Improved product and process

Abstract

Oral bioavailability of pharmaceutical substances drives drug developers to micronize, or reduce the size of active pharmaceutical ingredients. This invention relates to a novel, solid oral dose form of unmicronized moxidectin and a manufacturing process thereof that explicitly avoids a micronization or size reduction step.

Description

Improved product and process Related Application

[0001] This application claims priority to Australian provisional application no 2024902139 (filed 11 July 2024), the entire contents of which is incorporated herein by reference. Field of the invention

[0002] The invention relates to a novel, solid oral dose form of moxidectin and the manufacturing process thereof. Background of the invention

[0003] Oral bioavailability of pharmaceutical substances is driven by a number of factors including the rate and extent of dissolution of the active pharmaceutical ingredient (API), permeability and drug transporter-driven influx and efflux pathways (Bhalani et al., 2022; Vinarov et al., 2021). Of these drivers of bioavailability, solubility, or the rate and extent of dissolution of a solid, is the one factor over which drug developers can exert a level of control, without being reliant upon the intrinsic physical properties of either the drug molecule or the biology of the gut wall.

[0004] It is known that the rate of dissolution of a solid may in many cases be described by the Noyes–Whitney equation in which the dissolution rate is proportional to the concentration gradient and the surface area of the solid (Gao et al., 2021): dC / dT = kS(Cs-Ct) where the change in concentration over time (dC / dT) is a function of the dissolution rate constant k, surface area S, solubility Cs, and concentration in the bulk fluid Ct.

[0005] Of additional consideration is the spatial distribution of a drug substance within an individual dosage form, as failure to evenly distribute a drug in a single tablet may lead to formations of drug agglomerates and therefore poor therapeutic outcomes. Wagner-Hattler et al. [Int J of Pharmaceutics 573 (2020)] reported that uniform drug distribution within fast disintegrating tablets is a key quality measure to ensure a reliable, steady, and targeted release of the contained active pharmaceutical 1005841944ingredients. With this in mind, they used moxidectin as a model drug for developing a method of investigating drug particle distribution in mini-tablets, given the need to guarantee drug content and drug distribution within a tablet and the need to avoid possible agglomeration and segregation during blending and tableting.

[0006] Using moxidectin with a primary crystal size distribution of D(0.1) = 3.68 µm, D(0.5) = 13.21 µm, D(0.9) = 32 µm; sieved through a 500 µm sieve, the authors concluded that the drug was not uniformly distributed within the tablet, and for drug loads of more than 20%, revealing drug segregation and agglomeration effects during blending and an increasing drug load towards the tablets’ outer boundaries, indicative of a radial displacement of drug particles during compaction.

[0007] Given that the rate of particle dissolution is, in part, directly proportional to surface areas of the particles within a sample, a well-known strategy used in pharmaceutical manufacturing to increase the rate of dissolution of solid oral dose forms and, accordingly, optimize bioavailability, is to reduce the particle size of drug substances (also known as Active Pharmaceutical Ingredients; APIs), thereby increasing particle surface areas and increasing rate of dissolution. Numerous methods exist for particle size reduction including ball milling, micronization by mechanical- or jet- milling (micronization), and spray drying. It is generally accepted that application of these techniques will lead to a reduction in particle size, production of APIs of more consistent particle size distribution and an improvement in dissolution and bioavailability (Kumar et al., 2022).

[0008] Of the available techniques to produce APIs of more consistent particle size distribution within a tablet, the need to avoid possible agglomeration and segregation during blending and tableting and an improvement in dissolution and bioavailability, micronization has to date been the most consistently used.

[0009] Due to their low aqueous solubility, solid oral dose forms of moxidectin and ivermectin have relied on micronization as the means of optimizing the rate and extent of dissolution and therefore bioavailability. All existing and commercially available solid oral products and solid oral formulations containing moxidectin as the active pharmaceutical ingredient, and therefore all solid formulations of moxidectin in the prior art, are micronized. This is the standard process in the art for solid formulations. 1005841944

[0010] In the manufacture of moxidectin solid oral dose tablets, reduction of the particle size of moxidectin active pharmaceutical ingredient (API) by micronization is a defined manufacturing step and is controlled within an established specification. The rate of dissolution of moxidectin tablets made using micronized moxidectin API under controlled conditions is also well known and used as a test to confirm that tablets conform to their specifications before being released for human use.

[0011] However, there are disadvantages to having to micronize a substance. First and foremost, a universal disadvantage is the added time and cost it adds to a manufacturing process. In addition, the process can also negatively impact the substance itself as the properties of the micronized material may be different from those of non-micronized material. For example, agglomeration, poor flowability (meaning how poorly a powder flows during tablet manufacture, contributing to inaccurate and non- reproducible manufacture of tablets containing the intended dose), increased hygroscopicity and in some cases, conversion to a different crystalline polymorph, dehydration or desolvation, or production of amorphous content.

