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WO2024201057A1 - Compositions solides d'atovaquone - Google Patents

Compositions solides d'atovaquone Download PDF

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Publication number
WO2024201057A1
WO2024201057A1 PCT/GB2024/050860 GB2024050860W WO2024201057A1 WO 2024201057 A1 WO2024201057 A1 WO 2024201057A1 GB 2024050860 W GB2024050860 W GB 2024050860W WO 2024201057 A1 WO2024201057 A1 WO 2024201057A1
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WO
WIPO (PCT)
Prior art keywords
polyethylene glycol
polyvinyl alcohol
polyoxyethylene
atovaquone
microneedle array
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/GB2024/050860
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English (en)
Inventor
Steven Paul Rannard
Andrew Owen
Helen CAULDBECK
Sam MORRIS
Alison SAVAGE
Joanne SHARP
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University of Liverpool
Original Assignee
University of Liverpool
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Publication date
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Publication of WO2024201057A1 publication Critical patent/WO2024201057A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles

Definitions

  • the present invention relates to a chemical composition.
  • the invention relates, more particularly, but not exclusively, to a chemical composition for the treatment and prophylaxis of systemic infections, and has particular (but not exclusive) application in the treatment and prophylaxis of systemic parasitic and fungal infections, such as malaria, toxoplasmosis, and Pneumocystis pneumonia.
  • malaria is a vector-borne infectious disease that is widespread in tropical and subtropical regions. Over 200 million people are infected with malaria and there are almost 500,000 deaths annually, mostly among young children in sub- Saharan Africa. Furthermore, literature indicates that tens of millions of travellers per year required malaria prophylaxis (Leder K. et al., Clin. Infect Dis., 2004, 39, 1104- 1112). Malaria is caused by protozoan of the genus Plasmodium. The most serious form of the disease is caused by P. falciparum but other related species P. vivax, P. ovale, P. malariae and P. knowlesi can infect humans. This group of human- pathogenic Plasmodium species is usually referred to as the malaria parasites.
  • a combination preparation of atovaquone with proguanil hydrochloride is available under the trade name MalaroneTM, with a standard (adult) tablet containing 250 mg of atovaquone and 100 mg of proguanil hydrochloride.
  • MalaroneTM a standard (adult) tablet containing 250 mg of atovaquone and 100 mg of proguanil hydrochloride.
  • one standard tablet should be taken once a day 24 to 48 hours before entering a malarial area, continuing with one tablet once a day for the duration of stay in the malarial area, and further continuing for 7 days after leaving the malarial area, i.e. 2.25 to 2.5 g of atovaquone for just a one-day stay in a malarial area.
  • Atovaquone is a hydroxy-1, 4-naphthoquinone and is an antiprotozoal agent. It exists as a yellow crystalline solid that is practically insoluble in water, but is highly lipophilic. The structure of atovaquone is shown below.
  • the effective prophylaxis, control and treatment of malaria presents enormous challenges, especially in sub-Saharan Africa where access to medicines and health care is limited. Poor adherence to malaria prophylaxis regimes and antimalarial treatment, from both health workers and consumers, has been associated with prophylaxis/treatment failure, severe malaria and death. Poor adherence leads to sub- therapeutic drug concentrations in the body, which will not eradicate all malaria parasites and may allow growth of resistant parasites. Drug concentrations in the body can become sub-therapeutic either by missed doses and/or by doses being taken but not in a timely manner. Thus, high levels of patient adherence to malaria prophylactic regimes and antimalarial treatment are important in ensuring effectiveness of the prescribed preparations.
  • WO 2017/216564 A1 provides solid compositions comprising nanoparticles of atovaquone dispersed within one or more carrier materials, the one or more carrier materials being drawn from polymers and surfactants. Said solid compositions are in the form of solid nanoparticles of atovaquone dispersed within a porous matrix of polymer and surfactant.
  • WO 2017/216564 A1 further provides aqueous and oily dispersions, as well as subcutaneously and intramuscularly injectable formulations, said dispersions and injectable formulations suitable for use in the prophylaxis of parasitic or fungal infections, such as malaria.
  • An improved manner of treating and/or preventing malaria would therefore be desirable, from any one or more of the points of view of reduction in dosing, ease of administration, increased patient adherence/compliance and simplification of follow-up care.
  • An improved manner of treating and/or preventing any of the following other parasitic and fungal diseases such as toxoplasmosis (caused by the parasite Toxoplasma gondii), babesiosis (caused by the parasite Babesia microti) and Pneumocystis pneumonia (caused by the fungus Pneumocystis jirovecii), as briefly mentioned above, would also be desirable for many of the same reasons as provided for the desire to improve the treatment and/or prophylaxis of malaria.
  • toxoplasmosis caused by the parasite Toxoplasma gondii
  • babesiosis caused by the parasite Babesia microti
  • Pneumocystis pneumonia caused by the fungus Pneumocystis jirovecii
  • a first aspect of the present invention relates to a method of producing an implantable rod comprising the steps of compressing a solid composition, the solid comprising nanoparticles of atovaquone dispersed within one or more carrier materials, and heating the compressed solid composition for a period of time.
  • the solid composition may be compressed in a mould, optionally the mould being cylindrical in form.
  • the solid composition may be heated to a temperature from 60 to 160 °C, preferably from 80 to 140 °C, more preferably from 100 to 120 °C, most preferably about 110 °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 10 minutes.
  • the method may further comprise a step of cooling the rod, optionally the cooling taking place under a reduced pressure atmosphere.
  • a second 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, the solid comprising nanoparticles of atovaquone dispersed within one or more carrier materials, 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) are 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.
  • the one or more carrier materials comprise may be selected from hydrophilic polymers and surfactants, and are preferably selected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; D-a-tocopherol polyethylene glycol 1000 succinate; and polyethylene glycol (15)-hydroxystearate.
  • the one or more carrier materials comprise may be provided in any one or more of the following combinations: polyvinyl alcohol-polyethylene glycol graft copolymer AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monolaurate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyethylene glycol (15)-hydroxystearate; polyvinylpyrrolidone k30 AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monolaurate; polyvinylpyrrolidone
  • the one or more carrier materials comprise may be selected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; and D-a-tocopherol polyethylene glycol 1000 succinate.
  • the one or more carrier materials comprise may be provided in any one or more of the following combinations: polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate; polyvinylpyrrolidone K30 AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monolaurate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monooleate; polyvinyl alcohol AND sodium deoxycholate.
  • the nanoparticles of atovaquone may have an average particle size between 100 and 800 nm.
  • the polydispersity of the nanoparticles of atovaquone may be less than or equal to 0.8.
  • a third aspect of the present invention relates to an implantable rod produced by the method of the first aspect of the present invention.
  • a fourth aspect of the present invention relates to an implantable rod comprising nanoparticles of atovaquone dispersed within a monolith comprising one or more carrier materials, wherein the one or more carrier materials are pharmaceutically acceptable hydrophilic polymers and/or surfactants.
  • a fifth aspect of the present invention relates to a microneedle array produced by the method of the second aspect of the present invention.
  • a sixth aspect of the present invention relates to a microneedle array comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition, wherein the first composition comprises nanoparticles of atovaquone dispersed within a monolith comprising one or more carrier materials, wherein the one or more carrier materials are pharmaceutically acceptable hydrophilic polymers and/or surfactants, and at least one structural polymer
  • 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.
  • the one or more carrier materials may be selected from the list consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30 ; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; D-a-tocopherol polyethylene glycol 1000 succinate; and polyethylene glycol (15)-hydroxystearate, and combinations thereof.
  • the one or more carrier materials may be provided in any one or more of the following combinations: polyvinyl alcohol-polyethylene glycol graft copolymer AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monolaurate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyethylene glycol (15)-hydroxystearate; polyvinylpyrrolidone K30 AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monolaurate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monolaurate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monol
  • the one or more carrier materials may deselected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; and D-a-tocopherol polyethylene glycol 1000 succinate.
  • the one or more carrier materials may be provided in any one or more of the following combinations: polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate; polyvinylpyrrolidone K30 AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monolaurate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monooleate; polyvinyl alcohol AND sodium deoxycholate.
  • the nanoparticles of atovaquone may have an average particle size between 100 and 800 nm.
  • the polydispersity of the nanoparticles of atovaquone may be less than or equal to 0.8.
