EP4683617A1 - Rifapentine compositions - Google Patents

Rifapentine compositions

Info

Publication number
EP4683617A1
EP4683617A1 EP24715857.9A EP24715857A EP4683617A1 EP 4683617 A1 EP4683617 A1 EP 4683617A1 EP 24715857 A EP24715857 A EP 24715857A EP 4683617 A1 EP4683617 A1 EP 4683617A1
Authority
EP
European Patent Office
Prior art keywords
excipient
rifapentine
rifamycin
solid composition
aot
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24715857.9A
Other languages
German (de)
French (fr)
Inventor
Steven Paul Rannard
Andrew Owen
Jonathan MASSAM
James Hobson
Joanne SHARP
Ryan Donnelly
Mingshan LI
Yara NASER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Liverpool
Original Assignee
University of Liverpool
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Liverpool filed Critical University of Liverpool
Publication of EP4683617A1 publication Critical patent/EP4683617A1/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays or needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • the present invention relates to chemical compositions.
  • the invention relates, more particularly, but not exclusively, to chemical compositions for the treatment and prophylaxis of infections, and has particular (but not exclusive) application in the treatment and prophylaxis of bacterial infections, such as tuberculosis.
  • BACKGROUND Tuberculosis is an infectious disease primarily affecting the lungs and is usually caused by the bacterium Mycobacterium tuberculosis. The majority of cases are of latent tuberculosis and those with such an infection are non-symptomatic and non-infectious. A minority of cases, especially prevalent in those who are immunosuppressed, go on to develop symptoms.
  • M. tuberculosis is resistant to degradation by macrophages due to a thick capsule that helps protect them from reactive oxygen species within the phagolysosome.
  • granulomas form which isolate the bacteria, causing them to become dormant, resulting in a latent infection.
  • Public health initiatives prioritise the use of vaccines to limit the risk and spread of tuberculosis. However, these vaccines are not fully effective across the population and their effectiveness wanes over time. Therefore a number of treatment protocols have been developed to address active and latent tuberculosis, generally comprising the administration of antibiotics over an extended period of time.
  • treatment of latent tuberculosis takes at least one month, and typically takes three to nine months. Due to the lengths of these treatment protocols, it is not uncommon for antibiotic resistance to develop, an issue that is compounded by issues with patient compliance, which may be more common in latent tuberculosis as the patient is not suffering ill effects from the infection itself at the time of treatment. Accordingly, many protocols use combinations of antibiotics in addition to lasting for extended periods.
  • One family of antibiotics that are commonly used in treatments of tuberculosis are Rifamycins, which also find use in the treatment of leprosy.
  • This family of drugs includes Rifamycin SV, Rifampicin, Rifabutin, Rifapentine, Rifalazil, and Rifaximin.
  • the structure of Rifapentine is reproduced below: 69324247-2
  • a first aspect of the present invention relates to a solid composition comprising nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a matrix comprising a first excipient and a second excipient, wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene- polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
  • PVP polyvinylpyrrolidone
  • PEG polyethylene glycol
  • polyoxypropylene block copolymer polyoxypropylene block copolymer
  • lactose lactose
  • the first and second excipients may be selected from the following combinations: ⁇ PVP and benzalkonium chloride ⁇ PVP and AOT ⁇ PVP and Polysorbate 20 ⁇ PVP and Polysorbate 80 ⁇ lactose and AOT ⁇ lactose and poloxamer ⁇ sucrose and benzalkonium chloride ⁇ sucrose and AOT ⁇ sucrose and sorbitan monolaurate ⁇ sucrose and poloxomer ⁇ poloxamer and Polysorbate 20 69324247-2 ⁇ poloxamer and AOT ⁇ PEG and AOT ⁇ PEG and poloxamer
  • the first and second excipients may be selected from the following combinations: ⁇ PVP and AOT ⁇ lactose and AOT
  • the solid composition may comprise: 10 to 80 wt% of the Rifamycin, such as Rifapentine; 10 to 80 wt% of the first excipient; and 1 to 25 wt% of the second excipient.
  • the solid composition may comprise: 30 to 60 wt% of the Rifamycin, such as Rifapentine; 30 to 60 wt% of the first excipient; and 5 to 20 wt% of the second excipient.
  • the solid composition may comprise: 40 to 50 wt% of the Rifamycin, such as Rifapentine; 40 to 50 wt% of the first excipient; and 5 to 15 wt% of the second excipient.
  • the solid composition may comprise: 30 to 50 wt% of the Rifamycin, such as Rifapentine; 40 to 60 wt% of the first excipient; and 1 to 10 wt% of the second excipient,
  • the solid composition may comprise: 35 to 45 wt% of the Rifamycin, such as Rifapentine; 50 to 60 wt% of the first excipient; and 1 to 5 wt% of the second excipient.
  • the nanoparticles may have a particle diameter in the range of 10 to 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 200 and 800 nm.
  • a second aspect of the present invention relates to a process for preparing a solid composition according to the first aspect of the present invention, the process comprising: (a) preparing an oil-in-water emulsion comprising: - an oil phase comprising the Rifamycin, such as Rifapentine; and - an aqueous phase comprising a first and second excipient, each as defined in the first aspect of the present invention; and (b) removing the oil and water from the oil-in-water emulsion to form the solid composition.
  • a third aspect of the present invention relates to a process for preparing a solid composition according to the first aspect of the present invention, the process comprising: (a) providing an active solution comprising the Rifamycin, such as Rifapentine, in a water-miscible solvent; (b) providing a carrier material solution comprising a first and second excipient, each as defined in the first aspect of the present invention; (c) mixing the solutions prepared in steps (a) and (b); and (d) removing the mixed solvent to produce the solid composition or, the process comprising: (a) providing an active solution comprising the Rifamycin, such as Rifapentine, and the second excipient in a water-miscible solvent; (b) providing a carrier material solution comprising a first excipient, each as defined in any of claims 1 to 6; (c) mixing the solutions prepared in steps (a) and (b); and (d) removing the mixed solvent to produce the solid composition.
  • a fourth aspect of the present invention relates to an aqueous dispersion comprising a plurality of nanoparticles of the Rifamycin, such as Rifapentine, dispersed in an aqueous medium and stabilised by a mixture of a first excipient and a second excipient; wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
  • PVP polyvinylpyrrolidone
  • PEG polyethylene glycol
  • polyoxypropylene block copolymer polyoxyethylene-
  • the aqueous dispersion may comprise nanoparticles of the Rifamycin, such as Rifapentine, first excipients, and second excipients as defined in any of claims 2 to 8 in the aqueous medium.
  • the Rifamycin such as Rifapentine, may be present in the aqueous dispersion at a concentration of 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL.
  • a fifth aspect of the present invention relates to a process for preparing an aqueous dispersion according to the fourth aspect of the present invention, the process comprising dispersing a solid composition according to the first aspect of the present invention in an aqueous medium.
  • a sixth aspect of the present invention relates to a pharmaceutical composition comprising the solid composition of the first aspect of the present invention, or the aqueous dispersion of the fourth aspect of the present invention and, optionally, one or more further pharmaceutically acceptable excipients.
  • a seventh aspect of the present invention relates to an injectable formulation comprising the solid composition of the first aspect of the present invention, the aqueous dispersion of the fourth aspect of the present invention, or the pharmaceutical composition of the sixth aspect of the present invention.
  • the injectable formulation may be a subcutaneously or intramuscularly injectable formulation, optionally wherein the injectable formulation is suitable for provision in depot form.
  • An eighth aspect of the present invention relates to a method of producing an implantable rod comprising the steps of compressing a solid composition according to the first aspect of the present invention and heating the compressed solid composition for a period of time.
  • the solid composition may be compressed in a mould, optionally the mould being cylindrical in form.
  • the solid composition may be heated to a temperature from 60 to 160 °C, preferably from 80 to 140 °C, more preferably from 100 to 120 °C, most preferably about 105 °C.
  • the compression may occur under a reduced pressure atmosphere.
  • the heating step may take place for a period of from 1 minute to 40 minutes, preferably from 5 minutes 30 minutes, more preferably from 10 minutes to 25 minutes, most preferably about 20 minutes.
  • the method of the eighth aspect of the present invention may further comprise a step of cooling the rod, optionally the cooling taking place under a reduced pressure atmosphere.
  • a ninth aspect of the present invention relates to an implantable rod produced by the method of the eighth aspect of the present invention.
  • a tenth aspect of the present invention relates to an implantable rod comprising nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a monolith comprising a first excipient and a second excipient, wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene- polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
  • PVP polyvinylpyrrolidone
  • PEG polyethylene glycol
  • polyoxypropylene block copolymer polyoxyethylene- polyoxypropylene block copolymer
  • An eleventh aspect of the present invention relates to a method of producing a microneedle array comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition, the method comprising the steps of: a) dispersing a solid composition according to any one of claims 1 to 8 and at least one structural polymer in a solvent to form a microneedle precursor dispersion; b) placing the microneedle precursor dispersion into a mould; c) compressing the microneedle precursor dispersion in the mould and then drying to form microneedles comprising the first composition; d) adding a baseplate precursor solution into the mould; e) compressing the baseplate precursor solution and then drying to form the baseplate of the second composition; and f) releasing the microneedle array from the mould
  • Steps b) and c) may be repeated prior to steps d) to f).
  • the solvent may be an aqueous solvent, such as water.
  • the at least one structural polymer may be selected from PVA, PVP, and combinations thereof.
  • the baseplate precursor solution may comprise a base polymer selected from PVP and, optionally, one or more additives such as glycerol, dispersed in an aqueous solvent, such as water.
  • a twelfth aspect of the present invention relates to a microneedle array produced by the method of the eleventh aspect of the present invention.
  • a thirteenth aspect of the present invention relates to a microneedle array comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition, wherein the first composition comprises nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a monolith comprising a first excipient, a second excipient, and at least one structural polymer, wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block 69324247-2 copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
  • the nanoparticles of the Rifamycin, such as Rifapentine, first excipient, and/or second excipient may be as defined in the first aspect of the present invention.
  • the at least one structural polymer may be selected from PVA, PVP, and combinations thereof.
  • the second composition may comprise a base polymer, such as PVP, and, optionally, one or more additives such as glycerol.
  • a fourteenth aspect of the present invention relates to a solid composition according to the first aspect of the present invention, an aqueous dispersion according to the fourth aspect of the present invention, a pharmaceutical composition according to the sixth aspect of the present invention, an injectable formulation according to the seventh aspect of the present invention, an implantable rod according to ninth or tenth aspects of the present invention, or a microneedle array according to the twelfth or thirteenth aspects of the present invention, for use as a medicament.
  • a fifteenth aspect of the present invention relates to a solid composition according to the first aspect of the present invention, an aqueous dispersion according to the fourth aspect of the present invention, a pharmaceutical composition according to the sixth aspect of the present invention, an injectable formulation according to the seventh aspect of the present invention, an implantable rod according to ninth or tenth aspects of the present invention, or a microneedle array according to the twelfth or thirteenth aspects of the present invention, for use in the treatment and/or prevention of tuberculosis, such as latent tuberculosis.
  • An aqueous dispersion, a pharmaceutical composition, or an injectable formulation for use according to the fourteenth or fifteenth aspects of the present invention wherein the concentration of Rifapentine may be 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL.
  • An implantable rod for use according to the fourteenth or fifteenth aspects of the present invention, wherein the concentration of the Rifamycin, such as Rifapentine, in 69324247-2 the implantable rod may be in the range of 30 to 80 wt%, preferably 40 to 70 wt%, most preferably about 50 wt%.
  • a microneedle array for use according to the fourteenth or fifteenth aspects of the present invention wherein the microneedle array may contain a mass of the Rifamycin, such as Rifapentine, in the range of between 0.1 and 20 mg of Rifapentine, preferably between 0.5 and 10 mg, more preferably between 1 and 5 mg, most preferably between 1 and 2 mg.
  • Rifamycin such as Rifapentine
  • a sixteenth aspect of the present invention relates to a method of treating and/or preventing tuberculosis, the method comprising administering a therapeutically effective amount of a solid composition according to the first aspect of the present invention, an aqueous dispersion according to the fourth aspect of the present invention, a pharmaceutical composition according to the sixth aspect of the present invention, an injectable formulation according to the seventh aspect of the present invention, an implantable rod according to ninth or tenth aspects of the present invention, or a microneedle array according to the twelfth or thirteenth aspects of the present invention, to a patient suffering from or at risk of suffering from tuberculosis.
  • the concentration of the Rifamycin, such as Rifapentine, within the aqueous dispersion, the pharmaceutical composition, or the injectable formulation may be 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL.
  • the concentration of the Rifamycin, such as Rifapentine, in the implantable rod may be in the range of 40 to 80 wt%, preferably 50 to 70 wt%, most preferably about 60 wt%.
  • the microneedle array may contain a mass of the Rifamycin, such as Rifapentine, in the range of between 1 and 20 mg of Rifapentine, preferably between 2 and 10 mg, more preferably about 5 mg.
  • the aqueous dispersion, the pharmaceutical composition, the injectable formulation, or the implantable rod may form a depot within the body of the patient, optionally wherein the depot maintains a 69324247-2 therapeutically effective concentration of the Rifamycin, such as Rifapentine, within the body of the patient for a period of at least two weeks, preferably at least one more, more preferably at least two months, yet more preferably at least three months, and most preferably at least four months.
  • the Rifamycin such as Rifapentine
  • the microneedle array may gradually release the Rifamycin, such as Rifapentine, optionally wherein the microneedle array maintains a therapeutically effective concentration of the Rifamycin, such as Rifapentine, within the body of the patient for a period of at least 4 hours, preferably at least 6 hours, more preferably at least 12 hours, and most preferably at least 24 hours.
  • the patient may require dosing with the aqueous dispersion, the pharmaceutical composition, the injectable formulation, or the implantable rod up to three times, preferably up to two times, most preferably only once, to maintain a therapeutically effective concentration of the Rifamycin, such as Rifapentine, for the duration of the treatment.
  • the patient may require dosing of the microneedle array up to six times per day, preferably up to four times per day, more preferably twice a day, and most preferably once a day, to maintain a therapeutically effective concentration of the Rifamycin, such as Rifapentine, in the patient for the duration of the treatment.
  • Fig. 1 shows a plot of Rifapentine concentration in blood plasma obtained from male Sprague Dawley rats over time following intramuscular injection of an aqueous dispersion comprising Rifapentine nanoparticles according to the present invention, as described in Example 6.
  • Fig. 2 shows a plot of Rifapentine concentration in blood plasma obtained from male Sprague Dawley rats over time following implantation of an implant comprising Rifapentine nanoparticles according to the present invention, as described in Example 8.
  • Fig. 3 shows the needle penetration percentage through successive layers of Parafilm® M achieved by microneedles comprising Rifapentine nanoparticles according to the present invention, as described in Example 10.
  • Fig. 4 shows the Rifapentine permeation into the Franz diffusion cell (in ⁇ g) achieved by microneedles comprising Rifapentine nanoparticles according to the present invention, as described in Example 11.
  • FIG. 5 shows, on the left, the quantity of Rifapentine delivered (in ⁇ g) by drug permeation (blue, lower bar) and skin deposition (pink, higher bar) and, on the right, the percentage of Rifapentine delivered by drug permeation (blue, lower bar) and skin deposition (pink, higher bar), by microneedles comprising Rifapentine nanoparticles according to the present invention, as described in Example 11.
  • Fig.6 shows a plot of Rifapentine concentration in blood plasma obtained from female Sprague Dawley rats over time following application of a microneedle array comprising Rifapentine nanoparticles according to the present invention, as described in Example 12.
  • Fig. 7 shows a plot of Rifapentine concentration in blood plasma obtained from male Sprague Dawley rats over time following intramuscular injection of Rifapentine nanoparticles according to the present invention at a dosage of 150 mg/kg, as described in Example 14.
  • Fig. 7 shows a plot of Rifapentine concentration in blood plasma obtained from female Sprague Dawley rats over time following intramuscular injection of Rifapentine nanoparticles according to the present invention at a dosage of 150 mg/kg, as described in Example 14.
  • particle size is used herein to refer to the Z-average hydrodynamic diameter. Particle size and polydispersity may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron 69324247-2 microscopy). In an embodiment of the invention, particle diameter and polydispersity (i.e.
  • nanoparticle may be interpreted broadly to include particles with a particle size that is less than 5 ⁇ m, preferably less than 3 ⁇ m, or most preferably less than 1 ⁇ m. in embodiments, the particle size is in the range of 100 to 800 nm.
  • Rifamycin refers to antibiotic drugs in the Rifamycin family as well as pharmaceutically acceptable salts, solvates and derivatives thereof, prodrugs thereof, as well as any polymorphic or amorphous forms thereof.
  • Particular Rifamycins are Rifamycin SV, Rifampicin, Rifabutin, Rifapentine (the structure of which is illustrated in the background section), Rifalazil, and Rifaximin. These drugs are typically poorly soluble in water.
  • patient includes both human patients and animal patients.
  • SDN is an abbreviation for the term “solid drug nanoparticles”, used herein to refer to the solid compositions of the present invention.
  • other drugs is used herein to refer to the following (non-exhaustive) list of other drugs that may be used in combination with the Rifamycins indicated herein and formulated in accordance with the invention in a combination prophylactic and/or treatment therapy: ethambutol, isoniazid, pyrazinamide, streptomycin, aminoglycosides (e.g. amikacin, kanamycin), polypeptides (e.g. capreomycin, viomycin, enviomycin), fluoroquinolones (e.g. ciprofloxacin, levofloxacin, moxifloxacin), thioamides (e.g.
  • ethionamide ethionamide
  • prothionamide cycloserine
  • terizidone macrolides (e.g. clarithromycin, linezolid, thioacetazone, thioridazine, arginine, vitamin D, bedaquiline, as well as pharmaceutically acceptable salts, solvates and derivatives thereof, prodrugs thereof, and any polymorphic or amorphous forms thereof.
  • macrolides e.g. clarithromycin, linezolid, thioacetazone, thioridazine, arginine, vitamin D, bedaquiline, as well as pharmaceutically acceptable salts, solvates and derivatives thereof, prodrugs thereof, and any polymorphic or amorphous forms thereof.
  • references to “preventing” or “prevention” relate to prophylactic treatment and includes preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a patient that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.
  • references to “treatment” or “treating” of a state, disorder or condition includes: (1) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof; or (2) relieving or attenuating the disease, i.e.
  • the terms “preventing” or “prevention” should not be considered to refer only to medicaments which are completely effective in treating a specific state, disorder or condition, but also to cover medicaments which are partially effective as well. Moreover, when considered from the perspective of a population of patients for treatment, the terms “preventing” and “prevention” should be considered to cover medicaments which are useful at reducing the rate of incidence of a target disorder or condition (e.g. tuberculosis) in that target population, as well as medicaments which are useful at completely eradicating a target state, disorder or condition from that target population.
  • a target disorder or condition e.g. tuberculosis
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a patient for treating and/or preventing a disease, is sufficient to effect such treatment/prevention for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.
  • the term “consisting essentially of” is used herein to denote that a given product or method consists of only designated materials or steps and optionally other materials or steps that do not materially affect the characteristic(s) of the claimed invention.
  • a product which consists essentially of a designated material (or materials) comprises greater than or equal to 85% of the designated material, more suitably 69324247-2 greater than or equal to 90%, more suitably greater than or equal to 95%, most suitably greater than or equal to 98% of the designated material(s).
  • the weight percentages (“wt%”) discussed herein relate to the % by weight of a particular constituent as a proportion of the total weight of the composition.
  • References herein to a component being “(substantially) immiscible” with another component means that a mixture comprising the two components is unable to form a single phase. Syringeability is a measure of whether a solution, dispersion, or suspension is suitable for administration via injection.
  • a composition is considered to be syringable if it can be manually passed through a 25G needle. It will be understood that the combination of the composition and 25G needle is purely to establish that a given composition is syringable and that the compositions may be used in combination with needles of a lower gauge in practice. As is known in the art, 25G refers to a 25 gauge needle (i.e. a needle with an internal diameter of 0.26 mm and an external diameter of 0.514 mm).
  • Solid Compositions The first aspect of the present invention provides a solid composition comprising nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a solid excipient mixture comprising the first and second excipients.
  • the Rifamycin such as Rifapentine, which comprises the nanoparticles may be amorphous (i.e. substantially non-crystalline in nature).
  • the solid excipient mixture is in the form of a matrix.
  • the matrix is highly porous in nature and rapidly dissolves on contact with aqueous solutions.
  • the matrix is relatively dense, but still susceptible to dissolution on contact with aqueous solutions.
  • the solid composition of the present invention may be administered as it is to a patient, or further formulated to provide a pharmaceutical composition in the form of, for example, a tablet, capsule, lozenge, or a dispersible powder or granule formulation. In one embodiment, they may be formulated into an implantable rod.
  • the nanoparticles of the present invention have an average particle diameter of less than 5 micron ( ⁇ m).
  • the nanoparticles have an average particle diameter of between 10 nm and 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 100 and 500 nm.
  • the nanoparticles have a particle diameter in the range of 1 to 1000 nm. It will be understood that references to particle diameter are references to the Z-average hydrodynamic diameter of the nanoparticles.
  • the nanoparticles of the present invention may have a polydispersity less than or equal to 0.8, preferably less than or equal to 0.6, more preferably less than or equal to 0.5.
  • the particle diameter and polydispersity of the nanoparticles may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy).
  • Particle size and polydispersity may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy).
  • particle diameter and polydispersity i.e.
  • the solid composition may comprise particles or granules of larger size, for example, 5 to 30 microns ( ⁇ m) in size, but each particle or granule may contain a plurality of nanoparticles of the Rifamycin, such as Rifapentine, dispersed within a mixture of the first and second excipient.
  • the solid composition may comprise a larger monolith, of any suitable shape or dimension.
  • the solid composition comprises a first excipient and a second excipient.
  • the solid composition comprises further excipients selected from those listed herein as suitable first and/or second excipients.
  • the solid composition consists essentially of the Rifamycin, such as Rifapentine, the first excipient, and the second excipient.
  • the solid composition consists of the Rifamycin, such as Rifapentine, the first excipient, and the second excipient.
  • the first excipient is either a hydrophilic polymer or a sugar.
  • any hydrophilic polymer or sugar suitable for use in pharmaceutical formulations may be employed in the present invention.
  • Particularly suitable polymers include: polyvinylpyrrolidones (including PVP k30, such as is available as Kollidon TM 30, PVP k17, such as is available as Kollidon TM 17PF, PVP k15, such as is available as Plasdone TM C-15, and PVP k12, such as is available as Kollidon TM 12PF); polyethylene glycols (such as PEG 400, PEG 1000, and PEG 4000); and non-ionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), which are also known as poloxamers (such as those available in the Synperionics TM , Plur
  • the polyvinylpyrrolidone has a weight average molecular weight of 1000 to 1,000,000 g/mol. In a particular embodiment, the polyvinylpyrrolidone has a weight average molecular weight of 1000 to 40000 g/mol, preferably 2000 to 20000 g/mol. In embodiments, the polyvinylpyrrolidone has a K value between 5 and 30, preferably between 10 and 20, most preferably between 12 and 17. Alternatively the K value may be about 12, about 15, or about 17.
  • K value is derived from relative viscosity measurements and calculated according to Fikentscher’s equation.
  • a “poloxamer” is a non-ionic triblock copolymer comprising a central hydrophobic chain of polyoxypropylene, and hydrophilic chains of polyoxyethylene either side of this central hydrophobic chain.
  • a “poloxamer” is typically named with the letter “P” followed by three numerical digits (e.g. P407), where the first two digits multiplied by 100 gives the approximate molecular mass of the polyoxypropylene chain, and the third digit multiplied by 10 provides the percentage polyoxyethylene content of the poloxamer.
  • P407 is a poloxamer having a polyoxypropylene molecular mass of about 4,000 g/mol and a polyoxyethylene content of about 70%
  • P188 is a poloxamer 69324247-2 having a polyoxypropylene molecular mass of about 1,800 g/mol and a polyoxyethylene content of about 80%
  • Poloxamers are also known as Pluronics ® , as well as by several other commercial names.
  • the poloxamer is suitably a pharmaceutically acceptable poloxamer.
  • the poloxamer is P407 or P188.
  • Polyethylene glycol (PEG) is a polyether containing repeat units of ethylene oxide.
  • PEG may occur in linear, branched, comb, or star forms.
  • the PEG is a linear PEG.
  • the PEG may have a number average molecular weight of 100 to 20000 g/mol, preferably 500 to 10000 g/mol, more preferably 1000 to 8000 g/mol, most preferably about 4000 g/mol.
  • monosaccharides, disaccharides, and oligosaccharides may be suitable in the solid composition of the present invention.
  • Disaccharides are defined as carbohydrates consisting of two monosaccharide residues.
  • Oligosaccharides are defined herein as carbohydrates consisting of between 3 and 10 monosaccharide residues.
  • Monosaccharides may be selected from ribose, arabinose, xylose, lyxose, ribulose, xylulose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, and tagatose. Either of the D- or L- isomers may be used, with the naturally occurring isomer being preferred.
  • Disaccharides may be selected from any binary combination of the above monosaccharides. Preferred disaccharides are lactose and sucrose. Oligosaccharides may be selected from any combination of the above monosaccharides.
  • the first excipient is selected from those hydrophilic polymers and sugars that are capable of stabilising nanoparticles of a Rifamycin, such as Rifapentine, in an aqueous dispersion together with a second excipient as defined herein, and which are also suitable for pharmaceutical use (e.g. they are on the US Food and Drug Administration’s Center for Drug Evaluation and Research (FDA CDER) list of inactive ingredients, especially those indicated as suitable for intramuscular injection).
  • FDA CDER Center for Drug Evaluation and Research
  • the second excipient is a surfactant.
  • any surfactant suitable for use in pharmaceutical formulations may be employed in the present invention. Examples of such surfactants include: (a) non-ionic surfactants (e.g.
  • ethoxylated triglycerides fatty alcohol ethoxylates; alkylphenol ethoxylates; fatty acid ethoxylates; fatty amide ethoxylates; fatty amine ethoxylates; sorbitan alkanoates; ethylated sorbitan alkanoates; alkyl ethoxylates; PluronicsTM; alkyl polyglucosides; stearol ethoxylates; alkyl polyglycosides; sucrose fatty acid esters, anionic, cationic, amphoteric or zwitterionic); (b) anionic surfactants (e.g.
  • alkylether sulfates alkylether carboxylates; alkylbenzene sulfonates; alkylether phosphates; dialkyl sulfosuccinates; sarcosinates; alkyl sulfonates; soaps; alkyl sulfates; alkyl carboxylates; alkyl phosphates; paraffin sulfonates; secondary n-alkane sulfonates; alpha-olefin sulfonates; isethionate sulfonates; alginates); (c) cationic surfactants (e.g.
  • fatty amine salts fatty diamine salts; quaternary ammonium compounds; phosphonium surfactants; sulfonium surfactants; sulfonxonium surfactants); or (d) zwitterionic surfactants (e.g. N-alkyl derivatives of amino acids (such as glycine, betaine, aminopropionic acid); imidazoline surfactants; amine oxides; amidobetaines).