[0012] Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and / or combined with other pieces of prior art by a skilled person in the art. Summary of the invention

[0013] In one aspect of the invention there is provided a solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition comprises or consists of a. unmicronized moxidectin, or a pharmaceutically acceptable salt thereof; and b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and c. a pharmaceutically acceptable carrier.

[0014] Preferably, substantially all (ie ≥90%) of the unmicronized moxidectin particles are larger than 10 microns. 1005841944

[0015] In another aspect of the invention there is provided a solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition comprises or consists of a. moxidectin, or a pharmaceutically acceptable salt thereof, wherein the moxidectin, or a pharmaceutically acceptable salt thereof, has a particle size distribution (PSD) of a D10 of 2 microns and / or a median (D50) particle size of 10 microns and / or a D90 of 500 microns; and b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and c. a pharmaceutically acceptable carrier.

[0016] In one embodiment of this aspect of the invention the moxidectin has a D90 range of 20 to 500 microns; more preferably a D90 of 20 to 500 microns and a D10 of 2 microns; and most preferably a D90 of 20 to 500 microns, and a D10 of 2 microns and a D50 of 10 microns.

[0017] In another aspect of the invention there is provided a solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition comprises or consists of a. moxidectin, or a pharmaceutically acceptable salt thereof; and b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and c. a pharmaceutically acceptable carrier, with a proviso that particles of the moxidectin, or a pharmaceutically acceptable salt thereof, are unmicronized and / or are 90% or more of the particles are larger than 10 microns.

[0018] In preferred embodiments of each of these aspects of the invention, the solid oral dose composition of moxidectin is in the form of a tablet or a capsule, preferably with the proviso that the tablet or capsule is not a chewable tablet. Preferably the composition further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, binders, preservatives, and combinations thereof. 1005841944

[0019] In a further preferred embodiment the tablet or capsule has a dissolution profile in an aqueous solvent comparable to a solid oral dose composition of micronized moxidectin.

[0020] In another aspect of the invention there is provided a process for preparing a solid oral dose composition of moxidectin, comprising the steps of: i) blending moxidectin with pharmaceutically acceptable excipients; and ii) compressing the blend into a solid oral dose with the proviso that no size reduction or micronization of the moxidectin is conducted.

[0021] The moxidectin for use in the process may from be any manufacturer / supplier of moxidectin as an ingredient.

[0022] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings. Brief description of the drawings

[0023] Figure 1: Molecular Structure of Moxidectin

[0024] Figure 2: Dissolution rates of moxidectin tablets, 2mg

[0025] Figure 3A-F: Particle size distribution (PSD) for 6 different samples of 2mg unmicronized moxidectin tablets using a particle volume distribution and cumulative volume graph.

[0026] Figure 4A-C: Particle size distribution (PSD) for 3 different samples of 2mg micronized moxidectin tablets using a particle volume distribution and cumulative volume graph.

[0027] Figure 5: Mean plasma concentration vs time profile for micronized moxidectin and unmicronized moxidectin after oral gavage in Sprague-Dawley rats. Definitions

[0028] The term "moxidectin" as used herein, refers to (1R,4S,4'E,5'S,6R,6'S,8R,10E,13R,14E,16E,20R,21R,24S)-21,24-dihydroxy-4'- methoxyimino-5',11,13,22-tetramethyl-6'-[(E)-4-methylpent-2-en-2-yl]spiro[3,7,19- 1005841944trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22-tetraene-6,2'-oxane]-2-one, CAS [113507-06-5], also known as milbemycin B, a compound of molecular formula C37H53Cl2NO8 and as shown in Figure 1.

[0029] Any reference to moxidectin is to be understood to be a reference to moxidectin, or a pharmaceutically acceptable salt thereof.

[0030] Particle size distribution (PSD) as used herein refers to the range of particle sizes present in a sample. Percentages are specified per size interval (fraction) or cumulative values are used, in which the fractions are added up in ascending or descending order of size.

[0031] A D-value, or a Dv value, as used herein, is the diameter which, when all particles in a sample are arranged in order of ascending mass, divides the sample's mass into specified percentages. The percentage mass below the diameter of interest is the number expressed after the "D". The length unit, DX represents the X% of particles in the powders are smaller than this size. Typically, the unit is μm, ie microns. It can also be represented by a statistical symbols such as DV10 or DV(0.1). V means total volume. For example, D90, DV90 or DV(0.9) means that 90% of the total particles in a sample are smaller than this size. Any reference to a D value is to be understood to be equivalent to a DV volume and vice versa.

[0032] D50 is also referred to as the median particle size.