  • a seventh aspect of the present invention relates to an implantable rod as described in the third or fourth aspects of the present invention, or a microneedle array as described in the fifth or sixth aspects of the present invention, for use as a medicament.
  • An eighth aspect of the present invention relates to an implantable rod as described in the third or fourth aspects of the present invention, or a microneedle array as described in the fifth or sixth aspects of the present invention, for use in the treatment and/or prevention of parasitic and/or fungal infections.
  • An implantable rod or a microneedle array as described in the eighth aspect of the present invention wherein the parasitic infection is caused by parasites of the genus Plasmodium, or by parasites of the genus Toxoplasma, or by parasites of the genus Babesiidae, or wherein the fungal infection is caused by fungus of the genus Pneumocystis.
  • the parasitic infection may be malaria, toxoplasmosis, or babesiosis, or the fungal infection may be Pneumocystis pneumonia.
  • a ninth aspect of the present invention relates to a method of treating and/or preventing a fungal infection, the method comprising administering a therapeutically effective amount of an implantable rod as described in the third or fourth aspects of the present invention, or a microneedle array as described in the fifth or sixth aspects of the present invention, to a patient suffering from or at risk of suffering from a parasitic or fungal infection.
  • the parasitic infection is caused by parasites of the genus Plasmodium, or by parasites of the genus Toxoplasma, or by parasites of the genus Babesiidae, or wherein the fungal infection is caused by fungus of the genus Pneumocystis.
  • the parasitic infection may be malaria, toxoplasmosis, or babesiosis, or the fungal infection may be Pneumocystis pneumonia.
  • Figure 1 shows the particle size of the 11 combinations of carrier materials that were found to form high quality nanodispersions of atovaquone on dissolution in water.
  • Figure 2 shows 3D images (top row) and cross sections (bottom row) of individual microneedles produced by X-ray microtomography.
  • Figure 3 shows the variation in atovaquone concentration along a microneedle with a 0.72 mg loading of atovaquone, with higher concentrations at the tip of the microneedle and lower concentrations towards the base.
  • Figure 4 shows the variation in atovaquone concentration along microneedle with a 2 mg (triangles) or a 4 mg (squares) loading of atovaquone, with higher concentrations being found at the tips of the microneedles and lower concentrations towards the bases.
  • Figure 5 shows the E’ / N per needle for each of the microneedle arrays (with loadings of 0, 0.72, 2, and 4 mg of atovaquone), with no significant variation in strength occurring with atovaquone loading.
  • Figure 6 shows micrographs of microneedle arrays before and after compression, with no damage to the microneedles being observed.
  • Figure 7 shows the dissolution profile for each of the microneedle array loadings of 0.72, 2, and 4 mg of atovaquone, showing an inverse relationship between dissolution rate and atovaquone loading.
  • Figure 8 shows plots of the % of total atovaquone dose released to the compartment of the Franz cell through a porcine skin membrane (left) and cumulative mass of atovaquone released to the compartment of the Franz cell through the porcine skin membrane (right) over time.
  • Figure 9 shows plots of the % of total atovaquone dose deposited into the ex vivo porcine skin (left) and cumulative mass of atovaquone deposited into the ex vivo porcine skin (right) at given depths within the skin.
  • Figure 10 shows plots of the blood plasma concentration of atovaquone in rats to which microneedle arrays were applied for periods of 1, 12, or 24 hours. The figure shows that rats exposed to microneedle arrays for periods of 12 and 24 hours had therapeutically effective levels of atovaquone over a period of 24 hours, while those exposed for only 1 hour had lower levels of atovaquone.
  • FIG 11 shows plots of the blood plasma concentration of atovaquone in rats to which microneedle arrays were applied for periods of 2, 4, or 8 hours. The figure shows that rats exposed to microneedle arrays for each of these periods had therapeutically effective levels of atovaquone for periods of at least 100 hours.
  • particle size is used herein to refer to the Z-average hydrodynamic diameter.
  • Particle size and polydispersity may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy).
  • particle diameter and polydispersity i.e. Z-average hydrodynamic diameter
  • particle diameter and polydispersity are assessed by dispersing the solid composition in an aqueous medium at a concentration of 1 mg/mL and determining the particle diameter using dynamic light scattering, e.g. using a Malvern Panalytical Limited Zetasizer Ultra.
  • nanoparticle may be interpreted broadly to include particles with a particle size that is less than 5 pm, preferably less than 3 pm, or most preferably less than 1 pm. In embodiments, the particle size is in the range of 100 to 800 nm.
  • patient includes both human patients and animal patients.
  • Atovaquone is used herein to refer to the molecule illustrated in the background section as being atovaquone, and also includes pharmaceutically acceptable salts, solvates and derivatives thereof, prodrugs thereof, as well as any polymorphic or amorphous forms thereof.
  • SDN is an abbreviation for the term “solid drug nanoparticles”, used herein to refer to the solid compositions of the present invention.
  • other drugs is used herein to refer to the following (non-exhaustive) list of other drugs that may be used in combination with atovaquone formulated in accordance with the invention in a combination prophylactic and/or treatment therapy: proguanil, mefloquine, chloroquine, hydroxychloroquine, quinine, quinidine, artemether, lumefantrine, primaquine, doxycycline, tetracycline, clindamycin, dihydroartemisinin, piperaquine, and pyrimethamine with or without sulfadoxine, as well as pharmaceutically acceptable salts, solvates and derivatives thereof, prodrugs thereof, and any polymorphic or amorphous forms thereof.
  • references to “preventing” or “prevention” relate to prophylactic treatment and includes preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a patient that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.
  • malaria because malaria parasites are confined to the circulating bloodstream (in red blood cells), or for the first few days of infection, to the liver, the prophylactic effect of atovaquone extends to both the initial liver stage (causal prophylaxis) and the red blood cell stage (suppressive prophylaxis).
  • references to “treatment” or “treating” of a state, disorder or condition includes: (1) inhibiting the state, disorder or condition, /.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof; or (2) relieving or attenuating the disease, i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • the terms “preventing” or “prevention” should not be considered to refer only to medicaments which are completely effective in treating a specific state, disorder or condition, but also to cover medicaments which are partially effective as well.
  • the terms “preventing” and “prevention” should be considered to cover medicaments which are useful at reducing the rate of incidence of a target disorder or condition (e.g. malaria, toxoplasmosis, babesiosis, Pneumocystis pneumonia) in that target population, as well as medicaments which are useful at completely eradicating a target state, disorder or condition from that target population.
  • a target disorder or condition e.g. malaria, toxoplasmosis, babesiosis, Pneumocystis pneumonia
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a patient for treating and/or preventing a disease, is sufficient to effect such treatment/prevention for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.
  • 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.
  • references herein to a carrier material being “(substantially) immiscible” with another carrier material means that a mixture comprising the two carrier materials is unable to form a single phase.
  • Solid compositions as defined herein may be as described in WO 2017/216564 A1, hereby incorporated by reference in its entirety.
  • the solid compositions comprise nanoparticles of atovaquone dispersed within one or more carrier materials, wherein the atovaquone is present in an amount of at least 10 wt%.
  • the atovaquone is present in an amount of at least 15 wt%, further preferably at least 20 wt%, yet further preferably at least 25 wt%, yet further preferably at least 30 wt%, yet further preferably at least 40 wt%, yet further preferably at least 50 wt%, yet further preferably at least 60 wt%, yet further preferably 70 wt%, and most preferably at least 80 wt%.
  • the one or more carrier materials may provide hydrophilic polymeric and surfactant activity, and further preferably may be selected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone k30; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; D-a-tocopherol polyethylene glycol 1000 succinate; and polyethylene glycol (15)-hydroxystearate.
  • the one or more carrier materials may provide hydrophilic polymeric and surfactant activity”, by which it is meant that there may be a single carrier material providing both hydrophilic polymeric activity and surfactant activity, or there may be a plurality of carrier materials, in which case one (or more) carrier material(s) in the plurality may provide hydrophilic polymeric activity, while another carrier material (or carrier materials) in the plurality may provide surfactant activity.
  • the one or more carrier materials may be referred to simply as “(hydrophilic) polymers” or “surfactants”, for carrier materials providing hydrophilic polymeric activity and surfactant activity respectively, for simplicity.
