WO2023222755A1 - Traitement ou prévention d'une infection par le vih - Google Patents

Traitement ou prévention d'une infection par le vih Download PDF

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Publication number
WO2023222755A1
WO2023222755A1 PCT/EP2023/063239 EP2023063239W WO2023222755A1 WO 2023222755 A1 WO2023222755 A1 WO 2023222755A1 EP 2023063239 W EP2023063239 W EP 2023063239W WO 2023222755 A1 WO2023222755 A1 WO 2023222755A1
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WO
WIPO (PCT)
Prior art keywords
injection device
rilpivirine
pharmaceutically acceptable
acceptable salt
nanoparticles
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PCT/EP2023/063239
Other languages
English (en)
Inventor
Steven M. VESOLE
Guenter Karl Wilhelm KRAUS
Original Assignee
Janssen Sciences Ireland Unlimited Company
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Publication of WO2023222755A1 publication Critical patent/WO2023222755A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142—Pressure infusion, e.g. using pumps
    • A61M5/14244—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • A61M5/14248—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body of the skin patch type
    • 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
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/20—Automatic syringes, e.g. with automatically actuated piston rod, with automatic needle injection, filling automatically

Definitions

  • the present invention relates to the treatment or prevention of HIV infection using rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension, to a subcutaneous injection device, and to a method of administering rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension with a subcutaneous injection device.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • Rilpivirine is an anti-retroviral of the NNRTI class that is used for the treatment of HIV infection.
  • Rilpivirine is a second- generation NNRTI with higher potency and a reduced side effect profile compared with older NNRTIs.
  • Rilpivirine activity is mediated by non-competitive inhibition of HIV-1 reverse transcriptase.
  • Rilpivirine not only shows pronounced activity against wild type HIV, but also against many of its mutated variants. Rilpivirine, its pharmacological activity, as well as a number of procedures for its preparation have been described in WO 03/16306. Rilpivirine has been approved for the treatment of HIV infection and is commercially available as a single agent tablet (EDURANT®) containing 25 mg of rilpivirine base equivalent per tablet for once-daily oral administration as well as single tablet regimens for once-daily oral administration (COMPLERA®, ODEFSEY®, JULUCA®).
  • W02007/147882 discloses intramuscular or subcutaneous injection of a therapeutically effective amount of rilpivirine in micro- or nanoparticle form, having a surface modifier adsorbed to the surface thereof; and a pharmaceutically acceptable aqueous carrier; wherein the rilpivirine active ingredient is suspended.
  • a prolonged release suspension for injection of rilpivirine for administration in combination with a prolonged release suspension for injection of cabotegravir has been approved as co-pack CABENUVA® in e.g. the USA and Canada, and as REKAMBYS® in e.g. the EU. These are the first anti-retrovirals to be provided in a long-acting injectable formulation for administration at intervals of greater than one day.
  • rilpivirine or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of HIV infection in a subject, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of micro- or nanoparticles in suspension, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension and wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered intermittently at a time interval of about three months to about seven months.
  • a method for the treatment or prevention of HIV infection in a subject comprising administering to the subject a therapeutically effective amount of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension by subcutaneous injection at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension and wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered intermittently at a time interval of about three months to seven months.
  • a subcutaneous pharmaceutical injection device comprising a container containing a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously; and a driver configured to drive the rilpivirine or pharmaceutically acceptable salt from the container and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension.
  • a method of administering a pharmaceutical composition using a subcutaneous injection device comprising: inserting a discharge nozzle of the subcutaneous injection device into a subcutaneous layer of a patient; and causing a driver of the subcutaneous injection device to drive a volume of rilpivirine or pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension from a container of the injection device and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months.
  • a method of preparing a subcutaneous injection device for injection comprising: introducing a volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device, the rilpivirine or a pharmaceutically acceptable salt thereof being in the form of micro- or nanoparticles in suspension, and the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months.
  • a kit comprising: a subcutaneous pharmaceutical injection device, comprising: a container configured to contain a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously; and a driver configured to drive the rilpivirine or pharmaceutically acceptable salt from the container and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension; and a drug provision device containing a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine
  • kits comprising: a subcutaneous pharmaceutical injection device, comprising: a container configured to contain a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously; and a driver configured to drive the rilpivirine or pharmaceutically acceptable salt from the container and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension; and a drug provision device containing a volume of rilpivirine or
  • a subcutaneous pharmaceutical injection device comprising: a container containing a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1 .5 pm to about 2 pm and a D v 10 of from about 300 nm to about 500 nm, the volume being 2ml_ or greater and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously; and a driver configured to drive the rilpivirine or pharmaceutically acceptable salt from the container and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension.