[0033] A D value can refer to a range. For example, a D90 of 500 means that 90% of all particles in a sample are less than 500 microns. But in the context of a D90 range, it will be understood as meaning that 90% of the particles in the sample have a size range of 20-500 microns.

[0034] The term “micronize” or “micronization, as used herein, refers to a process of reducing the particle size of solid substances to micron-scale dimensions. By this it is understood that substantially all (ie 90% or more) of the particles in a micronized sample are smaller than 10 microns. A micronized sample may also be defined in terms of its particle size distribution of a D(10) = 1 µm, D(50) = 2 µm, D(90) = 10µm.

[0035] The term “unmicronized” as used herein refers to moxidectin that has not been intentionally or deliberately subjected to any particle size reduction or micronization 1005841944processes. The moxidectin may be sourced from any manufacturer / supplier of moxidectin as an ingredient.

[0036] The term “unmicronized moxidectin” may additionally, or alternatively, be characterised by the size of the particles in a sample. By this it is understood that substantially all (ie 90% or more) of the particles in an unmicronized sample are larger than 10 microns.

[0037] An unmicronized sample may additionally, or alternatively, be defined in terms of its particle size distribution. For example, unmicronized moxidectin might be defined as having: • a D90 of 500 microns; and / or • a D50 of 10 microns; and / or • a D10 of 2 microns.

[0038] As used herein in the context of a sample of unmicronized moxidectin, a sample “consists of” unmicronized moxidectin when substantially all of the moxidectin particles in the sample are larger than 10 microns and preferably have a size range of 20 to 500 microns. The term “substantially” is used herein to refer to greater than 90% (e.g., greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%). As would be understood by the skilled person and the nature of this art, this is not an absolute term that is intended to be construed too literally. There may be a small number of moxidectin particles smaller than 5-10 microns but the amount thereof is insignificant and does not materially affect the core characteristics or functionality of the invention as claimed. In this regard, “consists of” is intended to mean “consists essentially of”.

[0039] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.

[0040] The term "pharmaceutically acceptable" as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject 1005841944(e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation and for the end use.

[0041] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.

[0042] As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material which is included in the composition for a purpose other than pharmaceutical efficacy (this is not intended to exclude materials which may have some biological effect). Pharmaceutically acceptable excipients include binders, diluents, glidants, disintegrants, lubricants, and combinations thereof.

[0043] As used herein, “oral fixed dose tablet forms of moxidectin”, mean an oral tablet for a human that is to be swallowed, rather than a chewable tablet for a non- human animal. Detailed description of the embodiments

[0044] Macrocyclic lactones have pharmacokinetic properties which enhance their use against endo- and ectoparasites in animals and man. The macrocyclic lactones such as ivermectin and later moxidectin, have been extensively studied and developed as therapies for animals and more recently humans.

[0045] However, just like its predecessor ivermectin, due to its low aqueous solubility, solid oral dose forms of moxidectin have to date always relied on micronization as the means of optimizing bioavailability, and currently all known oral fixed dose tablet forms of moxidectin are synthesised with micronized forms of the compound. 1005841944

[0046] It therefore came as a great surprise and contrary to the conventional wisdom, that the inventors developed a new manufacturing process and an oral fixed dose tablet manufactured using unmicronized moxidectin that had a dissolution profile comparable to tablets manufactured using micronized moxidectin, and with preliminary data suggesting the potential to initially dissolves more rapidly than tablets made using micronized moxidectin.

[0047] The unmicronized moxidectin of the invention may be characterized in one or more ways. i) By process This refers to moxidectin that has not been intentionally or deliberately subjected to any particle size reduction or micronization processes. As micronization for pharmaceutical purposes typically seeks to reduce the particle size of the active to less than 10 microns, it is anticipated that substantially all (ie ≥90) of the particles of unmicronized moxidectin will be larger than 10 microns. ii) By particle size The moxidectin particles can be characterised by their size in microns (µM). Substantially all (ie ≥90%) of the particles have a diameter of greater than about 10 microns, greater than about 20 microns, greater than about 30 microns, greater than about 40 microns, greater than about 50 microns greater, than about 60 microns, greater than about 70 microns, greater than about 80 microns, greater than about 90 microns and greater than about 100 microns. Preferably substantially all of the particles have a diameter that is in the range of 20 to 500 microns. iii) By particle size distribution (PSD) Particle size distribution (PSD) refers to the range of particle sizes present in a sample. D50 is the most common way of defining the median particle size in a sample. Two points ie the D90 and D10 can be used to describe the coarsest and finest parts of the distribution. A three point specification featuring the D10, D50, and D90 can also be used. For example: 1005841944Unmicronized (µM) PSD Micronized (µM) 2 D10 1 10 D50 2 500 D90 10

[0048] Accordingly, there is provided a solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition comprises or consists of a. unmicronized moxidectin, or a pharmaceutically acceptable salt thereof; and b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and c. a pharmaceutically acceptable carrier.

