mg of API is completely dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling in 3 minutes or less.

[0082] The granules of the present disclosure may also be compressed into tablets, in which case dispersibility is measured by dispersing 1 to 4 tablets (having a core weight <150 mg) in 5 mL of water, or 5 to 8 tablets in 10 mL of water in a 30 mL dosing cup with gentle swirling for 1-3 min.

[0083] The granules of the present invention or oral preparations comprising the granules have good mouthfeel and palatability. Mouthfeel can be measured by standard techniques. For example, the amount of insoluble solids (e.g., microcrystalline cellulose) in the granules can be used as an indicator of mouthfeel, or the pharmacopoeia dispersion fineness test.

[0084] The granules or oral formulations comprising the granules are free-flowing to ensure weight uniformity and, therefore, content uniformity and to enable full dose measurement and / or recovery from the container in which they are stored. The free-flowing properties of the granules of the present disclosure can be characterized by a Carr Index value of ≤30% and an FFc value of ≥10. Thus, in one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, the granules comprising

[0085] a) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0086] b) about 15-75% (w / w) of a soluble filler;

[0087] c) about 20-60% (w / w) microcrystalline cellulose;

[0088] d) about 2-5% (w / w) of a binder; and

[0089] e) about 1.5-15% (w / w) of a disintegrant;

[0090] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0091] The particles have a diameter of ≤250 μm, a density of 0.4–0.6 g / mL, a Carr index value of ≤30% and an FFc value of ≥10.

[0092] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0093] a) about 0.1-60% (w / w) of one or more active pharmaceutical ingredients;

[0094] b) about 15-75% (w / w) of a soluble filler;

[0095] c) about 20-60% (w / w) microcrystalline cellulose;

[0096] d) about 2-5% (w / w) of a binder; and

[0097] e) about 1.5-15% (w / w) of a disintegrant;

[0098] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0099] The particles have a diameter of ≤250 μm, a density of 0.4–0.6 g / mL, a Carr index value of ≤30% and an FFc value of ≥10.

[0100] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0101] a) 0.1-60% (w / w) of one or more active pharmaceutical ingredients;

[0102] b) 15-75% (w / w) of a soluble filler;

[0103] c) 20-60% (w / w) microcrystalline cellulose;

[0104] d) 2-5% (w / w) of a binder; and

[0105] e) 1.5-15% (w / w) of a disintegrant;

[0106] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0107] The particles have a diameter of ≤250 μm, a density of 0.4–0.6 g / mL, a Carr index value of ≤30% and an FFc value of ≥10.

[0108] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0109] a) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0110] b) about 15-75% (w / w) of a soluble filler;

[0111] c) about 20-60% (w / w) microcrystalline cellulose;

[0112] d) about 2-5% (w / w) of a binder; and

[0113] e) about 1.5-15% (w / w) of a disintegrant;

[0114] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0115] The particles have a diameter of ≤250 μm, a density of 0.4–0.6 g / mL, a Carr index value of ≤30% and an FFC value of ≥10, and wherein a unit dose of the particles is dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling in 3 minutes or less.

[0116] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0117] a) about 0.1-60% (w / w) of one or more active pharmaceutical ingredients;

[0118] b) about 15-75% (w / w) of a soluble filler;

[0119] c) about 20-60% (w / w) microcrystalline cellulose;

[0120] d) about 2-5% (w / w) of a binder; and

[0121] e) about 1.5-15% (w / w) of a disintegrant;

[0122] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0123] The particles have a diameter of ≤250 μm, a density of 0.4–0.6 g / mL, a Carr index value of ≤30% and an FFC value of ≥10, and wherein a unit dose of the particles is dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling in 3 minutes or less.

[0124] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0125] a) 0.1-60% (w / w) of one or more active pharmaceutical ingredients;

[0126] b) 15-75% (w / w) of a soluble filler;

[0127] c) 20-60% (w / w) microcrystalline cellulose;

[0128] d) 2-5% (w / w) of a binder; and

[0129] e) 1.5-15% (w / w) of a disintegrant;

[0130] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0131] The particles have a diameter of ≤250 μm, a density of 0.4–0.6 g / mL, a Carr index value of ≤30% and an FFC value of ≥10, and wherein a unit dose of the particles is dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling in 3 minutes or less.

[0132] The suspension formed by dispersing the particles of the present disclosure or the oral formulation comprising the particles of the present disclosure is fluid and free-flowing.

[0133] To achieve this desired combination of properties, the inventors identified a number of key parameters that are critical to rapid dispersion and palatability. This work is described in the Examples.

[0134] The diameter of the particles and the density of the particles are important parameters for rapid dispersion. The diameter of the particles defines the distance that water needs to travel to penetrate the "core" of the particle. Example 1 shows that particles with a median diameter ≤ 250 microns achieve dispersion within 1 minute. The density of the particles reflects the extent of pores and channels within the particles, and also affects the dispersion time by providing pores and channels to allow water to quickly enter the particles. Example 1 shows that a particle density of 0.4–0.6 g / mL allows water to quickly enter the particles, causing the particles to decompose and release the active pharmaceutical ingredient. In one embodiment, the particles of the present disclosure have a particle density of about 0.45 to 0.60 g / mL.

[0135] Particle size and density are primarily controlled using granulation process parameters such as the amount of water added for granulation, spray rate and wet aggregation time, and then the size of oversized particles (e.g. >500 microns) is further reduced during the dry milling stage. Particle size and density are also controlled by the grade and level of excipients (binders and soluble and insoluble fillers).

[0136] Example 1 also shows that particle sizes of ≤ 250 microns in diameter disperse rapidly in water. In one embodiment, the particles of the present disclosure have a particle size of about 60 microns to about 250 microns. In one embodiment, the particles of the present disclosure have a particle size of about 80 microns to about 250 microns. Thus, in one embodiment, an oral formulation comprising particles is provided, the particles comprising

[0137] f) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0138] g) about 15-75% (w / w) of a soluble filler;

[0139] h) about 20-60% (w / w) microcrystalline cellulose;

[0140] i) about 2-5% (w / w) of a binder; and

[0141] j) about 1.5-15% (w / w) of a disintegrant;

[0142] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0143] The particles have a diameter of about 80 to about 250 microns and a density of 0.4-0.6 g / mL.

[0144] In another embodiment, an oral formulation of particles is provided, the particles comprising

[0145] f) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0146] g) about 15-75% (w / w) of a soluble filler;

[0147] h) about 20-60% (w / w) microcrystalline cellulose;

[0148] i) about 2-5% (w / w) of a binder; and

[0149] j) about 1.5-15% (w / w) of a disintegrant;

[0150] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0151] The particles have a diameter of about 80 to about 250 microns and a density of 0.4-0.6 g / mL.

[0152] As will be seen below, the physical structure of the particles affects the rate of dispersion. The composition of the particles also affects the rate of dispersion, as will be discussed further below.

[0153] Particle composition

[0154] The particles of the present disclosure contain up to 60% w / w of one or more active pharmaceutical ingredients ("API"). In one embodiment, the particles of the oral formulation of the present disclosure contain one, two or three different APIs. In one embodiment, the particles of the oral formulation of the present disclosure contain one or two different APIs. In one embodiment, the particles of the oral formulation of the present disclosure contain two different APIs. In one embodiment, the particles of the oral formulation of the present disclosure contain only one API.

[0155] Those skilled in the art will readily appreciate that the particles of the present disclosure disperse rapidly. It is therefore apparent that the physical properties of the API, and in particular its solubility, will have no effect on the dispersion time. The examples demonstrate that three very different APIs, daprodustat (N-[(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-diene-12-carboxamide) and gepodacin can be successfully formulated. The solubility of these APIs ranges widely, from almost insoluble to very soluble (daptostat 0.074 mg / mL, cadtegravir 2.9 mg / mL, gepodacin 175 mg / mL, all in water at 25°C). Thus, the examples show that surprisingly, different APIs can be formulated in the particles of the present disclosure and exhibit rapid dispersion, regardless of their solubility in water.

