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WO2023067350A1 - Compositions solides comprenant du ténofovir alafénamide et/ou du bictégravir - Google Patents

Compositions solides comprenant du ténofovir alafénamide et/ou du bictégravir Download PDF

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Publication number
WO2023067350A1
WO2023067350A1 PCT/GB2022/052684 GB2022052684W WO2023067350A1 WO 2023067350 A1 WO2023067350 A1 WO 2023067350A1 GB 2022052684 W GB2022052684 W GB 2022052684W WO 2023067350 A1 WO2023067350 A1 WO 2023067350A1
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WO
WIPO (PCT)
Prior art keywords
solid composition
bictegravir
oil
surfactant
tenofovir alafenamide
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.)
Ceased
Application number
PCT/GB2022/052684
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English (en)
Inventor
Steven Paul Rannard
Andrew Owen
James Hobson
Alison SAVAGE
Eleanor BARLOW
Paul CURLEY
Joanne SHARP
Ryan Donnelly
Chunyang Zhang
Yu Wu
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
Priority to CN202280083768.2A priority Critical patent/CN118414146A/zh
Priority to EP22797827.7A priority patent/EP4419073A1/fr
Publication of WO2023067350A1 publication Critical patent/WO2023067350A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • 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

Definitions

  • the present invention relates to solid compositions comprising microparticles of tenofovir alafenamide and/or bictegravir dispersed within a mixture of at least one hydrophilic polymer and at least one surfactant, and aqueous dispersions comprising microparticles of tenofovir alafenamide and/or bictegravir dispersed in an aqueous medium and stabilised by a mixture of at least one hydrophilic polymer and at least one surfactant.
  • the present invention also relates to methods of producing such compositions and dispersions, pharmaceutical compositions and injectable formulations, implantable rods and microneedle arrays derived from such compositions and dispersions, and medical uses for such compositions and dispersions and methods of treatment using such compositions and dispersions.
  • Tenofovir alafenamide is an antiviral drug in the nucleotide reverse transcriptase inhibitor (NRTI) class that is approved for use in the treatment of HIV and Hepatitis B.
  • NRTI nucleotide reverse transcriptase inhibitor
  • TAF is a prodrug of Tenofovir, and is converted to the active drug by cleavage of the phenyl and alanine isopropyl ester groups to unmask the phosphonic acid.
  • TAF is typically administered orally, being dosed once per day. The structure of TAF is shown below.
  • BIC Bictegravir
  • FTC emtricitabine
  • a first aspect of the present invention provides a solid composition comprising microparticles of tenofovir alafenamide and/or bictegravir dispersed within a mixture of at least one hydrophilic polymer and at least one surfactant; wherein the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, dextran, or a combination thereof; and wherein the surfactant is selected from vitamin-E-polyethylene glycol-succinate, sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, polyethylene glycol (15)-hydroxystearate, polyoxyethylene (20) cetyl ether, polyvinyl alcohol, or a combination thereof.
  • the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, dextran, or a combination thereof
  • the surfactant is selected from vitamin-E-polyethylene glycol-succinate, sodium deoxycholate, poly
  • the polydispersity of the microparticles of tenofovir alafenamide and/or bictegravir may be less than or equal to 0.8.
  • the solid composition comprises microparticles of tenofovir alafenamide;
  • the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, or a combination thereof; and the surfactant is selected from sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, polyoxyethylene (20) cetyl ether, or a combination thereof.
  • the solid composition comprises microparticles of tenofovir alafenamide;
  • the hydrophilic polymer is polyvinyl alcohol and the surfactant is selected from sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, and polyoxyethylene (20) cetyl ether; or the hydrophilic polymer is polyvinylpyrrolidone and the surfactant is sodium deoxycholate.
  • the solid composition comprises microparticles of tenofovir alafenamide;
  • the hydrophilic polymer is polyvinyl alcohol and the surfactant is selected from polysorbate 80 and polyoxyethylene (20) cetyl ether; or the hydrophilic polymer is polyvinylpyrrolidone and the surfactant is sodium deoxycholate.
  • the solid composition comprises microparticles of tenofovir alafenamide; the hydrophilic polymer is polyvinyl alcohol and the surfactant is polysorbate 80; or the hydrophilic polymer is polyvinylpyrrolidone and the surfactant is sodium deoxycholate.
  • the solid composition comprises microparticles of bictegravir; the hydrophilic polymer is polyvinyl alcohol; and the surfactant is selected from vitamin-E-polyethylene glycol-succinate, sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, polyethylene glycol (15)-hydroxystearate, polyoxyethylene (20) cetyl ether, or a combination thereof.
  • the solid composition comprises microparticles of bictegravir; the hydrophilic polymer is polyvinyl alcohol; and the surfactant is polysorbate 80.
  • the solid composition comprises microparticles of tenofovir alafenamide and bictegravir;
  • the hydrophobic polymer is polyvinyl alcohol;
  • the surfactant is selected from sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, polyoxyethylene (20) cetyl ether, or a combination thereof.
  • the solid composition comprises microparticles of tenofovir alafenamide and bictegravir;
  • the hydrophobic polymer is polyvinyl alcohol; and
  • the surfactant is selected from polysorbate 20, polysorbate 80 and dioctyl sulfosuccinate
  • the solid composition comprises microparticles of tenofovir alafenamide and bictegravir;
  • the hydrophobic polymer is polyvinyl alcohol; and
  • the surfactant is selected from polysorbate 80 and polyoxyethylene (20) cetyl ether.
  • the solid composition comprises microparticles of tenofovir alafenamide and bictegravir; the hydrophobic polymer is polyvinyl alcohol; and the surfactant is polysorbate 80.
  • the hydrophilic polymer and surfactant may both be polyvinyl alcohol.
  • the solid composition may further comprise one or more non-volatile oils.
  • the one or more nonvolatile oils may be selected from mineral oil, vitamin E, corn oil, peanut oil, soy bean oil, sesame oil, safflower oil, vegetable oil, avocado oil, rice bran oil, jojoba oil, Babassu oil, palm oil, coconut oil, castor oil, cotton seed oil, olive oil, flaxseed oil, rapeseed oil and mixtures thereof, preferably wherein the one or more non-volatile oils is selected from mineral oil, corn oil, peanut oil, and mixtures thereof.
  • a second aspect of the present invention provides a process for preparing a solid composition according to the first aspect of the present invention, the process comprising:
  • an oil phase comprising tenofovir alafenamide and/or bictegravir
  • aqueous phase comprising a hydrophilic polymer and a surfactant, each as defined in any embodiment of the first aspect of the present invention
  • the step of removing the oil and water from the oil-in-water emulsion may comprise spray drying or freeze-drying.
  • the oil phase may further comprise one or more nonvolatile oils as defined in the first aspect of the present invention.
  • a third aspect of the present invention provides a process for preparing a solid composition according to the first aspect of the present invention, the process comprising:
  • hydrophilic polymer and a surfactant each as defined in any embodiment of the first aspect of the present invention all in one or more solvents;
  • the step of removing the one or more solvents from the single phase solution may comprise spray drying or freeze-drying.
  • the single phase solution may further comprise one or more non-volatile oils as defined in the first aspect of the present invention.
  • a fourth aspect of the present invention provides an aqueous dispersion comprising a plurality of microparticles of tenofovir alafenamide and/or bictegravir dispersed in an aqueous medium and stabilised by a mixture of at least one hydrophilic polymer and at least one surfactant; wherein the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, dextran, or a combination thereof; and wherein the surfactant is selected from vitamin-E-polyethylene glycol-succinate, sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, polyethylene glycol (15)-hydroxystearate, polyoxyethylene (20) cetyl ether, polyvinyl alcohol, or a combination thereof.
  • the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, dextran, or a combination thereof
  • the surfactant is selected from vitamin-
  • the polydispersity of the microparticles of tenofovir alafenamide and/or bictegravir within the aqueous dispersion may be less than or equal to 0.8.
  • the microparticles of tenofovir alafenamide and/or bictegravir may further comprise one or more non-volatile oils.
  • a fifth aspect of the present invention provides 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 provides a pharmaceutical composition comprising a solid composition according to the first aspect of the present invention, or an aqueous dispersion according to the fourth aspect of the present invention, and optionally one or more additional pharmaceutically acceptable excipients.
  • a seventh aspect of the present invention provides an injectable formulation comprising a solid composition according to first aspect of the present invention, or an aqueous dispersion according to the fourth aspect of the present invention, or the pharmaceutical composition according to 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 provides 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 130 °C, most preferably about 120 °C.
  • the compression may occur under a reduced pressure atmosphere.
  • the heating step may take place for a period of from 1 minute to 30 minutes, preferably from 2 minutes to 25 minutes, more preferably from 5 minutes to 15 minutes, most preferably about 6 minutes.
  • the method 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 microparticles of tenofovir alafenamide and/or bictegravir dispersed within a monolith comprising a hydrophilic polymer and a surfactant, wherein the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, dextran, or a combination thereof; and wherein the surfactant is selected from vitamin-E-polyethylene glycol-succinate, sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, polyethylene glycol (15)-hydroxystearate, polyoxyethylene (20) cetyl ether, polyvinyl alcohol or a combination thereof.
  • the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, dextran, or a combination thereof
  • the surfactant is selected from vitamin-E-polyethylene glycol-succinate, sodium deoxychol
  • microparticles of tenofovir alafenamide and/or bictegravir, hydrophilic polymer, and/or surfactant may be as defined in the first aspect of the present invention.
  • the implantable rod may further comprise one or more non-volatile oils, optionally wherein the non-volatile oil is as defined in the first aspect of the present invention.
  • 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 15 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 produce 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 microparticles of tenofovir alafenamide and/or bictegravir dispersed within a monolith comprising: a hydrophilic polymer, wherein the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, dextran, or a combination thereof; and a surfactant, wherein the surfactant is selected from vitamin-E- polyethylene glycol-succinate, sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, polyethylene glycol (15)-hydroxystearate, polyoxyethylene (20) cetyl ether, polyvinyl alcohol or a combination thereof, and at least one structural polymer.
  • a hydrophilic polymer wherein the hydrophilic polymer is selected from poly
  • microparticles of tenofovir alafenamide and/or bictegravir, hydrophilic polymer, and/or surfactant are as defined in the first aspect of the present invention.
  • the microneedle array may further comprise one or more non-volatile oils, optionally the non-volatile oils are 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 provides a solid composition according to 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 the ninth or tenth aspects of the present invention, or a microneedle array according to the twelfth and thirteenth aspects of the present invention, for use as a medicament.
  • An fifteenth aspect of the present invention provides a solid composition according to 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 the ninth or tenth aspects of the present invention, or a microneedle array according to the twelfth and thirteenth aspects of the present invention, for use in the treatment and/or prevention of viral infections, optionally wherein the solid composition, aqueous dispersion, pharmaceutical composition, or injectable formulation is administered in combination with one or more other antiviral agents.