[0049] Substantially all of the particles of unmicronized moxidectin will be larger than 10 microns, preferably larger than 20 microns and most preferably in a size range of 20 to 500 microns.

[0050] In an alternative aspect of the invention there is provided a solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition comprises or consists of a. moxidectin, or a pharmaceutically acceptable salt thereof, wherein the moxidectin, or a pharmaceutically acceptable salt thereof, has a particle size distribution of a D10 of 2 microns and / or a median (D50) of 10 microns and / or a D90 of 500 microns; and b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and c. a pharmaceutically acceptable carrier.

[0051] In one embodiment of this aspect of the invention, the unmicronized moxidectin has a PSD with a D90 range of 20 to 500 microns. In another embodiment, the moxidectin has a D90 range of 20 to 500 microns and a D10 of about 2 microns. And in 1005841944yet another embodiment, the moxidectin has a D90 of 20 to 500 microns and a D10 of about 2 microns and a D50 of about 10 microns.

[0052] In an alternative aspect of the invention there is provided a solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition comprises or consists of a. moxidectin, or a pharmaceutically acceptable salt thereof, wherein at least 50% of the moxidectin particles are in the size range of about 20-500 microns; and b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and c. a pharmaceutically acceptable carrier.

[0053] In another embodiment, 70%, or 80% or 90% or more of the moxidectin particles are in the size range of about 20-500 microns. In the alternative, only 10% of the moxidectin particles in a sample are smaller than 10 microns and 90% of the particles of the moxidectin in are larger than 10 microns.

[0054] As would be understood by the skilled person, any technique may be utilised to determine the particle size and distribution, including but not limited to microscopy and image analysis, sifting, laser diffraction and most commonly dynamic light scattering (DLS). Preferably in each of the embodiments the particle size distribution is measured by a static light scattering instrument.

[0055] In yet another alternative aspect of the invention, there is provided a solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition comprises or consists of a. moxidectin, or a pharmaceutically acceptable salt thereof; and b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and c. a pharmaceutically acceptable carrier, 1005841944with a proviso that particles of the moxidectin, or a pharmaceutically acceptable salt thereof, are unmicronized and / or are larger than 10 microns.

[0056] The moxidectin particles in the solid oral dose composition can also be a combination of sizes provided substantially all (ie ≥90%) of the particles are larger than 10 microns, preferably larger than 20 or more microns.

[0057] In preferred embodiments, the moxidectin component in (a) consists of, or consists essentially of, unmicronized moxidectin, or a pharmaceutically acceptable salt thereof. As would be understood by the skilled person, this means that substantially all (ie 90% or more) of the moxidectin particles are larger than 10 microns. Accordingly there is provided a solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition consists of, or essentially consists of, as the sole active ingredient, either: a. unmicronized moxidectin, or a pharmaceutically acceptable salt thereof; or moxidectin, or a pharmaceutically acceptable salt thereof, wherein particles of the moxidectin, or a pharmaceutically acceptable salt thereof, have a D10 of 2 microns and / or a median (D50) of 10 microns and / or a D90 of 500 microns; optionally the D90 is a D90 range of 20 to 500 microns; or moxidectin, or a pharmaceutically acceptable salt thereof with a proviso that particles of the moxidectin, or a pharmaceutically acceptable salt thereof, are unmicronized and / or are substantially all (ie ≥90%) larger than 10 microns; and further comprises b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and c. a pharmaceutically acceptable carrier. Dosage

[0058] In preferred embodiments of the invention, the solid oral dose comprises moxidectin or pharmaceutically acceptable salt thereof, in an amount from 1mg to 300mg, preferably 1mg to 40mg, and more preferably 2mg to 30mg. That is, the solid oral dose comprises moxidectin or pharmaceutically acceptable salt thereof, in an 1005841944amount of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40mg.

[0059] The solid oral dose may alternatively be classified as a low dose or a medium dose or high dose solid oral tablet: - a low dose solid oral dose of the invention comprises 1-10mg of unmicronized moxidectin, preferably 8mg; - a medium dose solid oral dose of the invention comprises 10-20mg of unmicronized moxidectin, preferably 16mg; and - a high dose solid oral dose of the invention comprises 20-40mg of unmicronized moxidectin, preferably 32mg. Dosage forms

[0060] The solid oral dose of the invention may be in the form of a tablet or a capsule. The tablet or capsule can be formulated for use by any animal requiring treatment with moxidectin, but will most typically be formulated for use as a treatment for a mammal, and most preferably a human.