  • a method of administering a pharmaceutical using a subcutaneous injection device comprising: inserting a discharge nozzle of the subcutaneous injection device into a subcutaneous layer of a patient; and causing a driver of the subcutaneous injection device to drive a volume of rilpivirine or pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension from a container of the injection device and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension, wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1 .5 pm to about 2 pm and a D V 10 of from about 300 nm to about 500 nm, the volume being 2mL or greater and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months.
  • a method of preparing a subcutaneous injection device for injection comprising: introducing a volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device, the rilpivirine or a pharmaceutically acceptable salt thereof being in the form of micro- or nanoparticles in suspension, wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1 .5 pm to about 2 pm and a D V 10 of from about 300 nm to about 500 nm, and the volume being 2mL or greater and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months.
  • a kit comprising: a subcutaneous pharmaceutical injection device, comprising: a container configured to contain a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1 .5 pm to about 2 pm and a D V 10 of from about 300 nm to about 500 nm, the volume being 2ml_ or greater and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously; and a driver configured to drive the rilpivirine or pharmaceutically acceptable salt from the container and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension; and
  • the kit may comprise an introducer for introducing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into the container of the subcutaneous pharmaceutical injection device, or the container may be prefilled with the volume.
  • a kit comprising: a subcutaneous pharmaceutical injection device, comprising: a container configured to contain a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1 .5 pm to about 2 pm and a D V 10 of from about 300 nm to about 500 nm, the volume being 2ml_ or greater and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously; and a driver configured to drive the
  • Figure 1 A subcutaneous pharmaceutical injection device in the form of a syringe.
  • Figure 2 A subcutaneous pharmaceutical injection device in the form of an autoinjector.
  • Figure 3A A subcutaneous pharmaceutical injection device in the form of a patch pump.
  • Figure 3B A subcutaneous pharmaceutical injection device in the form of a patch pump.
  • Figure 4 A subcutaneous pharmaceutical injection device in the form of a subcutaneous infusion set.
  • Figure 5 A subcutaneous pharmaceutical injection device in the form of a syringe pump.
  • Figure 6 A subcutaneous pharmaceutical injection device in the form of an infusion pump.
  • Rilpivirine (4-[[4-[[4-[(1 E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]- amino]benzonitrile; TMC278) has the following structural formula:
  • rilpivirine it is meant rilpivirine having the structural formula shown above, i.e. the free base form.
  • the rilpivirine or a pharmaceutically acceptable salt thereof as used in the invention is in the form of micro- or nanoparticles in suspension, i.e. microparticles or nanoparticles of the rilpivirine or a pharmaceutically acceptable salt thereof in a suspension, in particular micro- or nanoparticles of the rilpivirine or a pharmaceutically acceptable salt thereof suspended in a pharmaceutically acceptable carrier, such as for example a pharmaceutically acceptable aqueous carrier.
  • compositions of rilpivirine means those where the counterion is pharmaceutically acceptable.
  • the pharmaceutically acceptable salts are meant to comprise the therapeutically active non-toxic acid addition salt forms which rilpivirine is able to form. These salt forms can conveniently be obtained by treating rilpivirine with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g.
  • the rilpivirine or a pharmaceutically acceptable salt thereof used in the invention is rilpivirine.
  • the size of the micro- or nanoparticles should be below a maximum size above which administration by subcutaneous or intramuscular injection becomes impaired or even is no longer possible.
  • the maximum size depends for example on the limitations imposed by the needle diameter or by adverse reactions of the body to large particles, or both.
  • the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of nanoparticles.
  • the rilpivirine or a pharmaceutically acceptable salt thereof micro- or nanoparticles have a D v 90 of less than or about 2 pm.
  • the micro- or nanoparticles may have a D v 90 of from about 100 nm to about 2 pm.
  • the micro- or nanoparticles may have a D v 90 of from 200 nm to about 2 pm.
  • the micro- or nanoparticles may have a D v 90 of from 300 nm to about 2 pm.
  • the micro- or nanoparticles may have a D v 90 of from 400 nm to about 2 pm.
  • D v 90 refers to the diameter below which 90% by volume of the particle population is found.
  • D v 50 refers to the diameter below which 50% by volume of the particle population is found.
  • D v 10 refers to the diameter below which 10% by volume of the particle population is found.