  • a sixteenth aspect of the present invention provides a method of treating and/or preventing a viral infection, the method comprising administering a therapeutically effective amount of a solid composition according to 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 the ninth or tenth aspects of the present invention, or a microneedle array according to the twelfth and thirteenth aspects of the present invention, to a patient suffering from or at risk of suffering from a viral infection, optionally wherein the solid composition, aqueous dispersion, pharmaceutical composition, or injectable formulation is administered in combination with one or more other antiviral agents.
  • viral infection is used herein to refer to viral infections in general, including by HIV and Hepatitis-B. Although the initial investigation is in the context of HIV and Hepatitis-B, it will be understood that the pharmaceutically active compounds disclosed herein also have broader antiviral activity.
  • Microparticles are, for the purposes of the present invention, considered to be any particle with a Z-average hydrodynamic diameter (as measured using dynamic light scattering - DLS) below 5 pm. This includes particles with sizes ranging from 1 to 1000 nm, commonly defined as nanoparticles.
  • particle size is used herein to refer to the z-average hydrodynamic diameter (D z ), which may be determined by Dynamic Light Scattering.
  • polydispersity index (Pdl) is in reference to the measurement provided by dynamic light scattering, in which perfect monodispersity is 0.
  • a product which consists essentially of a designated material (or materials) comprises greater than or equal to 85% of the designated material, more suitably 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).
  • weight percentages (“wt%”) discussed herein relate to the % by weight of a particular constituent as a proportion of the total weight of the composition.
  • weight/volume percentages (“w/v%”) discussed herein relate to the weight of the indicated material (in grams) per 100 mL of solvent.
  • references to “preventing” or “prevention” relate to prophylactic treatment and includes preventing, limiting or delaying a viral infection following a patient’s exposure to a virus. This may involve preventing, limiting or delaying the appearance of clinical symptoms developing in a patient that may be afflicted with or exposed to the virus but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition. Such prevention may prevent or reduce onward transmission of the virus.
  • references to “treatment” or “treating” of a viral infection includes: (1) inhibiting the symptoms of the infection, 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 infection, i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • Such treatment may prevent or reduce onward transmission of the virus.
  • preventing or “prevention” should not be considered to refer only to formulations which are completely effective in treating an infection, but also to cover formulations which are partially effective as well.
  • the terms “preventing” and “prevention” should be considered to cover formulations which are useful at reducing the rate of incidence of viral in that target population, as well as medicaments which are useful at completely eradicating the viral infection from that target population.
  • a “therapeutically effective amount” means the amount of pharmaceutically active compound that, when administered to a patient for treating and/or preventing a disease, is sufficient to effect such treatment/prevention for the viral, helminth or protozoal infection.
  • the "therapeutically effective amount” will vary depending on the pharmaceutically active compound (e.g. tenofovir alafenamide and/or bictegravir), the severity of the infection and the age, weight, etc., of the patient to be treated.
  • the present invention provides a solid composition comprising microparticles of tenofovir alafenamide and/or bictegravir dispersed within a mixture of at least one hydrophilic polymer and at least one surfactant; wherein the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, dextran, or a combination thereof; and wherein the surfactant is selected from vitamin-E-polyethylene glycol-succinate, sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, polyethylene glycol (15)-hydroxystearate, polyoxyethylene (20) cetyl ether, polyvinyl alcohol, or a combination thereof.
  • the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, dextran, or a combination thereof
  • the surfactant is selected from vitamin-E-polyethylene glycol-succinate, sodium deoxycholate, polysorbate 20, poly
  • microparticles of tenofovir alafenamide and/or bictegravir are dispersed within a solid excipient mixture comprising the hydrophilic polymer and the surfactant.
  • microparticles of tenofovir alafenamide and/or bictegravir may be microparticles of tenofovir alafenamide in the absence of bictegravir.
  • the microparticles of tenofovir alafenamide and/or bictegravir may be microparticles of bictegravir in the absence of tenofovir alafenamide.
  • microparticles of tenofovir alafenamide and/or bictegravir may be microparticles of tenofovir alafenamide and/or microparticles of bictegravir.
  • the solid composition comprises microparticles consisting of, or consisting essentially of, tenofovir alafenamide and/or microparticles consisting of, or consisting essentially of, bictegravir.
  • microparticles of tenofovir alafenamide and/or bictegravir may be microparticles of tenofovir alafenamide and bictegravir, wherein the microparticles comprise both tenofovir alafenamide and bictegravir.
  • the solid composition may comprise a mixture of the above microparticles.
  • the solid composition may comprise at least two of microparticles of tenofovir alafenamide, microparticles of bictegravir, and microparticles of both tenofovir alafenamide and bictegravir.
  • the tenofovir alafenamide and/or bictegravir which comprises the microparticles may be amorphous (i.e. substantially non-crystalline in nature).
  • the solid excipient mixture is in the form of a matrix, which is highly porous in nature and rapidly dissolves 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 microparticles of the present invention have an average particle diameter of less than 5 micron ( .m).
  • the microparticles 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 microparticles are nanoparticles (i.e. they have a particle diameter in the range of 1 to
  • references to particle diameter are references to the Z-average hydrodynamic diameter of the microparticles.
  • the microparticles of the present invention may have an average particle size of less than or equal to 1 micron (
  • microparticles of the present invention may have an average particles size of greater than 1 micron ( .m), i.e. greater than 1000 nm. In an embodiment the microparticles have an average particle size of between 1 and 10 micron. In a particular embodiment, the microparticles have an average particle size of between
  • the microparticles of bictegravir have a particle size between 1200 nm and 2600 nm. In other embodiments, the microparticles of bictegravir have particles sizes between 500 nm and 2600 nm.
  • Microparticles of the invention may have an average particle size of between 100 nm and 10 microns, preferably between 100 nm and 5 microns, more preferably between 100 nm and 3 microns.
  • the microparticles 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 size and polydispersity of the microparticles 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 size is assessed by dispersing the solid composition in an aqueous medium and determining the particle size with 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 contain a plurality of microparticles of tenofovir alafenamide and/or bictegravir dispersed within a mixture of the hydrophilic polymer and surfactant.
  • 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 microparticles of tenofovir alafenamide and/or bictegravir.
  • the solid composition comprises a single hydrophilic polymer and a single surfactant selected from those listed herein. In an alternative embodiment, the solid composition comprises two or more hydrophilic polymers and/or two or more surfactant selected from those listed herein may be present.
  • the solid composition may further comprise one or more non-volatile oils.
  • any hydrophilic polymer suitable for use in pharmaceutical formulations may be employed in the present invention.
  • Particularly suitable polymers include: polyvinylpyrrolidone k30 (PVP k30, such as is available as KollidonTM 30); polyvinylpyrrolidone k17 (PVP k17, such as is available as PlasdoneTM C-15); polyvinylpyrrolidone k12 (PVP k12, such as is available as KollidonTM 12PF); polyvinyl alcohol (PVA); hydroxypropylmethylcellulose (HPMC); polyethylene glycol 400 (PEG 400); polyethylene glycol 1000 (PEG 1000); polyethylene glycol 4000 (PEG 4000); polyvinyl alcohol-polyethylene glycol graft copolymers (such as those available in the KollicoatTM range); non-ionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), which are also known as poloxamers (such as those available in the
  • the hydrophilic polymer is selected from those hydrophilic polymers that are capable of stabilising microparticles of tenofovir alafenamide and/or bictegravir in an aqueous dispersion together with a surfactant as defined herein, and which are also suitable for pharmaceutical use (e.g. they are on the US Food and Drug Administration’s Generally Recognised as Safe (FDA GRAS) list).
  • hydrophilic polymers have been found to be particularly suitable for use in the present invention: polyvinyl alcohol, polyvinylpyrrolidones, and dextrans.
  • molecular weight (Mw) or molecular number (Mn) values quoted herein span the range of Mw and Mn values that may be present in the polymer.
  • the polyvinyl alcohol has an average molecular weight between 5000 and 200000 Da, suitably with a 75-90% hydrolysis level (i.e. % free hydroxyls). In a particular embodiment, the polyvinyl alcohol has a 75-90% hydrolysis level. In another embodiment, the polyvinyl alcohol has a 75-85% hydrolysis level. In a particular embodiment, the polyvinyl alcohol has an average molecular weight between 9000 and 10000 Da, suitably with an 80% hydrolysis level.
  • the polyvinylpyrrolidone has an average molecular weight of 2000 to 1 ,000,000 Da. In a particular embodiment, the polyvinylpyrrolidone has an average molecular weight of 30000 to 55000 Da. In a particular embodiment, the polyvinylpyrrolidone is polyvinylpyrrolidone K30 (PVP K30).
  • the hydrophilic polymer is polyvinyl alcohol or polyvinylpyrrolidone. In a particular embodiment, the hydrophilic polymer is polyvinyl alcohol.
  • any surfactant suitable for use in pharmaceutical formulations may be employed in the present invention.
  • surfactants include:
  • 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);
  • non-ionic surfactants e.g. ethoxylated triglycerides; fatty alcohol ethoxylates; alkylphenol ethoxylates; fatty acid ethoxylates; fatty amide ethoxylates; fatty amine ethoxylates;
  • 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);
  • anionic surfactants e.g. alkylether sulfates; alkylether carboxylates; alkylbenzene sulfonates; alkylether phosphates; dialkyl sulfosuccinates; sarcosinates; alkyl sulfonates; soaps; alkyl
  • cationic surfactants e.g. fatty amine salts; fatty diamine salts; quaternary ammonium compounds; phosphonium surfactants; sulfonium surfactants; sulfonxonium surfactants); or
  • zwitterionic surfactants e.g. N-alkyl derivatives of amino acids (such as glycine, betaine, aminopropionic acid); imidazoline surfactants; amine oxides; amidobetaines).
  • the surfactant is selected from those surfactants that are capable of stabilising microparticles of tenofovir alafenamide and/or bictegravir in an aqueous dispersion together with a hydrophilic polymer as defined herein, and which are also suitable for pharmaceutical use (e.g. they are on the US Food and Drug Administration’s Generally Recognised as Safe (FDA GRAS) list).
  • vitamin-E-polyethylene glycol-succinate also known as D-a- Tocopherol polyethylene glycol 1000 succinate (TPGS)
  • TPGS D-a- Tocopherol polyethylene glycol 1000 succinate
  • sodium deoxycholate polysorbate 20 (such as is available as TweenTM 20); polysorbate 80 (such as is available as TweenTM 80); dioctyl sulfosuccinate (also known as sodium docusate or AOT); polyethylene glycol (15)-hydroxystearate (such as it available as SolutolTM HS 15 or KolliphorTM HS 15); polyoxyethylene (20) cetyl ether (such as is available as BrijTM 58); alkyldimethylbenzylammonium chloride (also known as benzalkonium chloride); and polyvinyl alcohol.