[0156] Thus, in one embodiment, the granules of the present disclosure comprise about 0.1 to 60% w / w active pharmaceutical ingredient. In one embodiment, the granules of the present disclosure comprise about 0.1 to 1% w / w active pharmaceutical ingredient. In one embodiment, the granules of the present disclosure comprise about 2 to 9% w / w active pharmaceutical ingredient. In one embodiment, the granules of the present disclosure comprise about 40 to 60% w / w active pharmaceutical ingredient. In one embodiment, the granules of the present disclosure comprise about 45 to 60% w / w active pharmaceutical ingredient. In one embodiment, the granules of the present disclosure comprise about 50 to 60% w / w active pharmaceutical ingredient. In one embodiment, the granules of the present disclosure comprise about 55 to 60% w / w active pharmaceutical ingredient.

[0157] In one embodiment, the active pharmaceutical ingredient in the granules of the present disclosure is gepodacin or a pharmaceutically acceptable salt thereof. In another embodiment, the active pharmaceutical ingredient in the granules of the present disclosure is daptomycin or a pharmaceutically acceptable salt thereof. In another embodiment, the active pharmaceutical ingredient in the granules of the present disclosure is caltegravir or a pharmaceutically acceptable salt thereof.

[0158] The granules of the present disclosure can be prepared by any suitable method, such as direct compression, dry granulation or wet granulation. In one embodiment, a wet granulation method is employed.

[0159] Those skilled in the art will appreciate that wet granulation can be used to form the particles of the present disclosure. Compared to other formulation techniques (e.g., direct compression and dry granulation), wet granulation is complex and is generally performed only when other techniques are not suitable. Therefore, in one embodiment, the API in the oral formulation of the present disclosure is an API that is not suitable for formulation by direct compression or dry granulation using a low shear mixing method.

[0160] In general, wet granulation is particularly suitable when the drug load is low, because this technique ensures that the drug substance is evenly distributed and locked in the particles. In addition, the particles produced by wet granulation are generally better flow materials than ungranulated powders (for direct compression) or roller compacted granules. This also helps with content uniformity, because the particles with better flowability can ensure better weight control during further processing into tablets, stickpacks, pouches or bottles. Therefore, the present disclosure also provides a method for making the particles of the present disclosure by wet granulation. The particles produced by wet granulation also provide additional taste masking by reducing the surface area of ​​the drug in contact with the taste buds.

[0161] WO2016 / 12058 discloses dispersible tablets of bedaquiline fumarate, wherein silicified microcrystalline cellulose is used in the granules. However, the use of silicified microcrystalline cellulose in the granules is considered to interfere with the wet granulation process, limiting the control of the process necessary to obtain granules of appropriate size and density. In fact, it is noted that in WO2016 / 12058, the process of granule formation is complicated, 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 a glidant are omitted from the granules, wet granulation is much simpler. Therefore, in one embodiment, the granules of the oral formulation of the present disclosure do not contain silicified microcrystalline cellulose (SMCC) or a glidant.

[0162] In Example 2 below, it is shown that the fastest dispersion times were observed with 20-60% w / w intragranular microcrystalline cellulose, and it was also observed that this improved the robustness of the granulation process. Granules with between 20-30% (w / w) microcrystalline cellulose had the best mouthfeel and palatability. Therefore, in one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, the granules comprising between 20-30% (w / w) microcrystalline cellulose. In a more specific embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, the granules comprising about 20% (w / w) microcrystalline cellulose.

[0163] There are a variety of different grades of microcrystalline cellulose available. Those skilled in the art will appreciate that the grade selected should exhibit good compressibility and mouthfeel. The mouthfeel depends in part on the size of the particles. A size of no more than 125 microns is desirable, and a size of no more than 50 microns is ideal. AVICEL PH101 and CEOLUS KG-1000 are suitable grades. CEOLUS KG-1000 is the finest grade of microcrystalline cellulose and results in an improved mouthfeel. In one embodiment, the size of the MCC used in the granular formulation of the present disclosure does not exceed 50 microns.

[0164] Except containing active pharmaceutical ingredient and microcrystalline cellulose, particle must comprise binding agent additionally.Binder can be natural polymer, for example polysaccharide or polypeptide or its derivative, or synthetic polymer, for example polyalkylene oxide (for example PEG), polyacrylate, polyvinylpyrrolidone etc.Also can use mixed polymer, for example block copolymer and glycopeptide.In one embodiment, binding agent can be selected from hydroxypropyl methylcellulose, polyvinylpyrrolidone, maltodextrin or starch 1500.In another embodiment, binding agent can be selected from hydroxypropyl methylcellulose (HPMC, also referred to as hypromellose) and polyvinylpyrrolidone.

[0165] In one embodiment, the binder is hydroxypropyl methylcellulose, which contains enough hydroxypropyl and methoxy groups to make it water-soluble. HPMC with a methoxyl substitution degree of about 19.0 to about 30.0 and a hydroxypropoxy molar substitution degree of about 4.0 to about 12.0 is generally water-soluble. The methoxyl substitution degree refers to the average number of methyl ether groups present in each anhydroglucose unit of the cellulose molecule. The hydroxypropyl molar substitution degree refers to the average number of moles of propylene oxide reacted with each anhydroglucose unit of the cellulose molecule. Preferred HPMC is hydroxypropyl methylcellulose 2910 3mPa·s or hydroxypropyl methylcellulose 2910 5mPa·s, especially hydroxypropyl methylcellulose 2910 3mPa·s. Hydroxypropyl methylcellulose is the name adopted by the U.S. for hydroxypropyl methylcellulose (see Martindale, The Extra Pharmacopoeia, 29th edition, page 1435). In the four-digit number "2910", the first two digits indicate the approximate percentage of methoxy groups, and the third and fourth digits indicate the approximate percentage composition of hydroxypropoxy groups; 3mPa·s or 5mPa·s is a value indicating the apparent viscosity of a 2% aqueous solution at 20°C. In one embodiment, the hydroxypropyl methylcellulose binder is hydroxypropyl methylcellulose 29103mPa·s (i.e. 603).

[0166] Example 3 shows that the ratio of microcrystalline cellulose: binder in the granules should be ≥5:1 for rapid dispersion. In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, the granules comprising microcrystalline cellulose and a binder selected from HPMC or povidone, in a ratio of ≥5:1. In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising granules, the granules comprising microcrystalline cellulose and HPMC, in a ratio of ≥5:1. In one embodiment, the present disclosure provides an oral formulation of granules or an oral formulation comprising 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 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 granules, the granules comprising microcrystalline cellulose and a binder, in a ratio of about 10:1.

[0167] The granules additionally contain about 15-75% (w / w) of a soluble filler.In one embodiment, the disclosure provides an oral formulation of or comprising granules comprising microcrystalline cellulose, a binder, one or more soluble fillers, and one or more disintegrants, but without additional classes of excipients.

[0168] Granules containing about 15 to 75% w / w soluble fillers (e.g., mannitol) have higher mechanical strength (lower fines level) for downstream processing (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 dextrins, and sugars, 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, the granules comprising mannitol. Mannitol is superior to lactose because it has better tolerance, especially in pediatric populations. However, it should be understood that due to incompatibility, active pharmaceutical ingredients can limit the selected soluble fillers.

[0169] The use of soluble fillers in the granules keeps the total level of insoluble solids in the granules low to improve mouthfeel. Example 4 shows that 17 to 75% w / w of soluble fillers (e.g., mannitol) has greater mechanical strength (lower fine particle levels) for downstream processing. As will be appreciated, since widely varying levels of soluble fillers are allowed, widely varying levels of active pharmaceutical ingredients can be allowed in the granules, which can be compensated for by varying the level of soluble fillers. In one embodiment, the soluble filler is mannitol.