  • the one or more solid carrier materials may be provided in any one or more of the following combinations: polyvinyl alcohol-polyethylene glycol graft copolymer AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monolaurate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyethylene glycol (15)-hydroxystearate; polyvinylpyrrolidone k30 AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monolaurate; polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monooleate; polyvinylpyrrolidone k30 AND polyethylene glycol glycol
  • the one or more carrier materials may be selected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone k30; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; and D-a-tocopherol polyethylene glycol 1000 succinate.
  • the one or more solid carrier material may be provided in any one or more of the following combinations: polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate; polyvinylpyrrolidone k30 AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monolaurate; polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monooleate; polyvinyl alcohol AND sodium deoxycholate.
  • the one or more solid carrier materials are preferably water-soluble.
  • water-soluble as applied to the carrier material(s) means that its solubility in water at ambient temperature and pressure is at least 10g/L.
  • individual solid nanoparticles of atovaquone consist essentially of atovaquone.
  • the nanoparticles of atovaquone have an average particle diameter of less than 5 micron ( .m).
  • the nanoparticles have an average particle diameter of between 10 nm and 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 100 and 500 nm.
  • the nanoparticles have a particle diameter in the range of 1 to 1000 nm. It will be understood that references to particle diameter are references to the Z-average hydrodynamic diameter of the nanoparticles.
  • the polydispersity of the nanoparticles of atovaquone may be less than or equal to 0.8, preferably less than or equal to 0.6, and more preferably less than or equal to 0.4.
  • the polydispersity relates to the size of the atovaquone nanoparticles and may be determined by suitable techniques known in the art (e.g. laser diffraction, laser scattering, electron microscopy), in particular dynamic light scattering. Polydispersity of particle sizes of the nanoparticles of atovaquone herein have been assessed with a Malvern Zetasizer (Malvern Instruments Ltd).
  • the average zeta potential of the nanoparticles of atovaquone when dispersed in an aqueous medium may be between -100 and +100 mV. In one embodiment, the zeta potential of the nanoparticles of atovaquone may be between -30 and +30 mV. In another embodiment, the zeta potential of the nanoparticles of atovaquone may be between -25 and +25 mV. In yet another embodiment, the zeta potential of the nanoparticles of atovaquone may be between -25 and +10 mV. In general it has been found that zeta potentials of a relatively small magnitude (either positive or negative) allow the nanoparticles to better penetrate into and accumulate within cells. In accordance with the present invention, average zeta potentials can be measured by techniques known in the art, such as dynamic light scattering, for example using a Zetasizer (Malvern Instruments Ltd).
  • the solid composition may comprise solid particles or granules of larger size, for example, 5 to 30 microns ( .m) in size, wherein each particle or granule contains a plurality of solid nanoparticles of atovaquone dispersed within the one or more solid carrier materials. These larger particles or granules disperse when the solid composition is mixed with an aqueous medium to form discrete solid nanoparticles of atovaquone.
  • hydrophilic polymers are suitable for use in the solid compositions described herein: polyvinyl alcohol-polyethylene glycol graft copolymer (available under the trade name KollicoatTM); polyvinyl alcohol (‘PVA’); polyvinylpyrrolidone K30.
  • polyoxyethylene (20) sorbitan monolaurate also known as polysorbate 20 (available under the trade name TweenTM 20)
  • polyoxyethylene (20) sorbitan monooleate also known as polysorbate 80 (available under the trade name TweenTM 80); sodium deoxycholate;
  • D-a-tocopherol polyethylene glycol 1000 succinate polyethylene glycol (15)-hydroxystearate (available under the trade name SolutolTM HS).
  • polyoxyethylene (20) sorbitan monolaurate also known as polysorbate 20 (available under the trade name TweenTM 20)
  • polyoxyethylene (20) sorbitan monooleate also known as polysorbate 80 (available under the trade name TweenTM 80)
  • sodium deoxycholate sodium deoxycholate
  • the solid carrier material having surfactant activity is suitably selected from those surfactants that are capable of stabilising nanoparticles of atovaquone together with the carrier material having hydrophilic polymeric activity as defined herein, and which are also approved for pharmaceutical use (e.g. they are approved for use by the US Food and Drug Administration).
  • any one or more of the aforementioned hydrophilic polymers may be combined with any one or more of the aforementioned surfactants for use in the solid composition.
  • the following combinations of hydrophilic polymer(s) and surfactant(s) are particularly preferred for use in the solid compositions described herein: polyvinyl alcohol-polyethylene glycol graft copolymer AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monolaurate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyethylene glycol (15)-hydroxystearate; polyvinylpyrrolidone k30 AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinylpyrrolidone k30 AND polyoxyethylene (20)
  • the solid composition as described herein may comprise 10 to 99 wt% of atovaquone.
  • the solid composition may comprise 15 to 95 wt% of atovaquone.
  • the solid composition may comprise at least 20 wt%, more preferably or alternatively at least 40 wt%, yet further preferably or alternatively at least 60 wt%, and most preferably or alternatively at least 80 wt% of atovaquone.
  • the atovaquone is present in any amount of at least 10 wt%, such as in the range of from 10-99 wt%, or from 10-95 wt%, or from 10-90 wt%.
  • the atovaquone may be present in an amount of at least 15 wt%, such as in the range of from 15-99 wt%, or from 15-95 wt%, or from 15-90 wt%.
  • the atovaquone may be present in an amount of at least 20 wt%, such as in the range of from 20-99 wt%, or from 20-95 wt%, or from 20-90 wt%. Yet further alternatively, the atovaquone may be present in an amount of at least 25 wt%, such as in the range of from 25-99 wt%, or from 25-95 wt%, or from 25-90 wt%.
  • the atovaquone may be present in an amount of at least 30 wt%, such as in the range of from 30-99 wt%, or from 30-95 wt%, or from 30-90 wt%.
  • the atovaquone may be present in an amount of at least 40 wt%, such as in the range of from 40-99 wt%, or from 40-95 wt%, or from 40-90 wt%.
  • the atovaquone may be present in an amount of at least 50 wt%, such as in the range of from 50-99 wt%, or from 50-95 wt%, or from 50-90 wt%.
  • the atovaquone may be present in an amount of at least 60 wt%, such as in the range of from 60-99 wt%, or from 60-95 wt%, or from 60-90 wt%.
  • the atovaquone may be present in an amount of at least 70 wt%, such as in the range of from 70-99 wt%, or from 70-95 wt%, or from 70-90 wt%.
  • the atovaquone may be present in an amount of at least 80 wt%, such as in the range of from 80-99 wt%, or from 80-95 wt%, or from 80-90 wt%.
  • solid compositions as described herein therefore permit high drug loadings, which keeps the potentially toxic excipients (e.g. surfactants) to a minimum.
  • the solid composition may comprise 1 to 90 wt% of the one or more selected carrier materials.
  • the solid composition may comprise 5 to 85 wt% of the one or more carrier materials.
  • the solid composition may comprise 10 to 80 wt% of the one or more carrier materials.
  • the solid composition may comprise 20 to 60 wt% of the one or more selected carrier materials.
  • the percentage amount of the selected carrier materials refers to the total weight amount of all said selected carrier materials in that composition.
  • the solid composition may comprise 1 to 90 wt% of hydrophilic polymer.
  • the solid composition may comprise 8 to 70 wt% of hydrophilic polymer.
  • the solid composition may comprise 10 to 60 wt% of hydrophilic polymer.
  • the solid composition may comprise 10 to 50 wt% of hydrophilic polymer.
  • the solid composition may comprise 1 to 70 wt% of surfactant.
  • the solid composition may comprise 2 to 50 wt% of surfactant.
  • the solid composition may comprise 3 to 30 wt% of surfactant.
  • the solid composition may comprise the carrier material providing hydrophilic polymeric activity and the carrier material providing surfactant activity in a respective ratio of between 30:1 and 1 :10.
  • the solid composition may comprise the carrier material providing hydrophilic polymeric activity and the carrier material providing surfactant activity in a respective ratio of between 15:1 and 1 :2.
  • the solid composition may comprise the carrier material providing hydrophilic polymeric activity and the carrier material providing surfactant activity in a respective ratio of between 10:1 and 2:1.
  • the solid composition may comprise the carrier material providing hydrophilic polymeric activity and the carrier material providing surfactant activity in a respective ratio of between 6:1 and 3:1.
  • the solid composition comprises:
  • the solid composition comprises:
  • the solid composition comprises:
  • the solid composition comprises: about 80 wt% atovaquone; about 13 wt% of a carrier material providing hydrophilic polymeric activity; and about 7 wt% of a carrier material providing surfactant activity.