  • zwitterionic surfactants e.g. N-alkyl derivatives of amino acids (such as glycine, betaine, aminopropionic acid); imidazoline surfactants; amine oxides; amidobetaines).
  • Particularly suitable surfactants for the present invention may be selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene- polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
  • the surfactant is selected from those surfactants that are capable of stabilising nanoparticles of a Rifamycin, such as Rifapentine, in an aqueous dispersion together with a first excipient as defined herein, and which are also suitable for pharmaceutical use (e.g.
  • first and second excipient may be selected from any of those outlined above.
  • the first and second excipient may be selected from the following combinations: PVP and benzalkonium chloride; PVP and AOT; PVP and poloxamer; PVP and Polysorbate 20; PVP and Polysorbate 80; PVP and sorbitan monolaurate; PEG and benzalkonium chloride; PEG and AOT; PEG and poloxamer; PEG and Polysorbate 20; PEG and Polysorbate 80; PEG and sorbitan monolaurate; poloxamer and benzalkonium chloride; poloxamer and AOT; are both poloxamer; poloxamer and Polysorbate 20; poloxamer and Polysorbate 80; poloxamer and sorbitan monolaurate; sucrose and benzalkonium chloride; sucrose and AOT; sucrose and poloxamer; sucrose and Polysorbate 20; sucrose and Polysorbate 80; sucrose and sorbitan monolaurate; lactose and benzalkonium chloride; lactos
  • the first and second excipient may be the same. It will be understood that, in embodiments wherein both the first excipient and the second excipient are the same (e.g. in the case of poloxamer, listed as both a first and a second excipient), the quantities of the first and second excipients are to be combined to arrive at the quantity of the excipient required Combinations of first and second excipient that are particularly suitable for use in solid compositions comprising nanoparticles of a Rifamycin, such as Rifapentine: ⁇ PVP and benzalkonium chloride ⁇ PVP and AOT ⁇ PVP and Polysorbate 20 ⁇ PVP and Polysorbate 80 ⁇ lactose and AOT ⁇ lactose and poloxamer ⁇ sucrose and benzalkonium chloride ⁇ sucrose and AOT ⁇ sucrose and sorbitan monolaurate ⁇ sucrose and poloxomer ⁇ poloxamer and Polysorbate 20 69324247-2 ⁇ poloxamer
  • the solid composition as described herein may comprise 10 to 95 wt% of a Rifamycin, such as Rifapentine.
  • the solid composition may comprise 20 to 90 wt% of a Rifamycin, such as Rifapentine.
  • the solid composition may comprise 30 to 80 wt% of a Rifamycin, such as Rifapentine, 40 to 70 wt% of a Rifamycin, such as Rifapentine, or 45 to 60 wt% of a Rifamycin, such as Rifapentine.
  • the solid composition comprises 5 to 90 wt% of the first and second excipient combined. In another embodiment, the solid composition comprises 10 to 80 wt% of the first and second excipient combined. In another embodiment, the solid composition comprises 20 to 70 wt% of the first and second excipient combined, 30 to 60 wt% of the first and second excipient combined, or 40 to 55 wt% of the first and second excipient combined.
  • the first and second excipient may be present in a mass ratio in the range of 1:1 to 8:1; preferably about 2:1 to 6:1; more preferably about 4:1 to 5:1.
  • the solid composition may comprise 10 to 80 wt% of the first excipient; preferably 20 to 70 wt% of the first excipient; more preferably 30 to 60 wt% first excipient, most preferably 40 to 50 wt% first excipient.
  • the solid composition may comprise 1 to 25 wt% second excipient; preferably 3 to 20 wt% second excipient; more preferably 5 to 15 wt% second excipient.
  • the solid composition comprises about 10 wt% second excipient.
  • the solid composition comprises 10 to 80 wt% of a Rifamycin, such as Rifapentine; 10 to 80 wt% first excipient; and 1 to 25 wt% second excipient.
  • the solid composition comprises 30 to 60 wt% of a Rifamycin, such as Rifapentine; 30 to 60 wt% first excipient; and 5 to 20 wt% second excipient. More preferably, the solid composition comprises 40 to 50 wt% of a Rifamycin, such as Rifapentine; 40 to 50 wt% first excipient; and 5 to 15 wt% second excipient. Alternatively, the solid composition comprises 20 to 60 wt% of a Rifapentine, such as Rifamycin; 30 to 70 wt% first excipient; and 1 to 10 wt% second excipient.
  • the solid composition comprises 30 to 50 wt% of a Rifapentine, such as Rifamycin; 50 to 60 wt% first excipient; and 2 to 5 wt% second excipient. More preferably, the solid 69324247-2 composition comprises about 40 wt% of a Rifapentine, such as Rifamycin; about 57 wt% first excipient; and about 3 wt% second excipient. Unless otherwise stated, the above weight percentages relate to the % by weight of a particular constituent as a proportion of the total weight of the solid composition.
  • the solid composition may comprise additional excipients, for instance, to further facilitate dispersion or stabilisation of dispersions of the nanoparticles in an aqueous medium, a pharmaceutically acceptable diluent or in vivo.
  • Processes for Preparing Solid Compositions Solid compositions of the present invention may be prepared by a number of methods well known in the art, including ‘top-down’ physical methods such as nano (or bead) milling and high pressure homogenisation. Other suitable techniques for forming such compositions are described in general terms in Horn and Reiger, Angew. Chem. Int. Ed., 2001, 40, 4330-4361.
  • the solid compositions of the present invention are prepared by an oil-in-water emulsion technique whereby the Rifamycin, such as Rifapentine, is dissolved in the oil phase and the first and second excipients are present in the water phase.
  • the oil and water solvents are then removed by freeze drying, spray drying or spray granulation to provide a solid composition according to the invention.
  • a general process for preparing a solid composition comprising nanoparticles of a Rifamycin, such as Rifapentine, as defined herein, the process comprising: (a) preparing an oil-in-water emulsion comprising: - an oil phase comprising a Rifamycin, such as Rifapentine; and - an aqueous phase comprising a first excipient and a second excipient, each as defined herein; and (b) removing the oil and water from the oil-in-water emulsion to form the solid composition.
  • An advantage of the processes of the present invention is that the emulsions formed in the initial steps are sufficiently homogenous and stable to allow for effective and uniform drying upon removal of the oil and water. Furthermore, the nanoparticles formed are substantially uniform in their physical form (size, shape etc.). 69324247-2
  • the oil-in-water formation steps may be performed by methods well-known in the art. Any suitable method for forming the oil-in-water emulsions may therefore be used.
  • mixing of the oil and water phases to form the oil-in-water emulsion may be performed by methods well known in the art. For example, the mixing may involve stirring, sonication, homogenisation, or a combination thereof.
  • oil-in-water emulsion formation comprises: (i) providing an oil phase comprising a Rifamycin, such as Rifapentine; (ii) providing an aqueous phase comprising the first excipient and second excipient; and (iii) mixing the oil phase and aqueous phase to produce the oil-in-water emulsion.
  • the oil phase is provided by dissolving the Rifamycin, such as Rifapentine, in a suitable organic solvent.
  • the aqueous phase is provided by dissolving first excipient and second excipient in an aqueous medium, preferably in water.
  • the aqueous phase may be provided by mixing two separately prepared aqueous solutions of the first excipient and second excipient.
  • further aqueous medium e.g. water
  • organic solvent is added before or during mixing step (iii).
  • concentration of the Rifamycin, such as Rifapentine, in the oil-in-water emulsion is suitably as concentrated as possible to facilitate effective scale-up of the process.
  • the concentration of the Rifamycin, such as Rifapentine, in the oil phase is suitably 20 mg/ml or higher, more suitably 30 mg/ml or higher, even more suitably 40 mg/ml or higher, most suitably greater than 50 mg/ml.
  • the concentration of the first excipient in the aqueous phase is suitably 1 to 50 mg/mL, more suitably 2 to 30 mg/mL, even more suitably 5 to 20 mg/mL. 69324247-2
  • the concentration of the second excipient in the aqueous phase is suitably 0.1 to 25 mg/mL, more suitably 0.2 to 10 mg/mL, even more suitably 0.5 to 5 mg/mL.
  • the mass ratio of the first excipient to second excipient in the aqueous phase may be in the range of 9:1 to 1:1; preferably in the range of 7:1 to 2:1, more preferably in the range of 6:1 to 3:1.
  • the organic solvent forming the oil phase is (substantially) immiscible with water.
  • the organic solvent is aprotic.
  • the organic solvent has a boiling point less than 120°C, suitably less than 100°C, suitably less than 90°C.
  • the organic solvent is a selected from the Class 2 or 3 solvents listed in the International Conference on Harmonization (ICH) guidelines relating to residual solvents.
  • the organic solvent is selected from chloroform, dichloromethane, dichloroethane, tetrachloroethane, cyclohexane, hexane(s), isooctane, dodecane, decane, methylbutyl ketone (MBK), methylcyclohexane, tetrahydrofuran, toluene, xylene, butyl acetate, mineral oil, tert-butylmethyl ether, heptanes(s), isobutyl acetate, isopropyl acetate, methyl acetate, methylethyl ketone, ethyl acetate, ethyl ether, pentane, and propyl acetate, or any suitably combination thereof.
  • the organic solvent is chloroform.
  • the organic solvent may include a cosolvent.
  • the cosolvent may be selected from C1 to C4 alcohols (such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, sec- butanol, and iso-butanol) and C5 to C7 alkanes (such as pentane, hexane, and heptane).
  • the oil phase may comprise between 1 and 40 v/v% of the oil-in-water emulsion.
  • the oil phase comprises between 10 and 35 v/v% of the oil-in-water emulsion, most preferably between 15 and 30 v/v% of the oil-in-water emulsion. In an embodiment, the oil phase comprises about 25 v/v% of the oil-in-water emulsion.
  • Mixing step (iii) suitably produces a substantially uniform oil-in-water emulsion. As previously indicated, mixing may be performed using methods well known in the art. Suitably, mixing step (iii) involves stirring, sonication, homogenisation, or a combination thereof. In a particular embodiment, mixing step (iii) involves sonication and/or homogenisation.
  • Removing the oil and water may be performed using methods well known in the art. Suitably removing the oil and water involves freeze drying, spray drying or spray granulation. Removing the oil and water may be performed using methods described in WO 2004/011537 A1 (COOPER et al), the entire contents of which are hereby incorporated by reference. In a particular embodiment, removing the oil and water involves freeze drying the oil-in- water emulsion. As such, removing the oil and water may suitably comprise freezing the oil-in-water emulsion and then removing the solvents under vacuum. Preferably, the freezing of the oil-in-water emulsion may be performed by externally cooling the oil-in-water emulsion.
  • a vessel containing the oil-in-water emulsion may be externally cooled, for example, by submerging the vessel in a cooling medium, such as liquid nitrogen.
  • a cooling medium such as liquid nitrogen.
  • the vessel containing the oil-in-water emulsion may be provided with an external “jacket” through which coolant is circulated to freeze the oil-in-water emulsion.
  • the vessel may comprise an internal element through which coolant is circulated in order to freeze the oil-in-water emulsion.
  • the oil-in-water emulsion is frozen by being contacted directly with a cooling medium at a temperature effective for freezing the emulsion.
  • the cooling medium e.g.
  • liquid nitrogen may be added to the oil-in-water emulsion, or the oil-in-water emulsion may be added to the cooling medium.
  • the oil-in-water emulsion is added to the fluid medium (e.g. liquid nitrogen), suitably in a dropwise manner. This order of addition provides higher purities of final product.
  • frozen droplets of the oil-in-water emulsion may suitably form. Such frozen droplets may suitably be isolated (e.g. under vacuum to remove the fluid medium/liquid nitrogen). The solvent is then suitably removed from the frozen droplets under vacuum. The resulting solid composition is then isolated.
  • the oil and water are removed by spray drying as this removes the need to freeze the oil-in-water emulsion, with the nanoparticulate nature of the solid composition being retained through the rapid nature of the solvent evaporation.
  • the solid compositions of the present invention are prepared by a nanoprecipitation technique whereby the Rifamycin, such as Rifapentine, is dissolved in a water-miscible solvent and the first and second excipients are dissolved in water. The two solutions are combined to effect precipitation of the Rifamycin, such as Rifapentine, as nanoparticles.
  • the general procedure for such a preparation of the solid composition is as follows: (a) providing an active solution comprising the Rifamycin, such as Rifapentine in a water-miscible solvent; (b) providing a carrier material solution comprising the first and second excipients; (c) mixing the solutions prepared in steps (a) and (b); and (d) removing the mixed solvent to produce the solid composition.
  • the solutions are typically provided by dissolving the Rifamycin, such as Rifapentine in the water-miscible solvent and by dissolving the first and second excipients in the aqueous solvent.
  • the Rifamycin, such as Rifapentine, first excipient, and second excipient are drawn from those described for the solid composition.
  • An alternative procedure, for preparation of the solid composition is as follows: (a) providing an active solution comprising the Rifamycin, such as Rifapentine, and second excipient in a water-miscible solvent; (b) providing a carrier material solution comprising the first excipient; (c) mixing the solutions prepared in steps (a) and (b); and (d) removing the mixed solvent to produce the solid composition.
  • the solutions are typically provided by dissolving the Rifamycin, such as Rifapentine, and the second excipient in the water-miscible solvent and by dissolving the first excipient in the aqueous solvent.
  • the Rifamycin such as Rifapentine, first excipient, such as PVP, and second excipient, such as AOT, are drawn from those described for the solid composition.
  • Any water-miscible solvent that is capable of dissolving the Rifamycin, such as Rifapentine in the required concentrations may be used to process it.
  • Suitable water- 69324247-2 miscible solvents are acetone, propanone, butanone, butanol, dimethylsulfoxide (DMSO), dimethylformamide (DMF), ethanol, methanol, propanol and mixtures thereof.
  • Particularly suitable solvents are methanol, acetone/ethanol mixtures, acetone/methanol mixtures, and butanone/ethanol mixtures.
  • Acetone/ethanol mixtures may be in any suitable ratio.
  • Preferred volume ratios are in the range of 90/10 to 10/90, in the range of 70/30 to 30/70, or 50/50.
  • Acetone/ethanol mixtures may be in any suitable ratio.
  • Preferred volume ratios are in the range of 90/10 to 10/90, in the range of 70/30 to 30/70, or 50/50.
  • Butanone/ethanol mixtures may be in any suitable ratio.
  • Preferred volume ratios are in the range of 90/10 to 10/90, in the range of 70/30 to 30/70, or 50/50.
  • the Rifamycin such as Rifapentine, may be present in a concentration of at least 20 mg/mL, preferably at least 30 mg/mL, more preferably at least 40 mg/mL, most preferably at least 50 mg/mL.
  • the aqueous solvent is typically deionised water.
  • the first excipient may be present in the carrier material solution in a concentration of from 1 to 40 mg/mL, preferably from 5 to 30 mg/mL, more preferably from 10 to 20 mg/mL.
  • the second excipient may be present in the carrier material solution in a concentration of from 0.5 to 20 mg/mL, preferably from 1 to 10 mg/mL, more preferably in a concentration of from 2 to 5 mg/mL.
  • the solution of the Rifamycin, such as Rifapentine, and the solution of the first and second excipients are mixed in a volume ratio in the range of 1:15 and 1:1, preferably in the range of 1:9 and 3:4.
  • the volume ratio is in the range of 1:6 to 1:2, such as about 1:4.
  • the total solids content i.e. the sum of the Rifamycin, such as Rifapentine, and the first and second excipients in the mixed solvent
  • the total solids content may be in the range of 1 to 40 mg/mL, preferably 2 to 30 mg/mL, further preferably 5 to 25 mg/mL, most preferably 10 to 20 mg/mL.
  • the total solids content may be about 15 mg/mL.
  • the solutions may be mixed by any suitable method.
  • a rotary stirring system is used, such as a magnetic or overhead stirrer.
  • the pharmaceutically active compound has a reduced solubility in the mixed solvent system, resulting in a supersaturated solution.
  • the pharmaceutically active compound consequently precipitates from the solution, producing nanoparticles that are stabilised by the carrier materials.
  • the mixing may be instantaneous, or it may take place over a time period.
  • the latter may be achieved through the use of a pump, such as a peristaltic pump, 69324247-2 operating at a rate of 1 to 120 mL/min, preferably at a rate of 20 to 100 mL/min, more preferably at a rate of 40 to 80 mL/min, most preferably at a rate of about 60 mL/min.
  • a pump such as a peristaltic pump, 69324247-2 operating at a rate of 1 to 120 mL/min, preferably at a rate of 20 to 100 mL/min, more preferably at a rate of 40 to 80 mL/min, most preferably at a rate of about 60 mL/min.
  • Any suitable homogeniser may be used, such as a rotary homogeniser or microniser.
  • it may be beneficial to sonicate the mixed solutions.
  • Any suitable sonicator may be used, such as a probe sonicator.
  • the active solution is heated to increase the solubility of the pharmaceutically active compound therein, allowing higher concentrations to be used and increasing the degree of supersaturation on mixing with the carrier material solution, particularly as the carrier material solution is maintained at ambient temperature (approximately 25°C). Any suitable temperature may be used, for example 30 to 90°C, 40 to 80°C, 50 to 70°C, or about 60°C. Any suitable method of removing the mixed solvent may be used, on the condition that it does not provide the nanoparticles with the opportunity to aggregate. This may be achieved by either removing the solvent extremely rapidly, or by rapidly solidifying the dispersion and subliming the solid solvent (e.g. lyophilisation).
  • the former method is preferred, utilising spray-drying or spray-granulating techniques, due to their high throughput and acceptability in pharmaceutical applications.
  • the parameters of spray-drying and spray-granulation processes such as flow rate and temperature, may be varied to achieve effective drying and attain the desired powdery and granular products.
  • the resulting solid may be subjected to further drying procedures, such as being dried in vacuo, to remove any residual solvents.
  • the present invention also provides a solid composition obtainable by, obtained by, or directly obtained by any of the processes described herein.
  • Aqueous Dispersions The present invention also provides an aqueous dispersion, obtainable by, obtained by, or directly obtained by dispersing the solid composition as defined herein in an aqueous medium.
  • the first and second excipients are dissolved within the aqueous medium to release the nanoparticles of the 69324247-2 Rifamycin, such as Rifapentine, in a dispersed form.
  • the aqueous medium comprises 20 to 99.5 wt% of the total aqueous dispersion.
  • the aqueous medium comprises 50 to 98 wt% of the total aqueous dispersion. In a particular embodiment, the aqueous medium comprises 70 to 95 wt% of the total aqueous dispersion.
  • the remaining proportion of the aqueous dispersion consists essentially of the Rifamycin, such as Rifapentine, first excipient, and second excipient, whose proportions within the aqueous dispersion as a whole are accordingly calculated (and scaled) by reference to the proportions recited in relation to the solid composition.
  • the concentration of the Rifamycin may be at least 100 mg/mL, preferably at least 200 mg/mL, more preferably at least 300 mg/mL, and most preferably at least 500 mg/mL.
  • the concentration of the Rifamycin may be 100 to 1000 mg/mL, preferably 150 to 800 mg/mL, more preferably 200 to 600 mg/mL, yet more preferably 250 to 500 mg/mL and most preferably 300 to 400 mg/mL.
  • the aqueous medium is water.
  • the aqueous medium comprises water and one or more additional pharmaceutically acceptable diluents or excipients.
  • the aqueous medium comprises saline or a phosphate buffered saline (PBS).
  • the nanoparticles may have an average particle diameter of less than 5 micron ( ⁇ m).
  • the nanoparticles have an average particle diameter of between 10 nm and 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 100 and 500 nm.
  • the nanoparticles have a particle diameter in the range of 1 to 1000 nm. It will be understood that references to particle diameter are references to the Z-average hydrodynamic diameter of the nanoparticles.
  • the nanoparticles may have a polydispersity less than or equal to 0.8, preferably less than or equal to 0.6, more preferably less than or equal to 0.5.
  • the particle diameter and polydispersity of the nanoparticles may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy).
  • Particle size and polydispersity may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy).
  • particle diameter and polydispersity i.e.
  • Z-average hydrodynamic diameter are assessed by dispersing the solid composition in an aqueous medium at a concentration of 1 mg/mL and determining the particle diameter using dynamic light scattering, e.g. using a Malvern Panalytical Limited Zetasizer Ultra.
  • the aqueous dispersion may be used in the formulation of a microneedle array, for example, a microneedle array as is described later in this document.
  • Process for preparing an aqueous dispersion The present invention provides a process for preparing an aqueous dispersion, the process comprising dispersing a solid composition as defined herein in an aqueous medium.
  • the aqueous medium is water.
  • the aqueous medium comprises water and one or more additional excipients.
  • the aqueous medium comprises saline or a phosphate buffered saline (PBS).
  • Dispersing the solid composition in the aqueous medium may comprise adding the solid composition to an aqueous medium (or visa versa) and suitably agitating the resulting mixture (e.g. by shaking, homogenisation, sonication, stirring, etc.).
  • Pharmaceutical compositions The present invention provides a pharmaceutical composition comprising a solid composition or an aqueous dispersion as defined herein.
  • the pharmaceutical compositions of the present invention may further comprise one or more additional pharmaceutically acceptable excipients.
  • the solid compositions of the invention may be formulated into a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, or dispersible powders or 69324247-2 granules) by techniques known in the art.
  • the solid compositions of the invention may be mixed with one or more additional pharmaceutical excipients during this process, such as antiadherants, binders, coatings, enterics, disintegrants, fillers, diluents, flavours, colours, lubricants, glidants, preservatives, sorbents, and sweeteners.
  • the pharmaceutical composition is a tablet or capsule comprising the solid composition.
  • the aqueous dispersion of the present invention may be administered as it is or further formulated with one or more additional excipients to provide a dispersion, elixir or syrup that is suitable for oral use, or a dispersion that is suitable for parenteral administration (for example, a sterile aqueous dispersion for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing).
  • the pharmaceutical composition is an aqueous dispersion as described herein. Such dispersed formulations can be used to accurately measure smaller dosages, such as those suitable for administration to children.
  • the pharmaceutical composition is in a form suitable for parenteral delivery, whether via subcutaneous or intramuscular delivery.
  • compositions of the invention may be obtained by conventional procedures, using conventional pharmaceutical excipients, well known in the art.
  • the pharmaceutical compositions of the invention contain a therapeutically effective amount of the Rifamycin, such as Rifapentine.
  • a person skilled in the art will know how to determine and select an appropriate therapeutically effective amount of the Rifamycin, such as Rifapentine, to include in the pharmaceutical compositions of the invention.
  • injectable formulations The present invention provides an injectable formulation comprising the solid composition as described herein, the aqueous dispersion as described herein, or the pharmaceutical composition as described herein.
  • the injectable 69324247-2 formulation is intramuscularly injectable. In other embodiments, the injectable formulation is subcutaneously injectable.
  • Said formulations may be in solid form (or substantially solid form, e.g. a paste) or liquid form or semi-solid form, in which the Rifamycin, such as Rifapentine, is present in the form of nanoparticles.
  • the nanoparticles of a Rifamycin, such as Rifapentine may be dispersed within one or more carrier materials.
  • each nanoparticle of the Rifamycin, such as Rifapentine is stabilised by the first and second excipients.
  • Long Acting Injectable Formulations The present invention provides a long acting injectable formulation comprising the aqueous dispersion as described herein, or the pharmaceutical composition as described herein.
  • the long acting injectable formulation may be intramuscularly injectable or it may be subcutaneously injectable.
  • the long acting injectable formulation may, in addition to the nanoparticles of a Rifamycin, such as Rifapentine, and the aqueous medium, further comprise one or more additional pharmaceutically acceptable excipients, such as thickeners, preservatives, and stabilizers.
  • the injectable formulations of nanoparticles of a Rifamycin, such as Rifapentine may be long acting injectable formulations. Such formulations are advantageously designed for administration as an intramuscular or a subcutaneous injection that forms a depot at the site of the injection.
  • Long acting injectable formulations improve adherence to prophylaxis and/or treatment, especially in respect of viral illnesses which require extended treatment durations, such as tuberculosis, and the consequences that ensue. Furthermore, a depot injection is beneficial in that it may be easier to administer than conventional preparations and allows for simpler follow-up / on-going care.
  • the long acting injectable formulations of the present invention permit the formation of a depot of nanoparticles of a Rifamycin, such as Rifapentine, as these drugs are poorly soluble in aqueous media, preventing them from rapidly exiting the depot and entering the bloodstream of the patient.
  • long acting injectable formulations are administered intramuscularly or subcutaneously to certain sites, such as the deltoid, dorsogluteal, ventrogluteal, vastus lateralis, and rectus femoris muscles.
  • sites such as the deltoid, dorsogluteal, ventrogluteal, vastus lateralis, and rectus femoris muscles.
  • Each site has a limit on the maximum volume that may be injected without prompting excessive discomfort in the patient or losing effectiveness.
  • the maximum volume even for the 69324247-2 larger sites, is generally only as high as 3 mL.
  • the administration also takes longer than a standard injection, typically taking 10 seconds to administer 1 mL.
  • Rifamycin such as Rifapentine
  • the Rifamycin is thought to be released from the depot at a rate defined by its physicochemical properties (e.g. solubility controlling the rate at which each the Rifamycin dissolves from the surface of the nanoparticles) and the local physiological environment.
  • the amount that is released is a therapeutically effective amount (i.e. the concentration of the Rifamycin in the formulation must be sufficient to produce a therapeutically effective concentration of the Rifamycin in vivo).
  • the therapeutically effective amount of the Rifamycin must be maintained for the duration of the treatment, meaning that the depot must contain all of the Rifamycin required for the duration of the treatment.
  • the concentration of the Rifamycin may be at least 150 mg/mL, preferably at least 200 mg/mL, more preferably at least 300 mg/mL, and most preferably at least 500 mg/mL.
  • the concentration of the Rifamycin, such as Rifapentine may be 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL.
  • the Rifamycin such as Rifapentine
  • the depot of nanoparticles of the Rifamycin at a controlled rate such that a therapeutically effective amount of the Rifamycin is achieved over a period of at least about two weeks from the date of administration.
  • the therapeutically effective amount of the Rifamycin is achieved for at least about three weeks, more 69324247-2 preferably at least about one month, most preferably at least about two months from the date of administration of the injection.
  • Implantable Rods The present invention provides implantable rods comprising nanoparticles of a Rifamycin, such as Rifapentine, dispersed in a monolith of the first excipient and the second excipient.
  • the Rifamycin such as Rifapentine, which comprises the nanoparticles may be amorphous (i.e. substantially non-crystalline in nature).
  • the nanoparticles of the present invention have an average particle diameter of less than 5 micron ( ⁇ m). In a particular embodiment, the nanoparticles have an average particle diameter of between 10 nm and 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 100 and 500 nm. In embodiments, the nanoparticles have a particle diameter in the range of 1 to 1000 nm.
  • references to particle diameter are references to the Z-average hydrodynamic diameter of the nanoparticles.
  • the nanoparticles of the present invention may have a polydispersity less than or equal to 0.8, preferably less than or equal to 0.6, more preferably less than or equal to 0.5.
  • the particle diameter and polydispersity of the nanoparticles may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy).