[0170] Various grades of mannitol are available. As an example, Pearlitol 160C produces larger and better flowing particles than Pearlitol 50C.

[0171] Those skilled in the art will appreciate that the total amount of mannitol in the daily dose (noting that multiple unit doses may be dispersed in the carrier) should be within the recommended daily limit of 50 mg / kg / day (WHO Food additive series Toxicological monograph. 616. Mannitol (WHO Food Additives Series 21) (inchem.org)).

[0172] Example 5 shows the dispersion of tablets made from granules containing 1.5-15% disintegrant in less than 2 minutes. Any suitable disintegrant can be used in the granules. Suitable disintegrants include cross-linked polyvinyl pyrrolidone, modified cellulose gum, such as cross-linked sodium carboxymethyl cellulose (e.g. Ac-di-Sol), sodium starch glycolate, sodium carboxymethyl cellulose, sodium lauryl sulfate, modified corn starch, microcrystalline cellulose, magnesium aluminum silicate, alginic acid, alginates, powdered cellulose, cross-linked polyvinylpyrrolidone (e.g. POLYPLASDONE XL). Other disintegrants that may be considered include xanthan gum, gellan gum, soy polysaccharides, etc. The optimal amount of disintegrant will depend on which extragranular disintegrant is selected and can be easily determined by those skilled in the art. Disintegrants cause granules to swell and promote dispersion.

[0173] In one embodiment, the disintegrant is selected from cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone and sodium starch glycolate. In one embodiment, the disintegrant is selected from cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone XL-10 and sodium starch glycolate. In one embodiment, the disintegrant is cross-linked sodium carboxymethylcellulose. In a more specific embodiment, the disintegrant is cross-linked sodium carboxymethylcellulose, and it is used in the granules in an amount of about 1.5-3% w / w. In one embodiment, the disintegrant is cross-linked polyvinylpyrrolidone. In a more specific embodiment, the disintegrant is cross-linked polyvinylpyrrolidone, and it is used in the granules in an amount of about 5-15% w / w. In one embodiment, the disintegrant is cross-linked polyvinylpyrrolidone XL. In certain embodiments in which the disintegrant is cross-linked polyvinylpyrrolidone, a fine grade of cross-linked polyvinylpyrrolidone (e.g., POLYPLASDONE XL-10) can be used. In one embodiment, the disintegrant is sodium starch glycolate. In a more specific embodiment, the disintegrant is sodium starch glycolate, and it is used in the granules in an amount of about 3-5% w / w. It will be appreciated that the active pharmaceutical ingredient may influence the choice of disintegrant based on incompatibilities.

[0174] The particles of the present disclosure can be mixed with sweeteners (also known as taste masking agents or flavoring agents) for taste masking and improving patient acceptability and compliance. Whether a separate sweetener is needed depends on factors such as the taste of the active agent. Taste acceptability is important for once-daily chronic administration, especially in pediatric populations. Therefore, it may be necessary to mix a separate sweetener with the particles of the present disclosure, but it should be noted that some possible excipients used as fillers in soluble particles are sugars and may also have a positive effect on palatability. Suitable sweeteners include sugars and artificial sweeteners. The FDA has approved five artificial sweeteners for children: sucralose, aspartame, neotame, acesulfame potassium and saccharin. In one embodiment, the sweetener is sucralose or neotame. In a more specific embodiment, the sweetener is neotame or sucralose and is used in an oral formulation of the present disclosure at 1-3% w / w. In the presence of very bitter drugs, sucralose may also be used in combination with acesulfame potassium or neotame, or may be replaced by neotame alone, which is ~x20 times sweeter than sucralose. In one embodiment, a sweetener (eg, neotame) is used with a flavoring agent in an oral formulation.

[0175] In one embodiment, the particles of the present disclosure do not contain any lubricants. In one embodiment, the particles of the present disclosure do not contain any surfactants.

[0176] One aspect of the present disclosure is a method of preparing the granules of the present disclosure. The granules can be prepared by any suitable method, such as direct compression, dry granulation or wet granulation. In one embodiment, a wet granulation method is used.

[0177] 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 to form tablets and remains in the range of 0.4-0.6 g / mL.

[0178] The present disclosure provides an oral preparation of particles or an oral preparation comprising particles, wherein the particles comprise

[0179] a) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0180] b) about 15-75% (w / w) of a soluble filler;

[0181] c) about 20-60% (w / w) microcrystalline cellulose;

[0182] d) about 2-5% (w / w) HPMC; and

[0183] e) about 1.5-15% (w / w) of a disintegrant;

[0184] The ratio of microcrystalline cellulose to HPMC is ≥ 5:1; and

[0185] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0186] The present disclosure provides an oral preparation of particles or an oral preparation comprising particles, wherein the particles comprise

[0187] a) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0188] b) about 15-75% (w / w) mannitol;

[0189] c) about 20-60% (w / w) microcrystalline cellulose;

[0190] d) about 2-5% (w / w) of a binder; and

[0191] e) about 1.5-15% (w / w) of a disintegrant;

[0192] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0193] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0194] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0195] a) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0196] b) about 15-75% (w / w) mannitol;

[0197] c) about 20-60% (w / w) microcrystalline cellulose;

[0198] d) about 2-5% (w / w) HPMC; and

[0199] e) about 1.5-15% (w / w) of a disintegrant selected from croscarmellose sodium, sodium starch glycolate or crospovidone;

[0200] The ratio of microcrystalline cellulose to HPMC is ≥ 5:1; and

[0201] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0202] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0203] a) about 0.1-60% (w / w) of one or more active pharmaceutical ingredients;

[0204] b) about 15-75% (w / w) mannitol;

[0205] c) about 20-60% (w / w) microcrystalline cellulose;

[0206] d) about 2-5% (w / w) HPMC; and

[0207] e) about 1.5-15% (w / w) of a disintegrant selected from croscarmellose sodium, sodium starch glycolate or crospovidone;

[0208] The ratio of microcrystalline cellulose to HPMC is ≥ 5:1; and

[0209] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0210] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0211] a) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0212] b) about 15-75% (w / w) mannitol;

[0213] c) about 20-30% (w / w) microcrystalline cellulose;

[0214] d) about 2-5% (w / w) HPMC; and

[0215] e) about 1.5-15% (w / w) of a disintegrant selected from croscarmellose sodium, sodium starch glycolate or crospovidone;

[0216] The ratio of microcrystalline cellulose to HPMC is ≥ 5:1; and

[0217] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0218] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0219] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0220] a) about 0.1-60% (w / w) of one or more active pharmaceutical ingredients;

[0221] b) about 15-75% (w / w) mannitol;

[0222] c) about 20-30% (w / w) microcrystalline cellulose;

[0223] d) about 2-5% (w / w) HPMC; and

[0224] e) about 1.5-15% (w / w) of a disintegrant selected from croscarmellose sodium, sodium starch glycolate or crospovidone;

[0225] The ratio of microcrystalline cellulose to HPMC is ≥ 5:1; and

[0226] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0227] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0228] a) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0229] b) about 15-75% (w / w) mannitol;

[0230] c) about 20-30% (w / w) microcrystalline cellulose;

[0231] d) about 2-5% (w / w) HPMC; and

[0232] e) about 1.5-15% (w / w) of a disintegrant selected from croscarmellose sodium, sodium starch glycolate or crospovidone;

[0233] wherein the ratio of microcrystalline cellulose to HPMC is about 5:1 to 10:1; and

[0234] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0235] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0236] a) about 0.1-60% (w / w) of one or more active pharmaceutical ingredients;

[0237] b) about 15-75% (w / w) mannitol;

[0238] c) about 20-30% (w / w) microcrystalline cellulose;

[0239] d) about 2-5% (w / w) HPMC; and

[0240] e) about 1.5-15% (w / w) of a disintegrant selected from croscarmellose sodium, sodium starch glycolate or crospovidone;

[0241] wherein the ratio of microcrystalline cellulose to HPMC is about 5:1 to 10:1; and

[0242] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0243] In one embodiment, any of the above formulations of the present disclosure additionally comprises about 1-3% (w / w) of a sweetener.