  • the solid composition may comprise one or more additional excipients, for instance, to further facilitate dispersion or stabilisation of dispersions of the nanoparticles either in a pharmaceutically acceptable diluent or in vivo.
  • the solid atovaquone compositions as described herein are prepared by an oil-in-water (o/w) emulsion technique whereby the atovaquone is dissolved in the oil phase and the carrier material(s), e.g. providing hydrophilic polymeric and surfactant activity, 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.
  • the oil-in-water emulsion 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 emulsion 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 emulsion formation comprises:
  • the oil phase is provided by dissolving atovaquone in a suitable organic solvent.
  • the aqueous phase is provided by dissolving the one or more selected carrier materials in an aqueous medium, preferably in water.
  • the aqueous phase may be provided by mixing a corresponding number of separately prepared aqueous solutions of each selected carrier material.
  • aqueous medium e.g. water
  • organic solvent is added before or during mixing step (iii).
  • the concentration of atovaquone in the oil-in-water emulsion is suitably as concentrated as possible to facilitate effective scale-up of the process.
  • concentration of drug(s) in the oil phase is suitably 10 mg/mL or higher, more suitably 15 mg/mL or higher, even more suitably greater than 20 mg/mL or higher.
  • the concentration of the carrier material providing hydrophilic polymeric activity in the aqueous/water phase is suitably 0.5 to 50 mg/mL.
  • the concentration of the carrier material providing surfactant activity in the aqueous/water phase emulsion is suitably 0.5 to 50 mg/mL.
  • 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, terf-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 , and most suitably between 6:1 and 2:1.
  • 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 spraygranulation.
  • 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.
  • 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, by submerging the vessel in a cooling medium, such as liquid nitrogen.
  • a cooling medium such as liquid nitrogen.
  • Alternative media for use for freezing purposes will be well known to those of skill in the art.
  • 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 “temperature effective for freezing the emulsion” will be well understood by those of skill in the art based on the freezing temperature of the emulsion for freezing. It will be appreciated that the skilled person could readily determine what temperature would be so effective based on the freezing point of the emulsion and carrier materials thereof.
  • the cooling medium e.g. liquid nitrogen
  • the oil-in-water emulsion may be added to the cooling medium.
  • the oil-in-water emulsion is added to the fluid medium (e.g. liquid nitrogen), suitably in a dropwise manner, whereby frozen droplets of the oil-in- water emulsion may suitably form.
  • the fluid medium e.g. liquid nitrogen
  • frozen droplets of the oil-in- water emulsion may suitably form.
  • 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.
  • An alternative process for preparing a solid composition as described herein comprising: preparing a single phase solution comprising atovaquone, and one or more selected carrier materials, in one or more solvents; and removing the one or more solvents to form the solid composition.
  • the single phase solution comprising the atovaquone and one or more selected carrier materials are all dissolved in one solvent or two or more miscible solvents.
  • W02008/006712 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 atovaquone and the one or more selected carrier materials.
  • the single phase comprises a single solvent, for example ethanol or water.
  • Removing the one or more solvents may be performed using methods well known in the art.
  • Suitably removing the one or more solvents involves freeze-drying, spraydrying or spray-granulation.
  • removing the one or more solvents involves freeze drying the single phase solution.
  • Removing the one or more solvents may suitably comprise freezing the single phase solution and then removing the solvents under vacuum.
  • Implantable Rods The present invention provides implantable rods comprising nanoparticles of atovaquone dispersed within a monolith of one or more carrier materials.
  • the atovaquone which comprises the nanoparticles may be amorphous (i.e. substantially non-crystalline in nature).
  • the nanoparticles of the present invention have an average particle diameter of less than 5 micron ( .m).
  • the nanoparticles have an average particle diameter of between 10 nm and 2500 nm, preferably between 20 nm and 2000 nm, more preferably between 50 nm and 1500 nm, further preferably between 100 nm and 1000 nm, and most preferably between 100 and 500 nm.
  • the nanoparticles have a particle diameter in the range of 1 to 1000 nm. It will be understood that references to particle diameter are references to the Z-average hydrodynamic diameter of the nanoparticles.
  • the nanoparticles of the present invention may have a polydispersity less than or equal to 0.8, preferably less than or equal to 0.6, more preferably less than or equal to 0.5.
  • the particle diameter and polydispersity of the nanoparticles may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy).
  • particle diameter and polydispersity i.e. Z-average hydrodynamic diameter
  • particle diameter and polydispersity are assessed by dispersing the solid composition in an aqueous medium at a concentration of 1 mg/mL and determining the particle diameter using dynamic light scattering, e.g. using a Malvern Panalytical Limited Zetasizer Ultra.
  • the monolith of the one or more carrier materials is non-porous in nature.
  • the one or more carrier materials are selected from hydrophilic polymers and surfactants and may be as set out for the solid compositions as described herein.
  • the hydrophilic polymers and surfactants are selected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; D-a-tocopherol polyethylene glycol 1000 succinate; and polyethylene glycol (15)-hydroxystearate
  • the one or more carrier materials may be provided in any one or more of the following combinations: polyvinyl alcohol-polyethylene glycol graft copolymer AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monolaurate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyethylene glycol (15)-hydroxystearate; polyvinylpyrrolidone k30 AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monolaurate; polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monooleate; polyvinylpyrrolidone k30 AND polyethylene glycol
  • the hydrophilic polymers and surfactants are selected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; and D-a-tocopherol polyethylene glycol 1000 succinate.
  • the one or more carrier materials may be provided in any one or more of the following combinations are provided in any one or more of the following combinations: polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate; polyvinylpyrrolidone K30 AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monolaurate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monooleate; polyvinyl alcohol AND sodium deoxycholate.
  • the relative quantities of atovaquone and the one or more carrier materials may be as set out for the solid composition as described herein.
  • the implantable rod is suitable for implantation into a patient (e.g. subcutaneously).
  • the rods may be of any suitable shape or dimension for implantation.
  • the rods are cylindrical.
  • the length of the rods may be between 1 and 100 mm, preferably between 1 and 80 mm, more preferably between 2 and 50 mm, yet more preferably between 5 and 40 mm, and most preferably between 10 and 20 mm.
  • the diameter of the rods may be between 0.1 and 5 mm, preferably between 0.5 and 2.5 mm, more preferably between 1 and 2 mm.
  • 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 as described herein while heating in order to collapse the porous matrix of one or more carrier materials 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.
  • active compounds such as atovaquone
  • Using the solid compositions of the present invention to produce the implants makes higher concentrations of atovaquone accessible, while also retaining the highly dispersible nature of the nanoparticle formulation.
  • the compressive force may be applied under a reduced pressure atmosphere (e.g. a vacuum). Doing so assists in the removal of any remaining volatile substances, such as solvents, and reduces the incidence of bubbles by removing any gas that is entrained in the solid composition. Certain apparatus may also use the pressure differential to apply the compressive force to the solid composition.
  • 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 first and second excipients cohere under the pressure of the compression step. However, the temperature must be below that which would deteriorate the atovaquone.
  • the compressed solid composition may be heated to a temperature from 60 to 160 °C, preferably from 80 to 140 °C, more preferably from 100 to 120 °C, most preferably about 110 °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 10 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 nanoparticles of atovaquone dispersed within a monolith comprising one or more carrier materials and at least one structural polymer.
  • the first composition comprises nanoparticles of atovaquone dispersed within a monolith comprising one or more carrier materials and at least one structural polymer.
  • the atovaquone which comprises the nanoparticles may be amorphous (i.e. substantially non-crystalline in nature).
  • the nanoparticles of the present invention have an average particle diameter of less than 5 micron ( .m).
  • the 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 nanoparticles have a particle diameter in the range of 1 to 1000 nm. It will be understood that references to particle diameter are references to the Z-average hydrodynamic diameter of the microparticles.
  • the nanoparticles of the present invention may have a polydispersity less than or equal to 0.8, preferably less than or equal to 0.6, more preferably less than or equal to 0.5.
  • the particle diameter and polydispersity of the nanoparticles may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy).
  • particle 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 one or more carrier materials and at least one structural polymer is non-porous in nature.
  • the one or more carrier materials are selected from hydrophilic polymers and surfactants and may be as set out for the solid compositions as described herein.