  • Particle size and polydispersity may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy).
  • particle diameter and polydispersity i.e.
  • the monolith of the first excipient and second excipient is non-porous in nature.
  • the first excipient may be as described for the solid composition of the present invention.
  • the first excipient is selected from polyvinylpyrrolidone 69324247-2 (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose.
  • the second excipient may be as described for the solid composition of the present invention.
  • the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
  • the first and second excipients may be used in any combination as described for the solid composition of the present invention.
  • the relative quantities of the Rifapentine, such as Rifamycin, first excipient, and second excipient may be as described herein for the solid composition of the present invention.
  • the implantable rod is suitable for implantation into a patient (e.g. subcutaneously).
  • the rods may be of any suitable shape or dimension for implantation.
  • the rods are cylindrical.
  • the length of the rods may be between 1 and 100 mm, preferably between 1 and 80 mm, more preferably between 2 and 50 mm, yet more preferably between 5 and 40 mm, and most preferably between 10 and 20 mm.
  • the diameter of the rods may be between 0.1 and 5 mm, preferably between 0.5 and 2.5 mm, more preferably between 1 and 2 mm.
  • Processes for Preparing Implantable Rods Implantable rods may be prepared by any suitable process for the conversion of fine thermoplastic solids to cohered monoliths, such as injection moulding, extruding and other such methods known to those skilled in the art.
  • One suitable method comprises compressing the solid compositions of the first aspect of the present invention while heating in order to collapse the porous matrix of first and second excipient and to cohere discrete particles to form the monolith. Removing the porosity increases the density of the composition, making it easier to handle and making it viable to insert the composition as an implant. This also increases the time taken to dissolve the composition. Without wishing to be bound by theory, it is the experience of the inventors that the nanoparticulate nature of active compounds, such as Rifamycins like Rifapentine, is retained in the implantable rods following conversion.
  • the compressive force may be applied under a reduced pressure atmosphere (e.g. a vacuum). Doing so assists in the removal of any remaining volatile substances, such as solvents, and reduces the incidence of bubbles by removing any gas that is entrained in the solid composition.
  • Certain apparatus may also use the pressure differential to apply the compressive force to the solid composition. Heating the compressed solid composition requires increasing the temperature of the solid composition such that discrete volumes of the first and second excipients cohere under the pressure of the compression step.
  • the compressed solid composition may be heated to a temperature from 60 to 160 °C, preferably from 80 to 140 °C, more preferably from 100 to 120 °C, most preferably about 105 °C.
  • the elevated temperature is maintained for a period of from 1 minute to 40 minutes, preferably from 5 minutes to 30 minutes, more preferably from 10 minutes to 25 minutes, most preferably about 20 minutes.
  • the compressive force and/or vacuum is preferably maintained during the heating step.
  • Any suitable means may be used to supply heat for the heating step.
  • an electrical heater such as a hotplate.
  • the rod may be cooled. For example, through contact with a cold surface.
  • microneedle arrays comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition, wherein the first composition comprises nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a monolith comprising a first excipient, a second excipient and at least one structural polymer.
  • a Rifamycin such as Rifapentine
  • the Rifamycin, such as Rifapentine, which comprises the nanoparticles may be amorphous (i.e. substantially non-crystalline in nature).
  • the nanoparticles of the present invention have an average particle diameter of less than 5 micron ( ⁇ m).
  • the nanoparticles have an average particle diameter of between 10 nm and 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 100 and 500 nm.
  • the nanoparticles have a particle diameter in the range of 1 to 1000 nm.
  • references to particle diameter are references to the Z-average hydrodynamic diameter of the nanoparticles.
  • the nanoparticles of the present invention may have a polydispersity less than or equal to 0.8, preferably less than or equal to 0.6, more preferably less than or equal to 0.5.
  • the particle diameter and polydispersity of the nanoparticles may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy).
  • Particle size and polydispersity may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy).
  • particle diameter and polydispersity i.e.
  • the monolith of the first excipient and second excipient is non-porous in nature.
  • the first excipient may be as described for the solid composition of the present invention.
  • the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose.
  • the second excipient may be as described for the solid composition of the present invention.
  • the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
  • AOT dioctyl sodium sulfosuccinate
  • polyoxyethylene-polyoxypropylene block copolymer polysorbate 20
  • Polysorbate 80 Polysorbate 80
  • sorbitan monolaurate any hydrophilic polymer suitable for use in pharmaceutical formulations may be employed as a structural polymer, for example, the polymers that are suitable as first excipients.
  • the structural polymer is selected to be the same as a first excipient, as this helps to ensure compatibility.
  • the structural 69324247-2 polymer is selected from PVA, PVP, and combinations thereof.
  • Polymers with MW below 60 kDa are preferred as they are known to be swiftly eliminated from the human body via renal excretion.
  • the purpose of the structural polymer is to provide the microneedles with sufficient mechanical strength to enable insertion into skin and consequent delivery of the Rifamycin, such as Rifapentine.
  • the relative quantities of the Rifamycin, such as Rifapentine, first excipient, and second excipient may be as described herein for the solid composition of the present invention.
  • the ratio of the Rifamycin, first excipient, and second excipient to the structural polymer may be in the range of 10 to 80 wt% of a Rifamycin, such as Rifapentine; 10 to 80 wt% first excipient; and 1 to 25 wt% second excipient.
  • the solid composition comprises 30 to 60 wt% of a Rifamycin, such as Rifapentine; 30 to 60 wt% first excipient; and 5 to 20 wt% second excipient. More preferably, the solid composition comprises 40 to 50 wt% of a Rifamycin, such as Rifapentine; 40 to 50 wt% first excipient; and 5 to 15 wt% second excipient.
  • the baseplate comprises a base polymer.
  • any hydrophilic polymer suitable for use in pharmaceutical formulations may be employed as a base polymer, for example, the polymers that are suitable as first excipients.
  • the base polymer is selected to be the same as a first excipient and/or structural polymer.
  • the base polymer is PVP.
  • the base polymer will comprise high molecular weight polymer, such as PVP with a MW of 360 kDa, to impart a degree of rigidity to the base plate.
  • the base plate may further comprise one or more additives to improve the properties of the base plate, for example, a low molecular weight polyol, such as glycerol, may reduce brittleness of the base plate.
  • the additive and base polymer are used in a mass ratio from 1 : 40 to 1: 10, preferably a mass ratio of 1 : 30 to 1 :15, more preferably a mass ratio of about 1 : 20.
  • the relative quantities of first composition and second composition is determined by the physical dimensions of the microneedles relative to the base plate, with the majority of the microneedle volume comprising first composition and the remaining microneedle volume and base plate volume comprising second composition.
  • at least 50% of the microneedle volume comprises first composition, preferably at least 60%, further preferably at least 80 %, more preferably at least 90%, most preferably substantially all of the microneedle volume comprises first composition.
  • the microneedle array may be designed to contain substantially any suitable amount of the Rifamycin, such as Rifapentine.
  • the microneedle array contains between 0.1 and 20 mg of the Rifamycin, such as Rifapentine, preferably between 0.5 and 10 mg, more preferably between 1 and 5 mg, most preferably between 1 and 2 mg.
  • the dimensions of the microneedles and microneedle array are determined by the mould used in their production and can have substantially and suitable dimension.
  • the heights of the microneedles may be in the range of 50 to 1000 ⁇ m, preferably in the range of 500 to 900 ⁇ m.
  • the base width of the microneedles may be in the range of 50 to 500 ⁇ m, preferably in the range of 100 to 300 ⁇ m.
  • the interspacing between the needles may be in the range of 50 to 200 ⁇ m, preferably about 100 ⁇ m.
  • the area microneedle array may be in the range of 0.1 to 100 cm 2 , preferably in the range of 0.5 to 30 cm 2 .
  • the microneedle array may comprise between 2 and 2000 microneedles. Typically, the microneedles are arrayed in a grid, but substantially any arrangement may be used.
  • the needles of the microneedle array may be of any suitable geometry.
  • they may be conical, frustoconical, cylindrical, cuboid, obelisk, square-based pyramid, pentagonal-based pyramid, arrowhead, and so on.
  • Processes for Preparing Microneedle Arrays Microneedle arrays may be prepared by any suitable process known to those skilled in the art.
  • One suitable method comprises the steps of: a) dispersing a solid composition according to the present invention and at least one structural polymer in a solvent to form a microneedle precursor dispersion; b) placing the microneedle precursor dispersion into a mould; c) compressing the microneedle precursor dispersion in the mould and then drying to form microneedles; d) adding a baseplate precursor solution into the mould; e) compressing the baseplate precursor solution and then drying to form the baseplate; and f) releasing the microneedle array from the mould.
  • microneedles formed in steps b) and c) are retained in the 69324247-2 mould and the baseplate precursor solution is added over the top of them so as to form the microneedle array. Steps b) and c) may be repeated to increase the volume of the microneedle that is formed of the first composition.
  • the step of dispersing the solid composition according to the present invention and at least one structural polymer may comprise individual steps of dispersing the solid composition in a first quantity of the solvent, dissolving the at least one structural polymer in a second quantity of the solvent, and then mixing.
  • the microneedle precursor dispersion may comprise the solid composition in an amount of between 10 and 50 wt%, preferably between 20 and 40 wt%, more preferably between 25 and 35 wt%, most preferably about 30 wt%.
  • the microneedle precursor dispersion may comprise the at least one structural polymer in an amount between 1 and 20 wt%, preferably between 5 and 15 wt%, more preferably about 10 wt%.
  • the mould contains microcavities that correspond to the shape of the microneedles. The steps of placing the microneedle precursor dispersion into the mould, compressing and drying to form the microneedles may not fill the cavities of the mould. Accordingly, these steps may be repeated so as to increase the volume of the cavities that are filled.
  • the baseplate precursor solution comprises a base polymer, a solvent, and, optionally, one or more additives.
  • the solution may comprise between 10 and 50 wt% base polymer, preferably between 20 and 40 wt% base polymer, more preferably about 30 wt% base polymer. If present, the baseplate precursor solution comprises between 0.1 and 5 wt% additive, preferably between 0.5 and 3 wt%, more preferably about 1.5 wt%.
  • the solvent is typically water.
  • the components forming the microneedle array are all soluble in water, in addition to its other benefits (e.g. non-toxic, non-flammable, easily available).
  • the steps of compressing the solutions may use any suitable method known in the art, such as pressure chamber or centrifugation.
  • the step of compressing the microneedle precursor dispersion takes place in a pressure chamber. It is also preferred that compressing the baseplate precursor solution is done by centrifuge.
  • the drying steps may use any suitable method known in the art. Typically, the drying steps are performed under ambient conditions (i.e. the solvent is simply allowed to 69324247-2 evaporate). However, it will be understood that the rate of drying may be increased through the application of increased temperature, increased air flow over the samples, or the application of a reduced pressure.
  • the microneedle array may retain residual water following drying. The residual water does not exceed 15 wt% of the microneedle array.
  • the residual water content may be between 1 and 15 wt% of the microneedle array, typically between 5 and 10 wt% of the microneedle array.
  • Uses of the solid compositions, aqueous dispersions, pharmaceutical compositions, injectable formulations, implantable rods, and microneedle arrays The present invention provides a solid composition, an aqueous dispersion, a pharmaceutical composition, injectable formulation, implantable rod, or microneedle array as defined herein for use as a medicament.
  • the present invention provides a solid composition, an aqueous dispersion, a pharmaceutical composition, injectable formulation, implantable rod, or microneedle array as defined herein for use in the treatment and/or prevention of tuberculosis, such as latent tuberculosis.
  • the aqueous dispersion, pharmaceutical composition, injectable formulation for use in the treatment and/or prevention of tuberculosis has a concentration of a Rifamycin, such as Rifapentine, in the range of 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL.
  • the concentration of the Rifamycin is at least 150 mg/mL, preferably at least 200 mg/mL, more preferably at least 300 mg/mL, and most preferably at least 500 mg/mL.
  • the implantable rod for use in the treatment and/or prevention of tuberculosis has a concentration of the Rifamycin, such as Rifapentine in the range of 20 to 80 wt%, preferably 30 to 70 wt%, more preferably 40 to 60 wt%, most preferably about 50 wt%.
  • the microneedle array for use in the treatment and/or prevention of tuberculosis contains a mass of the Rifamycin, such as Rifapentine, in the range of between 1 and 20 mg of the Rifamycin, preferably between 2 and 10 mg, more 69324247-2 preferably about 5 mg. It will be understood that the dose of the Rifamycin provided to a patient may be varied by using larger and/or multiple microneedle arrays.
  • the present invention provides a method of treating and/or preventing tuberculosis, such as latent tuberculosis, the method comprising administering a therapeutically effective amount of a solid composition, an aqueous dispersion, a pharmaceutical composition, an injectable formulation, implantable rod, or microneedle array as defined herein to a patient suffering from or at risk of suffering from tuberculosis.
  • the aqueous dispersion, the pharmaceutical composition, or the injectable formulation has a concentration of a Rifamycin, such as Rifapentine, in the range of 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL.
  • the concentration of the Rifamycin is at least 150 mg/mL, preferably at least 200 mg/mL, more preferably at least 300 mg/mL, and most preferably at least 500 mg/mL.
  • the aqueous dispersion, pharmaceutical composition, the injectable formulation, or implantable rod may form a depot within the body of the patient, for example, in an intramuscular or subcutaneous site, optionally wherein the depot maintains a therapeutically effective concentration of the Rifamycin, such as Rifapentine, within the body of the patient for a period of at least two weeks, preferably at least one month, more preferably at least two months, yet more preferably at least three months, and most preferably at least two four.
  • the microneedle array or arrays gradually release the Rifamycin, such as Rifapentine, and optionally maintains a therapeutically effective concentration of the Rifamycin within the body of the patient for a period of at least 4 hours, preferably at least 6 hours, more preferably at least 12 hours, and most preferably at least 24 hours.
  • the microneedle array or arrays are removed from the skin of the patient and, if treatment is ongoing, replaced with a fresh microneedle array or arrays.
  • the method requires dosing of the aqueous dispersion, the pharmaceutical composition, the injectable formulation, or implantable rod up to three times, preferably up to two times, most preferably only once, to maintain a therapeutically effective concentration of the Rifamycin, such as Rifapentine, in the patient for the duration of the treatment.
  • the method requires dosing of the microneedle array up to six times per day, preferably up to four times per day, more preferably twice a day, and most preferably once a day, to maintain a therapeutically effective concentration of the Rifamycin, such as Rifapentine, in the patient for the duration of the treatment.
  • the administered form of nanoparticle of the Rifamycin preferably provides a controlled release bolus formulation of the Rifamycin, which, when administered to a patient, releases the Rifamycin into the bloodstream of the patient over a period of at least about two weeks from the date of administration. Further preferably the period of release is at least about one month, more preferably at least about two months, yet more preferably at least about three months, and most preferably at least about four months from the date of administration of the injection, insertion or application.
  • treatment includes curative and prophylactic treatment.
  • a “patient” means an animal, preferably a mammal, preferably a human, in need of treatment.
  • the amount of the Rifamycin, such as Rifapentine, administered should be a therapeutically effective amount where the Rifamycin is used for the treatment of a disease or condition and a prophylactically effective amount where the Rifamycin is used for the prevention of a disease or condition.
  • the term “therapeutically effective amount” used herein refers to the amount of the Rifamycin, such as Rifapentine, needed to treat or ameliorate tuberculosis.
  • prophylactically effective amount used herein refers to the amount of the Rifamycin needed to prevent tuberculosis.
  • the exact dosage will generally be dependent on the patient’s status at the time of administration. Factors that may be taken into consideration when determining dosage include the severity of the disease state in the patient, the general health of the patient, the age, weight, gender, diet, time, frequency and route of administration, drug combinations, reaction sensitivities and the patient’s tolerance or response to therapy. The precise amount can be determined by routine experimentation, but may ultimately lie with the judgement of the clinician.
  • An effective dose may in instances be from 0.01 mg/kg/day (mass of drug compared to mass of patient) to 1000 mg/kg/day, e.g.1 mg/kg/day to 100 mg/kg/day.
  • compositions may be 69324247-2 administered individually to a patient or may be administered in combination with other agents, drugs or hormones.
  • the composition may be administered in an amount sufficient to release the Rifamycin, such as Rifapentine, at the above rates.
  • the long acting injectable may be administered in an amount of 0.1 mL to 10 mL, at an amount of 0.2 mL to 6 mL, at an amount of 0.5 mL to 5 mL, or at an amount of 1 mL to 3 mL.
  • the solid compositions, aqueous dispersions, pharmaceutical compositions, injectable formulations, implantable rods, or microneedle arrays of the invention may be administered to a patient by any convenient route of administration. More than one route of administration may be used in combination within a defined treatment and/or prophylactic regime, especially for a combination therapy, in which one component of the combination may be administered via one route, whilst another component of the combination may be administered via a different route. All such combinations are hereby contemplated. Routes of administration include, but are not limited to, oral (e.g.
  • transdermal including, microneedle array e.g., by a patch, plaster, etc.
  • transmucosal including, e.g., by a patch, plaster, etc.
  • intranasal e.g., by nasal spray
  • ocular e.g., by eyedrops
  • pulmonary e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose
  • rectal e.g., by suppository or enema
  • vaginal e.g., by pessary
  • parenteral for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal
  • the route of administration is by injection (e.g. intramuscular or subcutaneous injection) of a depot or implantation of an implantable rod.
  • the route of administration is transdermal via a microneedle array.
  • the injectable formulation of the present invention is a depot formulation administered so as to provide a controlled release in the patient over at least a period of about two weeks from the date of administration. Further preferably the period of release is at least about one month, more preferably at least about two months, more 69324247-2 preferably at least about three months, and most preferably at least about four months from the date of administration of the injection.
  • the implantable rod of the present invention is a depot formulation administered so as to provide a controlled release in the patient over at least a period of about two weeks from the date of administration. Further preferably the period of release is at least about one month, more preferably at least about two months, yet more preferably at least about three months, and most preferably at least about four months from the date of implantation of the rod. Without wishing to be bound by theory, it is thought that the implant gradually dissolves to form a liquid depot and that the Rifamycin, such as Rifapentine, is gradually released from the implant and subsequent liquid depot.
  • the microneedle array of the present invention is a transdermal release formulation administered to provide a controlled release in a patient over a period of at least four hours, preferably at least 6 hours, more preferably at least 12 hours and most preferably at least 24 hours.
  • Kit of Parts The present invention provides a kit of parts comprising a solid composition as defined herein or pharmaceutical composition comprising the solid composition as defined herein, and a pharmaceutically acceptable aqueous diluent.
  • the solid composition or pharmaceutical composition comprising the solid composition as defined herein can be dispersed into the diluent to provide an aqueous dispersion as defined herein.
  • Either the entire dispersion can then be administered, or a proportion of it can be measured and then administered (thereby providing a means of administering different dosages to individual patients).
  • Rifapentine was dissolved in chloroform at a concentration of 100 mg/mL and each of the first and second excipients were dissolved in water at a concentration of 22.5 mg/mL to provide three stock solutions.50 ⁇ L of the Rifapentine solution, 178 ⁇ L of the first excipient solution and 44 ⁇ L of the second excipient solution were combined. The mixture was then emulsified using a Covaris S220x.
  • the resulting emulsions were then immediately frozen with liquid nitrogen and were freeze dried for approximately 48 hours using a VirTis Benchtop Pro.
  • the resulting solid product was in the form of a 69324247-2 monolith containing 50 wt% Rifapentine, 40 wt% first excipient and 10 wt% second excipient.
  • the first excipients tested were Plasdone C15, Kollidon 12 PF, lactose, sucrose, Pluronic F68, and PEG 4000.
  • the second excipients tested were Benzalkonium chloride, AOT, Pluronic F68, Tween 20, Tween 80, and Span 20.
  • Nanodispersion Quality Assessment Criteria A particle was determined a hit if it complied with the following criteria: (i) complete dispersion of the sample with no large particles visible; (ii) a particle Z-average ⁇ 1000 nm; (iii) a polydispersity index (PDI) ⁇ 0.4; (iv) a standard deviation between three scans ⁇ 5% from average Z-average; and (v) at least two of the three DLS scans pass the ‘size quality report’.
  • the ‘size quality report’ incorporates twelve tests on the reliability of the data recorded and is automatically applied to each measurement by the Malvern Zetasizer software.
  • Example 2 Rifapentine SDNs formed by Nanoprecipitation and Freeze Drying Rifapentine was dissolved in methanol at a concentration of 100 mg/mL and each of the first and second excipients were dissolved in water at a concentration of 22.5 mg/mL to provide three stock solutions.50 ⁇ L of the Rifapentine solution, 178 ⁇ L of the first excipient solution and 44 ⁇ L of the second excipient solution were combined and shaken by
  • the resulting suspensions were then immediately frozen with liquid nitrogen and were freeze dried for approximately 48 hours using a VirTis Benchtop Pro.
  • the resulting solid product was in the form of a monolith containing 50 wt% Rifapentine, 40 wt% first excipient and 10 wt% second excipient.
  • the first and second excipients and screening process and criteria were as described in Example 1. Eight combinations passed the screening criteria.
  • the Rifapentine stock solution (3mL) was then immediately added via peristaltic pump at a flow rate of 60 mL/min. Mixing was continued for approximately 15-20 seconds after addition was completed. Half of the resulting suspension was frozen in liquid nitrogen immediately, the remaining half was passed through an LV1 microfluidizer for 5 passes at 20,000 psi prior to being frozen in liquid nitrogen. The samples were freeze dried for ⁇ 48 hours using a VirTis Benchtop Pro with a condenser setting of -100°C and at a pressure of ⁇ 40 ⁇ Bar to give Rifapentine compositions containing 50 wt% Rifapentine, 40 wt% Plasdone C15, 10 wt% AOT.
  • the Rifapentine stock solution (4mL) was then immediately added via peristaltic pump at a flow rate of 60 mL/min. Mixing was continued for approximately 15-20 seconds after addition was completed. Half of the resulting suspension was immediately spray dried, the remaining half was passed through an LV1 microfluidizer for 5 passes at 20,000 psi prior to being spray dried.
  • the spray drier conditions were as follows: flow rate of 5 mL/min using a Buchi B-290 mini spray dryer (aspirator 100%, nitrogen at 5 bar pressure, Q-Flow gauge 45, Outlet temperature 650C).
  • the resulting compositions 50 wt% Rifapentine, 40 wt% Plasdone C15, 10 wt% AOT.
  • the samples were dispersed in water at 1 mg/mL with regard to Rifapentine and screened as described in Example 1.
  • the syringeability of each composition was tested at increasing concentrations of Rifapentine.
  • the dispersions were produced by vortex mixing the solid composition in water at the required concentrations for a period of 30 seconds. The dispersions were then passed through a 25G needle by hand. Those that passed through easily and without blockages, with a repeat one hour later, were considered to have passed.
  • Example 5 Rifapentine/Plasdone C15/AOT SDNs formed by Nanoprecipitation and Spray Drying
  • Rifapentine was dissolved in methanol at 40 mg/mL
  • Plasdone C15 was dissolved in water at 25 mg/mL
  • AOT was dissolved in water at 5 mg/mL.8mL of the Plasdone C15 stock solution and 8mL of the AOT stock solution were combined and mixed using an Ultra-Turrax T25 Digital Homogeniser set to 14,000 rpm.
  • the Rifapentine stock solution (4mL) was then immediately added via peristaltic pump at a flow rate of 60 mL/min. Mixing was continued for approximately 15-20 seconds after addition was completed.
  • the suspension was spray dried as set out in Example 4 to produce compositions containing 40 wt% RFP, 50 wt% Plasdone C15, 10 wt% AOT.
  • the samples were dispersed in water at 1 mg/mL with regard to Rifapentine and screened as described in Example 1.
  • Formulation Dz (nm) PdI repeat 1 226 0.070 2 238 0.040 3 239 0.070 The syringeability of the composition was tested as described in Example 4.
  • compositions were found to be syringeable at all tested concentrations up to 300 mg/mL (concentration with respect to the Rifapentine). 69324247-2 This process was repeated for alternative Rifapentine stock solutions using different solvent solutions: Solvent system Dz (nm) PdI 50% Acetone, 50% 329 0.100 Ethanol 90% Acetone, 10% 399 0.140 Methanol 50% butanone, 50% 638 0.100 Ethanol This process was also repeated for alternative first excipients: First excipient Second excipient Dz (nm) PdI Kollidon 17PF AOT 192 0.100 Lactose AOT 280 0.390
  • Example 6 In vivo Longevity of Rifapentine following Intramuscular Injection An aqueous dispersion of the Rifapentine formulation (Rifapentine 40 /Plasdone C15 50 /AOT 10 ) in water was produced with a total drug concentration of 300 mg/mL.
  • Example 7 Formulation into Implantable Rods Implantable rods were prepared by a vacuum compression moulding (VCM) method using a MeltPrep VCM Essentials instrument set-up consisting of a hot plate, nitrogen gas assisted cooling plate, vacuum pump, base plate, VCM sample chamber, VCM main body, 2mm internal diameter PTFE sample tube, 2 mm diameter PTFE-coated separation foils, 15 mm piston, and a low-pressure lid. 69324247-2 Prior to sample preparation, the hot plate was heated to a temperature of 105 °C and a vacuum pressure of -1 bar was maintained for approximately 20 minutes. The sample tube was inserted into the VCM sample chamber, which was then fitted onto the base plate.
  • VCM vacuum compression moulding
  • a separation foil was then inserted and positioned at the bottom of the tube before adding the powdered formulation ( ⁇ 30 mg) using a funnel, which was compacted as much as possible using a pin.
  • a second separation foil was then positioned on top of the sample before inserting a 15 mm piston into the sample tube.
  • the VCM main body was then positioned over this assembly before attaching the low- pressure lid.
  • a vacuum of -1 bar was applied to the sample chamber before placing it on the hot plate.
  • the sample was heated to 105 °C for four minutes before being transferred onto the cooling plate and cooled for 2 minutes.
  • Opaque, black coloured rods were obtained weighing ⁇ 30 mg and having a length of 8 mm and diameter of 2 mm.
  • Example 8 In vivo Longevity of Rifapentine following Implantation of a Rod This experiment was performed on male Sprague Dawley Rats (250-300g – Charles River). Each rat was implanted with two rods, the rods implanted subcutaneously into each scapular region.
  • the rods comprised the following Rifapentine formulation: Rifapentine40/Plasdone C1550/AOT10.
  • Example 9 Formulation into Microneedles A polymer stock solution was prepared containing 20% w/w PVA (Sigma Aldrich, nominal MW of 9-10 kDa, M w 9-10 kDa) and 20% w/w Plasdone K29/32 in deionised 69324247-2 water. A needle layer composition was prepared by mixing 27.8% w/w of the polymer stock solution with 27.8% w/w of the Rifapentine formulation (Rifapentine 40 /Plasdone C15 50 /AOT 10 ) and 44.4% w/w of deionised water using a SpeedmixerTM at 3500 rpm for 5 minutes.
  • PVA Sigma Aldrich, nominal MW of 9-10 kDa, M w 9-10 kDa
  • Plasdone K29/32 in deionised 69324247-2 water.