[0061] A tablet may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine moxidectin in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); glidants (e.g. colloidal silicon dioxide, talc, magnesium carbonate, fumed silica); disintegrants (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxy methyl cellulose); surface-active or dispersing or wetting agents (e.g. sodium lauryl sulfate); and preservatives (e.g. methyl p- hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated, scored or debossed and may be formulated so as to provide slow or control release of moxidectin therein using, for example, hydroxypropylmethyl cellulose (HPMC) in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. 1005841944

[0062] Preferably the tablet is not a chewable tablet. Oral tablets of the invention, intended to be swallowed, have very different excipients to those intended to be chewable.

[0063] A capsule may also be made by conventional means, and may include hard or soft gelatin capsules, enteric-coated capsules, modified released capsules and HPMC capsules (also known as vegetarian capsules). In some embodiments, the capsule is coated, wherein the coating includes, but is not limited to, immediate release coatings, protective coatings, enteric or delayed release coatings, sustained release coatings, barrier coatings, seal coatings, or combinations thereof. In some embodiments, a capsule herein is hard or soft. In some embodiments, the capsule is seamless. Examples of capsule shapes include, but are not limited to, round, oval, tubular, oblong, twist off, or a non-standard shape.

[0064] Hard or soft gelatin capsules may be manufactured in accordance with conventional methods as a single body unit comprising the standard capsule shape. The gelatin capsule may also be manufactured in accordance with conventional methods, for example, as a two-piece hard gelatin capsule. Compositions

[0065] Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.

[0066] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

[0067] General information on types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is as described in general texts such 1005841944as “Handbook of Pharmaceutical salts” P. H. Stahl, C. G. Wermuth, 1st edition, 2002, Wiley-VCH and S. M. Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1–19.

[0068] The solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, of the invention may comprise one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, binders, preservatives, and combinations thereof: Table 1 Purpose Examples Active ingredient Moxidectin, or a pharmaceutically acceptable salt thereof. The moxidectin is unmicronized and / or has a D10 of 2 microns, a median (D50) of 10 microns and a D90 of 500 microns. The moxidectin may be sourced from any manufacturer / supplier of moxidectin that supplies it as an ingredient. Diluent or filler Microcrystalline cellulose, lactose, anhydrous lactose, calcium hydrogen phosphate, starches, maltodextrins, and combinations thereof Surfactant Sodium lauryl sulfate, glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, cetyltrimethylammonium bromide, polysorbates (such as polysorbate 20 or 80), poloxamers (such as poloxamer 188 or 207), macrogols and combinations thereof. Glidant Colloidal silicon dioxide, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, talc and combinations thereof Disintegrant Croscarmellose sodium, sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxy methyl cellulose Lubricant Magnesium stearate, talc, silica, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, colloidal silicon dioxide and combinations thereof Binders Povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose, and combinations thereof Preservatives Methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid, parabens (methylparaben and / or propylparaben), benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thimerosal, and combinations thereof. 1005841944Functionality of the solid oral dose of moxidectin

[0069] The solid oral dose moxidectin compositions of the invention comprising, or consisting of, or consisting essentially of unmicronized moxidectin have a dissolution profile in an aqueous solvent comparable to solid oral dose compositions manufactured using micronized moxidectin. The solid oral dose compositions of the invention are therefore cheaper, easier and faster to manufacture, and at lower risk of the moxidectin having altered properties compared to solid oral dose compositions comprising micronized moxidectin. The solid oral dose moxidectin compositions of the invention may also initially dissolve more rapidly than solid oral dose compositions made using micronized moxidectin. “Initially” as used here is intended to refer to a time period of 0 to 25 minutes and preferably 5 to 20 minutes.

[0070] Accordingly, there is provided a solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition comprises, consists of, or essentially consists of either: a. unmicronized moxidectin, or a pharmaceutically acceptable salt thereof; or moxidectin, or a pharmaceutically acceptable salt thereof, wherein particles of the moxidectin, or a pharmaceutically acceptable salt thereof, have a D10 of 2 microns and / or a median (D50) of 10 microns and / or a D90 of 500 microns; or moxidectin, or a pharmaceutically acceptable salt thereof with a proviso that particles of the moxidectin, or a pharmaceutically acceptable salt thereof, are unmicronized and / or are substantially all (ie ≥90%) larger than 10 microns; and further comprises b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and c. a pharmaceutically acceptable carrier, wherein the solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, have a dissolution profile in an aqueous solvent comparable to solid oral dose compositions manufactured using micronized moxidectin. Optionally the D90 is a D90 range of 20 to 500 microns. 1005841944

[0071] In each of the above aspects and embodiments of the invention the solid oral dose compositions are preferably a tablet or capsule and are not a chewable tablet. Process for manufacturing solid oral dose of moxidectin

[0072] By omitting the need for micronizing the moxidectin before it is formulated for administration, the invention provides the advantage of a novel manufacturing process that is both faster, easier and cheaper, and at lower risk of the unmicronized moxidectin having altered properties compared to solid oral dose compositions comprising micronized moxidectin.