  • the hydrophilic polymers and surfactants are selected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; D-a-tocopherol polyethylene glycol 1000 succinate; and polyethylene glycol (15)-hydroxystearate
  • the one or more carrier materials may be provided in any one or more of the following combinations: polyvinyl alcohol-polyethylene glycol graft copolymer AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monolaurate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyethylene glycol (15)-hydroxystearate; polyvinylpyrrolidone k30 AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monolaurate; polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monooleate; polyvinylpyrrolidone k30 AND polyethylene glycol
  • the hydrophilic polymers and surfactants are selected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; and D-a-tocopherol polyethylene glycol 1000 succinate.
  • the one or more carrier materials may be provided in any one or more of the following combinations are provided in any one or more of the following combinations: polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate; polyvinylpyrrolidone K30 AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monolaurate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monooleate; polyvinyl alcohol AND sodium deoxycholate.
  • any hydrophilic polymer suitable for use in pharmaceutical formulations may be employed as a structural polymer, for example, the polymers that are suitable as the one or more carrier materials.
  • the structural polymer is selected to be the same as the, or one of the, one or more carrier materials, 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 atovaquone.
  • the relative quantities of atovaquone and the one or more carrier materials may be as set out for the solid composition as described herein.
  • the ratio of the combined atovaquone and one or more carrier materials to the structural polymer may be in the range of about 2 : 1 to about 1 : 10, preferably in the range of about 1 : 1 to about 1 : 5, most preferably the ratio is about 1 : 1 , such as 1 : 1.4.
  • the one or more carrier materials are a hydrophilic polymer and a surfactant
  • the first composition may comprise about 10 to 14 parts atovaquone, about 1 to 3 parts hydrophilic polymer, about 0.5 to 2 parts surfactant, and about 5 to 150 parts structural polymer.
  • the first composition comprises about 12 parts atovaquone, about 2 parts hydrophilic polymer, about 1 part surfactant, and about 10 to 120 parts structural polymer. In one embodiment, the first composition comprises about 12 parts atovaquone, about 2 parts hydrophilic polymer, about 1 part surfactant, and about 110 parts structural polymer. Alternatively, the first composition may, once dried, comprise about 5 to 40 wt% atovaquone, about 1 to 10 wt% hydrophilic polymer, about 0.5 to 5 wt% surfactant, and about 40 to 90 wt% structural polymer. In an embodiment, the composition comprises about 35 wt% atovaquone, about 5 wt% hydrophilic polymer, about 3 wt% surfactant, and about 57 wt% structural polymer.
  • the first composition comprises atovaquone, poly(ethylene oxide)20 sorbitan monooleate (Tween 80, as a surfactant), and PVP (as both hydrophilic polymer and structural polymer.
  • the quantity of atovaquone may be between about 10 and about 50 wt% of the first composition
  • the quantity of poly(ethylene oxide)20 sorbitan monooleate may be between about 0.5 and about 5 wt% of the first composition
  • the quantity of PVP may be between about 50 and 90 wt% of the first composition.
  • the quantity of atovaquone may be between about 25 and about 50 wt% of the first composition
  • the quantity of poly(ethylene oxide)20 sorbitan monooleate may be between about 2 and about 4 wt% of the first composition
  • the quantity of PVP may be between about 50 and 70 wt% of the first composition.
  • the quantity of atovaquone may be between about 40 and about 50 wt% of the first composition
  • the quantity of poly(ethylene oxide)20 sorbitan monooleate may be between about 3 and about 4 wt% of the first composition
  • the quantity of PVP may be between about 50 and 60 wt% of the first composition
  • the baseplate comprises a base polymer.
  • any hydrophilic polymer suitable for use in pharmaceutical formulations may be employed as a base polymer, for example, the polymers that are suitable as first excipients.
  • the base polymer is selected to be the same as a first excipient and/or structural polymer.
  • the base polymer is PVP.
  • the base polymer will comprise high molecular weight polymer, such as PVP with a MW of 360 kDa (PVP K90), 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.
  • a low molecular weight polyol such as glycerol
  • 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 first composition overfills the microneedle volume and additionally comprises a portion of the baseplate volume.
  • the microneedle array may be designed to contain substantially any suitable amount of atovaquone.
  • the microneedle array contains between 1 and 20 mg of atovaquone, 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 any 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.
  • the needles of the microneedle array may be of any suitable geometry.
  • they may be conical, frustoconical, cylindrical, cuboid, obelisk, square-based pyramid, pentagonal-based pyramid, arrowhead, and so on.
  • 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.
  • the nanoparticulate nature of the atovaquone is retained in the microneedles.
  • Using the solid compositions of atovaquone to produce the microneedle arrays allows for higher loading of the water insoluble drugs, while allowing them to remain in their water dispersible nanoparticulate form.
  • the microneedles formed in steps b) and c) are retained in the mould and the baseplate precursor solution is added over the top of them so as to form the microneedle array.
  • Steps b) and c) may be repeated to increase the volume of the microneedle that is formed of the first composition. It will be understood that such repetitions will occur prior to deposition of the baseplate.
  • the step of dispersing the solid composition according to the present invention and at least one structural polymer may comprise individual steps of dispersing the solid composition in a first quantity of the solvent, dissolving the at least one structural polymer in a second quantity of the solvent, and then mixing.
  • one of the solid composition and at least one structural polymer may be dispersed in the solvent, followed by the other.
  • both the solid composition and at least one structural polymer may be dispersed in the solvent simultaneously.
  • the microneedle precursor dispersion may comprise the solid composition in an amount of between 1 and 50 wt%, preferably between 5 and 25 wt%, more preferably between 10 and 20 wt%.
  • the microneedle precursor dispersion may comprise the at least one structural polymer in an amount between 1 and 60 wt%, preferably between 10 and 50 wt%, more preferably between 30 and 40 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 1 and 50 wt% base polymer, preferably between 5 and 40 wt% base polymer, more preferably between 10 and 30 wt% base polymer, most preferably about 15 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. nontoxic, 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.
  • 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 an implantable rod or microneedle array as defined herein for use as a medicament.
  • the present invention provides an implantable rod or microneedle array as defined herein for use in the treatment and/or prevention of parasitic and/or fungal infections.
  • the parasitic infection may be caused by parasites of the genus Plasmodium, or by parasites of the genus Toxoplasma, or by parasites of the genus Babesiidae, or wherein the fungal infection is caused by fungus of the genus Pneumocystis.
  • the parasitic infection may be malaria, toxoplasmosis, or babesiosis, or wherein the fungal infection is Pneumocystis pneumonia
  • the implantable rod for use in the treatment and/or prevention of parasitic and/or fungal infections has a concentration of atovaquone in the range of 40 to 90 wt%, preferably 60 to 90 wt%, more preferably 75 to 85 wt% atovaquone, most preferably about 80 wt%.
  • the microneedle array for use in the treatment and/or prevention of parasitic and/or fungal infections contains a mass of atovaquone in the range of between 1 and 20 mg of atovaquone, preferably between 2 and 10 mg, more preferably about 5 mg. It will be understood that the dose of atovaquone provided to a patient may be varied by using larger and/or multiple microneedle arrays.
  • the present invention provides a method of treating and/or preventing parasitic and/or fungal infections, the method comprising administering a therapeutically effective amount of an implantable rod or microneedle array as defined herein to a patient suffering from or at risk of suffering from parasitic and/or fungal infections.
  • the implantable rod may form a depot within the body of the patient, for example, in an intramuscular or subcutaneous site, optionally wherein the depot maintains a therapeutically effective concentration of atovaquone within the body of the patient for a period of at least two weeks, preferably at least one month, more preferably at least two months, yet more preferably at least three months, and most preferably at least four months.
  • the microneedle array gradually releases atovaquone, and optionally maintains a therapeutically effective concentration of atovaquone within the body of the patient for a period of at least 4 hours, preferably at least 6 hours, more preferably at least 12 hours, and most preferably at least 24 hours.
  • the microneedle array or arrays are removed from the skin of the patient and, if treatment is ongoing, replaced with a fresh microneedle array or arrays.
  • the method requires dosing of the microneedle array up to six times per day, preferably up to four times per day, more preferably twice a day, and most preferably once a day, to maintain a therapeutically effective concentration of atovaquone in the patient for the duration of the treatment.
  • the administered form of nanoparticles of atovaquone preferably provides a controlled release bolus formulation of atovaquone, which, when administered to a patient, releases atovaquone into the bloodstream of the patient over a period of at least about two weeks from the date of administration. Further preferably the period of release is at least about one month, more preferably at least about two months, yet more preferably at least about three months, and most preferably at least about four months from the date of administration of insertion.