  • the rilpivirine or a pharmaceutically acceptable salt thereof micro- or nanoparticles may have a D v 50 of less than or about 1 ,000 nm.
  • the micro- or nanoparticles may have a D v 50 of from about 10 nm to about 1 ,000 nm.
  • the micro- or nanoparticles may have a D v 50 of from about 50 nm to about 700 nm.
  • the micro- or nanoparticles may have a D v 50 of from about 100 nm to about 600 nm.
  • the micro- or nanoparticles may have a D v 50 of from about 150 nm to about 500 nm.
  • the micro- or nanoparticles have a D v 50 of from about 200 nm to about 500 nm.
  • the rilpivirine or a pharmaceutically acceptable salt thereof micro- or nanoparticles may have a D V 10 of less than or about 500 nm.
  • the micro- or nanoparticles may have a D v 10 of from about 10 nm to about 500 nm.
  • the micro- or nanoparticles may have a D v 10 of from about 25 nm to about 400 nm.
  • the micro- or nanoparticles may have a D v 10 of from about 50 nm to about 300 nm.
  • the micro- or nanoparticles may have a D v 10 of from about 50 nm to about 200 nm.
  • the micro- or nanoparticles have a D v 10 of from about 75 nm to about 200 nm.
  • the rilpivirine or a pharmaceutically acceptable salt thereof micro- or nanoparticles have a D v 90 of from about 500 nm to about 1 ,600 nm, a D v 50 of from about 200 nm to about 500 nm and a D v 10 of from about 75 nm to about 200 nm.
  • the rilpivirine or a pharmaceutically acceptable salt thereof micro- or nanoparticles have a D v 90 of from about 500 nm to about 1 ,000 nm, a D v 50 of from about 200 nm to about 500 nm and a D v 10 of from about 75 nm to about 200 nm.
  • the particles have a D v 90 of from about 500 nm to about 700 nm, a D v 50 of from about 200 nm to about 500 nm and a D v 10 of from about 75 nm to about 200 nm.
  • the rilpivirine or a pharmaceutically acceptable salt thereof micro- or nanoparticles may have a D v 90 of from about 1 pm to about 10 pm.
  • the micro- or nanoparticles may have a D v 90 of from about 2 pm to about 9 pm.
  • the micro- or nanoparticles may have a D v 90 of from about 3 pm to about 8 pm.
  • the micro- or nanoparticles may have a D v 90 of from about 3 pm to about 7 pm.
  • the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm.
  • the particles have a D v 90 of about 5 pm to about 6 pm, e.g. about 5 pm or about 6 pm.
  • the rilpivirine or a pharmaceutically acceptable salt thereof micro- or nanoparticles have a D v 50 of less than or about 3 pm.
  • the micro- or nanoparticles may have a D v 50 of less than about 2.5 pm.
  • the micro- or nanoparticles may have a D v 50 of from about 1 pm to about 2.5 pm.
  • the micro- or nanoparticles may have a D v 50 of from about 1 .2 pm to about 2.2 pm.
  • the micro- or nanoparticles have a D v 50 of from about 1 .5 pm to about 2 pm.
  • the rilpivirine or a pharmaceutically acceptable salt thereof micro- or nanoparticles may have a D V 10 of less than or about 1000 nm.
  • the micro- or nanoparticles may have a D v 10 of from about 10 nm to about 1000 nm.
  • the micro- or nanoparticles may have a D v 10 of from about 100 nm to about 700 nm.
  • the micro- or nanoparticles may have a D v 10 of from about 200 nm to about 600 nm.
  • the micro- or nanoparticles have a D v 10 of from about 300 nm to about 500 nm.
  • the rilpivirine or a pharmaceutically acceptable salt thereof micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1.5 pm to about 2 pm and a D v 10 of from about 300 nm to about 500 nm.
  • the D v 10, D v 50 and D v 90 as used herein are determined by routine laser diffraction techniques, e.g. in accordance with ISO 13320:2009.
  • Laser diffraction relies on the principle that a particle will scatter light at an angle that varies depending on the size the particle and a collection of particles will produce a pattern of scattered light defined by intensity and angle that can be correlated to a particle size distribution.
  • a number of laser diffraction instruments are commercially available for the rapid and reliable determination of particle size distributions.
  • particle size distribution may be measured by the conventional Malvern MastersizerTM 3000 particle size analyser from Malvern Instruments.