[0073] After synthesis of the crude reaction product, the commercial production process for moxidectin involves precipitation of moxidectin from solution using an anti- solvent using standard procedures, and filtration and drying of the precipitated moxidectin. This precipitation step of the manufacturing process yields amorphous, unmicronized moxidectin.

[0074] Accordingly, there is provided a process for preparing a solid oral dose composition of moxidectin of the invention, comprising the steps of: i) blending unmicronized moxidectin with pharmaceutically acceptable excipients; and ii) compressing the blend into a solid oral dose with the proviso that no size reduction or micronization of the moxidectin is conducted. That is, the moxidectin purchased is unmicronized, and the unmicronized moxidectin is used in step (i) of the process. The solid oral dose compositions produced by the process use moxidectin, and in turn the moxidectin in the solid oral dose has, a PSD of D10 of 2 and / or a D50 of 10 and / or a D90 of 500; optionally the D90 is a D90 range of 20-500 microns. The moxidectin used, and the moxidectin in the solid oral dose, may alternatively be defined as substantially all (≥90%) of the particles being larger than 10 microns.

[0075] The above process can include additional steps but specifically excludes any size reduction or micronization steps of the moxidectin. Moxidectin for use in the processes for preparing a solid oral dose composition of moxidectin may be sourced from any commercial supplier. 1005841944Examples i) Tablet formulations tested

[0076] Moxidectin tablet components are provided in the Table below. The dissolution profile of moxidectin tablets containing 2 mg of moxidectin supplied as 100 mg white to pale yellow, uncoated, oval-shaped tablets were tested. Table 2 Component Purpose 2-32mg Moxidectin* Active ingredient Microcrystalline cellulose Formulary Diluent Lactose, anhydrous Formulary Diluent Sodium lauryl sulfate Formulary Surfactant Colloidal silicon dioxide Formulary Glidant Croscarmellose sodium Formulary Disintegrant Magnesium stearate Formulary Lubricant * As either micronized or unmicronized for comparison purposes ii) Testing procedure

[0077] Particle size analysis was conducted using a Malvern Mastersizer 3000 (laser diffraction technique) calibrated to assay particle sizes in the range of 0.01-3500 microns. Laser settings were typically blue light LED, 470nm; and red light He-Ne Laser, 632.8nm.

[0078] Samples were homogenised inside a sample chamber prior to analysis. iii) Results

[0079] Figure 2 shows the dissolution profile of 2mg moxidectin tablets made either with or without micronization of moxidectin. The curves show that surprisingly, not only was the rate of dissolution of unmicronized moxidectin comparable to micronized moxidectin, but the early rate of dissolution of tablets made using unmicronized moxidectin was greater than the rate of dissolution of tablets made using micronized moxidectin. 1005841944

[0080] Figure 3A-F show the particle size distribution (PSD) for 6 different samples of 2mg unmicronized moxidectin tablets using a particle volume distribution and cumulative volume graph. The volume distribution shows the particles in a given size range by percentage of the total sample volume, while the cumulative volume curve tracks the total volume of all size ranges as they approach 100%.

[0081] The table below summarises the particle size distribution (in microns) for each of the unmicronized samples. Table 3 Figure D10 D50 D90 3A 1.02 7.20 23.7 3B 0.931 8.23 87.3 3C 1.02 9.23 105 3D 0.948 6.86 40.3 3E 0.824 8.35 412 3F 1.06 9.09 160

[0082] Figure 4A-C show the particle size distribution (PSD) for 3 different samples of 2mg micronized moxidectin tablets again using a particle volume distribution and cumulative volume graph. The table below summarises the particle size distribution (in microns) for each of the micronized samples. Table 4 Figure D10 D50 D90 4A 0.323 0.842 2.465 4B 0.343 0.915 4.512 4C 0.368 1.346 8.749 iv) Bioavailability

[0083] The rate and extent of dissolution is a driver of bioavailability. 1005841944

[0084] To confirm the oral bioavailability of unmicronized moxidectin given its unexpectedly good rates of dissolution, groups of about 3 rats were each dosed with an oral gavage consisting of a 0.2 mg / mL suspension of either unmicronized or micronized moxidectin in 0.5% methyl cellulose in water. Plasma samples were collected at representative timepoints of 5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h after oral dosing. Levels of moxidectin in plasma samples were analysed using liquid chromatography. Pharmacokinetic parameters including maximum plasma concentration (Cmax), area under the time-concentration curve (AUC) and half-life (t1 / 2) were respectively determined for rats dosed with either unmicronized or micronized moxidectin (Figure 5).