  • treatment includes curative and prophylactic treatment.
  • a “patient” means an animal, preferably a mammal, preferably a human, in need of treatment.
  • the amount of atovaquone administered should be a therapeutically effective amount where atovaquone is used for the treatment of a disease or condition and a prophylactically effective amount where the atovaquone is used for the prevention of a disease or condition.
  • therapeutically effective amount used herein refers to the amount of atovaquone needed to treat or ameliorate parasitic and/or fungal infections.
  • prophylactically effective amount used herein refers to the amount of atovaquone needed to prevent parasitic and/or fungal infections. 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.
  • the 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, buccal; sublingual; transdermal (including, microneedle array e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); or by implantation of a depot, reservoir, or implantable rod for example, subcutaneously or intramuscularly.
  • the route of administration is by implantation of an implantable rod.
  • the route of administration is transdermal via a microneedle array.
  • the implantable rod of the present invention is a depot formulation administered so as to provide a controlled release in the patient over at least a period of about two weeks from the date of administration. Further preferably the period of release is at least about one month, more preferably at least about two months, yet more preferably at least about three months, and most preferably at least about four months from the date of implantation. Without wishing to be bound by theory, it is thought that the implant gradually dissolves to form a liquid depot and that the atovaquone 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, further preferably at least 24 hours, yet further preferably at least 48 hours, still further preferably at least 72 hours, and most preferably at least 96 hours.
  • Poly(vinyl pyrrolidone) K30 (average Mn 40, 000 g mol -1 ), poly(vinyl pyrrolidone) K90 (average Mn 360, 000 g mol -1 ) were obtained from Sigma Aldrich.
  • Atovaquone was purchased from Quay Pharmaceuticals Ltd.
  • ProSafe + and TritiumCount + LSC cocktails were purchased from Meridian Biotechnologies Ltd. 3 H- atovaquone in tetrahydrofuran/ethanol was obtained from RC Tritec Ltd.
  • Atovaquone SDNs were prepared as described in WO 2017/216564 A1. Specifically, samples were prepared using an 80 mg/mL stock solution of atovaquone (A) in chloroform, a 22.5 mg/mL stock solution of polymer (P) and a 22.5 mg/mL stock solution of surfactant (S), both stock solutions being in water. Stock solutions were added in the following proportions: 100 pL (A); 63 pL (P) and 32 pL (S) with 305 pL water (the solid mass ratio therefore being: 80 % (A); 13 % (P) and 7 % (S) in an 1 :4 oil to water (O/W) mix). The mixtures were then emulsified using a Covaris S2x for 30 seconds with a duty cycle of 20, an intensity of 10 and 500 cycles/burst in frequency sweeping mode. Immediately after emulsification, the samples were cryogenically frozen.
  • NDC sodium deoxycholate
  • Vitamin E-TPGS D-a-Tocopherol polyethylene glycol 1000 succinate.
  • SolutolTM HS 15, also known as KolliphorTM HS 15, is polyethylene glycol (15)- hydroxystearate.
  • a particle was determined a hit if it complied with the following criteria:
  • the ‘size quality report’ incorporates twelve tests on the reliability of the data recorded and is automatically applied to each measurement by the Malvern Zetasizer software. These tests ensure that the sample is within a size range appropriate for DLS, has a PDI below 1, is within the correct concentration range and that the cumulant and distribution fit are good (i.e. the errors on the data are less than 0.005).
  • 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 ( ⁇ 54 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 25 minutes before being transferred onto the cooling plate and cooled for 15 minutes. Yellow coloured rods were obtained weighing ⁇ 54 mg and having a length of 13 mm and diameter of 2 mm.
  • a polymer stock solution was prepared containing 40 wt% PVP K30, into which sufficient atovaquone SDN (comprising 80 wt% atovaquone, 13 wt% PVP K30, and 7 wt% Tween 80) was dispersed to provide needle layer compositions with atovaquone concentrations of 69.90, 194.17 and 388.35 mg mL' 1 atovaquone to yield, when used as described below, microneedle arrays with atovaquone loadings of 0.72, 2, and 4 mg respectively.
  • the atovaquone loadings of the microneedle arrays refers to the mass of atovaquone that is deliverable (i.e. that is present in the needles of the microneedle array).
  • non-deliverable atovaquone may be present in the baseplate should the needle layer composition overfill the needle volume of the micromould.
  • the needle layer composition was cast into a 27 by 27 micromould, each conical needle having a height of 600 pm and a column width of 300 pm at the base, the centre-to-centre spacing between needles being 450 pm.
  • Each micromould was placed into a cylindrical mould for the baseplate to make a mould assembly.
  • the total needle volume was 10.3 pL and the total baseplate volume was approximately 1 mL.
  • each needle layer composition 15 pL was evenly pipetted across an individual micromould, ensuring each needle shaft was sufficiently filled.
  • the filled micromould was placed into a pressure chamber and subjected to a pressure of 5 bar for 30 minutes.
  • the loaded micromoulds were allowed to dry for 30 minutes in a high-velocity fume cupboard before a baseplate composition comprising 15 wt% PVP K90 (1 mL) was added to fill the cylindrical mould.
  • the mould assembly was then centrifuged at 3000 x g for 15 minutes. After 48 h of drying under ambient conditions, the atovaquone microneedle arrays were removed carefully from the mould assemblies. Radiolabelled arrays were prepared in the same way using 3 H-atovaquone SDNs.
  • the dry composition of the needle layer is as follows:
  • the dry composition of the microneedle array is as follows:
  • the baseplate contains additional atovaquone that may not be readily deliverable
  • the produced microneedle arrays were observed using optical microscopy (using a Leica DM4 B microscope fitted with a CMOS camera) to quantify the dimensions of the microneedles. The dimensions of five needles were measured and the mean value taken. The mean dimensions of the microneedles are 608 pm needle height, 315 pm base width and 450 pm interspacing from base-centre to base centre.
  • Atovaquone SDNs were prepared as described above and dispersed in water to an atovaquone concentration of 0.5 mg mL' 1 and analysed by DLS.
  • Atovaquone SDNs were also dispersed in 40 wt% PVP K30 (corresponding to the needle layer composition) to an atovaquone concentration of 1 mg mL -1 .
  • a portion of the dispersion was diluted to an atovaquone concentration of 0.5 mg mL -1 and analysed by DLS.
  • the remaining dispersion was then rolled for 24 hours prior to casting 400 pL of the dispersion into a baseplate mould, which was dried as described above.
  • the resulting baseplate was redispersed in water to atovaquone concentration of 0.5 mg mL -1 and analysed by DLS.
  • Microneedle arrays containing 0, 0.72, 2, and 4 mg loadings of atovaquone SDNs were subjected to X-ray microtomography to produce cross-sections and 3D views, with representative images provided in Fig. 2.
  • Brighter areas of the image indicate greater interaction with the X-rays due to higher density (e.g. heavier nuclei), implicitly indicating areas with higher concentrations of chlorine-containing atovaquone.
  • the samples show higher concentrations of atovaquone toward the tip of the microneedle, especially in the lowest dose of 0.72 mg.
  • Microneedle arrays containing 0, 0.72, 2, and 4 mg loadings of 3 H-atovaquone SDNs were embedded in wax and sectioned into 10 pm slices, which were subsequently counted for radioactivity in order to determine the atovaquone concentration at various depths. The results are shown in Figs. 3 and 4, with atovaquone concentrations being highest at the tip of the needle, especially for the 0.72 mg microneedle arrays.
  • Microneedle arrays containing 0, 0.72, 2, and 4 mg loadings of atovaquone SDNs were subjected to uniaxial compression testing using a CellScale UniVert uniaxial compression analyser fitted with a calibrated 50 N load cell. Samples were compressed at 500 pm s’ 1 until either the load cell reached its maximum force application, with measurements being performed in triplicate and the modulus calculated for each microneedle array. The results are summarised in Fig. 5, which shows that there is no significant variation in mechanical strength with atovaquone loading
  • micrographs were taken prior to compression and after compression (the latter both for an outer row of the needles within the array and the middle row of needles within the array), see Fig. 6, which showed that the microneedles were not damaged by the applied force.