  • the Malvern MastersizerTM 3000 particle size analyser operates by projecting a helium-neon gas laser beam through a transparent cell containing the particles of interest suspended in an aqueous solution.
  • Light rays which strike the particles are scattered through angles which are inversely proportional to the particle size and a photodetector array measures the intensity of light at several predetermined angles and the measured intensities at different angles are processed by a computer using standard theoretical principles to determine the particle size distribution.
  • Laser diffraction values may be obtained using a wet dispersion of the particles in distilled water.
  • D v 10, D v 50 and D v 90 include disc centrifugation, scanning electron microscope (SEM), sedimentation field flow fractionation and photon correlation spectroscopy.
  • the suspension comprises from about 100 to about 500 mg/mL rilpivirine or a pharmaceutically acceptable salt thereof. In an embodiment, the suspension comprises from about 150 to about 450 mg/mL rilpivirine or a pharmaceutically acceptable salt thereof. In an embodiment, the suspension comprises from about 200 to about 400 mg/mL rilpivirine or a pharmaceutically acceptable salt thereof. In an embodiment, the suspension comprises from about 250 to about 350 mg/mL rilpivirine or a pharmaceutically acceptable salt thereof, e.g. about 300 mg/mL, in particular 300 mg/mL of rilpivirine.
  • the micro- or nanoparticles have one or more surface modifiers adsorbed to their surface.
  • the surface modifier may be selected from known organic and inorganic pharmaceutical excipients, including various polymers, low molecular weight oligomers, natural products and surfactants. Particular surface modifiers that may be used in the invention include nonionic and anionic surfactants. Representative examples of surface modifiers include gelatin, casein, lecithin, salts of negatively charged phospholipids or the acid form thereof (such as phosphatidyl glycerol, phosphatidyl inosite, phosphatidyl serine, phosphatic acid, and their salts such as alkali metal salts, e.g.
  • the surface modifier is selected from a poloxamer, a-tocopheryl polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid ester, and salts of negatively charged phospholipids or the acid form thereof.
  • the surface modifier is selected from PluronicTM F108, Vitamin E TGPS (a-tocopheryl polyethylene glycol succinate, in particular a-tocopheryl polyethylene glycol 1000 succinate), polyoxyethylene sorbitan fatty acid esters such as TweenTM 80, and phosphatidyl glycerol, phosphatidyl inosite, phosphatidyl serine, phosphatic acid, and their salts such as alkali metal salts, e.g. their sodium salts, for example egg phosphatidyl glycerol sodium, such as the product available under the tradename LipoidTM EPG.
  • the surface modifier is a poloxamer, in particular PluronicTM F108.
  • PluronicTM F108 corresponds to poloxamer 338 and is the polyoxyethylene, polyoxypropylene block copolymer that conforms generally to the formula HO-[CH2CH2O]x-[CH(CH3)CH2O]y-[CH2CH 2 O]z-H in which the average values of x, y and z are respectively 128, 54 and 128.
  • Other commercial names of poloxamer 338 are Hodag NonionicTM 1108-F and SynperonicTM PE/F108.
  • the surface modifier comprises a combination of a polyoxyethylene sorbitan fatty acid ester and a phosphatidyl glycerol salt (in particular egg phosphatidyl glycerol sodium).
  • the relative amount (w/w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is from about 1 :2 to about 20: 1 , in particular from about 1 :1 to about 10:1 , e.g. from about 4:1 to about 6:1 , preferably about 6:1.
  • the surface modifier is preferably a poloxamer, e.g. poloxamer 338.
  • the micro- or nanoparticles of the invention comprise rilpivirine or a pharmaceutically acceptable salt thereof as defined herein and one or more surface modifiers as defined herein wherein the amount of rilpivirine or a pharmaceutically acceptable salt thereof is at least about 50% by weight of the micro- or nanoparticles, at least about 80% by weight of the micro- or nanoparticles, at least about 85% by weight of the micro- or nanoparticles, at least about 90% by weight of the micro- or nanoparticles, at least about 95% by weight of the micro- or nanoparticles, or at least about 99% by weight of the micro- or nanoparticles, in particular ranges between 80 % and 90 % by weight of the micro- or nanoparticles or ranges between 85 % and 90 % by weight of the micro- or nanoparticles.
  • the suspension comprises a pharmaceutically acceptable aqueous carrier in which the rilpivirine or pharmaceutically acceptable salt thereof micro- or nanoparticles are suspended.
  • the pharmaceutically acceptable aqueous carrier comprises sterile water, e.g. water for injection, optionally in admixture with other pharmaceutically acceptable ingredients.