[0085] Analysis of the samples showed that the bioavailability of moxidectin was not sensitive to whether the oral dose was of micronized or unmicronized moxidectin. Figure 5 shows that within normal experimental error, the plasma concentration versus time curves for rats dosed with micronized or unmicronized moxidectin were essentially superimposable, regardless of whether the oral dose was micronized or unmicronized moxidectin.

[0086] The below table shows pharmacokinetic parameters which were calculated from the plasma concentration vs time data. These data also show that systemic exposures to moxidectin were, once again within normal experimental error, very similar regardless of whether the oral dose was micronized or unmicronized moxidectin. Table 5 Vehicle 0.5% methylcellulose in water Form of Moxidectin Micronized Unmicronized Dose (mg / kg) 1 1 Dose route Per Oral Regimen Single Dose T1 / 2(h) 10.3 10.7 Tmax (h) 3.33 1.67 Cmax(ng / mL) 65.3 87 AUClast (h.ng / mL) 722 808

[0087] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features 1005841944mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention. Embodiments of the invention

[0088] Embodiment 1: A solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition comprises or consists of a. unmicronized moxidectin, or a pharmaceutically acceptable salt thereof; and b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and c. a pharmaceutically acceptable carrier.

[0089] Embodiment 2: A solid oral dose composition of moxidectin according to embodiment 1 wherein substantially all (ie ≥90%) of the unmicronized moxidectin particles are larger than 10 microns, preferably larger than 20 microns.

[0090] Embodiment 3: A solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition comprises or consists of a. moxidectin, or a pharmaceutically acceptable salt thereof, wherein the moxidectin, or a pharmaceutically acceptable salt thereof, has a particle size distribution (PSD) of D10 of 2 microns and / or a median (D50) of 10 microns and / or a D90 of 500 microns; optionally a D90 range of 20 to 500 microns; and b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and c. a pharmaceutically acceptable carrier.

[0091] Embodiment 4. A solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition comprises or consists of a. moxidectin, or a pharmaceutically acceptable salt thereof; and 1005841944b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and c. a pharmaceutically acceptable carrier, with a proviso that particles of the moxidectin, or a pharmaceutically acceptable salt thereof, are unmicronized and / or substantially all (≥90%) of the particles are larger than 10 microns.

[0092] Embodiment 5. A solid oral dose composition of moxidectin according to any one of embodiments 1 to 4 wherein the moxidectin is the sole active ingredient.

[0093] Embodiment 6. A solid oral dose composition of moxidectin according to any one of embodiments 1 to 5 comprising from about 1 mg to about 40 mg of moxidectin or a pharmaceutically acceptable salt and / or solvate thereof.

[0094] Embodiment 7. A solid oral dose composition of moxidectin according to any one of embodiments 1 to 6, wherein the composition is in the form of a tablet or a capsule.

[0095] Embodiment 8. A solid oral dose composition of moxidectin according to embodiment 7 further comprising one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, binders, preservatives, and combinations thereof.

[0096] Embodiment 9. A solid oral dose composition of moxidectin according to embodiment 7 or 8 wherein the tablet or capsule has a dissolution profile in an aqueous solvent comparable to a solid oral dose compositions of micronized moxidectin.

[0097] Embodiment 10: A process for preparing a solid oral dose composition of moxidectin, comprising the steps of: i) blending moxidectin with pharmaceutically acceptable excipients; and ii) compressing the blend into a solid oral dose with the proviso that no size reduction or micronization of the moxidectin is conducted.

[0098] Embodiment 11: A process for preparing a solid oral dose composition of moxidectin according to any one of embodiments 1 to 9, comprising the steps of: i) blending moxidectin with pharmaceutically acceptable excipients; and 1005841944ii) compressing the blend into a solid oral dose with the proviso that no size reduction or micronization of the moxidectin is conducted. References

[0099] Bhalani, D.V et al.2022. Bioavailability Enhancement Techniques for Poorly Aqueous Soluble Drugs and Therapeutics. Biomedicines 10. https: / / doi.org / 10.3390 / biomedicines10092055

[0100] Forrester, S.G., et al. 2002. A glutamate-gated chloride channel subunit from Haemonchus contortus: Expression in a mammalian cell line, ligand binding, and modulation of anthelmintic binding by glutamate. Biochem Pharmacol 63, 1061–1068. https: / / doi.org / 10.1016 / s0006-2952(02)00852-3

[0101] Gao, Y., et al.2021. Dissolution Kinetics of a BCS Class II Active Pharmaceutical Ingredient: Diffusion-Based Model Validation and Prediction. ACS Omega 6, 8056–8067. https: / / doi.org / 10.1021 / acsomega.0c05558