  • Microneedle arrays containing 0, 0.72, 2, and 4 mg loadings of atovaquone SDNs were subjected to insertion force analysis into freshly excised porcine skin using a CellScale UniVert uniaxial compression analyser fitted with a calibrated 50 N load cell at 50 pm s’ 1 until complete insertion was achieved. Force-displacement plots were generated in order to determine force required (N/array) for complete insertion into skin.
  • Microneedle arrays were formulated with 3 H-atovaquone loadings of 0.72, 2 and 4 mg 3 H-ATQ at specific activities of 3.80 x 10' 3 , 3.54 x 10' 3 and 3.50 x 10' 3 MBq mg -1 .
  • Each microneedle array was placed in a well of a 12-well plate and submerged in 1.5 mL of distilled water. The well plate was then placed in an orbital shaker at 300 RPM at 21 °C. 100 pL aliquots of the solution were taken every 10 seconds for 2 minutes, then every 60 seconds until a maximum of 20 minutes at which point, if necessary, additional timepoints were taken at 5-minute intervals up to 1 hour.
  • Timepoint aliquots were replaced with 100 pL of distilled water simultaneously with sampling. Timepoint samples were then mixed with 10 mL ProSafe+ liquid scintillation cocktail and submitted for liquid scintillation counting to determine the atovaquone concentrations within each well.
  • Each microneedle array fully dissolved, with complete dissolution being obtained at 50, 100, and 250 seconds respectively for the arrays with atovaquone loadings of 0.72, 2 and 4 mg. This shows an inverse relationship between the atovaquone concentration and the dissolution rate.
  • the dissolution profile is plotted in Fig. 7 and was used to determine dissolution rates, shown in the table below.
  • DMNs were prepared via the general DMN preparation procedure with loadings of 0.72, 2 and 4 mg within the needles.
  • Whole porcine ears excised from freshly slaughtered adult pigs were obtained from C S Morphet and Sons Abattoir (Widnes, UK). Skin from the dorsal side of the ear was prepared by removing cartilaginous tissue and 45 mm discs were then dissected. Prepared skin was refrigerated and used within 24 hours of slaughter.
  • Franz diffusion apparatus with reservoir volumes of 32 mL were equipped with magnetic stirrer bars and charged with freshly prepared PBS solution.
  • the Franz cells were placed in a water bath at 37 °C and allowed to equilibrate.
  • the discs of porcine skin were placed onto the receptor chamber and allowed to hydrate for 30 minutes at 37 °C. Briefly, the skin discs were removed from the Franz cells and microneedle arrays inserted with a digital force gauge applied at 15 N for 30 seconds.
  • the skin discs were quickly replaced on the receptor chamber of the Franz cell, and a donor chamber placed on top.
  • the donor chambers were sealed with Parafilm M before placing a metal clamp onto the apparatus.
  • An initial time-point was taken 30 minutes after needle insertion via sampling (1 mL) from the receptor chamber reservoir, and replaced with fresh PBS (1 mL).
  • Fig. 8 The results are shown in Fig. 8 in terms of cumulative % of total atovaquone dose released to the compartment and cumulative mass of atovaquone released to the compartment over time.
  • This effect results in the 0.72 and 2 mg dose microneedle arrays releasing similar masses of atovaquone, however, the 4 mg dose microneedle array releases more atovaquone, as would be expected from its higher initial atovaquone content.
  • the results are shown in Fig.
  • the dorsal hair of the rats 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), where microneedle arrays were affixed using firm thumb pressure onto a pinched section of skin on the back of the rats.
  • MicrofoamTM surgical tape was placed on top of the microneedle arrays and kinesiology tape applied to keep them in place.
  • the rats were divided into three cohorts, with the microneedle arrays being removed from the first cohort after one hour, from the second cohort after 12 hours, and from the third cohort after 24 hours.
  • Fig. 10 Blood plasma was collected from the tail veins periodically over the course of 24 hours and the atovaquone concentrations therein quantified using LC/MS-MS. This data is graphed in Fig. 10 and shows a consistent atovaquone concentration of around 1000 to 2000 ng/mL over the 24 hour period of the experiment when the microneedle arrays were applied for either 12 or 24 hours, and a lower consistent atovaquone concentration of around 5 to 10 ng/mL over the 24 hour period of the experiment when the microneedle arrays were applied for 1 hour.
  • 200 ng/mL is the target blood plasma concentration for prophylaxis against malaria.
  • the experiment clearly shows that the microneedle arrays may be used to maintain therapeutically effective concentrations of atovaquone for extended durations, such as 2 to 7 days or more, even after removal of the microneedle array.
  • Four microneedle arrays (each loaded with 2.91 mg of atovaquone for a total dose of 11.64 mg per rat) were applied to each rat.
  • the dorsal hair of the rats 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), where microneedle arrays were affixed using firm thumb pressure onto a pinched section of skin on the back of the rats.
  • MicrofoamTM surgical tape was placed on top of the microneedle arrays and kinesiology tape applied to keep them in place.
  • the rats were divided into three cohorts, with the microneedle arrays being removed from the first cohort after two hours, from the second cohort after four hours, and from the third cohort after eight hours.
  • Fig. 11 Blood plasma was collected from the tail veins periodically over the course of 14 days and the atovaquone concentrations therein quantified using LC/MS-MS. This data is graphed in Fig. 11 and shows that an effective concentration of atovaquone (i.e. in excess of 200 ng/mL) is maintained for at least 100 hours in all cases.
  • Clause 1 A method of producing an implantable rod comprising the steps of compressing a solid composition, the solid comprising nanoparticles of atovaquone dispersed within one or more carrier materials, and heating the compressed solid composition for a period of time.
  • Clause 3 The method of clause 1 or clause 2, wherein the solid composition is heated to a temperature from 60 to 160 °C, preferably from 80 to 140 °C, more preferably from 100 to 120 °C, most preferably about 110 °C.
  • Clause 4 The method of any one of clauses 1 to 3, wherein the compression occurs under a reduced pressure atmosphere.
  • Clause 5 The method of any one of clauses 1 to 4, wherein the heating step takes 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 10 minutes.
  • Clause 6 The method of any one of clauses 1 to 5, further comprising a step of cooling the rod, optionally the cooling taking place under a reduced pressure atmosphere.
  • a method of producing a microneedle array comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition comprising the steps of: a) dispersing a solid composition, the solid comprising nanoparticles of atovaquone dispersed within one or more carrier materials, and at least one structural polymer in a solvent to form a microneedle precursor dispersion; b) placing the microneedle precursor dispersion into a mould; c) compressing the microneedle precursor dispersion in the mould and then drying to form microneedles comprising the first composition; d) adding a baseplate precursor solution into the mould; e) compressing the baseplate precursor solution and then drying to form the baseplate of the second composition; and f) releasing the microneedle array from the mould. Clause 8. The method of clause 7, wherein steps b) and c) are repeated prior to steps d) to f).
  • Clause 10 The method of any one of clauses 7 to 9, wherein the at least one structural polymer is selected from PVA, PVP, and combinations thereof.
  • the baseplate precursor solution comprises a base polymer selected from PVP and, optionally, one or more additives such as glycerol, dispersed in an aqueous solvent, such as water.
  • Clause 12 The method of producing an implantable rod of any one of clauses 1 to 6, or the method of producing a microneedle array of any one of clauses 7 to 11 , wherein the one or more carrier materials comprise are selected from hydrophilic polymers and surfactants, and are preferably selected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; D-a-tocopherol polyethylene glycol 1000 succinate; and polyethylene glycol (15)-hydroxystearate.
  • the one or more carrier materials comprise are selected from hydrophilic polymers and surfactants, and are preferably selected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30; polyoxyethylene (20)
  • Clause 13 The method of producing an implantable rod or the method of producing a microneedle array of clause 12, wherein the one or more carrier materials are provided in any one or more of the following combinations: polyvinyl alcohol-polyethylene glycol graft copolymer AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monolaurate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate; polyvinyl alcohol-polyethylene glycol graft copolymer AND polyethylene glycol (15)-hydroxystearate; polyvinylpyrrolidone k30 AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monolaurate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan
  • Clause 14 The method of producing an implantable rod or the method of producing a microneedle array of clause 12, wherein the one or more carrier materials are selected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; and D-a-tocopherol polyethylene glycol 1000 succinate.
  • the one or more carrier materials are selected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; and D-a-tocopherol polyethylene glycol 1000 succinate.