[0244] In one embodiment, the particles of the present disclosure are present in a disposable stick pack or pouch. In another embodiment, the particles of the present disclosure are present in a disposable or multiple use bottle or container. Therefore, the present disclosure provides a container containing the particles of the present disclosure, such as a stick pack, pouch, bottle or other container. The particles of the present disclosure are suitable for ingestion by dissolving in water.

[0245] In one embodiment, an oral formulation of or comprising particles is provided, the particles being in a single-use or multiple-use bottle or container, the particles comprising

[0246] a) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0247] b) about 15-75% (w / w) of a soluble filler;

[0248] c) about 20-60% (w / w) microcrystalline cellulose;

[0249] d) about 2-5% (w / w) of a binder; and

[0250] e) about 1.5-15% (w / w) of a disintegrant;

[0251] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0252] The particles have a diameter of ≤250 μm, a density of 0.4–0.6 g / mL, a Carr index value of ≤30% and an FFc value of ≥10.

[0253] In one embodiment, an oral formulation of or comprising particles is provided, the particles being in a disposable container, the particles comprising

[0254] a) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0255] b) about 15-75% (w / w) of a soluble filler;

[0256] c) about 20-60% (w / w) microcrystalline cellulose;

[0257] d) about 2-5% (w / w) of a binder; and

[0258] e) about 1.5-15% (w / w) of a disintegrant;

[0259] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0260] The particles have a diameter of ≤250 μm, a density of 0.4–0.6 g / mL, a Carr index value of ≤30% and an FFc value of ≥10.

[0261] In one embodiment, an oral formulation of or comprising particles is provided, the particles being in a disposable container, the particles comprising

[0262] a) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0263] b) about 15-75% (w / w) of a soluble filler;

[0264] c) about 20-60% (w / w) microcrystalline cellulose;

[0265] d) about 2-5% (w / w) of a binder; and

[0266] e) about 1.5-15% (w / w) of a disintegrant;

[0267] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0268] The particles have a diameter of ≤250 μm, a density of 0.4–0.6 g / mL, and a unit dose of the particles is completely dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling in 3 minutes or less.

[0269] Gepodacin, cadaverine, and daptomycin granules

[0270] In one embodiment, the particles of the present disclosure comprise gepodacin or a pharmaceutically acceptable salt thereof.

[0271] International Patent Application Publication No. WO 2021 / 219637, incorporated herein in its entirety, describes certain crystalline forms of gepodacin, including gepodacin mesylate dihydrate, gepodacin mesylate anhydrate, gepodacin mesylate monohydrate, and gepodacin anhydrate (free base).

[0272] As mentioned above, gepodacin is sticky or viscous, has poor flow properties and tastes bitter. This makes it difficult to formulate, especially as a formulation for patients who have difficulty swallowing (e.g., pediatric patients). These challenging properties of gepodacin are overcome by the oral formulations of the present disclosure, which are surprisingly free-flowing and dispersible in water despite the inherent properties of gepodacin.

[0273] In one embodiment, the particles of the present disclosure comprise gepodacin mesylate dihydrate, gepodacin mesylate anhydrate, and / or gepodacin anhydrate.

[0274] In one embodiment, the particles of the present disclosure comprise gepodacin mesylate dihydrate.

[0275] In one embodiment, the particles of the present disclosure comprise about 40-60% w / w gepodaxin or a pharmaceutically acceptable salt thereof. In one embodiment, the particles of the present disclosure comprise about 45-60% w / w gepodaxin or a pharmaceutically acceptable salt thereof. In one embodiment, the particles of the present disclosure comprise about 50-60% w / w gepodaxin or a pharmaceutically acceptable salt thereof. In one embodiment, the particles of the present disclosure comprise about 55-60% w / w gepodaxin or a pharmaceutically acceptable salt thereof. In one embodiment, the particles of the present disclosure comprise about 60% w / w gepodaxin or a pharmaceutically acceptable salt thereof. In one embodiment, the particles of the present disclosure comprise about 55, 56, 57, 58, 59 or 60% w / w gepodaxin or a pharmaceutically acceptable salt thereof.

[0276] In one embodiment, the particles of the present disclosure comprise about 40-60% w / w gepodaxin mesylate dihydrate. In one embodiment, the particles of the present disclosure comprise about 45-60% w / w gepodaxin mesylate dihydrate. In one embodiment, the particles of the present disclosure comprise about 50-60% w / w gepodaxin mesylate dihydrate. In one embodiment, the particles of the present disclosure comprise about 55-60% w / w gepodaxin mesylate dihydrate. In one embodiment, the particles of the present disclosure comprise about 55, 56, 57, 58, 59 or 60% w / w gepodaxin mesylate dihydrate. In one embodiment, the particles of the present disclosure comprise about 60% w / w gepodaxin mesylate dihydrate.

[0277] Thus, in one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0278] a) up to about 60% (w / w) of gepodacin or a pharmaceutically acceptable salt thereof;

[0279] b) about 15-75% (w / w) of a soluble filler;

[0280] c) about 20-60% (w / w) microcrystalline cellulose;

[0281] d) about 2-5% (w / w) of a binder; and

[0282] e) about 1.5-15% (w / w) of a disintegrant;

[0283] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0284] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0285] In one embodiment, an oral formulation of or comprising particles is provided, the particles comprising

[0286] a) up to about 60% (w / w) of gepodacin or a pharmaceutically acceptable salt thereof;

[0287] b) about 15-75% (w / w) of a soluble filler;

[0288] c) about 20-60% (w / w) microcrystalline cellulose;

[0289] d) about 2-5% (w / w) of a binder; and

[0290] e) about 1.5-15% (w / w) of a disintegrant;

[0291] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0292] The particles have a diameter of about 80 to about 250 microns and a density of 0.4-0.6 g / mL.

[0293] In one embodiment, the particles comprise about 40-60% (w / w) gepodacin or a pharmaceutically acceptable salt thereof. In one embodiment, the particles comprise about 45-60% (w / w) gepodacin or a pharmaceutically acceptable salt thereof. In one embodiment, the particles comprise about 50-60% (w / w) gepodacin or a pharmaceutically acceptable salt thereof. In one embodiment, the particles comprise about 55-60% (w / w) gepodacin or a pharmaceutically acceptable salt thereof.

[0294] In one embodiment, the soluble filler is mannitol.

[0295] In one embodiment, the binder is HPMC.

[0296] In one embodiment, the disintegrant is selected from croscarmellose sodium, sodium starch glycolate, or crospovidone. In one embodiment, the disintegrant is croscarmellose sodium.

[0297] In one embodiment, the ratio of microcrystalline cellulose to HPMC is about 5:1 to 10:1.