  • TPGS D-a- Tocopherol polyethylene glycol 1000 succinate
  • sodium deoxycholate polysorbate 20 (such as is available as TweenTM 20); poly
  • the surfactant is selected from sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, polyoxyethylene (20) cetyl ether, and polyvinyl alcohol.
  • the surfactant is selected from polysorbate 80, polyoxyethylene (20) cetyl ether, and polyvinyl alcohol.
  • the surfactant is deoxycholate. In other embodiments, the surfactant is polysorbate 80. In yet other embodiments, the surfactant is polyvinyl alcohol.
  • polyvinyl alcohol may be used as the hydrophilic polymer, as the surfactant, or as both.
  • the role played by the polyvinyl alcohol can be determined by the other constituents of the composition.
  • any non-volatile oil suitable for use in pharmaceutical formulations may be employed in the present invention.
  • Non-volatile oils according to the present invention are immiscible with water and remain present in the solid composition after removal of the solvent.
  • Suitable non-volatile oils may be selected from mineral oil, vitamin E, corn oil, peanut oil, soy bean oil, sesame oil, safflower oil, vegetable oil, avocado oil, rice bran oil, jojoba oil, Babassu oil, palm oil, coconut oil, castor oil, cotton seed oil, olive oil, flaxseed oil, rapeseed oil and mixtures thereof.
  • non-volatile oils may be selected from mineral oil, corn oil, peanut oil, and mixtures thereof. Formulations of the solid composition
  • the solid composition as defined herein comprises 50 to 95 wt% of tenofovir alafenamide and/or bictegravir. In another embodiment, the solid composition comprises 60 to 85 wt% of tenofovir alafenamide and/or bictegravir. In another embodiment, the solid composition comprises 65 to 75 wt% of tenofovir alafenamide and/or bictegravir.
  • the solid composition may comprise about 70 wt% of tenofovir alafenamide and/or bictegravir; preferably about 80 wt% of tenofovir alafenamide and/or bictegravir; more preferably about 90 wt% of tenofovir alafenamide and/or bictegravir.
  • the solid composition comprises 65 to 95 wt% of tenofovir alafenamide and/or bictegravir.
  • the weight ratio of tenofovir alafenamide to bictegravir may be in the range of 2:1 to 1 :10, preferably in the range of 1 :1 to 1:5, more preferably about 1 :2.
  • the weight ratio of tenofovir alafenamide to bictegravir may be in the range of 2:1 to 1 :10, preferably in the range of 1 :1 to 1 :5, more preferably about 1 :2.
  • the solid composition comprises 5 to 50 wt% of the hydrophilic polymer and surfactant combined. In another embodiment, the solid composition comprises 15 to 40 wt% of the hydrophilic polymer and surfactant combined. In another embodiment, the solid composition comprises 25 to 35 wt% of the hydrophilic polymer and surfactant combined. Alternatively, the solid composition may comprise about 30 wt% of the hydrophilic polymer and surfactant combined; preferably about 20 wt% of the hydrophilic polymer and surfactant combined; more preferably about 10 wt% of the hydrophilic polymer and surfactant combined. Further alternatively, the solid composition comprises 5 to 35 wt% of the hydrophilic polymer and surfactant combined.
  • the hydrophilic polymer and surfactant may be present in a weight ratio in the range of 1 :1 to 4:1; preferably in the range of 2:1 to 3:1.
  • the solid composition may comprise 2 to 40 wt% of hydrophilic polymer; preferably 7 to 32 wt% of hydrophilic polymer; more preferably 12 to 28 wt% hydrophilic polymer.
  • the solid composition comprises about 20 wt% hydrophilic polymer; preferably about 15 wt% hydrophilic polymer; more preferably about 7.5 wt% hydrophilic polymer.
  • the solid composition may comprise 2 to 30 wt% hydrophilic polymer.
  • the solid composition may comprise 1 to 25 wt% surfactant; preferably 3 to 20 wt% surfactant; more preferably 5 to 18 wt% surfactant. In another embodiment, the solid composition comprises about 10 wt% surfactant; preferably about 5 wt% surfactant; more preferably about 2.5 wt% surfactant. Further alternatively, the solid composition may comprise 1 to 15 wt% surfactant.
  • the solid composition comprises 50 to 95 wt% of tenofovir alafenamide and/or bictegravir; 2 to 40 wt% hydrophilic polymer; and 1 to 15 wt% surfactant.
  • the solid composition comprises 65 to 95 wt% of tenofovir alafenamide and/or bictegravir; 2 to 30 wt% hydrophilic polymer; and 1 to 12 wt% surfactant.
  • the solid composition comprises 70 to 90 wt% of tenofovir alafenamide and/or bictegravir; 7.5 to 20 wt% hydrophilic polymer; and 2.5 to 10 wt% surfactant.
  • 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 one or more additional excipients, for instance, to further facilitate dispersion or stabilisation of dispersions of the microparticles either in a pharmaceutically acceptable diluent or in vivo.
  • the solid composition as defined herein may further comprise one or more non-volatile oils. Without wishing to be bound by theory, it is believed that the inclusion of one or more non-volatile oils may modify the rate of release of the TAF and/or BIC from long acting injectables, implantable rods, or microneedles according to the present invention.
  • the solid composition may comprise one or more non-volatile oils in an amount of 0.1 to 25 wt%, preferably in an amount of 1 to 20 wt%, more preferably in an amount of 5 to 15 wt%, most preferably in an amount of 10 wt%.
  • the solid composition comprises 50 to 90 wt%, tenofovir alafenamide and/or bictegravir, 5 to 30 wt% hydrophilic polymer, 1 to 15 wt% surfactant, and 1 to 20 wt% non-volatile oil, preferably comprises 60 to 80 wt% tenofovir alafenamide and/or bictegravir, 10 to 20 wt% hydrophilic polymer, 2 to 10 wt% surfactant, and 5 to 15 wt% non-volatile oil, and more preferably comprises 70 wt% tenofovir alafenamide and/or bictegravir, 15 wt% hydrophilic polymer, 5 wt% surfactant, and 10 wt% non-volatile oil.
  • the solid composition comprises microparticles of tenofovir alafenamide; the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, or a combination thereof; and the surfactant is selected from sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, polyoxyethylene (20) cetyl ether, polyvinyl alcohol or a combination thereof.
  • the solid composition comprises 50 to 75 wt% tenofovir alafenamide; 15 to 30 wt% hydrophilic polymer; and 5 to 20 wt% surfactant. More preferably, the solid composition comprises about 70 wt% tenofovir alafenamide; about 20 wt% hydrophilic polymer; and about 10 wt% surfactant.
  • the solid composition comprises microparticles of tenofovir alafenamide; the hydrophilic polymer is polyvinyl alcohol and the surfactant is selected from sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, and polyoxyethylene (20) cetyl ether.
  • the solid composition comprises 50 to 75 wt% tenofovir alafenamide; 15 to 30 wt% polyvinyl alcohol; and 5 to 20 wt% surfactant. More preferably, the solid composition comprises about 70 wt% tenofovir alafenamide; about 20 wt% polyvinyl alcohol; and about 10 wt% surfactant.
  • the solid composition comprises microparticles of tenofovir alafenamide; the hydrophilic polymer is polyvinyl alcohol and the surfactant is selected from polysorbate 80 and polyoxyethylene (20) cetyl ether.
  • the solid composition comprises 50 to 85 wt% tenofovir alafenamide; 10 to 30 wt% polyvinyl alcohol; and 2 to 20 wt% surfactant. More preferably, the solid composition comprises about 80 wt% tenofovir alafenamide; about 15 wt% polyvinyl alcohol; and about 5 wt% surfactant.
  • the solid composition comprises microparticles of tenofovir alafenamide; the hydrophilic polymer is polyvinyl alcohol and the surfactant is polysorbate 80.
  • the solid composition comprises 50 to 95 wt% tenofovir alafenamide; 2 to 30 wt% polyvinyl alcohol; and 2 to 20 wt% polysorbate 80. More preferably, the solid composition comprises about 90 wt% tenofovir alafenamide; about 7.5 wt% polyvinyl alcohol; and about 2.5 wt% polysorbate 80.
  • the solid composition comprises microparticles of tenofovir alafenamide; the hydrophilic polymer is polyvinylpyrrolidone and the surfactant is sodium deoxycholate.
  • the solid composition comprises 50 to 95 wt% tenofovir alafenamide; 5 to 30 wt% polyvinylpyrrolidone; and 2 to 20 wt% sodium deoxycholate.
  • the solid composition may comprise about 70 wt% tenofovir alafenamide; about 20 wt% polyvinylpyrrolidone; and about 10 wt% sodium deoxycholate.
  • the solid composition comprises about 80 wt% tenofovir alafenamide; about 15 wt% polyvinylpyrrolidone; and about 5 wt% sodium deoxycholate. More preferably, the solid composition comprises about 90 wt% tenofovir alafenamide; about 7.5 wt% polyvinylpyrrolidone; and about 2.5 wt% sodium deoxycholate.
  • the solid composition comprises microparticles of tenofovir alafenamide; and each of the hydrophilic polymer and the surfactant is polyvinyl alcohol.
  • the solid composition comprises 50 to 85 wt% tenofovir alafenamide and 15 to 50 wt% polyvinyl alcohol. More preferably, the solid composition comprises 60 to 80 wt% tenofovir alafenamide and 20 to 40 wt% polyvinyl alcohol. Most preferably, the solid composition comprises about 70 wt% tenofovir alafenamide and about 30 wt% polyvinyl alcohol.
  • the solid composition comprises microparticles of tenofovir alafenamide, each of the hydrophilic polymer and the surfactant is polyvinyl alcohol, and further comprises a non-volatile oil selected from mineral oil, corn oil, and peanut oil.
  • the solid composition comprises 50 to 85 wt% tenofovir alafenamide, 10 to 40 wt% polyvinyl alcohol, and 1 to 30 wt% of a non-volatile oil selected from mineral oil, corn oil, and peanut oil.
  • the solid composition comprises 60 to 80 wt% tenofovir alafenamide, 15 to 30 wt% polyvinyl alcohol, and 5 to 15 wt% of a non-volatile oil selected from mineral oil, corn oil, and peanut oil. Most preferably, the solid composition comprises about 70 wt% tenofovir alafenamide, about 20 wt% polyvinyl alcohol, and about 10 wt% of a non-volatile oil selected from mineral oil, corn oil, and peanut oil.
  • the solid composition comprises microparticles of bictegravir; the hydrophilic polymer is polyvinyl alcohol; and the surfactant is selected from vitamin- E-polyethylene glycol-succinate, sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, polyethylene glycol (15)-hydroxystearate, and polyoxyethylene (20) cetyl ether.
  • the solid composition comprises 65 to 85 wt% bictegravir; 10 to 30 wt% hydrophilic polymer; and 2 to 20 wt% surfactant.
  • the solid composition comprises about 70 wt% bictegravir; about 20 wt% hydrophilic polymer; and about 10 wt% surfactant; or the solid composition comprises about 80 wt% bictegravir; about 15 wt% hydrophilic polymer; and about 5 wt% surfactant.