  • a needle layer composition was prepared by mixing 27.8% w/w of the polymer stock solution with 27.8% w/
  • a baseplate composition was prepared by mixing 30% w/w PVP (Sigma Aldrich, nominal MW of 360 kDa, M n 360 kDa, K Value 80-100), 1.5% w/w glycerol and balance deionised water prior to sonication and centrifugation.
  • the needle layer composition was cast into a 16 by 16 array arranged on a 0.49 cm 2 area, each needle having a height of 850 ⁇ m (of which 600 ⁇ m is pyramidal tip and 250 ⁇ m is base column) and a column width of 300 ⁇ m, the spacing between needles being 100 ⁇ m.
  • the array was placed into a pressure chamber and subjected to a pressure of 5 bar for 3 minutes.
  • a second needle layer is cast and the array is placed in the pressure chamber and subjected to a pressure of 5 bar for a further 5 minutes.
  • the microneedles were left to dry overnight.
  • 650 ⁇ l of baseplate composition was cast onto the prepared needles and the arrays centrifuged for 15 minutes as 5000 rpm before drying under ambient conditions for 48 hours.
  • the set microneedle arrays were then released from the moulds and excess baseplate material cut away. Singly cast microneedle arrays were found to have a Rifapentine loading of 1.37 ⁇ 0.095 mg, while doubly cast microneedle arrays were found to have a Rifapentine loading of 1.72 ⁇ 0.15 mg.
  • Example 10 Insertion Efficiency of the Microneedle Arrays
  • the insertion efficiency of the microneedle arrays was determined by applying the microneedle arrays to layered Parafilm® M (each layer having a thickness of approximately 252 ⁇ m) as an in vitro skin model using 32 N of force (equivalent to that of a human thumb).
  • Microneedle arrays were applied to the skin using firm thumb pressure for 30 seconds.
  • a stainless-steel cylinder (diameter 11 mm, mass 11.5 g) was put on the top of each microneedle array to hold them in place throughout the experiment.
  • the receiver compartment was filled with 12 mL of 1% w/v SLS and 0.1% w/v ascorbic acid in PBS (pH 7.4).
  • the donor compartment was clamped on top of the receiver compartment and wrapped with Parafilm® M to prevent solvent evaporation. Samples of 200 ⁇ L of the receiver compartment were taken at predefined time points of 1, 2, 3, 4, 6, 10, and 24 hours and was replaced with the fresh release medium.
  • the Franz cells were disassembled, the skin surface dabbed clean to remove surface drug, and Rifapentine was extracted from the skins. Cumulative amounts of Rifapentine delivered from each formulation to both skin and receiver compartments were also determined.
  • skin samples collected at 24 hours were cut into small pieces, where 0.5 mL of water was added to each sample. They were then homogenised for 15 minutes using a Tissue Lyser LT. Subsequently, 1 mL of methanol was added, and samples were homogenised again for another 15 minutes. Then they were transferred to the tubes followed by adding 3.5 mL of methanol.
  • microneedle arrays each loaded with 1.4 mg of Rifapentine for a total dose of 5.6 mg per rat
  • the dorsal hair of the rats from the first cohort was removed prior to the experiment.
  • the bulk hair was shaved using an electric hair clipper and the remaining hair residuals were removed using depilatory hair removal cream. Rats were then left for a 24 hour period to allow the skin to recover and to ensure complete restoration of skin barrier function before affixing the microneedle arrays.
  • mice were sedated using a gaseous anaesthetic gas (2-4% v/v isoflurane in oxygen), where microneedle arrays were affixed using firm thumb pressure onto a pinched section of skin on the back of the rats in cohort 1.
  • TegadermTM film was placed on top of the microneedle arrays and kinesiology tape applied to keep them in place.
  • Blood plasma was collected from the tail veins periodically over the course of 24 hours and the Rifapentine concentrations therein quantified using LC/MS-MS. This data is graphed in Fig.6 and shows a consistent concentration of Rifapentine over the 24 hour period of the experiment, demonstrating that a relevant concentration of Rifapentine is maintained for the duration.
  • Rifapentine was dissolved in methanol at 50mg/mL
  • Plasdone C15 was dissolved in water at 14.25 mg/mL
  • AOT was dissolved in methanol at 15 mg/mL.0.8 mL of the AOT stock solution was added to 3.2 mL of the rifapentine stock solution and mixed using a vortex mixer for 30 seconds. The resulting mixture was immediately added via peristaltic pump at a flow rate of 5 mL/min to 16 mL of the Plasdone C15 stock solution with stirring from a stirrer bar.
  • the sample was allowed to stir for at least 5 minutes prior to spray drying.
  • the sample was then spray dried at a flow rate of 5 mL/min (with 69324247-2 stirring from a stirrer bar to prevent any possible sedimentation) using a Buchi B-290 mini spray dryer (aspirator 100%, nitrogen at 5 bar pressure, Q-Flow gauge 45, Outlet temperature 650C) to give a rifapentine composition containing approx. 40 wt% RFP, 57 wt% Plasdone C15, 3 wt% AOT.
  • the process was repeated on a larger scale, with 5 mL of the AOT stock solution and 20 mL of the rifapentine stock solution being added to 100 mL of the Plasdone C15 stock solution at a flow rate of 5 mL/min.
  • the samples were dispersed in water at 1 mg/mL with regard to active and screened as described in Example 1.
  • Plasdone C15 57 /AOT 3 reconstituted from spray-dried powder (control), by two injections of 150 ⁇ L each; 4.
  • Plasdone C15 50 /AOT 10 reconstituted from spray-dried powder (control), by two injections of 150 ⁇ L each; 5.
  • Cohorts 6 and 7 each comprised only one cage with four rats. Blood plasma was collected from the lateral tail veins periodically over the course of 56 days and the Rifapentine concentrations therein quantified using LC/MS-MS. This data is graphed in Fig. 7 for the 150 mg/kg cohort and in Fig. 8 for the 300 mg/kg cohort, neither showing significant difference between plasma blood concentrations of Rifapentine between the formulations. Clauses of the Invention: Clause 1.
  • a solid composition comprising nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a matrix comprising a first excipient and a second excipient, wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
  • PVP polyvinylpyrrolidone
  • PEG polyethylene glycol
  • polyoxypropylene block copolymer polyoxyethylene-polyoxypropylene block copolymer
  • lactose lactose
  • sucrose and wherein
  • the solid composition of clause 2 wherein the first and second excipients are selected from the following combinations: ⁇ PVP and AOT ⁇ lactose and AOT Clause 4.
  • the solid composition of any preceding clause wherein the composition comprises: 10 to 80 wt% of the Rifamycin, such as Rifapentine; 10 to 80 wt% of the first excipient; and 1 to 25 wt% of the second excipient.
  • Clause 5 The solid composition of clause 4, wherein the composition comprises: 30 to 60 wt% of the Rifamycin, such as Rifapentine; 30 to 60 wt% of the first excipient; and 1 to 20 wt% of the second excipient.
  • Clause 7. The solid composition of clause 5, wherein the composition comprises: 30 to 50 wt% of the Rifamycin, such as Rifapentine; 40 to 60 wt% of the first excipient; and 1 to 10 wt% of the second excipient.
  • the nanoparticles have a particle diameter in the range of 10 to 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 200 and 800 nm. 69324247-2 Clause 10.
  • a process for preparing a solid composition according to any one of clauses 1 to 10 comprising: (a) preparing an oil-in-water emulsion comprising: - an oil phase comprising the Rifamycin, such as Rifapentine; and - an aqueous phase comprising a first and second excipient, each as defined in any of clauses 1 to 10; and (b) removing the oil and water from the oil-in-water emulsion to form the solid composition.
  • a process for preparing a solid composition comprising: (a) providing an active solution comprising the Rifamycin, such as Rifapentine, in a water-miscible solvent; (b) providing a carrier material solution comprising a first and second excipient, each as defined in any of clauses 1 to 10; (c) mixing the solutions prepared in steps (a) and (b); and (d) removing the mixed solvent to produce the solid composition or, the process comprising: (a) providing an active solution comprising the Rifamycin, such as Rifapentine, and the second excipient in a water-miscible solvent; (b) providing a carrier material solution comprising a first excipient, each as defined in any of claims 1 to 10; (c) mixing the solutions prepared in steps (a) and (b); and (d) removing the mixed solvent to produce the solid composition.
  • An aqueous dispersion comprising a plurality of nanoparticles of the Rifamycin, such as Rifapentine, dispersed in an aqueous medium and stabilised by a mixture of a first excipient and a second excipient; wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
  • PVP polyvinylpyrrolidone
  • PEG polyethylene glycol
  • polyoxypropylene block copolymer polyoxyethylene-polyoxypropylene block copoly
  • Clause 15 The aqueous dispersion of clause 14, wherein the aqueous dispersion comprises nanoparticles of the Rifamycin, such as Rifapentine, first excipients, and second excipients as defined in any of clauses 2 to 10 in the aqueous medium.
  • Clause 16 The aqueous dispersion of clause 14 or clause 15, wherein the Rifamycin, such as Rifapentine, is present in the aqueous dispersion at a concentration of 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL.
  • a pharmaceutical composition comprising the solid composition of any of clauses 1 to 8, or the aqueous dispersion of any of clauses 14 to 16 and, optionally, one or more further pharmaceutically acceptable excipients.
  • An injectable formulation comprising the solid composition of any of clauses 1 to 10, the aqueous dispersion of any of clauses 14 to 16, or the pharmaceutical composition of clause 18.
  • Clause 21 A method of producing an implantable rod comprising the steps of compressing a solid composition according to any one of clauses 1 to 10 and heating the compressed solid composition for a period of time.
  • Clause 22 The method of clause 21, wherein the solid composition is compressed in a mould, optionally the mould being cylindrical in form.
  • Clause 23 The method of clause 21 or clause 22, wherein the solid composition is heated to a temperature from 60 to 160 °C, preferably from 80 to 140 °C, more preferably from 100 to 120 °C, most preferably about 105 °C.
  • An implantable rod comprising nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a monolith comprising a first excipient and a second excipient, wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
  • PVP polyvinylpyrrolidone
  • PEG polyethylene glycol
  • polyoxypropylene block copolymer polyoxyethylene-polyoxypropylene block copolymer
  • lactose lactose
  • sucrose and
  • a method of producing a microneedle array comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition comprising the steps of: a) dispersing a solid composition according to any one of clauses 1 to 10 and at least one structural polymer in a solvent to form a microneedle precursor dispersion; b) placing the microneedle precursor dispersion into a mould; c) compressing the microneedle precursor dispersion in the mould and then drying to form microneedles comprising the first composition; d) adding a baseplate precursor solution into the mould; e) compressing the baseplate precursor solution and then drying to form the baseplate of the second composition; and f) releasing the microneedle array from the mould.
  • Clause 31 The method of clause 30, wherein steps b) and c) are repeated prior to steps d) to f).
  • Clause 32 The method of clause 30 or clause 31, wherein the solvent is an aqueous solvent, such as water.
  • Clause 33 The method of any of clauses 30 to 32, wherein the at least one structural polymer is selected from PVA, PVP, and combinations thereof.
  • Clause 34 The method of any of clauses 31 to 33, wherein the baseplate precursor solution comprises a base polymer selected from PVP and, optionally, one or more additives such as glycerol, dispersed in an aqueous solvent, such as water.
  • Clause 35 A microneedle array produced by the method of any of clauses 31 to 34.
  • Clause 36 A microneedle array produced by the method of any of clauses 31 to 34.
  • a microneedle array comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition, wherein the first composition comprises nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a monolith comprising a first excipient, a second excipient and at least one structural polymer, 69324247-2 wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
  • PVP polyvinylpyrrolidone
  • Clause 37 The microneedle array of claim 36, wherein the nanoparticles of the Rifamycin, such as Rifapentine, first excipient, and/or second excipient are as defined in any one of clauses 2 to 10.
  • Clause 38 The microneedle array of clause 36 or clause 37, wherein the at least one structural polymer is selected from PVA, PVP, and combinations thereof.
  • Clause 39 The microneedle array of any of clauses 36 to 38, wherein the second composition comprises a base polymer, such as PVP, and, optionally, one or more additives such as glycerol. Clause 40.
  • microneedle array for use according to clause 40 or clause 41, wherein the microneedle array contains a mass of the Rifamycin, such as Rifapentine, in the range of between 0.1 and 20 mg of Rifapentine, preferably between 0.5 and 10 mg, more preferably between 1 and 5 mg, most preferably between 1 and 2 mg. Clause 45.
  • Rifamycin such as Rifapentine
  • a method of treating and/or preventing tuberculosis comprising administering a therapeutically effective amount of a solid composition according to any of clauses 1 to 10, an aqueous dispersion according to any of clauses 14 to 16, a pharmaceutical composition according to clause 18, an injectable formulation according to clause 19 or clause 20, an implantable rod according to any of clauses 27 to 29, or a microneedle array according to any one of clauses 35 to 39, to a patient suffering from or at risk of suffering from tuberculosis.
  • the concentration of the Rifamycin, such as Rifapentine, within the aqueous dispersion, the pharmaceutical composition, or the injectable formulation is 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL.
  • the concentration of the Rifamycin, such as Rifapentine, in the implantable rod is in the range of 40 to 80 wt%, preferably 50 to 70 wt%, most preferably about 60 wt%.
  • the microneedle array contains a mass of the Rifamycin, such as Rifapentine, in the range of between 1 and 20 mg of Rifapentine, preferably between 2 and 10 mg, more preferably about 5 mg.
  • aqueous dispersion, the pharmaceutical composition, the injectable formulation, or the implantable rod forms a depot within the body of the patient, optionally wherein the depot maintains a therapeutically effective concentration of the Rifamycin, such as Rifapentine, within the body of the patient for a period of at least two weeks, preferably at least one more, more preferably at least two months, yet more preferably at least three months, and most preferably at least four months.
  • the Rifamycin such as Rifapentine
  • Clause 55 The use of an implantable rod according to clause 53, wherein the concentration of the Rifamycin, such as Rifapentine, in the implantable rod is in the range of 30 to 80 wt%, preferably 40 to 70 wt%, most preferably about 50 wt%. 69324247-2 Clause 56.
  • microneedle array contains a mass of the Rifamycin, such as Rifapentine, in the range of between 0.1 and 20 mg of Rifapentine, preferably between 0.5 and 10 mg, more preferably between 1 and 5 mg, most preferably between 1 and 2 mg. 69324247-2

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Abstract

The present invention relates to solid compositions comprising nanoparticles of a Rifamycin, such a Rifapentine, dispersed within a matrix comprising a first excipient and a second excipient. The present invention also relates to microneedle arrays, implantable rods, aqueous dispersions, and pharmaceutical compositions derived from said solid compositions and uses for the same.

Description

Rifapentine Compositions The present invention relates to chemical compositions. The invention relates, more particularly, but not exclusively, to chemical compositions for the treatment and prophylaxis of infections, and has particular (but not exclusive) application in the treatment and prophylaxis of bacterial infections, such as tuberculosis. BACKGROUND Tuberculosis is an infectious disease primarily affecting the lungs and is usually caused by the bacterium Mycobacterium tuberculosis. The majority of cases are of latent tuberculosis and those with such an infection are non-symptomatic and non-infectious. A minority of cases, especially prevalent in those who are immunosuppressed, go on to develop symptoms. Accordingly, even though the latent infection provides little risk in itself, the fact that it may progress to active disease warrants treatment of affected individuals. M. tuberculosis is resistant to degradation by macrophages due to a thick capsule that helps protect them from reactive oxygen species within the phagolysosome. In addition, granulomas form which isolate the bacteria, causing them to become dormant, resulting in a latent infection. Public health initiatives prioritise the use of vaccines to limit the risk and spread of tuberculosis. However, these vaccines are not fully effective across the population and their effectiveness wanes over time. Therefore a number of treatment protocols have been developed to address active and latent tuberculosis, generally comprising the administration of antibiotics over an extended period of time. For example, treatment of latent tuberculosis (generally referred to as “tuberculosis prevention”) takes at least one month, and typically takes three to nine months. Due to the lengths of these treatment protocols, it is not uncommon for antibiotic resistance to develop, an issue that is compounded by issues with patient compliance, which may be more common in latent tuberculosis as the patient is not suffering ill effects from the infection itself at the time of treatment. Accordingly, many protocols use combinations of antibiotics in addition to lasting for extended periods. One family of antibiotics that are commonly used in treatments of tuberculosis (both latent and active) are Rifamycins, which also find use in the treatment of leprosy. This family of drugs includes Rifamycin SV, Rifampicin, Rifabutin, Rifapentine, Rifalazil, and Rifaximin. The structure of Rifapentine is reproduced below: 69324247-2 To increase patient compliance, and hence successful treatment of the infection, it would be desirable to provide formulations of these antibiotics that are more efficacious and/or less onerous for the patient. For example, alternative dosage forms and/or reduced dosage frequency. SUMMARY OF THE INVENTION A first aspect of the present invention relates to a solid composition comprising nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a matrix comprising a first excipient and a second excipient, wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene- polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate. The first and second excipients may be selected from the following combinations: ^ PVP and benzalkonium chloride ^ PVP and AOT ^ PVP and Polysorbate 20 ^ PVP and Polysorbate 80 ^ lactose and AOT ^ lactose and poloxamer ^ sucrose and benzalkonium chloride ^ sucrose and AOT ^ sucrose and sorbitan monolaurate ^ sucrose and poloxomer ^ poloxamer and Polysorbate 20 69324247-2 ^ poloxamer and AOT ^ PEG and AOT ^ PEG and poloxamer The first and second excipients may be selected from the following combinations: ^ PVP and AOT ^ lactose and AOT The solid composition may comprise: 10 to 80 wt% of the Rifamycin, such as Rifapentine; 10 to 80 wt% of the first excipient; and 1 to 25 wt% of the second excipient. The solid composition may comprise: 30 to 60 wt% of the Rifamycin, such as Rifapentine; 30 to 60 wt% of the first excipient; and 5 to 20 wt% of the second excipient. The solid composition may comprise: 40 to 50 wt% of the Rifamycin, such as Rifapentine; 40 to 50 wt% of the first excipient; and 5 to 15 wt% of the second excipient. The solid composition may comprise: 30 to 50 wt% of the Rifamycin, such as Rifapentine; 40 to 60 wt% of the first excipient; and 1 to 10 wt% of the second excipient, The solid composition may comprise: 35 to 45 wt% of the Rifamycin, such as Rifapentine; 50 to 60 wt% of the first excipient; and 1 to 5 wt% of the second excipient. The nanoparticles may have a particle diameter in the range of 10 to 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 200 and 800 nm. 69324247-2 The nanoparticles may have a polydispersity less than or equal to 0.8, preferably less than or equal to 0.6, more preferably less than or equal to 0.5. A second aspect of the present invention relates to a process for preparing a solid composition according to the first aspect of the present invention, the process comprising: (a) preparing an oil-in-water emulsion comprising: - an oil phase comprising the Rifamycin, such as Rifapentine; and - an aqueous phase comprising a first and second excipient, each as defined in the first aspect of the present invention; and (b) removing the oil and water from the oil-in-water emulsion to form the solid composition. A third aspect of the present invention relates to a process for preparing a solid composition according to the first aspect of the present invention, the process comprising: (a) providing an active solution comprising the Rifamycin, such as Rifapentine, in a water-miscible solvent; (b) providing a carrier material solution comprising a first and second excipient, each as defined in the first aspect of the present invention; (c) mixing the solutions prepared in steps (a) and (b); and (d) removing the mixed solvent to produce the solid composition or, the process comprising: (a) providing an active solution comprising the Rifamycin, such as Rifapentine, and the second excipient in a water-miscible solvent; (b) providing a carrier material solution comprising a first excipient, each as defined in any of claims 1 to 6; (c) mixing the solutions prepared in steps (a) and (b); and (d) removing the mixed solvent to produce the solid composition. The process of the second aspect of the present invention wherein the step of removing the oil and water from the oil-in-water emulsion, or the process of the third aspect of the present invention, wherein the step of removing the mixed solvent comprises spray drying or freeze-drying. 69324247-2 A fourth aspect of the present invention relates to an aqueous dispersion comprising a plurality of nanoparticles of the Rifamycin, such as Rifapentine, dispersed in an aqueous medium and stabilised by a mixture of a first excipient and a second excipient; wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate. The aqueous dispersion may comprise nanoparticles of the Rifamycin, such as Rifapentine, first excipients, and second excipients as defined in any of claims 2 to 8 in the aqueous medium. The Rifamycin, such as Rifapentine, may be present in the aqueous dispersion at a concentration of 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL. A fifth aspect of the present invention relates to a process for preparing an aqueous dispersion according to the fourth aspect of the present invention, the process comprising dispersing a solid composition according to the first aspect of the present invention in an aqueous medium. A sixth aspect of the present invention relates to a pharmaceutical composition comprising the solid composition of the first aspect of the present invention, or the aqueous dispersion of the fourth aspect of the present invention and, optionally, one or more further pharmaceutically acceptable excipients. A seventh aspect of the present invention relates to an injectable formulation comprising the solid composition of the first aspect of the present invention, the aqueous dispersion of the fourth aspect of the present invention, or the pharmaceutical composition of the sixth aspect of the present invention. The injectable formulation may be a subcutaneously or intramuscularly injectable formulation, optionally wherein the injectable formulation is suitable for provision in depot form. 69324247-2 An eighth aspect of the present invention relates to a method of producing an implantable rod comprising the steps of compressing a solid composition according to the first aspect of the present invention and heating the compressed solid composition for a period of time. The solid composition may be compressed in a mould, optionally the mould being cylindrical in form. The solid composition may be heated to a temperature from 60 to 160 °C, preferably from 80 to 140 °C, more preferably from 100 to 120 °C, most preferably about 105 °C. The compression may occur under a reduced pressure atmosphere. The heating step may take place for a period of from 1 minute to 40 minutes, preferably from 5 minutes 30 minutes, more preferably from 10 minutes to 25 minutes, most preferably about 20 minutes. The method of the eighth aspect of the present invention may further comprise a step of cooling the rod, optionally the cooling taking place under a reduced pressure atmosphere. A ninth aspect of the present invention relates to an implantable rod produced by the method of the eighth aspect of the present invention. A tenth aspect of the present invention relates to an implantable rod comprising nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a monolith comprising a first excipient and a second excipient, wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene- polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate. The nanoparticles of the Rifamycin, such as Rifapentine, first excipient, and/or second excipient may be as defined in the first aspect of the present invention. 69324247-2 An eleventh aspect of the present invention relates to a method of producing a microneedle array comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition, the method comprising the steps of: a) dispersing a solid composition according to any one of claims 1 to 8 and at least one structural polymer in a solvent to form a microneedle precursor dispersion; b) placing the microneedle precursor dispersion into a mould; c) compressing the microneedle precursor dispersion in the mould and then drying to form microneedles comprising the first composition; d) adding a baseplate precursor solution into the mould; e) compressing the baseplate precursor solution and then drying to form the baseplate of the second composition; and f) releasing the microneedle array from the mould. Steps b) and c) may be repeated prior to steps d) to f). The solvent may be an aqueous solvent, such as water. The at least one structural polymer may be selected from PVA, PVP, and combinations thereof. The baseplate precursor solution may comprise a base polymer selected from PVP and, optionally, one or more additives such as glycerol, dispersed in an aqueous solvent, such as water. A twelfth aspect of the present invention relates to a microneedle array produced by the method of the eleventh aspect of the present invention. A thirteenth aspect of the present invention relates to a microneedle array comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition, wherein the first composition comprises nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a monolith comprising a first excipient, a second excipient, and at least one structural polymer, wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block 69324247-2 copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate. The nanoparticles of the Rifamycin, such as Rifapentine, first excipient, and/or second excipient may be as defined in the first aspect of the present invention. The at least one structural polymer may be selected from PVA, PVP, and combinations thereof. The second composition may comprise a base polymer, such as PVP, and, optionally, one or more additives such as glycerol. A fourteenth aspect of the present invention relates to a solid composition according to the first aspect of the present invention, an aqueous dispersion according to the fourth aspect of the present invention, a pharmaceutical composition according to the sixth aspect of the present invention, an injectable formulation according to the seventh aspect of the present invention, an implantable rod according to ninth or tenth aspects of the present invention, or a microneedle array according to the twelfth or thirteenth aspects of the present invention, for use as a medicament. A fifteenth aspect of the present invention relates to a solid composition according to the first aspect of the present invention, an aqueous dispersion according to the fourth aspect of the present invention, a pharmaceutical composition according to the sixth aspect of the present invention, an injectable formulation according to the seventh aspect of the present invention, an implantable rod according to ninth or tenth aspects of the present invention, or a microneedle array according to the twelfth or thirteenth aspects of the present invention, for use in the treatment and/or prevention of tuberculosis, such as latent tuberculosis. An aqueous dispersion, a pharmaceutical composition, or an injectable formulation for use according to the fourteenth or fifteenth aspects of the present invention, wherein the concentration of Rifapentine may be 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL. An implantable rod for use according to the fourteenth or fifteenth aspects of the present invention, wherein the concentration of the Rifamycin, such as Rifapentine, in 69324247-2 the implantable rod may be in the range of 30 to 80 wt%, preferably 40 to 70 wt%, most preferably about 50 wt%. A microneedle array for use according to the fourteenth or fifteenth aspects of the present invention, wherein the microneedle array may contain a mass of the Rifamycin, such as Rifapentine, in the range of between 0.1 and 20 mg of Rifapentine, preferably between 0.5 and 10 mg, more preferably between 1 and 5 mg, most preferably between 1 and 2 mg. A sixteenth aspect of the present invention relates to a method of treating and/or preventing tuberculosis, the method comprising administering a therapeutically effective amount of a solid composition according to the first aspect of the present invention, an aqueous dispersion according to the fourth aspect of the present invention, a pharmaceutical composition according to the sixth aspect of the present invention, an injectable formulation according to the seventh aspect of the present invention, an implantable rod according to ninth or tenth aspects of the present invention, or a microneedle array according to the twelfth or thirteenth aspects of the present invention, to a patient suffering from or at risk of suffering from tuberculosis. In the method of the sixteenth aspect of the present invention, the concentration of the Rifamycin, such as Rifapentine, within the aqueous dispersion, the pharmaceutical composition, or the injectable formulation may be 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL. In the method of the sixteenth aspect of the present invention, the concentration of the Rifamycin, such as Rifapentine, in the implantable rod may be in the range of 40 to 80 wt%, preferably 50 to 70 wt%, most preferably about 60 wt%. In the method of the sixteenth aspect of the present invention,the microneedle array may contain a mass of the Rifamycin, such as Rifapentine, in the range of between 1 and 20 mg of Rifapentine, preferably between 2 and 10 mg, more preferably about 5 mg. In the method of the sixteenth aspect of the present invention, the aqueous dispersion, the pharmaceutical composition, the injectable formulation, or the implantable rod may form a depot within the body of the patient, optionally wherein the depot maintains a 69324247-2 therapeutically effective concentration of the Rifamycin, such as Rifapentine, within the body of the patient for a period of at least two weeks, preferably at least one more, more preferably at least two months, yet more preferably at least three months, and most preferably at least four months. In the method of the sixteenth aspect of the present invention, the microneedle array may gradually release the Rifamycin, such as Rifapentine, optionally wherein the microneedle array maintains a therapeutically effective concentration of the Rifamycin, such as Rifapentine, within the body of the patient for a period of at least 4 hours, preferably at least 6 hours, more preferably at least 12 hours, and most preferably at least 24 hours. In the method of the sixteenth aspect of the present invention, the patient may require dosing with the aqueous dispersion, the pharmaceutical composition, the injectable formulation, or the implantable rod up to three times, preferably up to two times, most preferably only once, to maintain a therapeutically effective concentration of the Rifamycin, such as Rifapentine, for the duration of the treatment. In the method of the sixteenth aspect of the present invention, the patient may require dosing of the microneedle array up to six times per day, preferably up to four times per day, more preferably twice a day, and most preferably once a day, to maintain a therapeutically effective concentration of the Rifamycin, such as Rifapentine, in the patient for the duration of the treatment. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows a plot of Rifapentine concentration in blood plasma obtained from male Sprague Dawley rats over time following intramuscular injection of an aqueous dispersion comprising Rifapentine nanoparticles according to the present invention, as described in Example 6. Fig. 2 shows a plot of Rifapentine concentration in blood plasma obtained from male Sprague Dawley rats over time following implantation of an implant comprising Rifapentine nanoparticles according to the present invention, as described in Example 8. For clarity, the trace for animals provided with two 15 mm implants has the highest concentration of Rifapentine at the end of the experiment, the trace for animals provided with one 15 mm implant had a lower concentration of Rifapentine, and the trace for animals with two 8 mm implants terminated at around 500 hours. 69324247-2 Fig. 3 shows the needle penetration percentage through successive layers of Parafilm® M achieved by microneedles comprising Rifapentine nanoparticles according to the present invention, as described in Example 10. Fig. 4 shows the Rifapentine permeation into the Franz diffusion cell (in µg) achieved by microneedles comprising Rifapentine nanoparticles according to the present invention, as described in Example 11. The higher line, showing a greater mass of Rifapentine permeating, is for a doubly cast microneedle array, whereas the lower line, showing a lesser mass of Rifapentine permeating, is for a singly cast microneedle array. Fig. 5 shows, on the left, the quantity of Rifapentine delivered (in µg) by drug permeation (blue, lower bar) and skin deposition (pink, higher bar) and, on the right, the percentage of Rifapentine delivered by drug permeation (blue, lower bar) and skin deposition (pink, higher bar), by microneedles comprising Rifapentine nanoparticles according to the present invention, as described in Example 11. Fig.6 shows a plot of Rifapentine concentration in blood plasma obtained from female Sprague Dawley rats over time following application of a microneedle array comprising Rifapentine nanoparticles according to the present invention, as described in Example 12. Fig. 7 shows a plot of Rifapentine concentration in blood plasma obtained from male Sprague Dawley rats over time following intramuscular injection of Rifapentine nanoparticles according to the present invention at a dosage of 150 mg/kg, as described in Example 14. Fig. 8 shows a plot of Rifapentine concentration in blood plasma obtained from male Sprague Dawley rats over time following intramuscular injection of Rifapentine nanoparticles according to the present invention at a dosage of 300 mg/kg, as described in Example 14. DEFINITIONS Unless otherwise stated, the term “particle size” is used herein to refer to the Z-average hydrodynamic diameter. Particle size and polydispersity may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron 69324247-2 microscopy). In an embodiment of the invention, particle diameter and polydispersity (i.e. Z-average hydrodynamic diameter) are assessed by dispersing the solid composition in an aqueous medium at a concentration of 1 mg/mL and determining the particle diameter using dynamic light scattering, e.g. using a Malvern Panalytical Limited Zetasizer Ultra. In the context of the present invention, the term nanoparticle may be interpreted broadly to include particles with a particle size that is less than 5 µm, preferably less than 3 µm, or most preferably less than 1 µm. in embodiments, the particle size is in the range of 100 to 800 nm. The term “Rifamycin” refers to antibiotic drugs in the Rifamycin family as well as pharmaceutically acceptable salts, solvates and derivatives thereof, prodrugs thereof, as well as any polymorphic or amorphous forms thereof. Particular Rifamycins are Rifamycin SV, Rifampicin, Rifabutin, Rifapentine (the structure of which is illustrated in the background section), Rifalazil, and Rifaximin. These drugs are typically poorly soluble in water. Unless otherwise stated, the term “patient” includes both human patients and animal patients. The term “SDN” is an abbreviation for the term “solid drug nanoparticles”, used herein to refer to the solid compositions of the present invention. The term “other drugs” is used herein to refer to the following (non-exhaustive) list of other drugs that may be used in combination with the Rifamycins indicated herein and formulated in accordance with the invention in a combination prophylactic and/or treatment therapy: ethambutol, isoniazid, pyrazinamide, streptomycin, aminoglycosides (e.g. amikacin, kanamycin), polypeptides (e.g. capreomycin, viomycin, enviomycin), fluoroquinolones (e.g. ciprofloxacin, levofloxacin, moxifloxacin), thioamides (e.g. ethionamide, prothionamide), cycloserine, terizidone, macrolides (e.g. clarithromycin, linezolid, thioacetazone, thioridazine, arginine, vitamin D, bedaquiline, as well as pharmaceutically acceptable salts, solvates and derivatives thereof, prodrugs thereof, and any polymorphic or amorphous forms thereof. 69324247-2 It is to be appreciated that references to “preventing” or “prevention” relate to prophylactic treatment and includes preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a patient that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition. It will be further appreciated that references to “treatment” or “treating” of a state, disorder or condition includes: (1) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof; or (2) relieving or attenuating the disease, i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. In the context of the invention, the terms “preventing” or “prevention” should not be considered to refer only to medicaments which are completely effective in treating a specific state, disorder or condition, but also to cover medicaments which are partially effective as well. Moreover, when considered from the perspective of a population of patients for treatment, the terms “preventing” and “prevention” should be considered to cover medicaments which are useful at reducing the rate of incidence of a target disorder or condition (e.g. tuberculosis) in that target population, as well as medicaments which are useful at completely eradicating a target state, disorder or condition from that target population. A “therapeutically effective amount” means the amount of a compound that, when administered to a patient for treating and/or preventing a disease, is sufficient to effect such treatment/prevention for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated. The term “consisting essentially of” is used herein to denote that a given product or method consists of only designated materials or steps and optionally other materials or steps that do not materially affect the characteristic(s) of the claimed invention. Suitably, a product which consists essentially of a designated material (or materials) comprises greater than or equal to 85% of the designated material, more suitably 69324247-2 greater than or equal to 90%, more suitably greater than or equal to 95%, most suitably greater than or equal to 98% of the designated material(s). Unless otherwise stated, the weight percentages (“wt%”) discussed herein relate to the % by weight of a particular constituent as a proportion of the total weight of the composition. References herein to a component being “(substantially) immiscible” with another component means that a mixture comprising the two components is unable to form a single phase. Syringeability is a measure of whether a solution, dispersion, or suspension is suitable for administration via injection. A composition is considered to be syringable if it can be manually passed through a 25G needle. It will be understood that the combination of the composition and 25G needle is purely to establish that a given composition is syringable and that the compositions may be used in combination with needles of a lower gauge in practice. As is known in the art, 25G refers to a 25 gauge needle (i.e. a needle with an internal diameter of 0.26 mm and an external diameter of 0.514 mm). Solid Compositions The first aspect of the present invention provides a solid composition comprising nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a solid excipient mixture comprising the first and second excipients. The Rifamycin, such as Rifapentine, which comprises the nanoparticles may be amorphous (i.e. substantially non-crystalline in nature). The solid excipient mixture is in the form of a matrix. In embodiments, the matrix is highly porous in nature and rapidly dissolves on contact with aqueous solutions. In alternative embodiments, the matrix is relatively dense, but still susceptible to dissolution on contact with aqueous solutions. The solid composition of the present invention may be administered as it is to a patient, or further formulated to provide a pharmaceutical composition in the form of, for example, a tablet, capsule, lozenge, or a dispersible powder or granule formulation. In one embodiment, they may be formulated into an implantable rod. 69324247-2 The nanoparticles of the present invention have an average particle diameter of less than 5 micron ( ^m). In a particular embodiment, the nanoparticles have an average particle diameter of between 10 nm and 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 100 and 500 nm. In embodiments, the nanoparticles have a particle diameter in the range of 1 to 1000 nm. It will be understood that references to particle diameter are references to the Z-average hydrodynamic diameter of the nanoparticles. The nanoparticles of the present invention may have a polydispersity less than or equal to 0.8, preferably less than or equal to 0.6, more preferably less than or equal to 0.5. The particle diameter and polydispersity of the nanoparticles may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy). Particle size and polydispersity may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy). In an embodiment of the invention, particle diameter and polydispersity (i.e. Z-average hydrodynamic diameter) are assessed by dispersing the solid composition in an aqueous medium at a concentration of 1 mg/mL and determining the particle diameter using dynamic light scattering, e.g. using a Malvern Panalytical Limited Zetasizer Ultra. The solid composition may comprise particles or granules of larger size, for example, 5 to 30 microns ( ^m) in size, but each particle or granule may contain a plurality of nanoparticles of the Rifamycin, such as Rifapentine, dispersed within a mixture of the first and second excipient. Alternatively, the solid composition may comprise a larger monolith, of any suitable shape or dimension. Furthermore, these monoliths, larger particles or granules disperse when the solid composition is mixed with an aqueous medium to form discrete nanoparticles of the Rifamycin. In an embodiment, the solid composition comprises a first excipient and a second excipient. In an alternative embodiment, the solid composition comprises further excipients selected from those listed herein as suitable first and/or second excipients. In an embodiment, the solid composition consists essentially of the Rifamycin, such as Rifapentine, the first excipient, and the second excipient. In a further embodiment, the solid composition consists of the Rifamycin, such as Rifapentine, the first excipient, and the second excipient. 69324247-2 First Excipient The first excipient is either a hydrophilic polymer or a sugar. In principle, any hydrophilic polymer or sugar suitable for use in pharmaceutical formulations may be employed in the present invention. Particularly suitable polymers include: polyvinylpyrrolidones (including PVP k30, such as is available as KollidonTM 30, PVP k17, such as is available as KollidonTM 17PF, PVP k15, such as is available as PlasdoneTM C-15, and PVP k12, such as is available as KollidonTM 12PF); polyethylene glycols (such as PEG 400, PEG 1000, and PEG 4000); and non-ionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), which are also known as poloxamers (such as those available in the SynperionicsTM, PluronicTM and KolliphorTM ranges, including PluronicTM F68 and PluronicTM F127). It shall be appreciated that any weight average molecular weight (Mw) or number average molecular weight (Mn) values quoted herein may be determined by any suitable method known in the art for the particular polymer. In embodiments, the polyvinylpyrrolidone has a weight average molecular weight of 1000 to 1,000,000 g/mol. In a particular embodiment, the polyvinylpyrrolidone has a weight average molecular weight of 1000 to 40000 g/mol, preferably 2000 to 20000 g/mol. In embodiments, the polyvinylpyrrolidone has a K value between 5 and 30, preferably between 10 and 20, most preferably between 12 and 17. Alternatively the K value may be about 12, about 15, or about 17. As is known in the art, K value is derived from relative viscosity measurements and calculated according to Fikentscher’s equation. A “poloxamer” is a non-ionic triblock copolymer comprising a central hydrophobic chain of polyoxypropylene, and hydrophilic chains of polyoxyethylene either side of this central hydrophobic chain. A “poloxamer” is typically named with the letter “P” followed by three numerical digits (e.g. P407), where the first two digits multiplied by 100 gives the approximate molecular mass of the polyoxypropylene chain, and the third digit multiplied by 10 provides the percentage polyoxyethylene content of the poloxamer. For example, P407 is a poloxamer having a polyoxypropylene molecular mass of about 4,000 g/mol and a polyoxyethylene content of about 70%, while P188 is a poloxamer 69324247-2 having a polyoxypropylene molecular mass of about 1,800 g/mol and a polyoxyethylene content of about 80%. Poloxamers are also known as Pluronics®, as well as by several other commercial names. The poloxamer is suitably a pharmaceutically acceptable poloxamer. In a particular embodiment, the poloxamer is P407 or P188. Polyethylene glycol (PEG) is a polyether containing repeat units of ethylene oxide. PEG may occur in linear, branched, comb, or star forms. Preferably, the PEG is a linear PEG. The PEG may have a number average molecular weight of 100 to 20000 g/mol, preferably 500 to 10000 g/mol, more preferably 1000 to 8000 g/mol, most preferably about 4000 g/mol. Generally, monosaccharides, disaccharides, and oligosaccharides may be suitable in the solid composition of the present invention. Disaccharides are defined as carbohydrates consisting of two monosaccharide residues. Oligosaccharides are defined herein as carbohydrates consisting of between 3 and 10 monosaccharide residues. Monosaccharides may be selected from ribose, arabinose, xylose, lyxose, ribulose, xylulose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, and tagatose. Either of the D- or L- isomers may be used, with the naturally occurring isomer being preferred. Disaccharides may be selected from any binary combination of the above monosaccharides. Preferred disaccharides are lactose and sucrose. Oligosaccharides may be selected from any combination of the above monosaccharides. In the present invention, the first excipient is selected from those hydrophilic polymers and sugars that are capable of stabilising nanoparticles of a Rifamycin, such as Rifapentine, in an aqueous dispersion together with a second excipient as defined herein, and which are also suitable for pharmaceutical use (e.g. they are on the US Food and Drug Administration’s Center for Drug Evaluation and Research (FDA CDER) list of inactive ingredients, especially those indicated as suitable for intramuscular injection). 69324247-2 Second Excipient The second excipient is a surfactant. In principle, any surfactant suitable for use in pharmaceutical formulations may be employed in the present invention. Examples of such surfactants include: (a) non-ionic surfactants (e.g. ethoxylated triglycerides; fatty alcohol ethoxylates; alkylphenol ethoxylates; fatty acid ethoxylates; fatty amide ethoxylates; fatty amine ethoxylates; sorbitan alkanoates; ethylated sorbitan alkanoates; alkyl ethoxylates; Pluronics™; alkyl polyglucosides; stearol ethoxylates; alkyl polyglycosides; sucrose fatty acid esters, anionic, cationic, amphoteric or zwitterionic); (b) anionic surfactants (e.g. alkylether sulfates; alkylether carboxylates; alkylbenzene sulfonates; alkylether phosphates; dialkyl sulfosuccinates; sarcosinates; alkyl sulfonates; soaps; alkyl sulfates; alkyl carboxylates; alkyl phosphates; paraffin sulfonates; secondary n-alkane sulfonates; alpha-olefin sulfonates; isethionate sulfonates; alginates); (c) cationic surfactants (e.g. fatty amine salts; fatty diamine salts; quaternary ammonium compounds; phosphonium surfactants; sulfonium surfactants; sulfonxonium surfactants); or (d) zwitterionic surfactants (e.g. N-alkyl derivatives of amino acids (such as glycine, betaine, aminopropionic acid); imidazoline surfactants; amine oxides; amidobetaines). Particularly suitable surfactants for the present invention may be selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene- polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate. In the present invention, the surfactant is selected from those surfactants that are capable of stabilising nanoparticles of a Rifamycin, such as Rifapentine, in an aqueous dispersion together with a first excipient as defined herein, and which are also suitable for pharmaceutical use (e.g. they are on the US Food and Drug Administration’s Center for Drug Evaluation and Research (FDA CDER) list of inactive ingredients, especially those indicated as suitable for intramuscular injection). Particular Combinations of First and Second Excipients 69324247-2 The first and second excipient may be selected from any of those outlined above. In particular, the first and second excipient may be selected from the following combinations: PVP and benzalkonium chloride; PVP and AOT; PVP and poloxamer; PVP and Polysorbate 20; PVP and Polysorbate 80; PVP and sorbitan monolaurate; PEG and benzalkonium chloride; PEG and AOT; PEG and poloxamer; PEG and Polysorbate 20; PEG and Polysorbate 80; PEG and sorbitan monolaurate; poloxamer and benzalkonium chloride; poloxamer and AOT; are both poloxamer; poloxamer and Polysorbate 20; poloxamer and Polysorbate 80; poloxamer and sorbitan monolaurate; sucrose and benzalkonium chloride; sucrose and AOT; sucrose and poloxamer; sucrose and Polysorbate 20; sucrose and Polysorbate 80; sucrose and sorbitan monolaurate; lactose and benzalkonium chloride; lactose and AOT; lactose and poloxamer; lactose and Polysorbate 20; lactose and Polysorbate 80; lactose and sorbitan monolaurate. The first and second excipient may be the same. It will be understood that, in embodiments wherein both the first excipient and the second excipient are the same (e.g. in the case of poloxamer, listed as both a first and a second excipient), the quantities of the first and second excipients are to be combined to arrive at the quantity of the excipient required Combinations of first and second excipient that are particularly suitable for use in solid compositions comprising nanoparticles of a Rifamycin, such as Rifapentine: ^ PVP and benzalkonium chloride ^ PVP and AOT ^ PVP and Polysorbate 20 ^ PVP and Polysorbate 80 ^ lactose and AOT ^ lactose and poloxamer ^ sucrose and benzalkonium chloride ^ sucrose and AOT ^ sucrose and sorbitan monolaurate ^ sucrose and poloxomer ^ poloxamer and Polysorbate 20 69324247-2 ^ poloxamer and AOT ^ PEG and AOT ^ PEG and poloxamer In embodiments, the combination of first and second excipient that are particularly suitable for use in solid compositions comprising nanoparticles of a Rifamycin, such as Rifapentine, may be selected from: ^ PVP and benzalkonium chloride ^ PVP and AOT ^ PVP and Polysorbate 20 ^ PVP and Polysorbate 80 ^ lactose and AOT ^ lactose and poloxamer ^ sucrose and benzalkonium chloride ^ sucrose and AOT ^ sucrose and sorbitan monolaurate ^ poloxamer and Polysorbate 20 In embodiments, the combination of first and second excipient that are particularly suitable for use in solid compositions comprising nanoparticles of a Rifamycin, such as Rifapentine, may be selected from: ^ PVP and AOT ^ lactose and AOT ^ sucrose and AOT ^ sucrose and poloxomer ^ poloxamer and AOT ^ PEG and AOT ^ PEG and poloxamer Particularly preferred combinations of first and second excipient for use in solid compositions comprising nanoparticles of a Rifamycin, such as Rifapentine, are: ^ PVP and AOT ^ lactose and AOT A most preferred combination of first and second excipient for use in solid compositions comprising nanoparticles of Rifamycin, such as Rifapentine, is PVP and AOT. 69324247-2 Formulations of the Solid Composition In a particular embodiment, the solid composition as described herein may comprise 10 to 95 wt% of a Rifamycin, such as Rifapentine. Preferably, or in another embodiment, the solid composition may comprise 20 to 90 wt% of a Rifamycin, such as Rifapentine. Further preferably, or in another embodiment, the solid composition may comprise 30 to 80 wt% of a Rifamycin, such as Rifapentine, 40 to 70 wt% of a Rifamycin, such as Rifapentine, or 45 to 60 wt% of a Rifamycin, such as Rifapentine. The solid composition comprises 5 to 90 wt% of the first and second excipient combined. In another embodiment, the solid composition comprises 10 to 80 wt% of the first and second excipient combined. In another embodiment, the solid composition comprises 20 to 70 wt% of the first and second excipient combined, 30 to 60 wt% of the first and second excipient combined, or 40 to 55 wt% of the first and second excipient combined. The first and second excipient may be present in a mass ratio in the range of 1:1 to 8:1; preferably about 2:1 to 6:1; more preferably about 4:1 to 5:1. The solid composition may comprise 10 to 80 wt% of the first excipient; preferably 20 to 70 wt% of the first excipient; more preferably 30 to 60 wt% first excipient, most preferably 40 to 50 wt% first excipient. The solid composition may comprise 1 to 25 wt% second excipient; preferably 3 to 20 wt% second excipient; more preferably 5 to 15 wt% second excipient. In another embodiment, the solid composition comprises about 10 wt% second excipient. In a particular embodiment, the solid composition comprises 10 to 80 wt% of a Rifamycin, such as Rifapentine; 10 to 80 wt% first excipient; and 1 to 25 wt% second excipient. Preferably, the solid composition comprises 30 to 60 wt% of a Rifamycin, such as Rifapentine; 30 to 60 wt% first excipient; and 5 to 20 wt% second excipient. More preferably, the solid composition comprises 40 to 50 wt% of a Rifamycin, such as Rifapentine; 40 to 50 wt% first excipient; and 5 to 15 wt% second excipient. Alternatively, the solid composition comprises 20 to 60 wt% of a Rifapentine, such as Rifamycin; 30 to 70 wt% first excipient; and 1 to 10 wt% second excipient. Preferably, the solid composition comprises 30 to 50 wt% of a Rifapentine, such as Rifamycin; 50 to 60 wt% first excipient; and 2 to 5 wt% second excipient. More preferably, the solid 69324247-2 composition comprises about 40 wt% of a Rifapentine, such as Rifamycin; about 57 wt% first excipient; and about 3 wt% second excipient. Unless otherwise stated, the above weight percentages relate to the % by weight of a particular constituent as a proportion of the total weight of the solid composition. The solid composition may comprise additional excipients, for instance, to further facilitate dispersion or stabilisation of dispersions of the nanoparticles in an aqueous medium, a pharmaceutically acceptable diluent or in vivo. Processes for Preparing Solid Compositions Solid compositions of the present invention may be prepared by a number of methods well known in the art, including ‘top-down’ physical methods such as nano (or bead) milling and high pressure homogenisation. Other suitable techniques for forming such compositions are described in general terms in Horn and Reiger, Angew. Chem. Int. Ed., 2001, 40, 4330-4361. In one preferred approach, the solid compositions of the present invention are prepared by an oil-in-water emulsion technique whereby the Rifamycin, such as Rifapentine, is dissolved in the oil phase and the first and second excipients are present in the water phase. The oil and water solvents are then removed by freeze drying, spray drying or spray granulation to provide a solid composition according to the invention. Thus, in accordance with one aspect of the present invention, there is provided a general process for preparing a solid composition comprising nanoparticles of a Rifamycin, such as Rifapentine, as defined herein, the process comprising: (a) preparing an oil-in-water emulsion comprising: - an oil phase comprising a Rifamycin, such as Rifapentine; and - an aqueous phase comprising a first excipient and a second excipient, each as defined herein; and (b) removing the oil and water from the oil-in-water emulsion to form the solid composition. An advantage of the processes of the present invention is that the emulsions formed in the initial steps are sufficiently homogenous and stable to allow for effective and uniform drying upon removal of the oil and water. Furthermore, the nanoparticles formed are substantially uniform in their physical form (size, shape etc.). 69324247-2 The oil-in-water formation steps may be performed by methods well-known in the art. Any suitable method for forming the oil-in-water emulsions may therefore be used. In particular, mixing of the oil and water phases to form the oil-in-water emulsion may be performed by methods well known in the art. For example, the mixing may involve stirring, sonication, homogenisation, or a combination thereof. In a particular embodiment, the mixing is facilitated by sonication and/or homogenisation. The oil-in-water formation steps may be performed, for example, by using the methods described in WO 2004/011537 A1 (COOPER et al), which is hereby duly incorporated by reference. In a particular embodiment, oil-in-water emulsion formation comprises: (i) providing an oil phase comprising a Rifamycin, such as Rifapentine; (ii) providing an aqueous phase comprising the first excipient and second excipient; and (iii) mixing the oil phase and aqueous phase to produce the oil-in-water emulsion. Suitably, the oil phase is provided by dissolving the Rifamycin, such as Rifapentine, in a suitable organic solvent. Suitably, the aqueous phase is provided by dissolving first excipient and second excipient in an aqueous medium, preferably in water. Alternatively the aqueous phase may be provided by mixing two separately prepared aqueous solutions of the first excipient and second excipient. In a particular embodiment, further aqueous medium (e.g. water) or organic solvent is added before or during mixing step (iii). The concentration of the Rifamycin, such as Rifapentine, in the oil-in-water emulsion is suitably as concentrated as possible to facilitate effective scale-up of the process. For example, the concentration of the Rifamycin, such as Rifapentine, in the oil phase is suitably 20 mg/ml or higher, more suitably 30 mg/ml or higher, even more suitably 40 mg/ml or higher, most suitably greater than 50 mg/ml. The concentration of the first excipient in the aqueous phase is suitably 1 to 50 mg/mL, more suitably 2 to 30 mg/mL, even more suitably 5 to 20 mg/mL. 69324247-2 The concentration of the second excipient in the aqueous phase is suitably 0.1 to 25 mg/mL, more suitably 0.2 to 10 mg/mL, even more suitably 0.5 to 5 mg/mL. The mass ratio of the first excipient to second excipient in the aqueous phase may be in the range of 9:1 to 1:1; preferably in the range of 7:1 to 2:1, more preferably in the range of 6:1 to 3:1. The organic solvent forming the oil phase is (substantially) immiscible with water. Suitably the organic solvent is aprotic. Suitably the organic solvent has a boiling point less than 120°C, suitably less than 100°C, suitably less than 90°C. In a particular embodiment, the organic solvent is a selected from the Class 2 or 3 solvents listed in the International Conference on Harmonization (ICH) guidelines relating to residual solvents. In a particular embodiment, the organic solvent is selected from chloroform, dichloromethane, dichloroethane, tetrachloroethane, cyclohexane, hexane(s), isooctane, dodecane, decane, methylbutyl ketone (MBK), methylcyclohexane, tetrahydrofuran, toluene, xylene, butyl acetate, mineral oil, tert-butylmethyl ether, heptanes(s), isobutyl acetate, isopropyl acetate, methyl acetate, methylethyl ketone, ethyl acetate, ethyl ether, pentane, and propyl acetate, or any suitably combination thereof. In a particular embodiment, the organic solvent is chloroform. The organic solvent may include a cosolvent. The cosolvent may be selected from C1 to C4 alcohols (such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, sec- butanol, and iso-butanol) and C5 to C7 alkanes (such as pentane, hexane, and heptane). The oil phase may comprise between 1 and 40 v/v% of the oil-in-water emulsion. Preferably, the oil phase comprises between 10 and 35 v/v% of the oil-in-water emulsion, most preferably between 15 and 30 v/v% of the oil-in-water emulsion. In an embodiment, the oil phase comprises about 25 v/v% of the oil-in-water emulsion. 