[0298] Thus, in one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0299] a) up to about 60% (w / w) of gepodacin or a pharmaceutically acceptable salt thereof;

[0300] b) about 15-75% (w / w) mannitol;

[0301] c) about 20-60% (w / w) microcrystalline cellulose;

[0302] d) about 2-5% (w / w) of a binder; and

[0303] e) about 1.5-15% (w / w) of a disintegrant;

[0304] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0305] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0306] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0307] a) up to about 60% (w / w) of gepodacin or a pharmaceutically acceptable salt thereof;

[0308] b) about 15-75% (w / w) of a soluble filler;

[0309] c) about 20-60% (w / w) microcrystalline cellulose;

[0310] d) about 2-5% (w / w) HPMC; and

[0311] e) about 1.5-15% (w / w) of a disintegrant;

[0312] The ratio of microcrystalline cellulose to HPMC is ≥ 5:1; and

[0313] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0314] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0315] a) up to about 60% (w / w) of gepodacin or a pharmaceutically acceptable salt thereof;

[0316] b) about 15-75% (w / w) of a soluble filler;

[0317] c) about 20-60% (w / w) microcrystalline cellulose;

[0318] d) about 2-5% (w / w) of a binder; and

[0319] e) about 1.5-15% (w / w) of a disintegrant;

[0320] wherein the ratio of microcrystalline cellulose to binder is about 5:1 to 10:1; and

[0321] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0322] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0323] a) up to about 60% (w / w) of gepodacin or a pharmaceutically acceptable salt thereof;

[0324] b) about 15-75% (w / w) of a soluble filler;

[0325] c) about 20-30% (w / w) microcrystalline cellulose;

[0326] d) about 2-5% (w / w) of a binder; and

[0327] e) about 1.5-15% (w / w) of a disintegrant;

[0328] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0329] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0330] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0331] a) about 50-60% (w / w) of gepodaxin or a pharmaceutically acceptable salt thereof;

[0332] b) about 15-75% (w / w) of a soluble filler;

[0333] c) about 20-60% (w / w) microcrystalline cellulose;

[0334] d) about 2-5% (w / w) of a binder; and

[0335] e) about 1.5-15% (w / w) of a disintegrant;

[0336] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0337] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0338] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0339] a) about 50-60% (w / w) of gepodaxin or a pharmaceutically acceptable salt thereof;

[0340] b) about 15-26.5% (w / w) of a soluble filler;

[0341] c) about 20-31.5% (w / w) microcrystalline cellulose;

[0342] d) about 2-5% (w / w) of a binder; and

[0343] e) about 1.5-15% (w / w) of a disintegrant;

[0344] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0345] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0346] In one embodiment, the present disclosure provides an oral formulation of gepodaxin particles, the gepodaxin particles comprising:

[0347] a) about 50-60% (w / w) of gepodaxin or a pharmaceutically acceptable salt thereof;

[0348] b) about 15-26.5% (w / w) mannitol;

[0349] c) about 20-31.5% (w / w) microcrystalline cellulose;

[0350] d) about 2-5% (w / w) HPMC; and

[0351] e) about 1.5-3% (w / w) croscarmellose sodium;

[0352] The ratio of microcrystalline cellulose to HPMC is ≥ 5:1; and

[0353] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0354] In one embodiment, the present disclosure provides an oral formulation of gepodaxin particles, the gepodaxin particles comprising:

[0355] a) about 50-60% (w / w) of gepodaxin or a pharmaceutically acceptable salt thereof;

[0356] b) about 15-26.5% (w / w) mannitol;

[0357] c) about 20-31.5% (w / w) microcrystalline cellulose;

[0358] d) about 2-5% (w / w) HPMC; and

[0359] e) about 1.5-3% (w / w) croscarmellose sodium;

[0360] wherein the ratio of microcrystalline cellulose to HPMC is about 5:1 to 10:1; and

[0361] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0362] In one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0363] a) about 55-60% (w / w) of gepodaxin or a pharmaceutically acceptable salt thereof;

[0364] b) about 15-21.5% (w / w) of a soluble filler;

[0365] c) about 20-26.5% (w / w) microcrystalline cellulose;

[0366] d) about 2-5% (w / w) of a binder; and

[0367] e) about 1.5-15% (w / w) of a disintegrant;

[0368] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0369] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0370] In one embodiment, the oral formulation of gepodaxine of the present disclosure additionally comprises a sweetener. In one embodiment, the sweetener is added at about 1-3% (w / w) of the oral formulation. In one embodiment, the sweetener is added after the granules of the present disclosure are formed (i.e., extragranular) and mixed with the granules. In one embodiment, neotame is added and mixed with the gepodaxine granules of the present disclosure (i.e., extragranular). In one embodiment, neotame is added at about 1% w / w.

[0371] In other words, in one embodiment, an oral formulation is provided, which comprises granules and an extragranular portion. Granules are as defined herein. The extragranular portion may comprise a sweetener and / or a flavoring agent, wherein the sweetener is selected from sucralose, aspartame, neotame, acesulfame potassium and saccharin. In one embodiment, the sweetener is sucralose or neotame. In a more specific embodiment, the sweetener is neotame or sucralose and is present in an amount of about 1-3% w / w of the total oral formulation (granules and extragranular portion). In one embodiment, the flavoring agent is present in an amount of about 2-3% w / w of the total oral formulation.

[0372] In one embodiment, the extragranular portion may further comprise a lubricant. In one embodiment, the lubricant is present in an amount of 0.5-3% w / w of the total oral formulation. In one embodiment, the lubricant is present in an amount of 0.5-1.5% w / w of the total oral formulation.

[0373] Suitable lubricants are pharmaceutically acceptable lubricants, such as magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate. The choice of lubricant must take into account incompatibility with the active pharmaceutical ingredient. In one embodiment, the lubricant is magnesium stearate (e.g., LIGAMED). In a more specific embodiment, the lubricant is magnesium stearate, and it is used at a level of 1% (w / w) of the total oral formulation.

[0374] In one embodiment, the present disclosure provides an oral formulation of or comprising gepodaxin particles, the particles consisting of:

[0375] a) about 50-60% (w / w) of gepodaxin or a pharmaceutically acceptable salt thereof;

[0376] b) about 15-75% (w / w) mannitol;

[0377] c) about 20-31.5% (w / w) microcrystalline cellulose;

[0378] d) about 2-5% (w / w) HPMC; and

[0379] e) about 1.5-3% (w / w) croscarmellose sodium;

[0380] The ratio of microcrystalline cellulose to HPMC is ≥ 5:1; and

[0381] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL;

[0382] And wherein the granules are optionally mixed with about 1-3% (w / w) of a sweetener.

[0383] In one embodiment, the present disclosure provides an oral formulation of or comprising gepodaxin particles, the particles consisting of:

[0384] a) about 50-60% (w / w) of gepodaxin or a pharmaceutically acceptable salt thereof;

[0385] b) about 15-26.5% (w / w) mannitol;

[0386] c) about 20-31.5% (w / w) microcrystalline cellulose;

[0387] d) about 2-5% (w / w) HPMC; and

[0388] e) about 1.5-3% (w / w) croscarmellose sodium;

[0389] The ratio of microcrystalline cellulose to HPMC is ≥ 5:1; and

[0390] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL;

[0391] And wherein optionally the granules are mixed with about 1-3% (w / w) of a sweetener.

[0392] In one embodiment, the present disclosure provides an oral formulation comprising gepodaxin particles consisting of:

[0393] a) about 50-60% (w / w) of gepodaxin or a pharmaceutically acceptable salt thereof;

[0394] b) about 15-26.5% (w / w) mannitol;

[0395] c) about 20-31.5% (w / w) microcrystalline cellulose;

[0396] d) about 2-5% (w / w) HPMC; and

[0397] e) about 1.5-3% (w / w) croscarmellose sodium;

[0398] The ratio of microcrystalline cellulose to HPMC is ≥ 5:1; and

[0399] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL;

[0400] And wherein optionally the particles are mixed with about 1-3% (w / w) of a sweetener.

[0401] In another embodiment, the present disclosure provides an oral formulation comprising gepodacin particles consisting of:

[0402] a) about 50-60% (w / w) of gepodaxin or a pharmaceutically acceptable salt thereof;

[0403] b) about 15-26.5% (w / w) mannitol;

[0404] c) about 20-31.5% (w / w) microcrystalline cellulose;

[0405] d) about 2-5% (w / w) HPMC; and

[0406] e) about 1.5-3% (w / w) croscarmellose sodium;

[0407] The ratio of microcrystalline cellulose to HPMC is ≥ 5:1; and

[0408] wherein the particles have a diameter of about 80 to about 250 microns and a density of 0.4–0.6 g / mL;

[0409] And wherein optionally the particles are mixed with about 1-3% (w / w) of a sweetener.