  • the solid composition comprises microparticles of bictegravir; the hydrophilic polymer is polyvinyl alcohol; and the surfactant is polysorbate 80.
  • the solid composition comprises 50 to 95 wt% bictegravir; 2 to 30 wt% polyvinyl alcohol; and 2 to 20 wt% polysorbate 80. More preferably, the solid composition comprises about 90 wt% bictegravir; about 7.5 wt% polyvinyl alcohol; and about 2.5 wt% polysorbate 80.
  • the solid composition comprises microparticles of bictegravir; and each of the hydrophilic polymer and the surfactant is polyvinyl alcohol.
  • the solid composition comprises 50 to 85 wt% bictegravir and 15 to 50 wt% polyvinyl alcohol. More preferably, the solid composition comprises 60 to 80 wt% bictegravir and 20 to 40 wt% polyvinyl alcohol. Most preferably, the solid composition comprises about 70 wt% bictegravir and about 30 wt% polyvinyl alcohol.
  • the solid composition comprises microparticles of bictegravir, each of the hydrophilic polymer and the surfactant is polyvinyl alcohol, and further comprises a non-volatile oil selected from mineral oil, corn oil, and peanut oil.
  • the solid composition comprises 50 to 85 wt% bictegravir, 10 to 40 wt% polyvinyl alcohol, and 1 to 30 wt% of a non-volatile oil selected from mineral oil, corn oil, and peanut oil.
  • the solid composition comprises 60 to 80 wt% bictegravir, 15 to 30 wt% polyvinyl alcohol, and 5 to 15 wt% of a non-volatile oil selected from mineral oil, corn oil, and peanut oil. Most preferably, the solid composition comprises about 70 wt% bictegravir, about 20 wt% polyvinyl alcohol, and about 10 wt% of a non-volatile oil selected from mineral oil, corn oil, and peanut oil.
  • the solid composition comprises microparticles of tenofovir alafenamide and microparticles of bictegravir.
  • Such compositions may be obtained by combining any of the solid compositions comprising tenofovir alafenamide outlined above with any of the solid compositions comprising bictegravir outlined above. Alternatively, they may be obtained through the mixing of the emulsions or single phase solutions from which each of the solid compositions are derived.
  • the solid composition comprises microparticles of tenofovir alafenamide and bictegravir.
  • Such compositions may be obtained by the mixing of the emulsions or single phase solutions from which each of the solid compositions are derived. Alternatively, they may be obtained by using combinations of hydrophilic polymers and surfactants that have been found to be effective for each of tenofovir alafenamide and bictegravir alone.
  • the solid composition comprises microparticles of tenofovir alafenamide and bictegravir;
  • the hydrophilic polymer is polyvinyl alcohol; and
  • the surfactant is selected from sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, and polyoxyethylene (20) cetyl ether.
  • the solid composition comprises 50 to 75 wt% tenofovir alafenamide and bictegravir combined; 15 to 30 wt% polyvinyl alcohol; and 5 to 20 wt% surfactant. More preferably, the solid composition comprises about 70 wt% tenofovir alafenamide and bictegravir combined; about 20 wt% polyvinyl alcohol; and about 10 wt% surfactant.
  • the solid composition comprises microparticles of tenofovir alafenamide and bictegravir; the hydrophilic polymer is polyvinyl alcohol; and the surfactant is selected from polysorbate 20, polysorbate 80 and dioctyl sulfosuccinate.
  • the solid composition comprises 50 to 85 wt% tenofovir alafenamide and bictegravir combined; 10 to 30 wt% polyvinyl alcohol; and 2 to 20 wt% surfactant.
  • the solid composition comprises about 70 wt% tenofovir alafenamide and bictegravir combined; about 20 wt% polyvinyl alcohol; and about 10 wt% surfactant.
  • the solid composition comprises microparticles of tenofovir alafenamide and bictegravir; the hydrophilic polymer is polyvinyl alcohol; and the surfactant is selected from polysorbate 80 and polyoxyethylene (20) cetyl ether.
  • the solid composition comprises 50 to 85 wt% tenofovir alafenamide and bictegravir combined; 10 to 30 wt% polyvinyl alcohol; and 2 to 20 wt% surfactant. More preferably, the solid composition comprises about 80 wt% tenofovir alafenamide and bictegravir combined; about 15 wt% polyvinyl alcohol; and about 5 wt% surfactant.
  • the solid composition comprises microparticles of tenofovir alafenamide and bictegravir; the hydrophilic polymer is polyvinyl alcohol; and the surfactant is polysorbate 80.
  • the solid composition comprises 50 to 95 wt% tenofovir alafenamide and bictegravir combined; 2 to 30 wt% polyvinyl alcohol; and 2 to 20 wt% polysorbate 80. More preferably, the solid composition comprises about 90 wt% tenofovir alafenamide and bictegravir combined; about 7.5 wt% polyvinyl alcohol; and about 2.5 wt% polysorbate 80.
  • the solid composition comprises microparticles of tenofovir alafenamide and bictegravir; and each of the hydrophilic polymer and the surfactant is polyvinyl alcohol.
  • the solid composition comprises 50 to 85 wt% tenofovir alafenamide and bictegravir combined and 15 to 50 wt% polyvinyl alcohol. More preferably, the solid composition comprises 60 to 80 wt% tenofovir alafenamide and bictegravir combined and 20 to 40 wt% polyvinyl alcohol. Most preferably, the solid composition comprises about 70 wt% tenofovir alafenamide and bictegravir combined and about 30 wt% polyvinyl alcohol.
  • the solid composition comprises microparticles of tenofovir alafenamide and bictegravir, each of the hydrophilic polymer and the surfactant is polyvinyl alcohol, and further comprises a non-volatile oil selected from mineral oil, corn oil, and peanut oil.
  • the solid composition comprises 50 to 85 wt% tenofovir alafenamide and bictegravir, 10 to 40 wt% polyvinyl alcohol, and 1 to 30 wt% of a nonvolatile oil selected from mineral oil, corn oil, and peanut oil.
  • the solid composition comprises 60 to 80 wt% tenofovir alafenamide and bictegravir, 15 to 30 wt% polyvinyl alcohol, and 5 to 15 wt% of a non-volatile oil selected from mineral oil, corn oil, and peanut oil. Most preferably, the solid composition comprises about 70 wt% tenofovir alafenamide and bictegravir combined, about 20 wt% polyvinyl alcohol, and about 10 wt% of a non-volatile oil selected from mineral oil, corn oil, and peanut oil.
  • compositions of the present invention may be prepared by a number of methods well known in the art. 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 composition may be prepared by milling a solid form of tenofovir alafenamide and/or bictegravir.
  • the milling may occur in the presence of the hydrophilic polymer and surfactant, or, alternatively, they may be mixed with the milled drugs after the milling step. If included, the milling may occur in the presence of the non-volatile oil, or, alternatively, the oil may be mixed with the milled drugs after the milling step.
  • the solid compositions of the present invention are prepared by an oil-in-water emulsion technique whereby the tenofovir alafenamide and/or bictegravir are dissolved in the oil phase and the hydrophilic polymer and surfactant 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. If included, the non-volatile oil is included in the oil phase.
  • the solid composition comprises individual microparticles comprising both tenofovir alafenamide and/or bictegravir, in which case both tenofovir alafenamide and/or bictegravir must be present during particle formation.
  • the solid composition comprises individual microparticles of tenofovir alafenamide and individual microparticles of bictegravir, in which case each set of individual microparticles are formed separately before being subsequently mixed or blended. A mixture of these two processes is also feasible.
  • a general process for preparing a solid composition comprising microparticles of tenofovir alafenamide and/or bictegravir as defined herein, the process comprising:
  • a process for preparing a solid composition comprising microparticles of tenofovir alafenamide as defined herein, the process comprising:
  • a process for preparing a solid composition comprising microparticles of bictegravir as defined herein, the process comprising:
  • a process for preparing a solid composition comprising microparticles of tenofovir alafenamide and microparticles of bictegravir as defined herein, the process comprising:
  • 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 microparticles formed are substantially uniform in their physical form (size, shape etc.).
  • 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.
  • the mixing may involve stirring, sonication, homogenisation, or a combination thereof.
  • the mixing is facilitated by sonication and/or homogenisation.
  • 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.
  • oil-in-water formation comprises:
  • the oil phase is provided by dissolving tenofovir alafenamide and/or bictegravir in a suitable organic solvent.
  • tenofovir alafenamide and bictegravir are dissolved, each of tenofovir alafenamide and bictegravir may be dissolved separately in a suitable organic solvent (optionally different organic solvents) and subsequently mixed to form the oil phase. Alternatively, they may be dissolved simultaneously.
  • the aqueous phase is provided by dissolving hydrophilic polymer and surfactant in an aqueous medium, preferably in water.
  • the aqueous phase may be provided by mixing two separately prepared aqueous solutions of the surfactant and hydrophilic polymer.
  • aqueous medium e.g. water
  • organic solvent is added before or during mixing step (iii).
  • the concentration of tenofovir alafenamide and/or bictegravir in the oil-in-water emulsion is suitably as concentrated as possible to facilitate effective scale-up of the process.
  • concentration of tenofovir alafenamide and/or bictegravir in the oil phase is suitably 60 mg/ml or higher, more suitably 70 mg/ml or higher, even more suitably 80 mg/ml or higher, most suitably greater than 90 mg/ml or higher.
  • the concentration of the hydrophilic polymer in the aqueous phase is suitably 0.1-50 mg/mL, more suitably 0.5 to 10 mg/mL, even more suitably 1 to 5 mg/mL.
  • the concentration of the surfactant 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 2 mg/mL.
  • one or more non-volatile oils may be incorporated into the oil phase.
  • concentration of the one or more non-volatile oil may be in the range of 1 to 20 mg/mL, preferably in the range of 5 to 15 mg/mL, more preferably about 10 mg/mL.
  • the ratio of the hydrophilic polymer to surfactant in the aqueous phase emulsion is suitably in the range of 1:1 to 4:1 ; preferably in the range of 2:1 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.
  • ICH International Conference on Harmonization
  • 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 selected from chloroform, dichloromethane, methylethyl ketone (MEK), methylbutylketone (MBK), and ethyl acetate.
  • the volume ratio of aqueous phase to oil phase in mixing step (iii) is suitably between 20:1 and 1:1, more suitably between 10:1 and 1 :1 , even more suitably between 6:1 and 2:1 , and most suitably about 4:1.
  • Mixing step (iii) suitably produces a substantially uniform oil-in-water emulsion.
  • mixing may be performed using methods well known in the art.
  • mixing step (iii) involves stirring, sonication, homogenisation, or a combination thereof.
  • 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.
  • removing the oil and water involves freeze drying the oil-in- water emulsion.