  • sterile water e.g. water for injection
  • other pharmaceutically acceptable ingredients optionally in admixture with other pharmaceutically acceptable ingredients.
  • the latter comprise any ingredients for use in injectable formulations. These ingredients may be selected from one or more of a suspending agent, a buffer, a pH adjusting agent, a preservative, an isotonizing agent, a surface modifier, a chelating agent and the like ingredients.
  • said ingredients are selected from one or more of a suspending agent, a buffer, a pH adjusting agent, and optionally, a preservative and an isotonizing agent. Particular ingredients may function as two or more of these agents simultaneously, e.g. behave like a preservative and a buffer, or behave like a buffer and an isotonizing agent. In an embodiment said ingredients are selected from one or more of a buffer, a pH adjusting agent, an isotonizing agent, a chelating agent and a surface modifier. In an embodiment said ingredients are selected from one or more of a buffer, a pH adjusting agent, an isotonizing agent, and a chelating agent.
  • the suspension additionally comprises a buffering agent and/or a pH adjusting agent.
  • Suitable buffering agents and pH adjusting agents should be used in amount sufficient to render the dispersion neutral to very slightly basic (up to pH 8.5), preferably in the pH range of 7 to 7.5.
  • Particular buffers are the salts of weak acids.
  • Buffering and pH adjusting agents that can be added may be selected from tartaric acid, maleic acid, glycine, sodium lactate/lactic acid, ascorbic acid, sodium citrates/citric acid, sodium acetate/acetic acid, sodium bicarbonate/carbonic acid, sodium succinate/succinic acid, sodium benzoate/benzoic acid, sodium phosphates, tris(hydroxymethyl)amino- methane, sodium bicarbonate/sodium carbonate, ammonium hydroxide, benzene sulfonic acid, benzoate sodium/acid, diethanolamine, glucono delta lactone, hydrochloric acid, hydrogen bromide, lysine, methanesulfonic acid, monoethanolamine, sodium hydroxide, tromethamine, gluconic, glyceric, gluratic, glutamic, ethylene diamine tetraacetic (EDTA), triethanolamine, including mixtures thereof.
  • the buffer is a sodium phosphate
  • the suspension additionally comprises a preservative.
  • Preservatives comprise antimicrobials and anti-oxidants which can be selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), chlorbutol, a gallate, a hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-y-piccolinium chloride, phenylmercuric acetate and thimerosal.
  • Radical scavengers include BHA, BHT, Vitamin E and ascorbyl palmitate, and mixtures thereof.
  • Oxygen scavengers include sodium ascorbate, sodium sulfite, L-cysteine, acetylcysteine, methionine, thioglycerol, acetone sodium bisulfite, isoacorbic acid, hydroxypropyl cyclodextrin.
  • Chelating agents include sodium citrate, sodium EDTA, citric acid and malic acid.
  • the chelating agent is citric acid, e.g. citric acid monohydrate.
  • the suspension additionally comprises an isotonizing agent.
  • An isotonizing agent or isotonifier may be present to ensure isotonicity of the pharmaceutical compositions of the present invention, and includes sugars such as glucose, dextrose, sucrose, fructose, trehalose, lactose; polyhydric sugar alcohols, preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol.
  • sugars such as glucose, dextrose, sucrose, fructose, trehalose, lactose
  • polyhydric sugar alcohols preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol.
  • sodium chloride, sodium sulfate, or other appropriate inorganic salts may be used to render the solutions is
  • each administration comprises up to about 150 mL of the suspension described herein. In another embodiment, each administration comprises from about 3 mL to about 150ml_ of the suspension. In another embodiment, each administration comprises from about 3 mL to about 10OmL of the suspension. In another embodiment, each administration comprises from about 3 mL to about 15mL of the suspension. In another embodiment, each administration comprises from about 5 mL to about 25 mL of the suspension.
  • each administration comprises from about 6 mL to about 20 mL of the suspension. In another embodiment, each administration comprises from about 6 mL to about 18 mL of the suspension. In another embodiment, each administration comprises from about 6 mL to about 15 mL of the suspension. In another embodiment, each administration comprises from about 6 mL to about 12 mL of the suspension. In another embodiment, each administration comprises from about 9 mL to about 18 mL of the suspension. In another embodiment, each administration comprises from about 9 mL to about 15 mL of the suspension. In another embodiment, each administration comprises from about 9 mL to about 12 mL of the suspension. In an embodiment, each administration comprises from about 8 mL to about 10 mL of the suspension.