69324247-2 Mixing step (iii) suitably produces a substantially uniform oil-in-water emulsion. As previously indicated, mixing may be performed using methods well known in the art. Suitably, mixing step (iii) involves stirring, sonication, homogenisation, or a combination thereof. In a particular embodiment, mixing step (iii) involves sonication and/or homogenisation. Removing the oil and water may be performed using methods well known in the art. Suitably removing the oil and water involves freeze drying, spray drying or spray granulation. Removing the oil and water may be performed using methods described in WO 2004/011537 A1 (COOPER et al), the entire contents of which are hereby incorporated by reference. In a particular embodiment, removing the oil and water involves freeze drying the oil-in- water emulsion. As such, removing the oil and water may suitably comprise freezing the oil-in-water emulsion and then removing the solvents under vacuum. Preferably, the freezing of the oil-in-water emulsion may be performed by externally cooling the oil-in-water emulsion. For example, a vessel containing the oil-in-water emulsion may be externally cooled, for example, by submerging the vessel in a cooling medium, such as liquid nitrogen. Alternatively, the vessel containing the oil-in-water emulsion may be provided with an external “jacket” through which coolant is circulated to freeze the oil-in-water emulsion. Alternatively, the vessel may comprise an internal element through which coolant is circulated in order to freeze the oil-in-water emulsion. In a further alternative, the oil-in-water emulsion is frozen by being contacted directly with a cooling medium at a temperature effective for freezing the emulsion. In such cases, the cooling medium (e.g. liquid nitrogen) may be added to the oil-in-water emulsion, or the oil-in-water emulsion may be added to the cooling medium. In a particular embodiment, the oil-in-water emulsion is added to the fluid medium (e.g. liquid nitrogen), suitably in a dropwise manner. This order of addition provides higher purities of final product. As such, frozen droplets of the oil-in-water emulsion may suitably form. Such frozen droplets may suitably be isolated (e.g. under vacuum to remove the fluid medium/liquid nitrogen). The solvent is then suitably removed from the frozen droplets under vacuum. The resulting solid composition is then isolated. 69324247-2 It is preferred that the oil and water are removed by spray drying as this removes the need to freeze the oil-in-water emulsion, with the nanoparticulate nature of the solid composition being retained through the rapid nature of the solvent evaporation. In another preferred approach, the solid compositions of the present invention are prepared by a nanoprecipitation technique whereby the Rifamycin, such as Rifapentine, is dissolved in a water-miscible solvent and the first and second excipients are dissolved in water. The two solutions are combined to effect precipitation of the Rifamycin, such as Rifapentine, as nanoparticles. The general procedure for such a preparation of the solid composition is as follows: (a) providing an active solution comprising the Rifamycin, such as Rifapentine in a water-miscible solvent; (b) providing a carrier material solution comprising the first and second excipients; (c) mixing the solutions prepared in steps (a) and (b); and (d) removing the mixed solvent to produce the solid composition. The solutions are typically provided by dissolving the Rifamycin, such as Rifapentine in the water-miscible solvent and by dissolving the first and second excipients in the aqueous solvent. The Rifamycin, such as Rifapentine, first excipient, and second excipient are drawn from those described for the solid composition. An alternative procedure, for preparation of the solid composition is as follows: (a) providing an active solution comprising the Rifamycin, such as Rifapentine, and second excipient in a water-miscible solvent; (b) providing a carrier material solution comprising the first excipient; (c) mixing the solutions prepared in steps (a) and (b); and (d) removing the mixed solvent to produce the solid composition. The solutions are typically provided by dissolving the Rifamycin, such as Rifapentine, and the second excipient in the water-miscible solvent and by dissolving the first excipient in the aqueous solvent. The Rifamycin, such as Rifapentine, first excipient, such as PVP, and second excipient, such as AOT, are drawn from those described for the solid composition. Any water-miscible solvent that is capable of dissolving the Rifamycin, such as Rifapentine in the required concentrations may be used to process it. Suitable water- 69324247-2 miscible solvents are acetone, propanone, butanone, butanol, dimethylsulfoxide (DMSO), dimethylformamide (DMF), ethanol, methanol, propanol and mixtures thereof. Particularly suitable solvents are methanol, acetone/ethanol mixtures, acetone/methanol mixtures, and butanone/ethanol mixtures. Acetone/ethanol mixtures may be in any suitable ratio. Preferred volume ratios are in the range of 90/10 to 10/90, in the range of 70/30 to 30/70, or 50/50. Acetone/ethanol mixtures may be in any suitable ratio. Preferred volume ratios are in the range of 90/10 to 10/90, in the range of 70/30 to 30/70, or 50/50. Butanone/ethanol mixtures may be in any suitable ratio. Preferred volume ratios are in the range of 90/10 to 10/90, in the range of 70/30 to 30/70, or 50/50. The Rifamycin, such as Rifapentine, may be present in a concentration of at least 20 mg/mL, preferably at least 30 mg/mL, more preferably at least 40 mg/mL, most preferably at least 50 mg/mL. The aqueous solvent is typically deionised water. The first excipient may be present in the carrier material solution in a concentration of from 1 to 40 mg/mL, preferably from 5 to 30 mg/mL, more preferably from 10 to 20 mg/mL. The second excipient may be present in the carrier material solution in a concentration of from 0.5 to 20 mg/mL, preferably from 1 to 10 mg/mL, more preferably in a concentration of from 2 to 5 mg/mL. The solution of the Rifamycin, such as Rifapentine, and the solution of the first and second excipients are mixed in a volume ratio in the range of 1:15 and 1:1, preferably in the range of 1:9 and 3:4. Preferably the volume ratio is in the range of 1:6 to 1:2, such as about 1:4. After mixing, the total solids content (i.e. the sum of the Rifamycin, such as Rifapentine, and the first and second excipients in the mixed solvent) may be in the range of 1 to 40 mg/mL, preferably 2 to 30 mg/mL, further preferably 5 to 25 mg/mL, most preferably 10 to 20 mg/mL. Alternatively, the total solids content may be about 15 mg/mL. The solutions may be mixed by any suitable method. Typically, a rotary stirring system is used, such as a magnetic or overhead stirrer. The pharmaceutically active compound has a reduced solubility in the mixed solvent system, resulting in a supersaturated solution. The pharmaceutically active compound consequently precipitates from the solution, producing nanoparticles that are stabilised by the carrier materials. The mixing may be instantaneous, or it may take place over a time period. The latter may be achieved through the use of a pump, such as a peristaltic pump, 69324247-2 operating at a rate of 1 to 120 mL/min, preferably at a rate of 20 to 100 mL/min, more preferably at a rate of 40 to 80 mL/min, most preferably at a rate of about 60 mL/min. It may be beneficial to homogenise the mixed solutions to reduce the incidence of aggregation and promote homogeneity in particle size. Any suitable homogeniser may be used, such as a rotary homogeniser or microniser. Similarly, it may be beneficial to sonicate the mixed solutions. Any suitable sonicator may be used, such as a probe sonicator. In some embodiments, the active solution is heated to increase the solubility of the pharmaceutically active compound therein, allowing higher concentrations to be used and increasing the degree of supersaturation on mixing with the carrier material solution, particularly as the carrier material solution is maintained at ambient temperature (approximately 25°C). Any suitable temperature may be used, for example 30 to 90°C, 40 to 80°C, 50 to 70°C, or about 60°C. Any suitable method of removing the mixed solvent may be used, on the condition that it does not provide the nanoparticles with the opportunity to aggregate. This may be achieved by either removing the solvent extremely rapidly, or by rapidly solidifying the dispersion and subliming the solid solvent (e.g. lyophilisation). The former method is preferred, utilising spray-drying or spray-granulating techniques, due to their high throughput and acceptability in pharmaceutical applications. It will be understood that the parameters of spray-drying and spray-granulation processes, such as flow rate and temperature, may be varied to achieve effective drying and attain the desired powdery and granular products. If required, the resulting solid may be subjected to further drying procedures, such as being dried in vacuo, to remove any residual solvents. The present invention also provides a solid composition obtainable by, obtained by, or directly obtained by any of the processes described herein. Aqueous Dispersions The present invention also provides an aqueous dispersion, obtainable by, obtained by, or directly obtained by dispersing the solid composition as defined herein in an aqueous medium. When the solid composition is dispersed in the aqueous medium, the first and second excipients are dissolved within the aqueous medium to release the nanoparticles of the 69324247-2 Rifamycin, such as Rifapentine, in a dispersed form. The nanoparticles of the Rifamycin, such as Rifapentine, which were formerly dispersed within a solid mixture of the first and second excipients, then becomes dispersed within the aqueous medium and are stabilized by the first and second excipients, thereby preventing premature coagulation and aggregation. In a particular embodiment, the aqueous medium comprises 20 to 99.5 wt% of the total aqueous dispersion. In a particular embodiment, the aqueous medium comprises 50 to 98 wt% of the total aqueous dispersion. In a particular embodiment, the aqueous medium comprises 70 to 95 wt% of the total aqueous dispersion. Suitably, the remaining proportion of the aqueous dispersion consists essentially of the Rifamycin, such as Rifapentine, first excipient, and second excipient, whose proportions within the aqueous dispersion as a whole are accordingly calculated (and scaled) by reference to the proportions recited in relation to the solid composition. For aqueous dispersions of nanoparticles of the Rifamycin, such as Rifapentine, the concentration of the Rifamycin may be at least 100 mg/mL, preferably at least 200 mg/mL, more preferably at least 300 mg/mL, and most preferably at least 500 mg/mL. Alternatively, the concentration of the Rifamycin may be 100 to 1000 mg/mL, preferably 150 to 800 mg/mL, more preferably 200 to 600 mg/mL, yet more preferably 250 to 500 mg/mL and most preferably 300 to 400 mg/mL. In a particular embodiment, the aqueous medium is water. In an alternative embodiment, the aqueous medium comprises water and one or more additional pharmaceutically acceptable diluents or excipients. In particular embodiments, the aqueous medium comprises saline or a phosphate buffered saline (PBS). The nanoparticles may have an average particle diameter of less than 5 micron ( ^m). In a particular embodiment, the nanoparticles have an average particle diameter of between 10 nm and 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 100 and 500 nm. In embodiments, the nanoparticles have a particle diameter in the range of 1 to 1000 nm. It will be understood that references to particle diameter are references to the Z-average hydrodynamic diameter of the nanoparticles. 69324247-2 The nanoparticles may have a polydispersity less than or equal to 0.8, preferably less than or equal to 0.6, more preferably less than or equal to 0.5. The particle diameter and polydispersity of the nanoparticles may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy). Particle size and polydispersity may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy). In an embodiment of the invention, particle diameter and polydispersity (i.e. Z-average hydrodynamic diameter) are assessed by dispersing the solid composition in an aqueous medium at a concentration of 1 mg/mL and determining the particle diameter using dynamic light scattering, e.g. using a Malvern Panalytical Limited Zetasizer Ultra. The aqueous dispersion may be used in the formulation of a microneedle array, for example, a microneedle array as is described later in this document. Process for preparing an aqueous dispersion The present invention provides a process for preparing an aqueous dispersion, the process comprising dispersing a solid composition as defined herein in an aqueous medium. In a particular embodiment, the aqueous medium is water. In an alternative embodiment, the aqueous medium comprises water and one or more additional excipients. In particular embodiments, the aqueous medium comprises saline or a phosphate buffered saline (PBS). Dispersing the solid composition in the aqueous medium may comprise adding the solid composition to an aqueous medium (or visa versa) and suitably agitating the resulting mixture (e.g. by shaking, homogenisation, sonication, stirring, etc.). Pharmaceutical compositions The present invention provides a pharmaceutical composition comprising a solid composition or an aqueous dispersion as defined herein. The pharmaceutical compositions of the present invention may further comprise one or more additional pharmaceutically acceptable excipients. The solid compositions of the invention may be formulated into a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, or dispersible powders or 69324247-2 granules) by techniques known in the art. As such, the solid compositions of the invention may be mixed with one or more additional pharmaceutical excipients during this process, such as antiadherants, binders, coatings, enterics, disintegrants, fillers, diluents, flavours, colours, lubricants, glidants, preservatives, sorbents, and sweeteners. In a particular embodiment, the pharmaceutical composition is a tablet or capsule comprising the solid composition. The aqueous dispersion of the present invention may be administered as it is or further formulated with one or more additional excipients to provide a dispersion, elixir or syrup that is suitable for oral use, or a dispersion that is suitable for parenteral administration (for example, a sterile aqueous dispersion for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing). In a particular embodiment, the pharmaceutical composition is an aqueous dispersion as described herein. Such dispersed formulations can be used to accurately measure smaller dosages, such as those suitable for administration to children. In a particular embodiment, the pharmaceutical composition is in a form suitable for parenteral delivery, whether via subcutaneous or intramuscular delivery. It will be appreciated that different pharmaceutical compositions of the invention may be obtained by conventional procedures, using conventional pharmaceutical excipients, well known in the art. The pharmaceutical compositions of the invention contain a therapeutically effective amount of the Rifamycin, such as Rifapentine. A person skilled in the art will know how to determine and select an appropriate therapeutically effective amount of the Rifamycin, such as Rifapentine, to include in the pharmaceutical compositions of the invention. Injectable formulations The present invention provides an injectable formulation comprising the solid composition as described herein, the aqueous dispersion as described herein, or the pharmaceutical composition as described herein. In embodiments, the injectable 69324247-2 formulation is intramuscularly injectable. In other embodiments, the injectable formulation is subcutaneously injectable. Said formulations may be in solid form (or substantially solid form, e.g. a paste) or liquid form or semi-solid form, in which the Rifamycin, such as Rifapentine, is present in the form of nanoparticles. The nanoparticles of a Rifamycin, such as Rifapentine, may be dispersed within one or more carrier materials. When in liquid form, each nanoparticle of the Rifamycin, such as Rifapentine, is stabilised by the first and second excipients. Long Acting Injectable Formulations The present invention provides a long acting injectable formulation comprising the aqueous dispersion as described herein, or the pharmaceutical composition as described herein. The long acting injectable formulation may be intramuscularly injectable or it may be subcutaneously injectable. The long acting injectable formulation may, in addition to the nanoparticles of a Rifamycin, such as Rifapentine, and the aqueous medium, further comprise one or more additional pharmaceutically acceptable excipients, such as thickeners, preservatives, and stabilizers. The injectable formulations of nanoparticles of a Rifamycin, such as Rifapentine, may be long acting injectable formulations. Such formulations are advantageously designed for administration as an intramuscular or a subcutaneous injection that forms a depot at the site of the injection. Long acting injectable formulations improve adherence to prophylaxis and/or treatment, especially in respect of viral illnesses which require extended treatment durations, such as tuberculosis, and the consequences that ensue. Furthermore, a depot injection is beneficial in that it may be easier to administer than conventional preparations and allows for simpler follow-up / on-going care. The long acting injectable formulations of the present invention permit the formation of a depot of nanoparticles of a Rifamycin, such as Rifapentine, as these drugs are poorly soluble in aqueous media, preventing them from rapidly exiting the depot and entering the bloodstream of the patient. Generally, long acting injectable formulations are administered intramuscularly or subcutaneously to certain sites, such as the deltoid, dorsogluteal, ventrogluteal, vastus lateralis, and rectus femoris muscles. Each site has a limit on the maximum volume that may be injected without prompting excessive discomfort in the patient or losing effectiveness. The maximum volume, even for the 69324247-2 larger sites, is generally only as high as 3 mL. The administration also takes longer than a standard injection, typically taking 10 seconds to administer 1 mL. This limitation on the number of suitable sites and volumes permitted in each means that it is important for the long acting injectable formulations to contain high concentrations of the Rifamycin, such as Rifapentine, so as to minimise the volume (and hence number and duration of injections) required to provide a depot capable of releasing a therapeutically effective amount of the Rifamycin. In addition, without wishing to be bound by theory, the Rifamycin, such as Rifapentine, is thought to be released from the depot at a rate defined by its physicochemical properties (e.g. solubility controlling the rate at which each the Rifamycin dissolves from the surface of the nanoparticles) and the local physiological environment. There is, therefore, a minimum concentration of the Rifamycin that must be present in the depot in order to ensure that, as the Rifamycin is released at the rate defined by its physicochemical properties and local physiological environments (which may themselves be further influenced by the introduction of the depot, e.g. through formulation of a granuloma around the depot), the amount that is released is a therapeutically effective amount (i.e. the concentration of the Rifamycin in the formulation must be sufficient to produce a therapeutically effective concentration of the Rifamycin in vivo). Furthermore, the therapeutically effective amount of the Rifamycin must be maintained for the duration of the treatment, meaning that the depot must contain all of the Rifamycin required for the duration of the treatment. For long acting injectable formulations of nanoparticles of a Rifamycin, such as Rifapentine, the concentration of the Rifamycin may be at least 150 mg/mL, preferably at least 200 mg/mL, more preferably at least 300 mg/mL, and most preferably at least 500 mg/mL. Alternatively, the concentration of the Rifamycin, such as Rifapentine, may be 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL. Preferably, the Rifamycin, such as Rifapentine, is released into the bloodstream of the patient from the depot of nanoparticles of the Rifamycin at a controlled rate such that a therapeutically effective amount of the Rifamycin is achieved over a period of at least about two weeks from the date of administration. Further preferably the therapeutically effective amount of the Rifamycin is achieved for at least about three weeks, more 69324247-2 preferably at least about one month, most preferably at least about two months from the date of administration of the injection. Implantable Rods The present invention provides implantable rods comprising nanoparticles of a Rifamycin, such as Rifapentine, dispersed in a monolith of the first excipient and the second excipient. The Rifamycin, such as Rifapentine, which comprises the nanoparticles may be amorphous (i.e. substantially non-crystalline in nature). The nanoparticles of the present invention have an average particle diameter of less than 5 micron ( ^m). In a particular embodiment, the nanoparticles have an average particle diameter of between 10 nm and 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 100 and 500 nm. In embodiments, the nanoparticles have a particle diameter in the range of 1 to 1000 nm. It will be understood that references to particle diameter are references to the Z-average hydrodynamic diameter of the nanoparticles. The nanoparticles of the present invention may have a polydispersity less than or equal to 0.8, preferably less than or equal to 0.6, more preferably less than or equal to 0.5. The particle diameter and polydispersity of the nanoparticles may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy). Particle size and polydispersity may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy). In an embodiment of the invention, particle diameter and polydispersity (i.e. Z-average hydrodynamic diameter) are assessed by dispersing the solid composition in an aqueous medium at a concentration of 1 mg/mL and determining the particle diameter using dynamic light scattering, e.g. using a Malvern Panalytical Limited Zetasizer Ultra. The monolith of the first excipient and second excipient is non-porous in nature. The first excipient may be as described for the solid composition of the present invention. In embodiments, the first excipient is selected from polyvinylpyrrolidone 69324247-2 (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose. The second excipient may be as described for the solid composition of the present invention. In embodiments, the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate. The first and second excipients may be used in any combination as described for the solid composition of the present invention. The relative quantities of the Rifapentine, such as Rifamycin, first excipient, and second excipient may be as described herein for the solid composition of the present invention. The implantable rod is suitable for implantation into a patient (e.g. subcutaneously). The rods may be of any suitable shape or dimension for implantation. In embodiments, the rods are cylindrical. The length of the rods may be between 1 and 100 mm, preferably between 1 and 80 mm, more preferably between 2 and 50 mm, yet more preferably between 5 and 40 mm, and most preferably between 10 and 20 mm. The diameter of the rods may be between 0.1 and 5 mm, preferably between 0.5 and 2.5 mm, more preferably between 1 and 2 mm. Processes for Preparing Implantable Rods Implantable rods may be prepared by any suitable process for the conversion of fine thermoplastic solids to cohered monoliths, such as injection moulding, extruding and other such methods known to those skilled in the art. One suitable method comprises compressing the solid compositions of the first aspect of the present invention while heating in order to collapse the porous matrix of first and second excipient and to cohere discrete particles to form the monolith. Removing the porosity increases the density of the composition, making it easier to handle and making it viable to insert the composition as an implant. This also increases the time taken to dissolve the composition. Without wishing to be bound by theory, it is the experience of the inventors that the nanoparticulate nature of active compounds, such as Rifamycins like Rifapentine, is retained in the implantable rods following conversion. Using the solid compositions of the present invention to produce the implants makes higher 69324247-2 concentrations of the Rifamycin accessible, while also retaining the highly dispersible nature of the nanoparticle formulation. The compressive force may be applied under a reduced pressure atmosphere (e.g. a vacuum). Doing so assists in the removal of any remaining volatile substances, such as solvents, and reduces the incidence of bubbles by removing any gas that is entrained in the solid composition. Certain apparatus may also use the pressure differential to apply the compressive force to the solid composition. Heating the compressed solid composition requires increasing the temperature of the solid composition such that discrete volumes of the first and second excipients cohere under the pressure of the compression step. However, the temperature must be below that which would deteriorate the Rifamycin, such as Rifapentine. The compressed solid composition may be heated to a temperature from 60 to 160 °C, preferably from 80 to 140 °C, more preferably from 100 to 120 °C, most preferably about 105 °C. The elevated temperature is maintained for a period of from 1 minute to 40 minutes, preferably from 5 minutes to 30 minutes, more preferably from 10 minutes to 25 minutes, most preferably about 20 minutes. The compressive force and/or vacuum is preferably maintained during the heating step. Any suitable means may be used to supply heat for the heating step. For example, an electrical heater, such as a hotplate. Optionally, following the heating step, the rod may be cooled. For example, through contact with a cold surface. Microneedle Arrays The present invention provides microneedle arrays comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition, wherein the first composition comprises nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a monolith comprising a first excipient, a second excipient and at least one structural polymer. By using nanoparticles of a Rifamycin, such as Rifapentine, especially those present in the solid composition of the present invention, higher loadings of the water-insoluble drugs may be obtained, while also retaining their highly dispersible nature. The Rifamycin, such as Rifapentine, which comprises the nanoparticles may be amorphous (i.e. substantially non-crystalline in nature). 69324247-2 The nanoparticles of the present invention have an average particle diameter of less than 5 micron ( ^m). In a particular embodiment, the nanoparticles have an average particle diameter of between 10 nm and 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 100 and 500 nm. In embodiments, the nanoparticles have a particle diameter in the range of 1 to 1000 nm. It will be understood that references to particle diameter are references to the Z-average hydrodynamic diameter of the nanoparticles. The nanoparticles of the present invention may have a polydispersity less than or equal to 0.8, preferably less than or equal to 0.6, more preferably less than or equal to 0.5. The particle diameter and polydispersity of the nanoparticles may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy). Particle size and polydispersity may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy). In an embodiment of the invention, particle diameter and polydispersity (i.e. Z-average hydrodynamic diameter) are assessed by dispersing the solid composition in an aqueous medium at a concentration of 1 mg/mL and determining the particle diameter using dynamic light scattering, e.g. using a Malvern Panalytical Limited Zetasizer Ultra. The monolith of the first excipient and second excipient is non-porous in nature. The first excipient may be as described for the solid composition of the present invention. In embodiments, the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose. The second excipient may be as described for the solid composition of the present invention. In embodiments, the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate. In principle, any hydrophilic polymer suitable for use in pharmaceutical formulations may be employed as a structural polymer, for example, the polymers that are suitable as first excipients. In embodiments, the structural polymer is selected to be the same as a first excipient, as this helps to ensure compatibility. In embodiments, the structural 69324247-2 polymer is selected from PVA, PVP, and combinations thereof. Polymers with MW below 60 kDa (for example, PVA with MW of 9-10 and PVP with MW of 58 kDa) are preferred as they are known to be swiftly eliminated from the human body via renal excretion. The purpose of the structural polymer is to provide the microneedles with sufficient mechanical strength to enable insertion into skin and consequent delivery of the Rifamycin, such as Rifapentine. The relative quantities of the Rifamycin, such as Rifapentine, first excipient, and second excipient may be as described herein for the solid composition of the present invention. The ratio of the Rifamycin, first excipient, and second excipient to the structural polymer may be in the range of 10 to 80 wt% of a Rifamycin, such as Rifapentine; 10 to 80 wt% first excipient; and 1 to 25 wt% second excipient. Preferably, the solid composition comprises 30 to 60 wt% of a Rifamycin, such as Rifapentine; 30 to 60 wt% first excipient; and 5 to 20 wt% second excipient. More preferably, the solid composition comprises 40 to 50 wt% of a Rifamycin, such as Rifapentine; 40 to 50 wt% first excipient; and 5 to 15 wt% second excipient. The baseplate comprises a base polymer. In principle, any hydrophilic polymer suitable for use in pharmaceutical formulations may be employed as a base polymer, for example, the polymers that are suitable as first excipients. In embodiments, the base polymer is selected to be the same as a first excipient and/or structural polymer. In embodiments, the base polymer is PVP. Typically, the base polymer will comprise high molecular weight polymer, such as PVP with a MW of 360 kDa, to impart a degree of rigidity to the base plate. The base plate may further comprise one or more additives to improve the properties of the base plate, for example, a low molecular weight polyol, such as glycerol, may reduce brittleness of the base plate. If present, the additive and base polymer are used in a mass ratio from 1 : 40 to 1: 10, preferably a mass ratio of 1 : 30 to 1 :15, more preferably a mass ratio of about 1 : 20. The relative quantities of first composition and second composition is determined by the physical dimensions of the microneedles relative to the base plate, with the majority of the microneedle volume comprising first composition and the remaining microneedle volume and base plate volume comprising second composition. In embodiments, at least 50% of the microneedle volume comprises first composition, preferably at least 60%, further preferably at least 80 %, more preferably at least 90%, most preferably substantially all of the microneedle volume comprises first composition. 