  • removing the oil and water may suitably comprise freezing the oil-in-water emulsion and then removing the solvents under vacuum.
  • 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.
  • 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
  • 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 blending may suitably employ methods well known in the art. Blending suitably provides a substantially homogeneous solid composition.
  • the present invention provides a process for preparing a solid composition as defined herein, the process comprising:
  • the single phase solution comprising the tenofovir alafenamide and/or bictegravir, hydrophilic polymer, and surfactant are all dissolved in one solvent or two or more miscible solvents.
  • WO 2008/006712 also lists suitable solvents and combinations thereof for forming the single phase solution.
  • the single phase solution comprises two or more solvents (e.g. ethanol and water) which together solubilise tenofovir alafenamide and/or bictegravir, hydrophilic polymer, and the surfactant.
  • the single phase comprises a single solvent, for example ethanol or water.
  • the single phase solution may further comprise one or more non-volatile oils.
  • Removing the one or more solvents may be performed using methods well known in the art.
  • removing the one or more solvents involves freeze drying, spray drying or spray granulation.
  • removal of the one or more solvents from the single phase fluid mixture may involve spray drying - again WO 2008/006712 details suitable spray-drying conditions.
  • removal of the one or more solvents may comprise freezing the single phase fluid mixture and then removing the solvents under vacuum.
  • the present invention also provides a solid composition obtainable by, obtained by, or directly obtained by any of the processes described herein.
  • the present invention provides an aqueous dispersion comprising a plurality of microparticles of tenofovir alafenamide and/or bictegravir dispersed in an aqueous medium and stabilised by a mixture of at least one hydrophilic polymer and at least one surfactant; wherein the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, dextran, or a combination thereof; and wherein the surfactant is selected from vitamin-E-polyethylene glycol-succinate, sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, polyethylene glycol (15)-hydroxystearate, polyoxyethylene (20) cetyl ether, polyvinyl alcohol or a combination thereof.
  • the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, dextran, or a combination thereof
  • the surfactant is selected from vitamin-E-polyethylene
  • microparticles of tenofovir alafenamide and/or bictegravir may refer to: microparticles comprising tenofovir alafenamide and bictegravir; microparticles comprising tenofovir alafenamide in the absence of bictegravir; microparticles comprising bictegravir in the absence of tenofovir alafenamide; and/or microparticles comprising tenofovir alafenamide and microparticles comprising bictegravir.
  • microparticles of tenofovir alafenamide and/or bictegravir may further comprise one or more non-volatile oils.
  • 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 hydrophilic polymer and/or surfactant When the solid composition is dispersed in the aqueous medium, the hydrophilic polymer and/or surfactant is dissolved within the aqueous medium to release the microparticles of tenofovir alafenamide and/or bictegravir in a dispersed form.
  • the microparticles of tenofovir alafenamide and/or bictegravir which were formerly dispersed within a solid mixture of the hydrophilic polymer and surfactant, then become dispersed within the aqueous medium and are stabilized by the hydrophilic polymer and surfactant, thereby preventing premature coagulation and aggregation.
  • 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.
  • the remaining proportion of the aqueous dispersion essentially consists of tenofovir alafenamide and/or bictegravir, hydrophilic polymer, and surfactant, 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 aqueous medium is water.
  • the aqueous medium comprises water and one or more additional pharmaceutically acceptable diluents or excipients.
  • microparticles 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 microparticles of the present invention have an average particle diameter of less than 5 micron ( .m).
  • the microparticles 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 microparticles are nanoparticles (i.e. they 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 microparticles.
  • Microparticles of the invention may have an average particle size of between 100 nm and 10 microns, preferably between 100 nm and 5 microns, more preferably between 100 nm and 3 microns.
  • the particle size and polydispersity of the microparticles may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy).
  • particle size is assessed by dispersing the solid composition in an aqueous medium and determining the particle size with a Malvern Panalytical Limited Zetasizer Ultra.
  • the aqueous dispersion may be used in the formulation of a microneedle array.
  • the present invention provides a process for preparing an aqueous dispersion, 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.
  • Dispersing the solid composition in the aqueous medium may comprise adding the solid composition to an aqueous medium and suitably agitating the resulting mixture (e.g. by shaking, homogenisation, sonication, stirring, etc.).
  • 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 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.
  • 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 a 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 intravenous or intramuscular delivery.
  • compositions of the invention may be obtained by conventional procedures, using conventional pharmaceutical excipients, well known in the art.
  • compositions of the invention contain a therapeutically effective amount of tenofovir alafenamide and/or bictegravir.
  • a person skilled in the art will know how to determine and select an appropriate therapeutically effective amount of tenofovir alafenamide and/or bictegravir to include in the pharmaceutical compositions of the invention.
  • 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 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 tenofovir alafenamide and/or bictegravir is present in the form of microparticles.
  • the microparticles of tenofovir alafenamide and/or bictegravir may be dispersed within one or more carrier materials.
  • each nanoparticle of tenofovir alafenamide and/or bictegravir is stabilised by the hydrophilic polymer and surfactant.
  • the injectable formulations of microparticles of tenofovir alafenamide and/or bictegravir are advantageously designed for administration as a depot injection, so as to improve adherence to prophylaxis and/or treatment, especially in respect of as yet incurable viral illnesses which require open-ended treatment durations (such as HIV or hepatitis- B), and the consequences that ensue.
  • a depot injection is beneficial is that it may be easier to administer than conventional preparations and allows for simpler follow-up I on-going care.
  • the injectable formulation of microparticles of tenofovir alafenamide and/or bictegravir provide a controlled release bolus formulation of tenofovir alafenamide and/or bictegravir, which, when administered to a patient (v/a intramuscular or subcutaneous injection), releases the tenofovir alafenamide and/or bictegravir into the bloodstream of the patient over a period of at least about two weeks from the date of administration.
  • the period of release is at least about three weeks, yet further preferably at least about one month, more preferably at least about three months, and most preferably at least about six months, from the date of administration of the injection.
  • the present invention provides implantable rods comprising microparticles of tenofovir alafenamide and/or bictegravir dispersed in a monolith of the at least one hydrophilic polymer and the at least one surfactant.
  • microparticles of tenofovir alafenamide and/or bictegravir may be microparticles of tenofovir alafenamide in the absence of bictegravir.
  • the microparticles of tenofovir alafenamide and/or bictegravir may be microparticles of bictegravir in the absence of tenofovir alafenamide.
  • microparticles of tenofovir alafenamide and/or bictegravir may be microparticles of tenofovir alafenamide and/or bictegravir.
  • the solid composition comprises microparticles consisting of, or consisting essentially of, tenofovir alafenamide and/or microparticles consisting of, or consisting essentially of, bictegravir.
  • microparticles of tenofovir alafenamide and/or bictegravir may be microparticles of tenofovir alafenamide and bictegravir, wherein the microparticles comprise both tenofovir alafenamide and bictegravir.
  • the implantable rods may comprise a mixture of the above microparticles.
  • the implantable rods may comprise at least two of microparticles of tenofovir alafenamide, microparticles of bictegravir, and microparticles of both tenofovir alafenamide and bictegravir.
  • the tenofovir alafenamide and/or bictegravir which comprises the microparticles may be amorphous (i.e. substantially non-crystalline in nature).
  • the microparticles of the present invention have an average particle diameter of less than 5 micron ( .m).
  • the microparticles 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 microparticles are nanoparticles (i.e. they 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 microparticles.
  • microparticles of the present invention have an average particle size of less than or equal to 1 micron ( .m). In a particular embodiment, the microparticles have an average particle size of between 100 and 1000 nm. In particular embodiments, the particles of tenofovir alafenamide are microparticles, which have a particle size between 100 and 300 nm.
  • the microparticles of the present invention have an average particles size of greater than 1 micron ( .m), i.e. greater than 1000 nm. In an embodiment the microparticles have an average particle size of between 1 and 10 micron. In a particular embodiment, the microparticles have an average particle size of between 1001 nm and 3000 nm. In particular embodiments, the microparticles of bictegravir have a particle size between 1200 nm and 2600 nm. In other embodiments, the microparticles of bictegravir have particles sizes between 500 nm and 2600 nm. Microparticles of the invention may have an average particle size of between 100 nm and 10 microns, preferably between 100 nm and 5 microns, more preferably between 100 nm and 3 microns.
  • microparticles 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 microparticles may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy).
  • particle diameter i.e. Z-average hydrodynamic diameter
  • particle diameter is assessed by dispersing the solid composition in an aqueous medium and determining the particle diameter with a Malvern Panalytical Limited Zetasizer Ultra.
  • the monolith of the at least one hydrophilic polymer and at least one surfactant is non- porous in nature.
  • the hydrophilic polymer may be as described for the solid composition of the present invention.
  • the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, dextran, or a combination thereof.
  • the surfactant may be as described for the solid composition of the present invention.
  • the surfactant is selected from vitamin-E-polyethylene glycolsuccinate, sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, polyethylene glycol (15)-hydroxystearate, polyoxyethylene (20) cetyl ether, polyvinyl alcohol or a combination thereof.
  • the hydrophilic polymer and surfactant may be used in any combination as described for the solid composition of the present invention.
  • the hydrophilic polymer and surfactant may be the same, such as polyvinyl alcohol.
  • the implantable rod further comprises one or more non-volatile oils.
  • the one or more non-volatile oils may be selected from mineral oil, vitamin E, corn oil, peanut oil, soy bean oil, sesame oil, safflower oil, vegetable oil, avocado oil, rice bran oil, jojoba oil, Babassu oil, palm oil, coconut oil, castor oil, cotton seed oil, olive oil, flaxseed oil, rapeseed oil and mixtures thereof, preferably the one or more non-volatile oils is selected from mineral oil, corn oil, peanut oil, and mixtures thereof.
  • the relative quantities of tenofovir alafenamide and/or bictegravir, hydrophilic polymer, surfactant, and, if present, non-volatile oil 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 4 and 40 mm, and most preferably between 5 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.
  • 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 hydrophilic polymer and surfactant 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.
  • 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.
  • a reduced pressure atmosphere e.g. a vacuum
  • Heating the compressed solid composition requires increasing the temperature of the solid composition such that discrete volumes of the hydrophilic polymer and surfactant cohere under the pressure of the compression step. However, the temperature must be below that which would deteriorate the tenofovir alafenamide and/or bictegravir.
  • 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 130 °C, most preferably about 120 °C.
  • the elevated temperature is maintained for a period of from 1 minute to 30 minutes, preferably from 2 minutes to 25 minutes, more preferably from 5 minutes to 15 minutes, most preferably about 6 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.
  • the rod may, optionally, be cooled. For example, through contact with a cold surface.
  • 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 microparticles of bictegravir and/or tenofovir alafenamide dispersed within a monolith comprising a hydrophilic polymer, a surfactant and at least one structural polymer.
  • the microparticles of bictegravir and/or tenofovir alafenamide may be microparticles of bictegravir in the absence of tenofovir alafenamide.