[0410] In an embodiment, the present disclosure provides an oral formulation of gepodacin particles, wherein a unit dose of particles containing 500 mg or 750 mg of gepodacin (measured as free base) is completely dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling in 3 minutes or less.

[0411] In one embodiment, the oral formulation of gepodaxin or its pharmaceutically acceptable salt of the present disclosure is present in a disposable stick package or pouch. Therefore, the present disclosure provides a disposable stick package or pouch containing the particles of gepodaxin or its pharmaceutically acceptable salt of the present disclosure. In one embodiment, the stick package or pouch contains 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg or 800mg of gepodaxin (measured as free base). In one embodiment, the stick pack or sachet contains a unit dose of 325, 500, 650 or 750 mg of gepodacin (measured as free base). In one embodiment, the stick pack or sachet contains a unit dose of 500 or 750 mg of gepodacin (measured as free base).

[0412] The present disclosure also provides a bottle or container containing the particles of the present disclosure, the particles comprising gepodaxin or a pharmaceutically acceptable salt thereof. Therefore, in another embodiment, the oral formulation of gepodaxin or a pharmaceutically acceptable salt thereof is in a disposable bottle or container containing 1500 mg of gepodaxin (measured as free base).

[0413] In one embodiment, the particles of the present disclosure comprise dapnostat or a pharmaceutically acceptable salt thereof. Dapoxetine is the USAN, INN and JAN names 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 the compound is N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine). Dapoxetine is a HIF prolyl hydroxylase inhibitor that is being developed for the treatment of anemia associated with chronic kidney disease in patients on and not on dialysis. Anemia associated with chronic kidney disease rarely occurs in children, including infants as young as 3 months old. As mentioned above, dialysis patients need to restrict volume intake, so for dapnostat, a dispersible oral formulation (e.g., granules or tablets) that can be quickly dispersed in a very small volume to produce a palatable suspension is highly desirable. Therefore, in one embodiment, the present disclosure provides an oral formulation of particles or an oral formulation comprising particles, the particles comprising daptostat or a pharmaceutically acceptable salt thereof, wherein a unit dose of the particles is dispersed in 5 mL of water in a 30 mL dosing cup using gentle swirling for 1-3 min. The unit dose of particles can be in the form of a tablet.

[0414] Dapomostat exhibits keto / enol tautomerism. All tautomers of dapnostat, including mixtures thereof, are intended to be encompassed within the scope of the present disclosure.

[0415] Thus, in one embodiment, the present disclosure provides an oral formulation of or comprising particles comprising

[0416] a) up to about 60% (w / w) of daptomycin or a pharmaceutically acceptable salt thereof;

[0417] b) about 15-75% (w / w) of a soluble filler;

[0418] c) about 20-60% (w / w) microcrystalline cellulose;

[0419] d) about 2-5% (w / w) of a binder; and

[0420] e) about 1.5-15% (w / w) of a disintegrant;

[0421] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0422] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0423] In one embodiment, the particles of the present disclosure comprise cartegravir or a pharmaceutically acceptable salt thereof, such as cartegravir sodium. Thus, in one embodiment, the present disclosure provides an oral formulation of particles or an oral formulation comprising particles, the particles comprising

[0424] a) up to about 60% (w / w) of cartegravir or a pharmaceutically acceptable salt thereof;

[0425] b) about 15-75% (w / w) of a soluble filler;

[0426] c) about 20-60% (w / w) microcrystalline cellulose;

[0427] d) about 2-5% (w / w) of a binder; and

[0428] e) about 1.5-15% (w / w) of a disintegrant;

[0429] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0430] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0431] In one embodiment, the present disclosure provides an oral formulation of the following particles:

[0432]

[0433] * Measured as free acid

[0434] ** Measured as free base

[0435] a Croscarmellose Sodium

[0436] b Sodium starch glycolate

[0437] Medical Uses

[0438] The present disclosure provides oral formulations of the present disclosure for use in therapy.

[0439] The present application provides a method for treating a bacterial infection, comprising administering an oral formulation of the present disclosure to a human subject in need thereof, the formulation comprising gepodaxin or a pharmaceutically acceptable salt thereof. Bacterial infections can be caused by a wide range of organisms, including Gram-negative and Gram-positive organisms, and infections include but are not limited to upper and / or lower respiratory tract infections, skin and soft tissue infections, urinary tract infections, and gonorrhea. In some embodiments, the infection is a urinary tract infection. In some embodiments, the infection is gonorrhea. Methods for treating bacterial infections using gepodaxin are disclosed in WO2008 / 128942, WO2016 / 027249, and WO2020 / 201833, all of which are incorporated herein by reference in their entirety.

[0440] In some embodiments, the infection is a urinary tract infection caused by Escherichia coli (E.coli), Staphylococcus saprophyticus, Citrobacter kremerii, 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.

[0441] Thus, the present disclosure provides an oral formulation of the present disclosure comprising gepodacin or a pharmaceutically acceptable salt thereof for treating a bacterial infection in a human subject. In one embodiment, the infection is uUTI or gonorrhea. The present disclosure also provides the use of gepodacin or a pharmaceutically acceptable salt thereof in the manufacture of an oral formulation of the present disclosure for treating a bacterial infection in a human subject. In one embodiment, the infection is uUTI or gonorrhea. In another embodiment, the present disclosure provides a method of treating a bacterial infection in a human subject in need thereof, comprising administering to the human a particle of the present disclosure comprising gepodacin or a pharmaceutically acceptable salt thereof.

[0442] In a specific embodiment, the human subject is a pediatric patient under the age of 18. In one embodiment, the human subject is a pediatric patient under the age of 12. In one embodiment, the human subject is a pediatric patient under the age of 6. In one embodiment, the human subject is a pediatric patient between the ages of 6 and 12. In one embodiment, the human subject is a pediatric patient between the ages of 3 months and 12. In another embodiment, the human subject is a pediatric patient under the age of 8. In a more specific embodiment, the human subject is a pediatric patient between the ages of 3 months and 8.

[0443] In one embodiment, the human subject is a pediatric subject, an adolescent subject, or an adult female subject.

[0444] As used herein, the term "treating" refers to alleviating a particular disorder, eliminating or alleviating one or more symptoms of a disorder, slowing or eliminating the progression of a disorder, and preventing or delaying the recurrence of a disorder in a previously afflicted or diagnosed patient or subject.

[0445] As used herein, the term "effective amount" refers to that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human subject that is being sought, for example, by a researcher or clinician.

[0446] In one embodiment, the present application provides a method of treating urinary tract infection (UTI), comprising administering the particles of the present disclosure in a therapeutically effective amount in a human subject in need thereof, wherein gepodacin is administered at 500, 750 or 1500 mg twice daily, 6-12 hours apart, depending on age group and / or body weight.

[0447] In one embodiment, the present application provides a method for treating a urinary tract infection (UTI), comprising administering the gepodacin particles of the present invention to a human subject in need thereof in a therapeutically effective amount, wherein the subject weighs between 10 and 20 kg, and the gepodacin particles are administered at 500 mg, twice daily, 6-12 hours apart, for 2, 3, 4 or 5 days. In one embodiment, the present application provides a method for treating a urinary tract infection (UTI), comprising administering the gepodacin particles of the present invention to a human subject in need thereof in a therapeutically effective amount, wherein the subject weighs between 10 and 20 kg, and the gepodacin particles are administered at 500 mg, twice daily, 6-12 hours apart, for 5 days.