69324247-2 By control of the loading of the Rifamycin, such as Rifapentine, and the dimensions of the microneedle array, the microneedle array may be designed to contain substantially any suitable amount of the Rifamycin, such as Rifapentine. In embodiments, the microneedle array contains between 0.1 and 20 mg of the Rifamycin, such as Rifapentine, preferably between 0.5 and 10 mg, more preferably between 1 and 5 mg, most preferably between 1 and 2 mg. The dimensions of the microneedles and microneedle array are determined by the mould used in their production and can have substantially and suitable dimension. The heights of the microneedles may be in the range of 50 to 1000 µm, preferably in the range of 500 to 900 µm. The base width of the microneedles may be in the range of 50 to 500 µm, preferably in the range of 100 to 300 µm. The interspacing between the needles may be in the range of 50 to 200 µm, preferably about 100 µm. The area microneedle array may be in the range of 0.1 to 100 cm2, preferably in the range of 0.5 to 30 cm2. The microneedle array may comprise between 2 and 2000 microneedles. Typically, the microneedles are arrayed in a grid, but substantially any arrangement may be used. The needles of the microneedle array may be of any suitable geometry. For example, they may be conical, frustoconical, cylindrical, cuboid, obelisk, square-based pyramid, pentagonal-based pyramid, arrowhead, and so on. Processes for Preparing Microneedle Arrays Microneedle arrays may be prepared by any suitable process known to those skilled in the art. One suitable method comprises the steps of: a) dispersing a solid composition according to the present invention and at least one structural polymer in a solvent to form a microneedle precursor dispersion; b) placing the microneedle precursor dispersion into a mould; c) compressing the microneedle precursor dispersion in the mould and then drying to form microneedles; d) adding a baseplate precursor solution into the mould; e) compressing the baseplate precursor solution and then drying to form the baseplate; and f) releasing the microneedle array from the mould. Without wishing to be bound by theory, it is the experience of the inventors that the nanoparticulate nature of active compounds, such as a Rifamycin like Rifapentine, is retained in the microneedles. Using the solid compositions of the present invention to produce the microneedle arrays allows for higher loading of the water insoluble drugs, while allowing them to remain in their water dispersible nanoparticulate form. For the avoidance of doubt, the microneedles formed in steps b) and c) are retained in the 69324247-2 mould and the baseplate precursor solution is added over the top of them so as to form the microneedle array. Steps b) and c) may be repeated to increase the volume of the microneedle that is formed of the first composition. It will be understood that such repetitions will occur prior to deposition of the baseplate. The step of dispersing the solid composition according to the present invention and at least one structural polymer may comprise individual steps of dispersing the solid composition in a first quantity of the solvent, dissolving the at least one structural polymer in a second quantity of the solvent, and then mixing. The microneedle precursor dispersion may comprise the solid composition in an amount of between 10 and 50 wt%, preferably between 20 and 40 wt%, more preferably between 25 and 35 wt%, most preferably about 30 wt%. The microneedle precursor dispersion may comprise the at least one structural polymer in an amount between 1 and 20 wt%, preferably between 5 and 15 wt%, more preferably about 10 wt%. The mould contains microcavities that correspond to the shape of the microneedles. The steps of placing the microneedle precursor dispersion into the mould, compressing and drying to form the microneedles may not fill the cavities of the mould. Accordingly, these steps may be repeated so as to increase the volume of the cavities that are filled. The baseplate precursor solution comprises a base polymer, a solvent, and, optionally, one or more additives. The solution may comprise between 10 and 50 wt% base polymer, preferably between 20 and 40 wt% base polymer, more preferably about 30 wt% base polymer. If present, the baseplate precursor solution comprises between 0.1 and 5 wt% additive, preferably between 0.5 and 3 wt%, more preferably about 1.5 wt%. The solvent is typically water. Other than the Rifamycin, such as Rifapentine, the components forming the microneedle array are all soluble in water, in addition to its other benefits (e.g. non-toxic, non-flammable, easily available). The steps of compressing the solutions may use any suitable method known in the art, such as pressure chamber or centrifugation. It is preferred that the step of compressing the microneedle precursor dispersion takes place in a pressure chamber. It is also preferred that compressing the baseplate precursor solution is done by centrifuge. The drying steps may use any suitable method known in the art. Typically, the drying steps are performed under ambient conditions (i.e. the solvent is simply allowed to 69324247-2 evaporate). However, it will be understood that the rate of drying may be increased through the application of increased temperature, increased air flow over the samples, or the application of a reduced pressure. The microneedle array may retain residual water following drying. The residual water does not exceed 15 wt% of the microneedle array. The residual water content may be between 1 and 15 wt% of the microneedle array, typically between 5 and 10 wt% of the microneedle array. Uses of the solid compositions, aqueous dispersions, pharmaceutical compositions, injectable formulations, implantable rods, and microneedle arrays The present invention provides a solid composition, an aqueous dispersion, a pharmaceutical composition, injectable formulation, implantable rod, or microneedle array as defined herein for use as a medicament. The present invention provides a solid composition, an aqueous dispersion, a pharmaceutical composition, injectable formulation, implantable rod, or microneedle array as defined herein for use in the treatment and/or prevention of tuberculosis, such as latent tuberculosis. In embodiments, the aqueous dispersion, pharmaceutical composition, injectable formulation for use in the treatment and/or prevention of tuberculosis has a concentration of a Rifamycin, such as Rifapentine, in the range of 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL. Alternatively, the concentration of the Rifamycin, such as Rifapentine is at least 150 mg/mL, preferably at least 200 mg/mL, more preferably at least 300 mg/mL, and most preferably at least 500 mg/mL. In embodiments, the implantable rod for use in the treatment and/or prevention of tuberculosis has a concentration of the Rifamycin, such as Rifapentine in the range of 20 to 80 wt%, preferably 30 to 70 wt%, more preferably 40 to 60 wt%, most preferably about 50 wt%. In embodiments, the microneedle array for use in the treatment and/or prevention of tuberculosis contains a mass of the Rifamycin, such as Rifapentine, in the range of between 1 and 20 mg of the Rifamycin, preferably between 2 and 10 mg, more 69324247-2 preferably about 5 mg. It will be understood that the dose of the Rifamycin provided to a patient may be varied by using larger and/or multiple microneedle arrays. The present invention provides a method of treating and/or preventing tuberculosis, such as latent tuberculosis, the method comprising administering a therapeutically effective amount of a solid composition, an aqueous dispersion, a pharmaceutical composition, an injectable formulation, implantable rod, or microneedle array as defined herein to a patient suffering from or at risk of suffering from tuberculosis. In embodiments, the aqueous dispersion, the pharmaceutical composition, or the injectable formulation has a concentration of a Rifamycin, such as Rifapentine, in the range of 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL. Alternatively, the concentration of the Rifamycin is at least 150 mg/mL, preferably at least 200 mg/mL, more preferably at least 300 mg/mL, and most preferably at least 500 mg/mL. The aqueous dispersion, pharmaceutical composition, the injectable formulation, or implantable rod may form a depot within the body of the patient, for example, in an intramuscular or subcutaneous site, optionally wherein the depot maintains a therapeutically effective concentration of the Rifamycin, such as Rifapentine, within the body of the patient for a period of at least two weeks, preferably at least one month, more preferably at least two months, yet more preferably at least three months, and most preferably at least two four. Once affixed to the skin, the microneedle array or arrays gradually release the Rifamycin, such as Rifapentine, and optionally maintains a therapeutically effective concentration of the Rifamycin within the body of the patient for a period of at least 4 hours, preferably at least 6 hours, more preferably at least 12 hours, and most preferably at least 24 hours. At the end of the period, the microneedle array or arrays are removed from the skin of the patient and, if treatment is ongoing, replaced with a fresh microneedle array or arrays. In embodiments, the method requires dosing of the aqueous dispersion, the pharmaceutical composition, the injectable formulation, or implantable rod up to three times, preferably up to two times, most preferably only once, to maintain a therapeutically effective concentration of the Rifamycin, such as Rifapentine, in the patient for the duration of the treatment. 69324247-2 In embodiments, the method requires dosing of the microneedle array up to six times per day, preferably up to four times per day, more preferably twice a day, and most preferably once a day, to maintain a therapeutically effective concentration of the Rifamycin, such as Rifapentine, in the patient for the duration of the treatment. In any or all of the above-described uses and methods, the administered form of nanoparticle of the Rifamycin, such as Rifapentine, preferably provides a controlled release bolus formulation of the Rifamycin, which, when administered to a patient, releases the Rifamycin into the bloodstream of the patient over a period of at least about two weeks from the date of administration. Further preferably the period of release is at least about one month, more preferably at least about two months, yet more preferably at least about three months, and most preferably at least about four months from the date of administration of the injection, insertion or application. Therapeutic definitions As used herein, “treatment” includes curative and prophylactic treatment. As used herein, a “patient” means an animal, preferably a mammal, preferably a human, in need of treatment. The amount of the Rifamycin, such as Rifapentine, administered should be a therapeutically effective amount where the Rifamycin is used for the treatment of a disease or condition and a prophylactically effective amount where the Rifamycin is used for the prevention of a disease or condition. The term “therapeutically effective amount” used herein refers to the amount of the Rifamycin, such as Rifapentine, needed to treat or ameliorate tuberculosis. The term “prophylactically effective amount” used herein refers to the amount of the Rifamycin needed to prevent tuberculosis. The exact dosage will generally be dependent on the patient’s status at the time of administration. Factors that may be taken into consideration when determining dosage include the severity of the disease state in the patient, the general health of the patient, the age, weight, gender, diet, time, frequency and route of administration, drug combinations, reaction sensitivities and the patient’s tolerance or response to therapy. The precise amount can be determined by routine experimentation, but may ultimately lie with the judgement of the clinician. An effective dose may in instances be from 0.01 mg/kg/day (mass of drug compared to mass of patient) to 1000 mg/kg/day, e.g.1 mg/kg/day to 100 mg/kg/day. Compositions may be 69324247-2 administered individually to a patient or may be administered in combination with other agents, drugs or hormones. For a long acting injectable, the composition may be administered in an amount sufficient to release the Rifamycin, such as Rifapentine, at the above rates. Alternatively, the long acting injectable may be administered in an amount of 0.1 mL to 10 mL, at an amount of 0.2 mL to 6 mL, at an amount of 0.5 mL to 5 mL, or at an amount of 1 mL to 3 mL. Routes of administration The solid compositions, aqueous dispersions, pharmaceutical compositions, injectable formulations, implantable rods, or microneedle arrays of the invention, may be administered to a patient by any convenient route of administration. More than one route of administration may be used in combination within a defined treatment and/or prophylactic regime, especially for a combination therapy, in which one component of the combination may be administered via one route, whilst another component of the combination may be administered via a different route. All such combinations are hereby contemplated. Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, microneedle array e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; or by implantation of a depot, reservoir, or implantable rod for example, subcutaneously or intramuscularly. Most preferably, the route of administration is by injection (e.g. intramuscular or subcutaneous injection) of a depot or implantation of an implantable rod. Alternatively, the route of administration is transdermal via a microneedle array. Preferably, the injectable formulation of the present invention is a depot formulation administered so as to provide a controlled release in the patient over at least a period of about two weeks from the date of administration. Further preferably the period of release is at least about one month, more preferably at least about two months, more 69324247-2 preferably at least about three months, and most preferably at least about four months from the date of administration of the injection. The implantable rod of the present invention is a depot formulation administered so as to provide a controlled release in the patient over at least a period of about two weeks from the date of administration. Further preferably the period of release is at least about one month, more preferably at least about two months, yet more preferably at least about three months, and most preferably at least about four months from the date of implantation of the rod. Without wishing to be bound by theory, it is thought that the implant gradually dissolves to form a liquid depot and that the Rifamycin, such as Rifapentine, is gradually released from the implant and subsequent liquid depot. The microneedle array of the present invention is a transdermal release formulation administered to provide a controlled release in a patient over a period of at least four hours, preferably at least 6 hours, more preferably at least 12 hours and most preferably at least 24 hours. Kit of Parts The present invention provides a kit of parts comprising a solid composition as defined herein or pharmaceutical composition comprising the solid composition as defined herein, and a pharmaceutically acceptable aqueous diluent. The solid composition or pharmaceutical composition comprising the solid composition as defined herein can be dispersed into the diluent to provide an aqueous dispersion as defined herein. Either the entire dispersion can then be administered, or a proportion of it can be measured and then administered (thereby providing a means of administering different dosages to individual patients). EXAMPLES Example 1: Rifapentine SDNs formed by Emulsion-Templated Freeze Drying Rifapentine was dissolved in chloroform at a concentration of 100 mg/mL and each of the first and second excipients were dissolved in water at a concentration of 22.5 mg/mL to provide three stock solutions.50 µL of the Rifapentine solution, 178 µL of the first excipient solution and 44 µL of the second excipient solution were combined. The mixture was then emulsified using a Covaris S220x. The resulting emulsions were then immediately frozen with liquid nitrogen and were freeze dried for approximately 48 hours using a VirTis Benchtop Pro. The resulting solid product was in the form of a 69324247-2 monolith containing 50 wt% Rifapentine, 40 wt% first excipient and 10 wt% second excipient. The first excipients tested were Plasdone C15, Kollidon 12 PF, lactose, sucrose, Pluronic F68, and PEG 4000. The second excipients tested were Benzalkonium chloride, AOT, Pluronic F68, Tween 20, Tween 80, and Span 20. Screen Analysis Samples were dispersed in water at a Rifapentine concentration of 1 mg/mL. The particle size of the nanoparticulate dispersion was then measured by dynamic light scattering (DLS) using a Malvern Zetasizer Nano ZS. Three measurements using automatic measurement optimisation, Malvern Zetasizer software version 7.11 was used for data analysis. The particles were considered hits if the below criteria were met. Nanodispersion Quality Assessment Criteria A particle was determined a hit if it complied with the following criteria: (i) complete dispersion of the sample with no large particles visible; (ii) a particle Z-average <1000 nm; (iii) a polydispersity index (PDI) <0.4; (iv) a standard deviation between three scans <5% from average Z-average; and (v) at least two of the three DLS scans pass the ‘size quality report’. The ‘size quality report’ incorporates twelve tests on the reliability of the data recorded and is automatically applied to each measurement by the Malvern Zetasizer software. These tests ensure that the sample is within a size range appropriate for DLS, has a PDI below 1, is within the correct concentration range and that the cumulant and distribution fit are good (i.e. the errors on the data are less than 0.005). Ten combinations passed the selection criteria. First excipient Second excipient Dz (nm) PdI Plasdone C15 Benzalkonium 880 0.492 Chloride AOT 483 0.594 Kollidon 12PF Tween 20 400 0.494 Tween 80 477 0.477 69324247-2 Lactose AOT 648 0.377 Pluronic F68 903 0.450 Sucrose Benzalkonium 1448 0.365 Chloride AOT 919 0.400 Span 20 430 0.317 Pluronic F68 Tween 20 498 0.442 Example 2: Rifapentine SDNs formed by Nanoprecipitation and Freeze Drying Rifapentine was dissolved in methanol at a concentration of 100 mg/mL and each of the first and second excipients were dissolved in water at a concentration of 22.5 mg/mL to provide three stock solutions.50 µL of the Rifapentine solution, 178 µL of the first excipient solution and 44 µL of the second excipient solution were combined and shaken by hand to induce nanoprecipitation. The resulting suspensions were then immediately frozen with liquid nitrogen and were freeze dried for approximately 48 hours using a VirTis Benchtop Pro. The resulting solid product was in the form of a monolith containing 50 wt% Rifapentine, 40 wt% first excipient and 10 wt% second excipient. The first and second excipients and screening process and criteria were as described in Example 1. Eight combinations passed the screening criteria. First excipient Second excipient Dz (nm) PdI Plasdone C15 AOT 622 0.555 Kollidon 12PF AOT 597 0.521 Lactose AOT 353 0.395 Sucrose AOT 292 0.267 Pluronic F68 898 0.554 Pluronic F68 AOT 359 0.240 PEG 4000 AOT 489 0.535 Pluronic F68 806 0.509 Example 3: Rifapentine/Plasdone C15/AOT SDNs formed by Nanoprecipitation and Freeze Drying Rifapentine was dissolved in methanol at a concentration of 50 mg/mL, Plasdone C15 was dissolved in water at a concentration of 20 mg/mL and AOT was dissolved in water at a concentration of 5 mg/mL.6mL of the Plasdone C15 stock solution and 6mL of the 69324247-2 AOT stock solution were combined and mixed using an Ultra-Turrax T25 Digital Homogeniser set to 14,000 rpm. The Rifapentine stock solution (3mL) was then immediately added via peristaltic pump at a flow rate of 60 mL/min. Mixing was continued for approximately 15-20 seconds after addition was completed. Half of the resulting suspension was frozen in liquid nitrogen immediately, the remaining half was passed through an LV1 microfluidizer for 5 passes at 20,000 psi prior to being frozen in liquid nitrogen. The samples were freeze dried for ~48 hours using a VirTis Benchtop Pro with a condenser setting of -100°C and at a pressure of <40 µBar to give Rifapentine compositions containing 50 wt% Rifapentine, 40 wt% Plasdone C15, 10 wt% AOT. The samples were dispersed in water at 1 mg/mL with regard to active and screened as described in Example 1. Unaltered LV1, 5 passes, Formulation 20,000 psi repeat Dz (nm) PdI Dz (nm) PdI 1 229 0.160 222 0.120 2 235 0.170 247 0.170 3 267 0.220 272 0.170 Example 4: Rifapentine/Plasdone C15/AOT SDNs formed by Nanoprecipitation and Spray Drying Rifapentine was dissolved in methanol at a concentration of 50 mg/mL, Plasdone C15 was dissolved in water at a concentration of 20 mg/mL and AOT was dissolved in water at a concentration of 5 mg/mL.8mL of the Plasdone C15 stock solution and 8mL of the AOT stock solution were combined and mixed using an Ultra-Turrax T25 Digital Homogeniser set to 14,000 rpm. The Rifapentine stock solution (4mL) was then immediately added via peristaltic pump at a flow rate of 60 mL/min. Mixing was continued for approximately 15-20 seconds after addition was completed. Half of the resulting suspension was immediately spray dried, the remaining half was passed through an LV1 microfluidizer for 5 passes at 20,000 psi prior to being spray dried. The spray drier conditions were as follows: flow rate of 5 mL/min using a Buchi B-290 mini spray dryer (aspirator 100%, nitrogen at 5 bar pressure, Q-Flow gauge 45, Outlet temperature 65⁰C). The resulting compositions 50 wt% Rifapentine, 40 wt% Plasdone C15, 10 wt% AOT. The samples were dispersed in water at 1 mg/mL with regard to Rifapentine and screened as described in Example 1. 69324247-2 Formulation Dz (nm) PdI repeat 1 (spray dried 229 0.160 directly) 2 (spray dried after 201 0.06 microfluidizer) The syringeability of each composition was tested at increasing concentrations of Rifapentine. The dispersions were produced by vortex mixing the solid composition in water at the required concentrations for a period of 30 seconds. The dispersions were then passed through a 25G needle by hand. Those that passed through easily and without blockages, with a repeat one hour later, were considered to have passed. The compositions were found to be syringeable at all tested concentrations up to 250 mg/mL (concentration with respect to the Rifapentine). Example 5: Rifapentine/Plasdone C15/AOT SDNs formed by Nanoprecipitation and Spray Drying Rifapentine was dissolved in methanol at 40 mg/mL, Plasdone C15 was dissolved in water at 25 mg/mL and AOT was dissolved in water at 5 mg/mL.8mL of the Plasdone C15 stock solution and 8mL of the AOT stock solution were combined and mixed using an Ultra-Turrax T25 Digital Homogeniser set to 14,000 rpm. The Rifapentine stock solution (4mL) was then immediately added via peristaltic pump at a flow rate of 60 mL/min. Mixing was continued for approximately 15-20 seconds after addition was completed. The suspension was spray dried as set out in Example 4 to produce compositions containing 40 wt% RFP, 50 wt% Plasdone C15, 10 wt% AOT. The samples were dispersed in water at 1 mg/mL with regard to Rifapentine and screened as described in Example 1. Formulation Dz (nm) PdI repeat 1 226 0.070 2 238 0.040 3 239 0.070 The syringeability of the composition was tested as described in Example 4. The compositions were found to be syringeable at all tested concentrations up to 300 mg/mL (concentration with respect to the Rifapentine). 69324247-2 This process was repeated for alternative Rifapentine stock solutions using different solvent solutions: Solvent system Dz (nm) PdI 50% Acetone, 50% 329 0.100 Ethanol 90% Acetone, 10% 399 0.140 Methanol 50% butanone, 50% 638 0.100 Ethanol This process was also repeated for alternative first excipients: First excipient Second excipient Dz (nm) PdI Kollidon 17PF AOT 192 0.100 Lactose AOT 280 0.390 Example 6: In vivo Longevity of Rifapentine following Intramuscular Injection An aqueous dispersion of the Rifapentine formulation (Rifapentine40/Plasdone C1550/AOT10) in water was produced with a total drug concentration of 300 mg/mL. Male Sprague Dawley Rats (250-300g – Charles River) were injected intramuscularly into both thighs with different volumes (150 µl per thigh) of the aqueous dispersion for each group of four animals. Blood plasma was collected from the tail veins periodically over the course of 28-days and the Rifapentine concentrations therein quantified using LC/MS-MS. This data is graphed in Fig. 1 and shows a gradual decline in the concentration of Rifapentine over the 28-day period of the experiment, demonstrating that a relevant concentration of Rifapentine is maintained for the duration. Example 7: Formulation into Implantable Rods Implantable rods were prepared by a vacuum compression moulding (VCM) method using a MeltPrep VCM Essentials instrument set-up consisting of a hot plate, nitrogen gas assisted cooling plate, vacuum pump, base plate, VCM sample chamber, VCM main body, 2mm internal diameter PTFE sample tube, 2 mm diameter PTFE-coated separation foils, 15 mm piston, and a low-pressure lid. 69324247-2 Prior to sample preparation, the hot plate was heated to a temperature of 105 °C and a vacuum pressure of -1 bar was maintained for approximately 20 minutes. The sample tube was inserted into the VCM sample chamber, which was then fitted onto the base plate. A separation foil was then inserted and positioned at the bottom of the tube before adding the powdered formulation (~30 mg) using a funnel, which was compacted as much as possible using a pin. A second separation foil was then positioned on top of the sample before inserting a 15 mm piston into the sample tube. The VCM main body was then positioned over this assembly before attaching the low- pressure lid. A vacuum of -1 bar was applied to the sample chamber before placing it on the hot plate. The sample was heated to 105 °C for four minutes before being transferred onto the cooling plate and cooled for 2 minutes. Opaque, black coloured rods were obtained weighing ~30 mg and having a length of 8 mm and diameter of 2 mm. Example 8: In vivo Longevity of Rifapentine following Implantation of a Rod This experiment was performed on male Sprague Dawley Rats (250-300g – Charles River). Each rat was implanted with two rods, the rods implanted subcutaneously into each scapular region. The rods comprised the following Rifapentine formulation: Rifapentine40/Plasdone C1550/AOT10. There were four study groups, varying the size and/or number of implants to control the Rifapentine dosage: 1 - Two 15 mm implants per animal (dose of approx.46 mg of Rifapentine per animal); 2 – One 15 mm implant per animal (dose of approx. 23 mg of Rifapentine per animal); 3 – Two 8 mm implants per animal (dose of 26 mg of Rifapentine); and 4 – Two excipient only implants per animal (dose of 0 mg of Rifapentine). Blood plasma was collected from the tail veins periodically over the course of 35 days and the Rifapentine concentrations therein quantified using LC/MS-MS. This data is graphed in Fig 2 and shows a gradual decline in the concentration of Rifapentine over the 35 day period of the experiment, demonstrating that a relevant concentration of Rifapentine is maintained for the duration. Example 9: Formulation into Microneedles A polymer stock solution was prepared containing 20% w/w PVA (Sigma Aldrich, nominal MW of 9-10 kDa, Mw 9-10 kDa) and 20% w/w Plasdone K29/32 in deionised 69324247-2 water. A needle layer composition was prepared by mixing 27.8% w/w of the polymer stock solution with 27.8% w/w of the Rifapentine formulation (Rifapentine40/Plasdone C1550/AOT10) and 44.4% w/w of deionised water using a Speedmixer™ at 3500 rpm for 5 minutes. A baseplate composition was prepared by mixing 30% w/w PVP (Sigma Aldrich, nominal MW of 360 kDa, Mn 360 kDa, K Value 80-100), 1.5% w/w glycerol and balance deionised water prior to sonication and centrifugation. The needle layer composition was cast into a 16 by 16 array arranged on a 0.49 cm2 area, each needle having a height of 850 µm (of which 600 µm is pyramidal tip and 250 µm is base column) and a column width of 300 µm, the spacing between needles being 100 µm. The array was placed into a pressure chamber and subjected to a pressure of 5 bar for 3 minutes. In some embodiments a second needle layer is cast and the array is placed in the pressure chamber and subjected to a pressure of 5 bar for a further 5 minutes. The microneedles were left to dry overnight. 650 µl of baseplate composition was cast onto the prepared needles and the arrays centrifuged for 15 minutes as 5000 rpm before drying under ambient conditions for 48 hours. The set microneedle arrays were then released from the moulds and excess baseplate material cut away. Singly cast microneedle arrays were found to have a Rifapentine loading of 1.37±0.095 mg, while doubly cast microneedle arrays were found to have a Rifapentine loading of 1.72±0.15 mg. Example 10: Insertion Efficiency of the Microneedle Arrays The insertion efficiency of the microneedle arrays was determined by applying the microneedle arrays to layered Parafilm® M (each layer having a thickness of approximately 252 µm) as an in vitro skin model using 32 N of force (equivalent to that of a human thumb). The number of holes punctured in each layer of Parafilm ® M was used to calculate the % insertion for each layer using the following equation: ^^^^^^ ^^ ℎ^^^^ ^^^^^^^^ ^^^^^^^^^ % = × 100 ^^^^^^ ^^ ^^^^^^^ ^^ ^^^^^ Puncture marks made in four successive layers of Parafilm® M are shown for one example in Fig.3. It can be seen that the microneedle array completely penetrates the first two layers of Parafilm® M and maintains some penetration through to the fourth layer of Parafilm® M. 69324247-2 Example 11: Ex vivo Assessment of the Microneedles Ex vivo skin deposition experiments were carried out utilising a modified Franz diffusion cell. Full thickness skin was collected and excised within 24 hours of birth. On the day of the experiment, the skin was first pre-equilibrated in PBS at pH 7.4 for 30 minutes until totally thawed and then carefully shaved using a razor. It was then cyanoacrylate- glued to the donor compartment of the Franz diffusion cells to ensure its adhesion to the set up during the microneedle insertion and throughout the experiment. Microneedle arrays were applied to the skin using firm thumb pressure for 30 seconds. A stainless-steel cylinder (diameter 11 mm, mass 11.5 g) was put on the top of each microneedle array to hold them in place throughout the experiment. The receiver compartment was filled with 12 mL of 1% w/v SLS and 0.1% w/v ascorbic acid in PBS (pH 7.4). The donor compartment was clamped on top of the receiver compartment and wrapped with Parafilm® M to prevent solvent evaporation. Samples of 200 μL of the receiver compartment were taken at predefined time points of 1, 2, 3, 4, 6, 10, and 24 hours and was replaced with the fresh release medium. At 24 hours, the Franz cells were disassembled, the skin surface dabbed clean to remove surface drug, and Rifapentine was extracted from the skins. Cumulative amounts of Rifapentine delivered from each formulation to both skin and receiver compartments were also determined. To extract the drug from the skin, skin samples collected at 24 hours were cut into small pieces, where 0.5 mL of water was added to each sample. They were then homogenised for 15 minutes using a Tissue Lyser LT. Subsequently, 1 mL of methanol was added, and samples were homogenised again for another 15 minutes. Then they were transferred to the tubes followed by adding 3.5 mL of methanol. After a 30-min sonication, 100 μL of the samples were diluted to 1 mL by PBS buffer (including 1% w/v SLS and 0.1% w/v ascorbic acid. The samples were vortexed and centrifuged, then analysed by HPLC. The data is summarised in Figs.4 and 5. Over 24h, 114.6 ± 20.8 μg of Rifapentine was delivered to the receiver compartment of the Franz diffusion cells and 729.6 ± 85.4 μg of Rifapentine was delivered into the skin over 24h by the singly cast microneedle arrays. For the doubly cast microneedle arrays, 138.7 ± 25.7 μg of Rifapentine was delivered to the receiver compartment of the Franz diffusion cells and 817.7 ± 174.7 μg of Rifapentine was delivered into the skin over 24h This brings up the total amount delivered to the skin and receiver compartment over 24 hours to 842.2 ± 79.5 μg of Rifapentine, or 61.4% of the Rifapentine initially present in the singly cast microneedle arrays. For the doubly cast microneedle arrays, the total amount delivered to the skin 69324247-2 and receiver compartment over 24 hours to 956.4 ± 158.0 μg of Rifapentine, or 55.6% of the Rifapentine initially present The majority of the delivered Rifapentine remained in the skin, which is believed to be due to the high hydrophobicity of these compounds. Example 12: In vivo Longevity of Rifapentine following Application of Microneedle Arrays Female Sprague-Dawley rats (total n= 64), 11-12 weeks of age and possessing a mean weight of 271.5 ± 22.3 g, were acclimatised for seven days prior to the experiment. Four microneedle arrays (each loaded with 1.4 mg of Rifapentine for a total dose of 5.6 mg per rat) were applied to rat. To minimise the interference of hair in application of the microneedle arrays, the dorsal hair of the rats from the first cohort (rats 1-6) was removed prior to the experiment. The bulk hair was shaved using an electric hair clipper and the remaining hair residuals were removed using depilatory hair removal cream. Rats were then left for a 24 hour period to allow the skin to recover and to ensure complete restoration of skin barrier function before affixing the microneedle arrays. The following day, rats were sedated using a gaseous anaesthetic gas (2-4% v/v isoflurane in oxygen), where microneedle arrays were affixed using firm thumb pressure onto a pinched section of skin on the back of the rats in cohort 1. Afterwards, Tegaderm™ film was placed on top of the microneedle arrays and kinesiology tape applied to keep them in place. Blood plasma was collected from the tail veins periodically over the course of 24 hours and the Rifapentine concentrations therein quantified using LC/MS-MS. This data is graphed in Fig.6 and shows a consistent concentration of Rifapentine over the 24 hour period of the experiment, demonstrating that a relevant concentration of Rifapentine is maintained for the duration. Example 13 - Rifapentine/Plasdone C15/AOT SDNs formed by Nanoprecipitation and Spray Drying Rifapentine was dissolved in methanol at 50mg/mL, Plasdone C15 was dissolved in water at 14.25 mg/mL and AOT was dissolved in methanol at 15 mg/mL.0.8 mL of the AOT stock solution was added to 3.2 mL of the rifapentine stock solution and mixed using a vortex mixer for 30 seconds. The resulting mixture was immediately added via peristaltic pump at a flow rate of 5 mL/min to 16 mL of the Plasdone C15 stock solution with stirring from a stirrer bar. The sample was allowed to stir for at least 5 minutes prior to spray drying. The sample was then spray dried at a flow rate of 5 mL/min (with 69324247-2 stirring from a stirrer bar to prevent any possible sedimentation) using a Buchi B-290 mini spray dryer (aspirator 100%, nitrogen at 5 bar pressure, Q-Flow gauge 45, Outlet temperature 65⁰C) to give a rifapentine composition containing approx. 