  • the microparticles of bictegravir and/or tenofovir alafenamide may be microparticles of tenofovir alafenamide in the absence of bictegravir.
  • the microparticles of bictegravir and/or tenofovir alafenamide may be microparticles of bictegravir and/or microparticles of tenofovir alafenamide.
  • the solid composition comprises microparticles consisting of, or consisting essentially of, bictegravir and/or microparticles consisting of, or consisting essentially of, tenofovir alafenamide.
  • microparticles of bictegravir and/or tenofovir alafenamide may be microparticles of bictegravir and tenofovir alafenamide, wherein the microparticles comprise both bictegravir and tenofovir alafenamide.
  • the solid composition may comprise a mixture of the above microparticles.
  • the solid composition may comprise at least two of microparticles of bictegravir, microparticles of tenofovir alafenamide, and microparticles of both bictegravir and tenofovir alafenamide.
  • the bictegravir and/or tenofovir alafenamide which comprises the microparticles may be amorphous (i.e. substantially non-crystalline in nature).
  • the microparticles of the present invention have an average particle diameter of less than 5 micron ( .m).
  • the microparticles 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 microparticles are nanoparticles (i.e. they 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 microparticles.
  • microparticles 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 microparticles may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy).
  • particle diameter i.e. Z-average hydrodynamic diameter
  • particle diameter is assessed by dispersing the solid composition in an aqueous medium and determining the particle diameter with a Malvern Panalytical Limited Zetasizer Ultra.
  • the monolith of the hydrophilic polymer and surfactant is non-porous in nature.
  • the hydrophilic polymer may be as described for the solid composition of the present invention.
  • the hydrophilic polymer is selected from polyvinyl alcohol, polyvinylpyrrolidone, dextran, or a combination thereof.
  • the surfactant may be as described for the solid composition of the present invention.
  • the surfactant is selected from vitamin-E-polyethylene glycolsuccinate, sodium deoxycholate, polysorbate 20, polysorbate 80, dioctyl sulfosuccinate, polyethylene glycol (15)-hydroxystearate, polyoxyethylene (20) cetyl ether, polyvinyl alcohol or a combination thereof.
  • the microneedle arrays further comprises one or more non-volatile oils.
  • the one or more non-volatile oils may be selected from mineral oil, vitamin E, corn oil, peanut oil, soy bean oil, sesame oil, safflower oil, vegetable oil, avocado oil, rice bran oil, jojoba oil, Babassu oil, palm oil, coconut oil, castor oil, cotton seed oil, olive oil, flaxseed oil, rapeseed oil and mixtures thereof, preferably the one or more non-volatile oils is selected from mineral oil, corn oil, peanut oil, and mixtures thereof.
  • any hydrophilic polymer suitable for use in pharmaceutical formulations may be employed as a structural polymer, for example, the polymers that are suitable as hydrophilic polymers.
  • the structural polymer is selected to be the same as the hydrophilic polymer, as this helps to ensure compatibility.
  • the structural 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 bictegravir and/or tenofovir alafenamide.
  • the relative quantities of bictegravir and/or tenofovir alafenamide, hydrophilic polymer, surfactant, and, optionally, non-volatile oil may be as described herein for the solid composition of the present invention.
  • the ratio of the bictegravir and/or tenofovir alafenamide, hydrophilic polymer, surfactant, and, optionally, non-volatile oil to the structural polymer may be in the range of 10 : 1 to 1 : 10, preferably in the range of 1 : 5 to 6 : 5, most preferably the ratio is about 3 : 4 or 3 : 5.
  • the first composition may comprise 1 to 4 parts bictegravir and/or tenofovir alafenamide, 2 to 4 parts hydrophilic polymer, 0.1 to 2 parts surfactant, and 5 to 15 parts structural polymer.
  • the first composition comprises 4 parts bictegravir and/or tenofovir alafenamide, 1 part hydrophilic polymer, 0.5 part surfactant, and 10 parts structural polymer.
  • 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 hydrophilic polymers.
  • the base polymer is selected to be the same as a hydrophilic polymer 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. If present, the additive and base polymer are used in a ratio from 1 : 40 to 1 : 10, preferably a ratio of 1 : 30 to 1 : 15, more preferably a 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 bictegravir and/or tenofovir alafenamide.
  • the microneedle array contains between 1 and 20 mg of bictegravir and/or tenofovir alafenamide, preferably between 2 and 10 mg, more preferably about 5 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 pm, preferably in the range of 500 to 900 pm.
  • the base width of the microneedles may be in the range of 50 to 500 pm, preferably in the range of 100 to 300 pm.
  • the interspacing between the needles may be in the range of 50 to 200 pm, preferably about 100 pm.
  • 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.
  • 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.
  • microparticulate nature of active compounds such as bictegravir and tenofovir alafenamide
  • solid compositions of the present invention allows for higher loading of the water insoluble drugs, while allowing them to remain in their water dispersible microparticulate form.
  • 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 50 wt%, preferably between 10 and 40 wt%, more preferably between 20 and 30, and most 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. 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 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. Multiple drying steps may be used, for example, the microneedle array may be allowed to dry under ambient conditions for a period and subsequently dried at an elevated temperature. 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.
  • 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 viral infections, optionally wherein the solid composition, aqueous dispersion, pharmaceutical composition, or injectable formulation is administered in combination with one or more other antiviral agents.
  • the present invention provides a method of treating and/or preventing a viral infection, the method comprising administering a therapeutically effective amount of a solid composition, an aqueous dispersion, a pharmaceutical composition, an injectable formulation, an implantable rod, or a microneedle array as defined herein to a patient suffering from or at risk of suffering from a viral infection, optionally wherein the solid composition, aqueous dispersion, pharmaceutical composition, injectable formulation, implantable rod, or microneedle array is administered in combination with one or more other antiviral agents.
  • the viral infection to be treated in the above uses or methods of treatment may be any virus, particularly retroviruses, that is known to be susceptible to tenofovir alafenamide and/or bictegravir.
  • the viral infection may be caused by HIV, or hepatitis B virus.
  • compositions of the present invention may be used for the treatment and/or prevention of HIV via either pre-exposure prophylaxis (PrEP) and/or post-exposure prophylaxis (PEP) applications.
  • antiviral agents include, but are not limited to, abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine, efavirenz, etravirine, nevirapine, rilpivirine, atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, enfuvirtide, maraviroc, dolutegravir, elvitegravir, raltegravir, cobicistat or any combination thereof.
  • antiviral agents may also include combinations such as, but not limited to, epzicom (abacavir and lamivudine), triumeq (abacavir, dolutegravir, and lamivudine), trizivir (abacavir, lamivudine, and zidovudine), evotaz (atazanavir and cobicistat), prezcobix (darunavir and cobicistat), atripla (efavirenz, emtricitabine, and tenofovir disoproxil fumarate), striject (elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate), odefsey (emtricitabine, rilpivirine, and tenofovir alafenamide), complera (emtricitabine, rilpivirine, and tenofovir disoproxil
  • the administered form of microparticles of tenofovir alafenamide and/or bictegravir preferably provides a controlled release bolus formulation of tenofovir alafenamide and/or bictegravir, which, when administered to a patient, releases tenofovir alafenamide and/or bictegravir 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 three weeks, yet further preferably at least about one month, more preferably at least about three months, and most preferably at least about six months, from the date of administration of the injection.
  • treatment includes curative and prophylactic treatment.
  • a “patient” means an animal, preferably a mammal, preferably a human, in need of treatment.
  • the amount of tenofovir alafenamide and/or bictegravir administered should be a therapeutically effective amount where tenofovir alafenamide and/or bictegravir is used for the treatment of a disease or condition and a prophylactically effective amount where the tenofovir alafenamide and/or bictegravir is used for the prevention of a disease or condition.
  • therapeutically effective amount used herein refers to the amount of tenofovir alafenamide and/or bictegravir needed to treat or ameliorate a targeted disease or condition.
  • prophylactically effective amount refers to the amount of tenofovir alafenamide and/or bictegravir needed to prevent a targeted disease or condition.
  • 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 administered individually to a patient or may be administered in combination with other agents, drugs or hormones.
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the formulations or compositions of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • a pharmaceutical composition comprising a solid composition or an aqueous dispersion as defined herein; and one or more other antiretroviral agents.
  • the pharmaceutical composition is a single dosage form.
  • 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,
  • the route of administration is by parenteral insertion 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 weeks, preferably months.
  • 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 three weeks, more preferably at least about one month, most preferably at least about two months from the date of administration of the injection. Without wishing to be bound by theory, it is thought that the implant gradually dissolves to form a liquid depot and that the bictegravir and/or tenofovir alafenamide 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.
  • 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).
  • Figure 1 graphically depicts the results of DLS analysis performed on 70 wt% TAF formulations in the form of a bar chart.
  • the z axis indicates the polymer tested, the x axis indicates the surfactant tested, and the y axis indicates the Z-average hydrodynamic diameter.
  • Figure 2 graphically depicts the results of DLS analysis performed on 70 wt% BIC formulations in the form of a bar chart.
  • the z axis indicates the polymer tested, the x axis indicates the surfactant tested, and the y axis indicates the Z-average hydrodynamic diameter.
  • Figures 3A to 3D graphically depict the blood plasma concentrations of TAF (3A and 3B) and BIC (3C and 3D) over time following subcutaneous implantation in male Sprague Dawley rats of rods formed from the TAF70/PVA30 and BIC70/PVA30 formulations, as set out in Example 10.
  • Figure 4 graphically depicts the results of the ex vivo testing performed on the BIC microneedle arrays as described in Example 14.
  • Figure 4A shows the mass of BIC recovered from the skin for samples B1, B3, and B6 (labelled as F1, F3, and F6 respectively).
  • Figure 4B shows the cumulative mass of BIC into the compartment over time for samples B1 , B3, and B6 (labelled as F1, F3, and F6 respectively).
  • Figure 5 graphically depict the results of the ex vivo testing performed on the TAF microneedle arrays as described in Example 14.
  • Figure 5A shows the mass of TAF recovered from the skin for samples T2, T4, and T6 (labelled as F2, F4, and F6 respectively).
  • Figure 5B shows the cumulative mass of TAF into the compartment over time for samples T2, T4, and T6 (labelled as F2, F4, and F6 respectively).
  • Figure 6 graphically depicts the results of the in vivo testing performed on the BIC microneedle arrays as compared with intramuscular injection of aqueous dispersions of BIC as described in Example 15.
  • the graph shows the blood plasma concentration of BIC in Sprague-Dawley rats for 21 days following administration.
  • Figure 7 graphically depicts the results of the in vivo testing performed on the TAF microneedle arrays as compared with intramuscular injection of aqueous dispersions of TAF as described in Example 15.
  • the graph shows the blood plasma concentration of TFV in Sprague-Dawley rats for 21 days following administration (NB TAF is rapidly hydrolysed to TFV in rodents and so the latter was monitored as a proxy).