[0448] In one embodiment, the present application provides a method for treating a urinary tract infection (UTI), comprising administering the gepodacin particles of the present invention to a human subject in need thereof in a therapeutically effective amount, wherein the subject weighs between 20 and 40 kg, and the gepodacin particles are administered at 750 mg twice daily, 6-12 hours apart, for 2, 3, 4, or 5 days. In one embodiment, the present application provides a method for treating a urinary tract infection (UTI), comprising administering the gepodacin particles of the present invention to a human subject in need thereof in a therapeutically effective amount, wherein the subject weighs between 20 and 40 kg, and the gepodacin particles are administered at 750 mg twice daily, 6-12 hours apart, for 5 days. In one embodiment, the present application provides a method for treating a urinary tract infection (UTI), comprising administering the gepodacin particles of the present invention to a human subject in need thereof in a therapeutically effective amount, wherein the subject weighs 40 kg or more, and the gepodacin particles are administered at 1500 mg twice daily, 6-12 hours apart, for 2, 3, 4, or 5 days. In one embodiment, the present application provides a method for treating urinary tract infection (UTI), comprising administering the gepodacin particles of the present disclosure in a therapeutically effective amount to a human subject in need thereof, wherein the subject weighs 40 kg or more, and the gepodacin particles are administered at 1500 mg, twice daily, 6-12 hours apart, for 5 days.

[0449] In one embodiment, the present application provides a method for treating a urinary tract infection (UTI), comprising administering the gepodacin particles of the present invention to a human subject in need thereof in a therapeutically effective amount, wherein the subject is between 2-6 years old, and the gepodacin particles are administered at 500 mg, twice daily, 6-12 hours apart, for 2, 3, 4 or 5 days. In one embodiment, the present application provides a method for treating a urinary tract infection (UTI), comprising administering the gepodacin particles of the present invention to a human subject in need thereof in a therapeutically effective amount, wherein the subject is between 2-6 years old, and the gepodacin particles are administered at 500 mg, twice daily, 6-12 hours apart, for 5 days.

[0450] In one embodiment, the present application provides a method for treating a urinary tract infection (UTI), comprising administering the gepodacin particles of the present invention to a human subject in need thereof in a therapeutically effective amount, wherein the subject is between 6-12 years old, and the gepodacin particles are administered at 750 mg, twice daily, 6-12 hours apart, for 2, 3, 4 or 5 days. In one embodiment, the present application provides a method for treating a urinary tract infection (UTI), comprising administering the gepodacin particles of the present invention to a human subject in need thereof in a therapeutically effective amount, wherein the subject is between 6-12 years old, and the gepodacin particles are administered at 750 mg, twice daily, 6-12 hours apart, for 5 days.

[0451] In one embodiment, the present application provides a method for treating a urinary tract infection (UTI), comprising administering the gepodacin particles of the present invention to a human subject in need thereof in a therapeutically effective amount, wherein the subject is over 12 years old, and the gepodacin particles are administered at 1500 mg, twice daily, 6-12 hours apart, for 2, 3, 4 or 5 days. In one embodiment, the present application provides a method for treating a urinary tract infection (UTI), comprising administering the gepodacin particles of the present invention to a human subject in need thereof in a therapeutically effective amount, wherein the subject is over 12 years old, and the gepodacin particles are administered at 500 mg, twice daily, 6-12 hours apart, for 5 days.

[0452] In one embodiment, in any of the above methods for treating UTI disclosed herein, the twice daily dose is taken about 12 hours apart. In one embodiment, the UTI is an uncomplicated UTI. Specifically, the particles of the present application are present in a unit dose and are preferably taken 1 to 5 times a day, for example once or twice a day, to achieve the desired effect.

[0453] In one embodiment, the gepodaxin particles of the present disclosure are administered twice daily. In one embodiment, gepodaxin is administered for any one of 2, 3, 4, 5, 6 or 7 consecutive days. In one embodiment, in any aspect of the present application, gepodaxin is administered for 5 consecutive days.

[0454] In another embodiment, the present application provides a method for treating Neisseria gonorrhoeae infection, comprising administering the gepodacin particles disclosed herein to a human subject in need thereof in a therapeutically effective amount, wherein the gepodacin particles are administered twice, 3000 mg each time, 6-12 hours apart. In one embodiment, the gepodacin particles are administered twice, 3000 mg each time, 10-12 hours apart.

[0455] Dapoxetine granules can be used for therapy, more specifically, for the treatment of anemia. In a specific embodiment, the Dapoxetine granules of the present disclosure can be used to treat anemia associated with chronic kidney disease (also known as renal anemia). In yet another embodiment, the present disclosure provides the use of Dapoxetine or a pharmaceutically acceptable salt thereof in the manufacture of Dapoxetine granules of the present disclosure for the treatment of anemia caused by chronic kidney disease. In another embodiment, the present disclosure provides a method for treating anemia caused by chronic kidney disease in a subject in need thereof, comprising administering Dapoxetine granules of the present disclosure to the subject.

[0456] manufacture

[0457] One aspect of the present disclosure is a method for preparing particles of the present disclosure. Particles can be prepared by any suitable method, such as direct compression, dry granulation or wet granulation. In one embodiment, a wet granulation method is adopted. In wet granulation, particles can be prepared by contacting or mixing the relevant components with a vehicle, and the vehicle can be aqueous or non-aqueous, or a combination. In one embodiment, the vehicle is water (qs), more specifically purified water (qs). In one embodiment, this wet granulation method is a batch high shear granulation method. Compared with top spray granulation or dry granulation (i.e., roller compaction), using a batch high shear wet granulation method results in better control of particle size and reduced levels of fine powder.

[0458] As shown in Example 4, the use of a soluble filler in the granulation improves wet granulation, and granules containing 15 to 75% w / w soluble filler (eg mannitol) have greater mechanical strength (lower fines levels) for downstream processing.

[0459] The use of a batch high shear wet granulation process results in improved granule properties (flow properties, particle size distribution control, fines level) and improves the palatability of the granules by reducing the drug surface area in contact with taste buds.

[0460] The following are examples of implementations:

[0461] 1. An oral dosage form of granules, the granules comprising

[0462] a) up to about 60% (w / w) of one or more active pharmaceutical ingredients;

[0463] b) about 15-75% (w / w) of a soluble filler;

[0464] c) about 20-60% (w / w) microcrystalline cellulose;

[0465] d) about 2-5% (w / w) of a binder; and

[0466] e) about 1.5-15% (w / w) of a disintegrant;

[0467] The ratio of microcrystalline cellulose to binder is ≥ 5:1; and

[0468] The diameter of the particles is ≤250 μm and the density is 0.4–0.6 g / mL.

[0469] 2. The oral dosage form according to clause 1, wherein the granules have a Carr index value of ≤30% and an FFc value of ≥10.

[0470] 3. An oral formulation according to clause 1 or clause 2, wherein one unit dose of the granules is completely dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling in 3 minutes or less.

[0471] 4. The oral dosage form according to any one of clauses 1 to 3, wherein the binder is HPMC or povidone.

[0472] 5. The oral dosage form according to any one of clauses 1 to 4, wherein the ratio of microcrystalline cellulose to binder is about 5:1 to 10:1.

[0473] 6. An oral dosage form according to any one of clauses 1 to 5, wherein the soluble filler is mannitol.

[0474] 7. An oral formulation according to any one of clauses 1 to 6, wherein the disintegrant is selected from croscarmellose sodium, crospovidone and sodium starch glycolate.

[0475] 8. An oral formulation according to any one of clauses 1 to 7, wherein the active pharmaceutical ingredient is gepodacin or a pharmaceutically acceptable salt thereof.

[0476] 9. The oral formulation according to clause 8, wherein the granules comprise gepodacin mesylate dihydrate.

[0477] 10. An oral formulation according to any one of clauses 1 to 9 for use in therapy.

[0478] 11. An oral formulation according to clauses 8-9 for use in treating a bacterial infection in a human subject.

[0479] 12. Use of gepodacin or a pharmaceutically acceptable salt thereof in the manufacture of an oral formulation for treating a bacterial infection in a human subject according to any one of clauses 1 to 9.

[0480] 13. A method of treating a bacterial infection comprising administering an oral formulation according to clauses 8-9 in a therapeutically effective amount to a human subject in need thereof.

[0481] 14. The use or method according to clauses 12-13, wherein the human subject is a pediatric patient under 12 years of age.