40 wt% RFP, 57 wt% Plasdone C15, 3 wt% AOT. The process was repeated on a larger scale, with 5 mL of the AOT stock solution and 20 mL of the rifapentine stock solution being added to 100 mL of the Plasdone C15 stock solution at a flow rate of 5 mL/min. The samples were dispersed in water at 1 mg/mL with regard to active and screened as described in Example 1. Scale Dz (nm) PdI Small scale 198.7 0.14 Large scale 237.2 0.27 Example 14: In vivo Longevity of Rifapentine following Administration in a Long-acting Injectable Formulation containing differing Concentrations of the Excipient AOT Male Sprague-Dawley rats (total n= 68), 11-12 weeks of age and possessing a mean weight of 315.6 ± 15.3 g, were acclimatised for seven days prior to the experiment. The rats were divided into cohorts, which were administered the following by intramuscular injection: 1. Rifapentine40/Plasdone C1557/AOT3 SDNs at a dosing of 300 mg/kg of Rifapentine, by two injections of 150 µL each; 2. Rifapentine40/Plasdone C1550/AOT10 SDNs at a dosing of 300 mg/kg of Rifapentine, by two injections of 150 µL each; 3. Plasdone C1557/AOT3 reconstituted from spray-dried powder (control), by two injections of 150 µL each; 4. Plasdone C1550/AOT10 reconstituted from spray-dried powder (control), by two injections of 150 µL each; 5. water (control), by two injections of 150 µL each; 6. Rifapentine40/Plasdone C1557/AOT3 SDNs at a dosing of 150 mg/ kg of Rifapentine, by two injections of 75 µL each; and 7. Rifapentine40/Plasdone C1550/AOT10 SDNs at a dosing of 150 mg/ kg of Rifapentine, by two injections of 75 µL each. Formulations were dispersed in water for injection prior to injection. All rats were administered buprenorphine subcutaneously for pain relief prior to intramuscular injections. 69324247-2 Cohorts 1 to 5 each comprised three cages, each cage containing four mice. Cohorts 6 and 7 each comprised only one cage with four rats. Blood plasma was collected from the lateral tail veins periodically over the course of 56 days and the Rifapentine concentrations therein quantified using LC/MS-MS. This data is graphed in Fig. 7 for the 150 mg/kg cohort and in Fig. 8 for the 300 mg/kg cohort, neither showing significant difference between plasma blood concentrations of Rifapentine between the formulations. Clauses of the Invention: Clause 1. A solid composition comprising nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a matrix comprising a first excipient and a second excipient, wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate. Clause 2. The solid composition of clause 1, wherein the first and second excipients are selected from the following combinations: ^ PVP and benzalkonium chloride ^ PVP and AOT ^ PVP and Polysorbate 20 ^ PVP and Polysorbate 80 ^ lactose and AOT ^ lactose and poloxamer ^ sucrose and benzalkonium chloride ^ sucrose and AOT ^ sucrose and sorbitan monolaurate ^ sucrose and poloxomer ^ poloxamer and Polysorbate 20 ^ poloxamer and AOT ^ PEG and AOT ^ PEG and poloxamer 69324247-2 Clause 3. The solid composition of clause 2, wherein the first and second excipients are selected from the following combinations: ^ PVP and AOT ^ lactose and AOT Clause 4. The solid composition of any preceding clause, wherein the composition comprises: 10 to 80 wt% of the Rifamycin, such as Rifapentine; 10 to 80 wt% of the first excipient; and 1 to 25 wt% of the second excipient. Clause 5. The solid composition of clause 4, wherein the composition comprises: 30 to 60 wt% of the Rifamycin, such as Rifapentine; 30 to 60 wt% of the first excipient; and 1 to 20 wt% of the second excipient. Clause 6. The solid composition of clause 5, wherein the composition comprises: 40 to 50 wt% of the Rifamycin, such as Rifapentine; 40 to 50 wt% of the first excipient; and 5 to 15 wt% of the second excipient. Clause 7. The solid composition of clause 5, wherein the composition comprises: 30 to 50 wt% of the Rifamycin, such as Rifapentine; 40 to 60 wt% of the first excipient; and 1 to 10 wt% of the second excipient. Clause 8. The solid composition of clause 7, wherein the composition comprises: 35 to 45 wt% of the Rifamycin, such as Rifapentine; 50 to 60 wt% of the first excipient; and 1 to 5 wt% of the second excipient. Clause 9. The solid composition of any preceding clause, wherein the nanoparticles have a particle diameter in the range of 10 to 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 200 and 800 nm. 69324247-2 Clause 10. The solid composition of any preceding clause, wherein the nanoparticles have a polydispersity less than or equal to 0.8, preferably less than or equal to 0.6, more preferably less than or equal to 0.5. Clause 11. A process for preparing a solid composition according to any one of clauses 1 to 10, the process comprising: (a) preparing an oil-in-water emulsion comprising: - an oil phase comprising the Rifamycin, such as Rifapentine; and - an aqueous phase comprising a first and second excipient, each as defined in any of clauses 1 to 10; and (b) removing the oil and water from the oil-in-water emulsion to form the solid composition. Clause 12. A process for preparing a solid composition according to any one of clauses 1 to 10, the process comprising: (a) providing an active solution comprising the Rifamycin, such as Rifapentine, in a water-miscible solvent; (b) providing a carrier material solution comprising a first and second excipient, each as defined in any of clauses 1 to 10; (c) mixing the solutions prepared in steps (a) and (b); and (d) removing the mixed solvent to produce the solid composition or, the process comprising: (a) providing an active solution comprising the Rifamycin, such as Rifapentine, and the second excipient in a water-miscible solvent; (b) providing a carrier material solution comprising a first excipient, each as defined in any of claims 1 to 10; (c) mixing the solutions prepared in steps (a) and (b); and (d) removing the mixed solvent to produce the solid composition. Clause 13. The process of clause 11 wherein the step of removing the oil and water from the oil-in-water emulsion or the process of clause 12 wherein the step of removing the mixed solvent comprises spray drying or freeze-drying. 69324247-2 Clause 14. An aqueous dispersion comprising a plurality of nanoparticles of the Rifamycin, such as Rifapentine, dispersed in an aqueous medium and stabilised by a mixture of a first excipient and a second excipient; wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate. Clause 15. The aqueous dispersion of clause 14, wherein the aqueous dispersion comprises nanoparticles of the Rifamycin, such as Rifapentine, first excipients, and second excipients as defined in any of clauses 2 to 10 in the aqueous medium. Clause 16. The aqueous dispersion of clause 14 or clause 15, wherein the Rifamycin, such as Rifapentine, is present in the aqueous dispersion at a concentration of 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL. Clause 17. A process for preparing an aqueous dispersion according to any of clauses 14 to 16, the process comprising dispersing a solid composition according to any of clauses 1 to 10 in an aqueous medium. Clause 18. A pharmaceutical composition comprising the solid composition of any of clauses 1 to 8, or the aqueous dispersion of any of clauses 14 to 16 and, optionally, one or more further pharmaceutically acceptable excipients. Clause 19. An injectable formulation comprising the solid composition of any of clauses 1 to 10, the aqueous dispersion of any of clauses 14 to 16, or the pharmaceutical composition of clause 18. Clause 20. The injectable formulation of clause 19, wherein the injectable formulation is a subcutaneously or intramuscularly injectable formulation, optionally wherein the injectable formulation is suitable for provision in depot form. 69324247-2 Clause 21. A method of producing an implantable rod comprising the steps of compressing a solid composition according to any one of clauses 1 to 10 and heating the compressed solid composition for a period of time. Clause 22. The method of clause 21, wherein the solid composition is compressed in a mould, optionally the mould being cylindrical in form. Clause 23. The method of clause 21 or clause 22, wherein the solid composition is heated to a temperature from 60 to 160 °C, preferably from 80 to 140 °C, more preferably from 100 to 120 °C, most preferably about 105 °C. Clause 24. The method of any one of clauses 21 to 23, wherein the compression occurs under a reduced pressure atmosphere. Clause 25. The method of any one of clauses 21 to 24, wherein the heating step takes place for a period of from 1 minute to 40 minutes, preferably from 5 minutes 30 minutes, more preferably from 10 minutes to 25 minutes, most preferably about 20 minutes. Clause 26. The method of any one of clauses 21 to 25, further comprising a step of cooling the rod, optionally the cooling taking place under a reduced pressure atmosphere. Clause 27. An implantable rod produced by the method of any one of clauses 21 to 25. Clause 28. An implantable rod comprising nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a monolith comprising a first excipient and a second excipient, wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate. 69324247-2 Clause 29. The implantable rod of clause 28, wherein the nanoparticles of the Rifamycin, such as Rifapentine, first excipient, and/or second excipient are as defined in any one of clauses 2 to 10. Clause 30. A method of producing a microneedle array comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition, the method comprising the steps of: a) dispersing a solid composition according to any one of clauses 1 to 10 and at least one structural polymer in a solvent to form a microneedle precursor dispersion; b) placing the microneedle precursor dispersion into a mould; c) compressing the microneedle precursor dispersion in the mould and then drying to form microneedles comprising the first composition; d) adding a baseplate precursor solution into the mould; e) compressing the baseplate precursor solution and then drying to form the baseplate of the second composition; and f) releasing the microneedle array from the mould. Clause 31. The method of clause 30, wherein steps b) and c) are repeated prior to steps d) to f). Clause 32. The method of clause 30 or clause 31, wherein the solvent is an aqueous solvent, such as water. Clause 33. The method of any of clauses 30 to 32, wherein the at least one structural polymer is selected from PVA, PVP, and combinations thereof. Clause 34. The method of any of clauses 31 to 33, wherein the baseplate precursor solution comprises a base polymer selected from PVP and, optionally, one or more additives such as glycerol, dispersed in an aqueous solvent, such as water. Clause 35. A microneedle array produced by the method of any of clauses 31 to 34. Clause 36. A microneedle array comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition, wherein the first composition comprises nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a monolith comprising a first excipient, a second excipient and at least one structural polymer, 69324247-2 wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate. Clause 37. The microneedle array of claim 36, wherein the nanoparticles of the Rifamycin, such as Rifapentine, first excipient, and/or second excipient are as defined in any one of clauses 2 to 10. Clause 38. The microneedle array of clause 36 or clause 37, wherein the at least one structural polymer is selected from PVA, PVP, and combinations thereof. Clause 39. The microneedle array of any of clauses 36 to 38, wherein the second composition comprises a base polymer, such as PVP, and, optionally, one or more additives such as glycerol. Clause 40. A solid composition according to any of clauses 1 to 10, an aqueous dispersion according to any of clauses 14 to 16, a pharmaceutical composition according to clause 18, an injectable formulation according to clause 19 or clause 20, an implantable rod according to any of clauses 27 to 29, or a microneedle array according to any one of clauses 35 to 39, for use as a medicament. Clause 41. A solid composition according to any of clauses 1 to 10, an aqueous dispersion according to any of clauses 14 to 16, a pharmaceutical composition according to clause 18, an injectable formulation according to clause 19 or clause 20, an implantable rod according to any of clauses 27 to 29, or a microneedle array according to any one of clauses 35 to 39, for use in the treatment and/or prevention of tuberculosis, such as latent tuberculosis. Clause 42. An aqueous dispersion, a pharmaceutical composition, or an injectable formulation for use according to clause 40 or clause 41, wherein the concentration of Rifapentine is 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL. 69324247-2 Clause 43. An implantable rod for use according to clause 40 or clause 41, wherein the concentration of the Rifamycin, such as Rifapentine, in the implantable rod is in the range of 30 to 80 wt%, preferably 40 to 70 wt%, most preferably about 50 wt%. Clause 44. A microneedle array for use according to clause 40 or clause 41, wherein the microneedle array contains a mass of the Rifamycin, such as Rifapentine, in the range of between 0.1 and 20 mg of Rifapentine, preferably between 0.5 and 10 mg, more preferably between 1 and 5 mg, most preferably between 1 and 2 mg. Clause 45. A method of treating and/or preventing tuberculosis, the method comprising administering a therapeutically effective amount of a solid composition according to any of clauses 1 to 10, an aqueous dispersion according to any of clauses 14 to 16, a pharmaceutical composition according to clause 18, an injectable formulation according to clause 19 or clause 20, an implantable rod according to any of clauses 27 to 29, or a microneedle array according to any one of clauses 35 to 39, to a patient suffering from or at risk of suffering from tuberculosis. Clause 46. The method of clause 45, wherein the concentration of the Rifamycin, such as Rifapentine, within the aqueous dispersion, the pharmaceutical composition, or the injectable formulation is 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL. Clause 47. The method of clause 45, wherein the concentration of the Rifamycin, such as Rifapentine, in the implantable rod is in the range of 40 to 80 wt%, preferably 50 to 70 wt%, most preferably about 60 wt%. Clause 48. The method of clause 45, wherein the microneedle array contains a mass of the Rifamycin, such as Rifapentine, in the range of between 1 and 20 mg of Rifapentine, preferably between 2 and 10 mg, more preferably about 5 mg. Clause 49. The method of any of clauses 45 to 47, wherein the aqueous dispersion, the pharmaceutical composition, the injectable formulation, or the implantable rod forms a depot within the body of the patient, optionally wherein the depot maintains a therapeutically effective concentration of the Rifamycin, such as Rifapentine, within the body of the patient for a period of at least two weeks, preferably at least one more, more preferably at least two months, yet more preferably at least three months, and most preferably at least four months. 69324247-2 Clause 50. The method of clause 45 or clause 48, wherein the microneedle array gradually releases the Rifamycin, such as Rifapentine, optionally wherein the microneedle array maintains a therapeutically effective concentration of the Rifamycin, such as Rifapentine, within the body of the patient for a period of at least 4 hours, preferably at least 6 hours, more preferably at least 12 hours, and most preferably at least 24 hours. Clause 51. The method of any of clauses 45 to 47, and 49, wherein the patient requires dosing with the aqueous dispersion, the pharmaceutical composition, the injectable formulation, or the implantable rod up to three times, preferably up to two times, most preferably only once, to maintain a therapeutically effective concentration of the Rifamycin, such as Rifapentine, for the duration of the treatment. Clause 52. The method of any of clauses 45, 48, and 50, wherein the patient requires dosing of the microneedle array up to six times per day, preferably up to four times per day, more preferably twice a day, and most preferably once a day, to maintain a therapeutically effective concentration of the Rifamycin, such as Rifapentine, in the patient for the duration of the treatment. Clause 53. The use of a solid composition according to any of clauses 1 to 10, an aqueous dispersion according to any of clauses 14 to 16, a pharmaceutical composition according to clause 18, an injectable formulation according to clause 19 or clause 20, an implantable rod according to any of clauses 27 to 29, or a microneedle array according to any one of clauses 35 to 39 for the manufacture of a medicament for the treatment and/or prevention of tuberculosis, such as latent tuberculosis. Clause 54. The use of an aqueous dispersion, a pharmaceutical composition, or an injectable formulation according to clause 53, wherein the concentration of Rifapentine is 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL. Clause 55. The use of an implantable rod according to clause 53, wherein the concentration of the Rifamycin, such as Rifapentine, in the implantable rod is in the range of 30 to 80 wt%, preferably 40 to 70 wt%, most preferably about 50 wt%. 69324247-2 Clause 56. The use of a microneedle array according to clause 53, wherein the microneedle array contains a mass of the Rifamycin, such as Rifapentine, in the range of between 0.1 and 20 mg of Rifapentine, preferably between 0.5 and 10 mg, more preferably between 1 and 5 mg, most preferably between 1 and 2 mg. 69324247-2

Claims

CLAIMS: 1. A solid composition comprising nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a matrix comprising a first excipient and a second excipient, wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
2. The solid composition of claim 1, wherein the first and second excipients are selected from the following combinations: ^ PVP and benzalkonium chloride ^ PVP and AOT ^ PVP and Polysorbate 20 ^ PVP and Polysorbate 80 ^ lactose and AOT ^ lactose and poloxamer ^ sucrose and benzalkonium chloride ^ sucrose and AOT ^ sucrose and sorbitan monolaurate ^ sucrose and poloxomer ^ poloxamer and Polysorbate 20 ^ poloxamer and AOT ^ PEG and AOT ^ PEG and poloxamer preferably, the first and second excipients are selected from the following combinations: ^ PVP and AOT ^ lactose and AOT 69324247-2
3. The solid composition of any preceding claim, wherein the composition comprises: 10 to 80 wt% of the Rifamycin, such as Rifapentine; 10 to 80 wt% of the first excipient; and 1 to 25 wt% of the second excipient, preferably the composition comprises: 30 to 60 wt% of the Rifamycin, such as Rifapentine; 30 to 60 wt% of the first excipient; and 5 to 20 wt% of the second excipient.
4. The solid composition of claim 3, wherein the composition comprises: 40 to 50 wt% of the Rifamycin, such as Rifapentine; 40 to 50 wt% of the first excipient; and 5 to 15 wt% of the second excipient.
5. The solid composition of claim 3, wherein the composition comprises: 30 to 50 wt% of the Rifamycin, such as Rifapentine; 40 to 60 wt% of the first excipient; and 1 to 10 wt% of the second excipient, preferably wherein the composition comprises: 35 to 45 wt% of the Rifamycin, such as Rifapentine; 50 to 60 wt% of the first excipient; and 1 to 5 wt% of the second excipient. 6. The solid composition of any preceding claim, wherein the nanoparticles have: (i) a particle diameter in the range of 10 to 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 200 and 800 nm; and/or (ii) a polydispersity less than or equal to 0.8, preferably less than or equal to 0.
6, more preferably less than or equal to 0.5.
7. A process for preparing a solid composition according to any one of claims 1 to 6, the process comprising: (a) preparing an oil-in-water emulsion comprising: - an oil phase comprising the Rifamycin, such as Rifapentine; and 69324247-2 - an aqueous phase comprising a first and second excipient, each as defined in any of claims 1 to 6; and (b) removing the oil and water from the oil-in-water emulsion to form the solid composition.
8. A process for preparing a solid composition according to any one of claims 1 to 6, the process comprising: (a) providing an active solution comprising the Rifamycin, such as Rifapentine, in a water-miscible solvent; (b) providing a carrier material solution comprising a first and second excipient, each as defined in any of claims 1 to 6; (c) mixing the solutions prepared in steps (a) and (b); and (d) removing the mixed solvent to produce the solid composition; or, the process comprising: (a) providing an active solution comprising the Rifamycin, such as Rifapentine, and the second excipient in a water-miscible solvent; (b) providing a carrier material solution comprising a first excipient, each as defined in any of claims 1 to 6; (c) mixing the solutions prepared in steps (a) and (b); and (d) removing the mixed solvent to produce the solid composition.
9. The process of claim 7 wherein the step of removing the oil and water from the oil-in-water emulsion or the process of claim 8 wherein the step of removing the mixed solvent comprises spray drying or freeze-drying.
10. An aqueous dispersion comprising a plurality of nanoparticles of the Rifamycin, such as Rifapentine, dispersed in an aqueous medium and stabilised by a mixture of a first excipient and a second excipient; wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
11. The aqueous dispersion of claim 10, wherein: 69324247-2 (i) the aqueous dispersion comprises nanoparticles of the Rifamycin, such as Rifapentine, first excipients, and second excipients as defined in any of claims 2 to 6 in the aqueous medium; and/or (ii) the Rifamycin, such as Rifapentine, is present in the aqueous dispersion at a concentration of 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL.
12. A process for preparing an aqueous dispersion according to claim 10 or claim 11, the process comprising dispersing a solid composition according to any of claims 1 to 6 in an aqueous medium.
13. A pharmaceutical composition comprising the solid composition of any of claims 1 to 6, or the aqueous dispersion of claim 10 or claim 11 and, optionally, one or more further pharmaceutically acceptable excipients.
14. An injectable formulation comprising the solid composition of any of claims 1 to 6, the aqueous dispersion of claim 10 or claim 11, or the pharmaceutical composition of claim 13, optionally wherein the injectable formulation is a subcutaneously or intramuscularly injectable formulation, further optionally wherein the injectable formulation is suitable for provision in depot form.
15. A method of producing an implantable rod comprising the steps of compressing a solid composition according to any one of claims 1 to 6 and heating the compressed solid composition for a period of time.
16. The method of claim 15, wherein the solid composition is: (i) compressed in a mould, optionally the mould being cylindrical in form; and/or (ii) heated to a temperature from 60 to 160 °C, preferably from 80 to 140 °C, more preferably from 100 to 120 °C, most preferably about 105 °C.
17. The method of any one of claims 15 to 16, wherein the compression occurs under a reduced pressure atmosphere.
18. The method of any one of claims 15 to 17, wherein the heating step takes place for a period of from 1 minute to 40 minutes, preferably from 5 minutes 30 minutes, more preferably from 10 minutes to 25 minutes, most preferably about 20 minutes. 69324247-2
19. The method of any one of claims 15 to 18, further comprising a step of cooling the rod, optionally the cooling taking place under a reduced pressure atmosphere.
20. An implantable rod produced by the method of any one of claims 15 to 19.
21. An implantable rod comprising nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a monolith comprising a first excipient and a second excipient, wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
22. The implantable rod of claim 21, wherein the nanoparticles of the Rifamycin, such as Rifapentine, first excipient, and/or second excipient are as defined in any one of claims 2 to 6.
23. A method of producing a microneedle array comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition, the method comprising the steps of: a) dispersing a solid composition according to any one of claims 1 to 6 and at least one structural polymer in a solvent to form a microneedle precursor dispersion; b) placing the microneedle precursor dispersion into a mould; c) compressing the microneedle precursor dispersion in the mould and then drying to form microneedles comprising the first composition; d) adding a baseplate precursor solution into the mould; e) compressing the baseplate precursor solution and then drying to form the baseplate of the second composition; and f) releasing the microneedle array from the mould.
24. The method of claim 23, wherein: (i) steps b) and c) are repeated prior to steps d) to f); and/or (ii) the solvent is an aqueous solvent, such as water; and/or (iii) the at least one structural polymer is selected from PVA, PVP, and combinations thereof; and/or 69324247-2 (iv) the baseplate precursor solution comprises a base polymer selected from PVP and, optionally, one or more additives such as glycerol, dispersed in an aqueous solvent, such as water.
25. A microneedle array produced by the method of claim 23 or claim 24.
26. A microneedle array comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition, wherein the first composition comprises nanoparticles of a Rifamycin, such as Rifapentine, dispersed within a monolith comprising a first excipient, a second excipient and at least one structural polymer, wherein the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), lactose, and sucrose, and wherein the second excipient is selected from benzalkonium chloride, dioctyl sodium sulfosuccinate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxamer), Polysorbate 20, Polysorbate 80, and sorbitan monolaurate.
27. The microneedle array of claim 26, wherein: (i) the nanoparticles of the Rifamycin, such as Rifapentine, first excipient, and/or second excipient are as defined in any one of claims 2 to 6; and/or (ii) the at least one structural polymer is selected from PVA, PVP, and combinations thereof; and/or (iii) the second composition comprises a base polymer, such as PVP, and, optionally, one or more additives such as glycerol.
28. A solid composition according to any of claims 1 to 6, an aqueous dispersion according to claim 10 or claim 11, a pharmaceutical composition according to claim 13, an injectable formulation according to claim 14, an implantable rod according to any of claims 20 to 22, or a microneedle array according to any one of claims 25 to 27, for use as a medicament.
29. A solid composition according to any of claims 1 to 6, an aqueous dispersion according to claim 10 or claim 11, a pharmaceutical composition according to claim 13, an injectable formulation according to claim 14, an implantable rod according to any of 69324247-2 claims 20 to 22, or a microneedle array according to any one of claims 25 to 27, for use in the treatment and/or prevention of tuberculosis, such as latent tuberculosis.
30. An aqueous dispersion, a pharmaceutical composition, or an injectable formulation for use according to claim 28 or claim 29, wherein the concentration of Rifapentine is 100 to 1000 mg/mL, preferably 200 to 900 mg/mL, more preferably 300 to 800 mg/mL, and most preferably 500 to 700 mg/mL.
31. An implantable rod for use according to claim 28 or claim 29, wherein the concentration of the Rifamycin, such as Rifapentine, in the implantable rod is in the range of 30 to 80 wt%, preferably 40 to 70 wt%, most preferably about 50 wt%.
32. A microneedle array for use according to claim 28 or claim 29, wherein the microneedle array contains a mass of the Rifamycin, such as Rifapentine, in the range of between 0.1 and 20 mg of Rifapentine, preferably between 0.5 and 10 mg, more preferably between 1 and 5 mg, most preferably between 1 and 2 mg. 69324247-2
EP24715857.9A 2023-03-23 2024-03-22 Rifapentine compositions Pending EP4683617A1 (en)

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GBGB2304248.4A GB202304248D0 (en) 2023-03-23 2023-03-23 Rifapentine compositions
PCT/GB2024/050783 WO2024194655A1 (en) 2023-03-23 2024-03-22 Rifapentine compositions

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