  • PVA polyvinyl alcohol
  • the polyvinylpyrrolidone K30 (PVPK30) had a K value of 30 and was obtained from Sigma-Aldrich.
  • the dextran had an average molecular weight of 9,000-11 ,000; 35,000-45,000; 200,000; or 1.5-2.8 million Daltons.
  • Example 1 Screening for formulations of TAF and BIC at a loading of 70 wt%
  • Table 1 The polymers and surfactants selected from the FDA’s GRAS list for testing.
  • Samples were prepared at a drug loading of 70 wt% using a 70 mgml' 1 stock solution of either TAF or BIC in dichloromethane, a 22.5 mgml -1 stock solution of polymer and a 22.5 mgml -1 stock solution of surfactant.
  • 90 pl polymer solution and 45 pl surfactant solution were mixed with 265 pl water to produce 400 pl of aqueous phase.
  • 100 pl of the drug solution was then added to give a 1 :4 organic solvent to water (O/W) mix.
  • the mixtures are the emulsified using a Covaris S2x for 15 seconds with a duty cycle of 20, an intensity of 250 and 500 cycles/burst in frequency sweeping mode to achieve an average power output of ⁇ 70 watts.
  • the homogeneous emulsions were immediately frozen by immersion in liquid nitrogen followed by freeze-drying for 48 hours using a VirTis Benchtop Pro with a condenser setting of -100°C and at a pressure of ⁇ 40 pBar.
  • the resulting solid product was in the form of a monolith containing 70 wt% of either TAF or BIC, 20 wt% polymer, and 10 wt% surfactant.
  • Three examples of each polymer/surfactant combination were produced and screened as outlined below.
  • samples were dispersed in water at a concentration of: 2 mg/mL relative to tenofovir alafenamide (TAF), and 1 mg/mL relative to bictegravir (BIC).
  • TAF tenofovir alafenamide
  • BIC bictegravir
  • Particle size of the resulting nanoparticulate or micro particulate dispersions were then measured by dynamic light scattering (DLS - sometimes referred to as Photon Correlation Spectroscopy (PCS)) using a Zetasizer Ultra available from Malvern Panalytical Limited. The measurements were performed in triplicate, the instrument operating at a temperature of 25°C and a measurement angle of 172° (backscatter). Data analysis was conducted using the general-purpose model within the ZS Xplorer software.
  • DLS dynamic light scattering
  • PCS Photon Correlation Spectroscopy
  • the combinations of polymer and surfactants were overall considered to be “hits” if the resulting dispersions had a z-average hydrodynamic diameter (Dz), measured in at least one experiment, of less than 3000 nm, preferably less than 2600 nm, and a PDI value of less than 0.5. It should be noted that many of the hits had Dz values of less than 1500 nm, and further subset has Dz values of less than 1000 nm.
  • Dz z-average hydrodynamic diameter
  • Figures 1 and 2 show Solid bars indicate formulations that meet the assessment criteria and are considered to be ‘hits’. Hollow bars indicate formulations that only narrowly miss the assessment criteria.
  • Table 2 DLS analysis results of the hits for solid compositions comprising 70 wt% TA
  • Table 3 DLS analysis results of the hits for so id compositions comprising 70 wt% BIC Example 2 - Formulations of TAF and BIC at a loading of 80 wt%
  • Samples were prepared at a drug loading of 80 wt% using a 80 mgml' 1 stock solution of either TAF or BIC in dichloromethane, a 7.5 mgml -1 stock solution of polymer and a 2.5 mgml -1 stock solution of surfactant. 200 pl polymer solution and 200 pl surfactant solution were mixed to produce 400 pl of aqueous phase. 100 pl of the drug solution was then added to give a 1 :4 organic solvent to water (O/W) mix. The mixture was then emulsified using sonication and the homogeneous emulsion freeze-dried as described in Example 1.
  • the resulting solid compositions had a composition of 80 wt% TAF or BIC, 15 wt% polymer, and 5 wt% surfactant. Three examples of each polymer/surfactant combination tested were produced and screened.
  • Example 1 Each of the solid composition was dispersed in water and screened as described in Example 1.
  • Example 3 Formulations of TAF and BIC at a loading of 90 wt%
  • Samples were prepared at a drug loading of 90 wt% using a 90 mgml' 1 stock solution of either TAF or BIC in dichloromethane, a 3.75 mgml -1 stock solution of polymer and a 1.25 mgml -1 stock solution of surfactant. 200 pl polymer solution and 200 pl surfactant solution were mixed to produce 400 pl of aqueous phase. 100 pl of the drug solution was then added to give a 1 :4 organic solvent to water (O/W) mix. The mixture was then emulsified using sonication and the homogeneous emulsion freeze-dried as described in Example 1.
  • the resulting solid compositions had a composition of 90 wt% TAF or BIC, 7.5 wt% polymer, and 2.5 wt% surfactant. Three examples of each polymer/surfactant combination tested were produced and screened.
  • Example 1 Each of the solid composition was dispersed in water and screened as described in Example 1.
  • Table 7 DLS analysis resu ts of the hits for solid compositions comprising 90 wt% B C
  • Example 4 Formulations of both TAF and BIC at a loading of 50 wt%
  • the procedure of Example 1 was followed using TAF and BIC in a 1 :1 mass ratio, modified to produce solid products comprising 25 wt% TAF, 25wt% BIC, 40 wt% polymer, and 10 wt% surfactant.
  • Three examples of each of the monoliths of solid product were produced and the resulting aqueous dispersions screened as outlined in Example 1.
  • Table 8 DLS analysis results of the hits for solid compositions comprising 25 wt% TAF and 25 wt% BIC
  • Example 5 Formulations of both TAF and BIC at a loading of 70 wt%
  • Example 1 The procedure of Example 1 was followed using TAF and BIC in a 1 :1 mass ratio, modified to produce solid products comprising 35 wt% TAF, 35wt% BIC, 20 wt% polymer, and 10 wt% surfactant. Three examples of each of the monoliths of solid product were produced and the resulting aqueous dispersions screened as outlined in Example 1.
  • Table 8 DLS analysis results of the hits for solid compositions comprising 35 wt% TA and 35 wt% BIC
  • Example 6 Formulation of TAF at a loading of 70% with Polyvinyl Alcohol as polymer and surfactant
  • Samples were prepared at a drug loading of 70 wt% using a 70 mgml' 1 stock solution of TAF in dichloromethane and a 7.5 mgml -1 stock solution of PVA. 400 pl PVA solution and 100 pl of the drug solution were combined to give a 1 :4 organic solvent to water (O/W) mix. The mixture was then emulsified using sonication and the homogeneous emulsion freeze-dried as described in Example 1.
  • the resulting solid compositions had a composition of 70 wt% TAF and 30 wt% PVA.
  • Table 9 DLS analysis results of the hits for solid compositions comprising 70 wt% TA and 30 wt% PVA
  • Example 7 Formulation of BIC at a loading of 70% with Polyvinyl Alcohol as polymer and surfactant
  • Samples were prepared at a drug loading of 70 wt% using a 70 mgml' 1 stock solution of BIC in dichloromethane and a 7.5 mgml -1 stock solution of PVA. 400 pl PVA solution and 100 pl of the drug solution were combined to give a 1 :4 organic solvent to water (O/W) mix. The mixture was then emulsified using sonication and the homogeneous emulsion freeze-dried as described in Example 1.
  • the resulting solid compositions had a composition of 70 wt% BIC and 30 wt% PVA.
  • able 9 DLS analysis results of the hits for solid compositions comprising 70 wt% BIC and 30 wt% PVA
  • 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.
  • VCM vacuum compression moulding
  • the hot-plate Prior to sample preparation, the hot-plate was heated to a temperature of 120 °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 ( ⁇ 35 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 barg was applied to the sample chamber before placing it on the hot plate.
  • the sample was heated to 120 °C for 6 minutes before being transferred onto the cooling plate and cooled for 5 minutes. Translucent, yellow coloured rods were obtained weighing ⁇ 35 mg and having a length of 8 mm and diameter of 2 mm.
  • 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.
  • VCM vacuum compression moulding
  • the hot-plate Prior to sample preparation, the hot-plate was heated to a temperature of 110 °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 ( ⁇ 35 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 barg was applied to the sample chamber before placing it on the hot plate.
  • the sample was heated to 110 °C for 6 minutes before being transferred onto the cooling plate and cooled for 5 minutes. Translucent, white coloured rods were obtained weighing ⁇ 35 mg and having a length of 8 mm and diameter of 2 mm.
  • Example 10 Implantable Rod In Vivo data
  • a TAF/BIC cohort provided with a subcutaneous TAF implant comprising TAF70PVA30 and a subcutaneous BIC implant comprising BIC70PVA30, the implants containing 16.8 mg of TAF and 16.8 mg of BIC between them.
  • FIG. 3A-D Blood plasma was collected from the tail veins periodically over the course of 1200 hours and the BIC/TFV concentrations therein quantified using LC/MS-MS. This data is graphed in Figures 3A-D.
  • Figures 3A and 3B show the concentration of TFV over time for Cohorts 1 and 3 respectively and from these figures is can be seen that the TFV concentration gradually decreases over the first 192 to 360 hours (NB TFV is being quantified as a proxy for TAF, as TAF is rapidly hydrolysed to TFV in rodents).
  • Figures 3C and 3D show the concentration of BIC over time for Cohorts 2 and 3 respectively and from these figures is can be seen that the BIC concentration remaining consistent at around 10,000 ng/mL for the entirety of the 1200 hours of the study.
  • Example 11 Formulation of TAF at a loading of 70% with Polyvinyl Alcohol as polymer and surfactant, further comprising a non-volatile oil
  • Samples were prepared at a drug loading of 70 wt% using a stock solution containing 70 mgml -1 TAF and 10 mgml -1 non-volatile oil in dichloromethane and a 5 mgml -1 stock solution of PVA. 400 pl PVA solution and 100 pl of the drug solution were combined to give a 1 :4 organic solvent to water (O/W) mix. The mixture was then emulsified using sonication and the homogeneous emulsion freeze-dried as described in Example 1.
  • the resulting solid compositions had a composition of 70 wt% TAF, 20 wt% PVA, and 10 wt% non-volatile oil.
  • Table 10 DLS analysis results of the hits for solid compositions comprising 70 wt% TAF, 20 wt% PVA, and 10 wt% of a non-volatile oil
  • Example 12 Formulation of BIC at a loading of 70% with Polyvinyl Alcohol as polymer and surfactant, further comprising a non-volatile oil
  • Samples were prepared at a drug loading of 70 wt% using a stock solution containing 70 mgml -1 BIC and 10 mgml -1 non-volatile oil in dichloromethane and a 5 mgml -1 stock solution of PVA. 400 pl PVA solution and 100 pl of the drug solution were combined to give a 1 :4 organic solvent to water (O/W) mix. The mixture was then emulsified using sonication and the homogeneous emulsion freeze-dried as described in Example 1.