  • Clause 15 The method of producing an implantable rod or the method of producing a microneedle array of clause 14, wherein the one or more carrier materials are provided in any one or more of the following combinations: polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate; polyvinylpyrrolidone K30 AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monolaurate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monooleate; polyvinyl alcohol AND sodium deoxycholate.
  • Clause 16 The method of producing an implantable rod of any one of clauses 1 to 6 or 12 to 15, or the method of producing a microneedle array of any one of clauses 7 to 15, wherein the nanoparticles of atovaquone have an average particle size between 100 and 800 nm.
  • Clause 17 The method of producing an implantable rod of any one of clauses 1 to 6 or 12 to 16, or the method of producing a microneedle array of any one of clauses 7 to 16, wherein the polydispersity of the nanoparticles of atovaquone is less than or equal to 0.8.
  • Clause 18 An implantable rod produced by the method of any one of clauses 1 to 6 or 12 to 17.
  • An implantable rod comprising nanoparticles of atovaquone dispersed within a monolith comprising one or more carrier materials, wherein the one or more carrier materials are pharmaceutically acceptable hydrophilic polymers and/or surfactants.
  • a microneedle array comprising microneedles of a first composition arrayed on one face of a baseplate of a second composition, wherein the first composition comprises nanoparticles of atovaquone dispersed within a monolith comprising one or more carrier materials, wherein the one or more carrier materials are pharmaceutically acceptable hydrophilic polymers and/or surfactants, and at least one structural polymer
  • Clause 22 The microneedle array of clause 21 , wherein the at least one structural polymer is selected from PVA, PVP, and combinations thereof.
  • Clause 24 The implantable rod of clause 18 or clause 19, or the microneedle array of any one of clauses 21 to 23, wherein the one or more carrier materials are selected from the list consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30 ; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; D-a-tocopherol polyethylene glycol 1000 succinate; and polyethylene glycol (15)-hydroxystearate, and combinations thereof.
  • the one or more carrier materials are selected from the list consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30 ; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; D-a-tocopherol polyethylene glycol 1000 succ
  • Clause 26 The implantable rod of any one of clauses 18, 19, 24, or 25, or the microneedle array of any one of clauses 21 to 25, wherein the one or more carrier materials are selected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; and D-a-tocopherol polyethylene glycol 1000 succinate.
  • the one or more carrier materials are selected from the group consisting of: polyvinyl alcohol-polyethylene glycol graft copolymer; polyvinyl alcohol; polyvinylpyrrolidone K30; polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monooleate; sodium deoxycholate; and D-a-tocopherol polyethylene glycol 1000 succinate.
  • Clause 27 The implantable rod or the microneedle array of clause 26, wherein the one or more carrier materials are provided in any one or more of the following combinations: polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate; polyvinylpyrrolidone K30 AND D-a-tocopherol polyethylene glycol 1000 succinate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monolaurate; polyvinylpyrrolidone K30 AND polyoxyethylene (20) sorbitan monooleate; polyvinyl alcohol AND sodium deoxycholate.
  • Clause 28 The implantable rod of any one of clauses 18, 19, or 24 to 27, or the microneedle array of any one of clauses 21 to 27, wherein the nanoparticles of atovaquone have an average particle size between 100 and 800 nm.
  • Clause 29 The implantable rod of any one of clauses 18, 19, or 24 to 28, or the microneedle array of any one of clauses 21 to 28, wherein the polydispersity of the nanoparticles of atovaquone is less than or equal to 0.8.
  • Clause 30 An implantable rod as described in any one of clauses 18, 19, or 24 to 29, or a microneedle array as described in any one of clauses 21 to 29, for use as a medicament.
  • Clause 31 An implantable rod as described in any one of clauses 18, 19, or 24 to 29, or a microneedle array as described in any one of clauses 21 to 29, for use in the treatment and/or prevention of parasitic and/or fungal infections.
  • Clause 32 An implantable rod or a microneedle array as described in clause 31 , wherein the parasitic infection is caused by parasites of the genus Plasmodium, or by parasites of the genus Toxoplasma, or by parasites of the genus Babesiidae, or wherein the fungal infection is caused by fungus of the genus Pneumocystis.
  • Clause 34 A method of treating and/or preventing a fungal infection, the method comprising administering a therapeutically effective amount of an implantable rod as described in any one of clauses 18, 19, or 24 to 29, or a microneedle array as described in any one of clauses 21 to 29, to a patient suffering from or at risk of suffering from a parasitic or fungal infection.
  • Clause 35 A method as described in clause 34, wherein the parasitic infection is caused by parasites of the genus Plasmodium, or by parasites of the genus Toxoplasma, or by parasites of the genus Babesiidae, or wherein the fungal infection is caused by fungus of the genus Pneumocystis.
  • Clause 36 A method as described in clause 35, wherein the parasitic infection is malaria, toxoplasmosis, or babesiosis, or wherein the fungal infection is Pneumocystis pneumonia.
  • Clause 37 The use of an implantable rod as described in any one of clauses 18, 19, or 24 to 29, or a microneedle array as described in any one of clauses 21 to 29, for the manufacture of a medicament for the treatment and/or prevention of parasitic and/or fungal infections.
  • Clause 38 The use of an implantable rod as described in any one of clauses 18, 19, or 24 to 29, or a microneedle array as described in any one of clauses 21 to 29, for the manufacture of a medicament for the treatment and/or prevention of parasitic infection caused by parasites of the genus Plasmodium, or by parasites of the genus Toxoplasma, or by parasites of the genus Babesiidae, or for the treatment and/or prevention of fungal infection caused by fungus of the genus Pneumocystis.
  • Clause 39 The use of an implantable rod as described in any one of clauses 18, 19, or 24 to 29, or a microneedle array as described in any one of clauses 21 to 29, for the manufacture of a medicament for the treatment and/or prevention of malaria, toxoplasmosis, babesiosis, or Pneumocystis pneumonia.

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  • Medicinal Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
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Abstract

La présente invention concerne des procédés de production de tiges implantables et de réseaux de micro-aiguilles comprenant des nanoparticules d'atovaquone, ainsi que de telles tiges implantables et réseaux de micro-aiguilles et leurs utilisations thérapeutiques.
PCT/GB2024/050860 2023-03-29 2024-03-28 Compositions solides d'atovaquone Pending WO2024201057A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB2304657.6A GB202304657D0 (en) 2023-03-29 2023-03-29 Atovaquine compositions
GB2304657.6 2023-03-29

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WO2024201057A1 true WO2024201057A1 (fr) 2024-10-03

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004011537A1 (fr) 2002-07-30 2004-02-05 Unilever N.V. Billes poreuses et leur procede de production
WO2008006712A2 (fr) 2006-07-13 2008-01-17 Unilever Plc Améliorations concernant des nanodispersions
US20100028425A1 (en) * 2008-07-31 2010-02-04 Glenmark Generics Ltd. Pharmaceutical composition of atovaquone
US20130189342A1 (en) * 2010-03-16 2013-07-25 Titan Pharmaceuticals, Inc. Heterogeneous implantable devices for drug delivery
WO2017216564A1 (fr) 2016-06-16 2017-12-21 The University Of Liverpool Composition chimique
US20210007973A1 (en) * 2016-10-05 2021-01-14 Titan Pharmaceuticals, Inc. Implantable devices for drug delivery with reduced burst release

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004011537A1 (fr) 2002-07-30 2004-02-05 Unilever N.V. Billes poreuses et leur procede de production
WO2008006712A2 (fr) 2006-07-13 2008-01-17 Unilever Plc Améliorations concernant des nanodispersions
US20100028425A1 (en) * 2008-07-31 2010-02-04 Glenmark Generics Ltd. Pharmaceutical composition of atovaquone
US20130189342A1 (en) * 2010-03-16 2013-07-25 Titan Pharmaceuticals, Inc. Heterogeneous implantable devices for drug delivery
WO2017216564A1 (fr) 2016-06-16 2017-12-21 The University Of Liverpool Composition chimique
US20210007973A1 (en) * 2016-10-05 2021-01-14 Titan Pharmaceuticals, Inc. Implantable devices for drug delivery with reduced burst release

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HIROYUKI TAKABE ET AL: "A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier", PHARMACEUTICS, vol. 10, no. 2, 19 May 2018 (2018-05-19), pages 60, XP055512580, DOI: 10.3390/pharmaceutics10020060 *
LEDER K. ET AL., CLIN. INFECT DIS., vol. 39, 2004, pages 1104 - 1112

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