[0102] Huynh, N., et al, 2017. Preclinical development of moxidectin as a novel therapeutic for alcohol use disorder. Neuropharmacology 113, 60–70. https: / / doi.org / 10.1016 / j.neuropharm.2016.09.016

[0103] Janko, C., and Geyer, J., 2013. Moxidectin has a lower neurotoxic potential but comparable brain penetration in P-glycoprotein-deficient CF-1 mice compared to ivermectin. J Vet Pharmacol Ther 36, 275–84.2885.2012.01424.x

[0104] Kumar, R., et al.2022. Particle Size Reduction Techniques of Pharmaceutical Compounds for the Enhancement of Their Dissolution Rate and Bioavailability 17, 333– 352. https: / / doi.org / 10.1007 / s12247-020-09530-5

[0105] Martin, R.J., et al., 2002. Mode of action of the macrocyclic lactones. Macrocyclic Lactones in Antiparasitic Therapy 125–140.

[0106] Menez, C., et al. 2012. Relative neurotoxicity of ivermectin and moxidectin in Mdr1ab (- / -) mice and effects on mammalian GABA(A) channel activity. PLoS Negl Trop Dis 6, e1883. https: / / doi.org / 10.1371 / journal.pntd.0001883 1005841944

[0107] Paul, A.J., et al.2000. Safety of moxidectin in avermectin-sensitive collies. Am J Vet Res 61, 482–3.

[0108] Prichard, R., and Geary, T.G., 2019. Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelmintic resistance. Int J Parasitol Drugs Drug Resist 10, 69–83. https: / / doi.org / 10.1016 / j.ijpddr.2019.06.002

[0109] Prichard, R., et al.2012. Moxidectin and the avermectins: Consanguinity but not identity. Int. J. Parasitol.: Drugs Drug Resist.2, 134–153.

[0110] Vinarov, Z., et al.2021. Current challenges and future perspectives in oral absorption research: An opinion of the UNGAP network 171, 289–331. https: / / doi.org / 10.1016 / j.addr.2021.02.001

[0111] Wolstenholme, A.J., 2012. Glutamate-gated chloride channels. J Biol Chem 287, 40232–8. https: / / doi.org / 10.1074 / jbc.r112.406280

[0112] Wolstenholme, A.J., and Rogers, A.T., 2005. Glutamate-gated chloride channels and the mode of action of the avermectin / milbemycin anthelmintics. Parasitology 131 Suppl, S85-95. https: / / doi.org / 10.1017 / s0031182005008218 1005841944

Claims

CLAIMS 1. A solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition comprises or consists of a. unmicronized moxidectin, or a pharmaceutically acceptable salt thereof; and b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and c. a pharmaceutically acceptable carrier.

2. A solid oral dose composition of moxidectin according to claim 1 wherein substantially all (≥90%) of the unmicronized moxidectin particles are larger than 10 microns.

3. A solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition comprises or consists of a. moxidectin, or a pharmaceutically acceptable salt thereof, wherein the moxidectin, or a pharmaceutically acceptable salt thereof, has a particle size distribution (PSD) of D10 of 2 microns and / or a median (D50) of 10 microns and / or a D90 of 500 microns; optionally a D90 range of 20 to 500 microns; and b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and c. a pharmaceutically acceptable carrier.

4. A solid oral dose composition of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the solid oral dose composition comprises or consists of a. moxidectin, or a pharmaceutically acceptable salt thereof; and b. one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, and combinations thereof; and 1005841944c. a pharmaceutically acceptable carrier, with a proviso that particles of the moxidectin, or a pharmaceutically acceptable salt thereof, are unmicronized and / or substantially all (≥90%) of the particles are larger than 10 microns.

5. A solid oral dose composition of moxidectin according to any one of claims 1 to 4 wherein the moxidectin is the sole active ingredient.

6. A solid oral dose composition of moxidectin according to any one of claims 1 to 5 comprising from about 1 mg to about 40 mg of moxidectin or a pharmaceutically acceptable salt and / or solvate thereof.

7. A solid oral dose composition of moxidectin according to any one of claims 1 to 6, wherein the composition is in the form of a tablet or a capsule.

8. A solid oral dose composition of moxidectin according to claim 7 further comprising one or more pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, disintegrants, lubricants, binders, preservatives, and combinations thereof.

9. A solid oral dose composition of moxidectin according to claim 7 or 8 wherein the tablet or capsule has a dissolution profile in an aqueous solvent comparable to a solid oral dose compositions of micronized moxidectin.

10. A process for preparing a solid oral dose composition of moxidectin, comprising the steps of: i) blending the moxidectin with pharmaceutically acceptable excipients; and ii) compressing the blend into a solid oral dose with the proviso that no size reduction or micronization of the moxidectin is conducted. 1005841944

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