  • the resulting solid compositions had a composition of 70 wt% BIC, 20 wt% PVA, and 10 wt% non-volatile oil.
  • T able 11 DLS analysis results of the hits for solid compositions comprising 70 wt%
  • Example 13 Formulation of BIC and TAF solid compositions into Microneedle Arrays
  • Two polymer stock solutions were prepared for forming the microneedles by dissolving polymer in deionised water.
  • the two stock solutions contained 50 wt% PVP (58 kDa, K Value of 29 to 32) or 20 wt% PVA (Sigma Aldrich, nominal MW of 9-10 kDa, M w 9-10 kDa) and 20 wt% PVP (58 kDa, K Value of 29 to 32) respectively.
  • 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 pm and a column width of 300 pm, the spacing between needles being 100 pm.
  • the array was placed into a pressure chamber and subjected to a pressure of 5 bar for 3 to 5 hours.
  • a further polymer stock solution of 30 wt% PVP (Sigma Aldrich, nominal MW of 360 kDa, M n 360 kDa, K Value 80-100) and 1.5% w/w glycerol was prepared for forming the base plate by dissolving the polymer and polyol in deionised water.
  • the base plate solution was placed was cast onto the prepared needles and the arrays centrifuged for 10 minutes at 3500 rpm before drying under ambient conditions for 36 hours and then at 37.5 °C for a further 24 hours.
  • the set microneedle arrays were then released from the moulds and excess baseplate material cut away.
  • each microneedle array was determined by dissolving an array in 5 mL of water and dissolving under sonication. A 100 pL sample was diluted with 1900 pL of acetonitrile, vortexed and centrifuged. The supernatant was collected and analysed by HPLC, with the process being repeated in triplicate. able 12: BIC and TAF microneedle arrays and their calculated drug contents (%w/w) and measured drug loadings (pg/array)
  • 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 either with 12 mL of 1% w/v SLS in PBS (pH 7.4) for the BIC microneedle arrays or with 12 mL of 30 mM ammonium acetal buffer (pH 6.0) for the TAF microneedle arrays.
  • the donor compartment was clamped on top of the receiver compartment and wrapped with Parafilm® M to prevent solvent evaporation. Samples of 300 pL of the receiver compartment were taken at predefined time points of 1 , 2, 4, 6, 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 BIC or TAF were extracted from skins.
  • Cumulative amounts of BIC or TAF 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 organic solvent (acetonitrile for BIC, methanol for TAF) 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 the organic solvent. The samples were vortexed and centrifuged, then analysed by HPLC.
  • organic solvent acetonitrile for BIC, methanol for TAF
  • the data for the BIC microneedle arrays is summarised in Figure 4. Over 24h, 145.06 ⁇ 10.02, 148.12 ⁇ 60.15 and 122.22 ⁇ 27.66 pg BIC were delivered and detected in the receiver compartment of Franz diffusion cell after the application of B1 , B3 and B6, respectively and 175.81 ⁇ 98.27, 161.00 ⁇ 20.50 and 152.97 ⁇ 17.84 pg BIC were deposited into the skin in the same period. This brings up the total amount delivered to the skin and receiver compartment over 24 hours to 320, 309 and 275 pg of BIC by B1 , B3 and B6, respectively. The majority of the delivered BIC remained in the skin, which is believed to be due to its high hydrophobicity.
  • TAF microneedle arrays The data for the TAF microneedle arrays is summarised in Figure 5. Over 24h, 947.28 ⁇ 237.24, 777.29 ⁇ 173.29 and 936.25 ⁇ 110.41 pg TAF were delivered and detected in the receiver compartment of Franz diffusion cell after the application of T2, T4 and T6, respectively and 57.496 ⁇ 25.63, 38.79 ⁇ 5.63 and 33.67 ⁇ 12.59 pg TAF were deposited into the skin after the application of T2, T4 and T6, respectively were deposited into the skin in the same period. This brings up the total amount delivered to the skin and receiver compartment over 24 hours to 1005, 816 and 970 pg of TAF by T2, T4 and T6, respectively. The majority of the delivered TAF remained in the skin, which is believed to be due to its high hydrophobicity.
  • Example 15 In vivo Assessment of the Microneedles compared to Intramuscularly Administered BIC and TAF
  • 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.
  • rats were sedated using a gaseous anaesthetic gas (2-4% v/v isoflurane in oxygen), and microneedle arrays (two of BIC and two of TAF) were affixed using firm thumb pressure onto a pinched section of skin on the back of the rats in cohort 1.
  • MicrofoamTM surgical tape was placed on top of the microneedle arrays and kinesiology tape applied to keep them in place.
  • a total of 18.28 mg BCO and 57.14 mg TPO were dispersed in 1 mL sterilised water.
  • Each rat in the cohort was received a 50 L intramuscular injection of both BIC and TAF nanoparticles into a thigh.
  • Each rat approximately received 0.9 mg of BCO nanoparticles and 2.86 mg TPO nanoparticles, respectively.
  • Blood samples were collected from each rat via tail prick bleed using heparin rinsed 23G butterfly needles at determined time points: 0.5h, 1 h, 3h, 6h and 1 d, 2d, 3d, 4d, 5d, 7d, 10 d, 14d, and 21 d.
  • the rats were placed into a heat box at ⁇ 39°C for a minimum of 10 min, after which they were restrained using a surgical cloth. Then, a maximum of 200 plblood was collected form the lateral tail venous into a 1.5 mL poly(propylene) tube, previously rinsed with 10 pL of heparin. Samples were centrifuged at 2000g for 10 mins to obtain plasma, which was stored in -20°C freezer. For TAF blood samples, a total of 8 pL formic acid (20% w/v) was added in 100 pL plasma and stored in -20°C freezer.
  • BIC and TFV* in rat plasma were quantified using HPLC-MS.
  • Basic pharmacokinetic parameters were calculated following a single microneedle application.
  • Noncompartmental pharmacokinetic analysis of the plasma concentration profiles was applied using PK Solver.
  • the maximum plasma concentration (Cmax) of BIC and TFV observed respectively.
  • Relative bioavailability (F) of BIC and TAF after intradermal delivery of BIC and TAF loaded microneedle arrays compared with intramuscular injection was calculated using Equation 1.
  • the relative bioavailability was defined by comparing the AUC of BIC and TAF in plasma after the administration of two different formulations of the same compound (e.g., microneedle array vs. intramuscular injection).
  • AUCMN is the AUC of plasma from microneedle administration
  • ALICIM is the AUC of plasma from intramuscular injection.
  • Total dose delivered from the microneedles and delivery efficiency were calculated using the Equation 2 and 3.
  • the plasma concentration of BIC for the microneedle arrays and intramuscular injections is shown in Figure 6.
  • BIC was detectable from the first measurement at 0.5 hours and persisted to 21 days.
  • the Cmax frorn the intramuscularly administered cohort at 3 days (16.11 pg/mL) was comparable to the Cmax of the microneedle cohort (13.06 pg/mL) at 2 days.
  • the plasma concentration gradually decreased while maintaining the therapeutic relevant concentration until 21 days for MN cohort (0.37 ⁇ 0.29 pg/mL) and IM control cohort (1.04 ⁇ 0.86 pg/mL).
  • Statistical analysis using unpaired T-test showed no significant between Cmax of the microneedle cohort and the intramuscularly administered cohort (p > 0.05).
  • the AUCto-28 days obtained from the intramuscularly administered and microneedle cohorts were 146.11 ⁇ 78.74 pg.d/mL and 90.53 ⁇ 35.65 pg.d/mL, respectively.
  • Statistical analysis using unpaired T-test showed no significant difference between Cmax of the microneedle cohort and the intramuscularly administered cohort (p > 0.05).
  • the relative bioavailability of BIC from microneedles was 9.62 ⁇ 3.79%. Therefore, the dose delivered via dissolving microneedles was estimated at 0.28 ⁇ 0.11 mg/patch. The drug delivery efficiency was found to be 9.62 ⁇ 3.79%.
  • TFV plasma concentration of TFV for the microneedle arrays and intramuscular injections is shown in Figure 7.
  • the pharmacokinetic profiles indicate a rapid absorption and metabolism of TAF to TFV, since the detected presence of the parent drug (TAF) in plasma was negligible.
  • TAF parent drug
  • Both intramuscularly administer and microneedle array application resulted in an early peak in TFV plasma levels (1278.73 ⁇ 406.72 ng/mL and 536.29 ⁇ 46.88 ng/mL, respectively) observed within 1 h, followed by a rapid decrease in the plasma concentrations.
  • the concentration of TFV in the microneedle cohort was maintained at 17 ng/m and at day 3 the plasma levels of TFV were 1.29 ⁇ 0.22 ng/mL. Concentrations of TFV above the LLQ of the bioanalytical method were found in the plasma samples corresponding to the intramuscularly administered TAF until day 5 of the study (1 .18 ⁇ 0.22 ng/mL).
  • the AUCto-28 days obtained from the intramuscularly administered and microneedle array cohorts were 352.19 ⁇ 133.74 ng.d/mL and 64.56 ⁇ 19.40 ng.d/mL, respectively.
  • the relative bioavailability of TFV from TAF microneedle arrays was 9.07%. Therefore, the dose delivered via microneedle arrays was estimated at 0.262 mg/patch. The drug delivery efficiency was found to be 9.07%.
  • solid compositions comprising microparticles of tenofovir alafenamide and/or bictegravir may be formed through combination with hydrophilic polymers and surfactants.
  • the solid compositions have also been shown to form stable dispersions on mixing with water. Either of the solid compositions and aqueous dispersions are expected to be therapeutically useful based on the known properties of tenofovir alafenamide and bictegravir and the well-tolerated nature of the hydrophilic polymers and surfactants used.
  • the form of the solid composition and aqueous dispersion are expected to provide enhanced pharmacokinetic properties and therapeutic benefits when formulated into an injectable formulation, when compared to conventional tenofovir alafenamide and bictegravir orally-dosed formulations.

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Abstract

La présente invention se rapporte à des compositions solides comprenant des microparticules de ténofovir alafénamide et/ou de bictégravir dispersées dans une matrice comprenant un premier excipient et un second excipient. La présente invention se rapporte également à des réseaux de micro-aiguilles, des tiges implantables, des dispersions aqueuses, et des compositions pharmaceutiques dérivées desdites compositions solides et leurs utilisations.
PCT/GB2022/052684 2021-10-20 2022-10-20 Compositions solides comprenant du ténofovir alafénamide et/ou du bictégravir Ceased WO2023067350A1 (fr)

Priority Applications (2)

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CN202280083768.2A CN118414146A (zh) 2021-10-20 2022-10-20 包含丙酚替诺福韦和/或比克替拉韦的固体组合物
EP22797827.7A EP4419073A1 (fr) 2021-10-20 2022-10-20 Compositions solides comprenant du ténofovir alafénamide et/ou du bictégravir

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