[0482] 15. A method of manufacturing an oral dosage form according to any one of clauses 1 to 9, wherein the granules are formed by wet granulation. Example

[0483] Scheme for measuring dispersion time:

[0484] Method 1 (granules): Dispersion time is measured using the patient instruction method, where an amount of particles equivalent to one unit dose of API (e.g. 750 mg equivalent gepodacin free base) is dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling. The time to form a uniform fine dispersion is measured.

[0485] Method 2 (Tablet): Using USP Method <701> Measuring disintegration

[0486] Method 3 (Tablet) : Dispersibility was measured using the patient instruction method, where 1 to 4 tablets were dispersed in 5 mL of water and 5 to 8 tablets were dispersed in 10 mL of water in a 30 mL dosing cup using gentle swirling for 1-3 min.

[0487] It was observed that the dispersion times measured using methods 2 and 3 showed good correlation. All examples using granules used method 1. All examples using tablets used either method 2 or 3.

[0488] Example 1 - Particle Size

[0489] The particle diameter is ≤250 microns, the density is 0.4-0.6 g / mL, it passes the European Pharmacopoeia dispersion fineness test, and it disperses very quickly in water in less than 60 seconds to form a uniform fine dispersion. The particles with a median size of 300 microns are too large and fail the European Pharmacopoeia dispersion fineness test.

[0490] All of the following granules have good flowability and good content uniformity, Carr index <30%, and FFc value ≥10.

[0491] Table 1

[0492]

[0493]

[0494] The composition of Formulation 4 is shown in Table 2 below.

[0495] Table 2

[0496]

[0497] As described above, the oral formulation may further comprise an extragranular portion. The following table provides examples of oral formulations comprising the granules of Formulation 4 and an extragranular portion.

[0498] Table 2a

[0499]

[0500] Example 2 - MCC Content

[0501] Table 3a shows that granules containing 20-60% w / w microcrystalline cellulose (MCC) disperse rapidly in water. Dispersion Test Method 1 was used. The median particle size of Formulation 4 used in this example was 149 microns (the particle size of Formulations 5 and 6 was not tested). Among the amounts tested, the fastest dispersion time of the gepodaxin particles was observed with 20% w / w microcrystalline cellulose, and this was also optimal for the robustness of the granulation process.

[0502] Table 3a

[0503]

[0504] Table 3b shows the rapid dispersion time of tablets made from granules containing 20-60% w / w microcrystalline cellulose (MCC). Dispersion test methods 2 and 3 were used. Although the dosage form tested was a tablet, the granules in the tablet aided in the rapid dispersion of the tablet due to the size, density and composition of the granules. Compression into tablets made the dispersion of the granules more challenging, but the results still showed that the tablets were fully dispersed in less than 2 minutes.

[0505] Table 3b

[0506]

[0507] Table 4 gives the composition of Formulations 1, 2, 3, 4, 5, 6, 8, 9. The intragranular components shown in the table are the components of the granules. The additional tablet components of Formulations 1, 2, 3, 8 and 9 are shown in the table as "Tablet Formulation".

[0508] Table 4

[0509]

[0510] Example 3 - MCC Binder Ratio

[0511] Table 5 shows that gepodacin particles having MCC:binder ratios of 5:1 to 10:1 disperse very quickly in water.

[0512] Table 5

[0513]

[0514] The compositions of Formulations 4 and 7 are shown in Table 6.

[0515] Table 6

[0516] Components Formulation 4 (% w / w) Formulation 7 (% w / w) Drug substances 57.8 57.8 Mannitol 17.2 15.2 MCC 20.0 20.0 Binder (Hydroxypropyl Methylcellulose) 2.0 4.0 Croscarmellose Sodium 3.0 3.0 Total 100.0 100.0

[0517] Example 4 - Soluble Filler

[0518] Table 7 shows that granules containing a soluble filler in addition to MCC and tablets made from the granules have lower amounts of insoluble solids and therefore have an improved mouthfeel.

[0519] Formulation 4 was tested as granules and tablets. The dispersion time of Formulation 4 was measured from the granules (no extragranular components were added and before compression). The dispersion time of Tablet Formulations 1, 3, 4 and 8 was measured from the tablet dosage form with a target average tablet tensile strength of 2 MPa (± 0.5 MPa). Due to the size, density and composition of the granules, the granules in the tablets facilitate rapid dispersion of the tablets when compressed into tablets. Compression into tablets makes the dispersion of the granules more challenging, but the results still show complete dispersion in less than 2 minutes.

[0520] Table 7

[0521]

[0522]

[0523] Table 8 shows the compositions of Formulations 1, 3, 4, and 8. Formulation 4 was tested both as a granulate containing only the following intragranular components and separately as a compressed tablet form containing the following tablet formulation components as described above.

[0524] Table 8

[0525]

[0526]

[0527] Example 5 - Disintegrant

[0528] Table 9 shows that granules containing intragranular disintegrants (e.g., croscarmellose sodium, sodium starch glycolate, and crospovidone XL-10) disperse in less than 3 min when compressed into tablets with a target average tensile strength of 2 MPa (± 0.5 MPa). 1.5-3% w / w croscarmellose sodium, 5-15% w / w crospovidone XL, and 3-5% w / w sodium starch glycolate were successfully used in granules to produce a rapidly dispersing drug product (dispersed within 30 s). Test Methods 2 and 3 described above were used to measure tablet dispersion / disintegration. Table 9 shows the disintegration times of tablets containing granules containing optimal levels of disintegrants: 3% w / w croscarmellose sodium, 4% w / w sodium starch glycolate, and 5% w / w crospovidone XL-10.

[0529] Table 9

[0530]

[0531] Table 10 shows the compositions of Formulations 1, 3, and 10.

[0532] Table 10

[0533]

[0534]

[0535] Example 6

[0536] Other examples of oral granule dosages include:

[0537] Table 11

[0538]

[0539] *Measured as free acid

[0540] **Measured as free base

[0541] a Croscarmellose Sodium b Sodium starch glycolate

[0542] Examples of the weight amounts of the components of the granules comprising gepodacin mesylate dihydrate of the present disclosure are shown in Table 12.

[0543] Table 12

[0544]

Claims

1. An oral preparation comprising particles comprising f. up to about 60% (w / w) of gepodaxin or a pharmaceutically acceptable salt thereof; g. about 15-75% (w / w) of a soluble filler; h. about 20-60% (w / w) microcrystalline cellulose; i. about 2-5% (w / w) of a binder; and j. about 1.5-15% (w / w) of a disintegrant; The ratio of microcrystalline cellulose to binder is ≥ 5:1; and The diameter of the particles is ≤250 microns and the density is 0.4-0.6 g / mL. 2 . The oral formulation of claim 1 , wherein the particles have a Carr index value of ≤30% and an FFc value of ≥10.

3. The oral formulation of claim 1 or claim 2, wherein one unit dose of the granules is completely dispersed in 15 mL of water in a 60 mL dosing cup using gentle swirling in 3 minutes or less.

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

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

1.

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

7. The oral formulation according to any one of claims 1 to 6, wherein the disintegrant is selected from cross-linked carboxymethylcellulose sodium, cross-linked polyvidone and sodium starch glycolate.

8. The oral formulation of any one of claims 1 to 7, wherein the active pharmaceutical ingredient is gepodacin mesylate.

9. The oral formulation of claim 8, wherein the active pharmaceutical ingredient is gepodacin mesylate dihydrate.

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

11. An oral formulation according to any one of claims 1 to 10 for use in therapy.

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

13. An oral formulation according to any one of claims 1 to 10 for use in treating a bacterial infection in a human subject.

14. Use of gepodacin or a pharmaceutically acceptable salt thereof in the manufacture of an oral formulation according to any one of claims 1 to 10 for treating a bacterial infection in a human subject.

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

16. The use or method of claim 14 or claim 15, wherein the human subject is a pediatric patient under 12 years of age.

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

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