  • each administration comprises about 3 mL of the suspension. In another embodiment, each administration comprises about 4 mL of the suspension. In another embodiment, each administration comprises about 5 mL of the suspension. In another embodiment, each administration comprises about 6 mL of the suspension. In another embodiment, each administration comprises about 7 mL of the suspension. In another embodiment, each administration comprises about 8 mL of the suspension. In another embodiment, each administration comprises about 9 mL of the suspension. In another embodiment, each administration comprises about 12 mL of the suspension. In another embodiment, each administration comprises about 15 mL of the suspension. In another embodiment, each administration comprises about 18 mL of the suspension.
  • the dose to be administered may be calculated on a basis of about 300 mg to about 1200 mg/month, or about 350 mg to about 900 mg/month.
  • the dose to be administered may be calculated on a basis of about 350 mg to about 550 mg/month, or about 400 mg to about 500 mg/month, or 450 mg/month.
  • the dose to be administered may be calculated on a basis of about 500 mg to about 700 mg/month, or about 550 mg to about 650 mg/month, or 600 mg/month.
  • Doses for other dosing regimens can readily be calculated by multiplying the monthly dose with the number of months between each administration.
  • the dose is 450 mg/month
  • the dose to be administered in each administration in the case of a time interval of 3 months between each administration the dose to be administered in each administration is 1350 mg
  • the dose to be administered in each administration in the case of a time interval of 4 months between each administration the dose to be administered in each administration is 1800 mg
  • the dose to be administered in each administration in the case of a time interval of 5 months between each administration the dose to be administered in each administration is 2250 mg
  • the dose to be administered in each administration is 2700 mg
  • the dose to be administered in each administration in the case of a time interval of 7 months between each administration the dose to be administered in each administration is 3150 mg.
  • the dose to be administered in each administration is 600 mg/month
  • the dose to be administered in each administration in the case of a time interval of 3 months between each administration the dose to be administered in each administration is 1800 mg
  • the dose to be administered in each administration in the case of a time interval of 4 months between each administration the dose to be administered in each administration is 2400 mg
  • in the case of a time interval of 5 months between each administration the dose to be administered in each administration is 3000 mg
  • in the case of a time interval of 6 months between each administration the dose to be administered in each administration is 3600 mg
  • a time interval of 7 months between each administration the dose to be administered in each administration is 4200 mg.
  • the indicated “mg” corresponds to mg of rilpivirine.
  • 1 mg of rilpivirine corresponds to 1.1 mg of rilpivirine hydrochloride.
  • the dose to be administered may be calculated on a basis of about 300 mg to about 1200 mg/4 weeks (28 days), or about 350 mg to about 900 mg/4 weeks (28 days).
  • the dose to be administered may be calculated on a basis of about 350 mg to about 550 mg/4 weeks (28 days), or about 400 mg to about 500 mg/4 weeks (28 days) or 450 mg/4 weeks (28 days).
  • the dose to be administered may be calculated on a basis of about or about 500 mg to about 700 mg/4 weeks (28 days), or about 550 mg to about 650 mg/4 weeks (28 days), or 600 mg/4 weeks (28 days).
  • Doses for other dosing regimens can readily be calculated by multiplying the week or day dose with the number of weeks between each administration. For example, where dose is 450 mg/4 weeks, in the case of a time interval of 12 weeks between each administration the dose to be administered in each administration is 1350 mg, in the case of a time interval of 16 weeks between each administration the dose to be administered in each administration is 1800 mg, in the case of a time interval of 20 weeks between each administration the dose to be administered in each administration is 2250 mg, in the case of a time interval of 24 weeks between each administration the dose to be administered in each administration is 2700 mg, and in the case of a time interval of 28 weeks between each administration the dose to be administered in each administration is 3150 mg.
  • rilpivirine i.e. rilpivirine in its free base form
  • 1 mg of rilpivirine corresponds to 1 .1 mg of rilpivirine hydrochloride.
  • the suspension of rilpivirine or a pharmaceutically acceptable salt thereof as described herein is administered by subcutaneous injection at a flow rate of from about 0.1 mL/min to about 15 mL/min of the suspension. In another embodiment, the suspension of rilpivirine is administered by subcutaneous injection at a flow rate of from about 0.25 mL/min to about 9 mL/min of the suspension. In another embodiment, the suspension of rilpivirine is administered by subcutaneous injection at a flow rate of from about 0.3 mL/min to about 6 mL/min of the suspension.
  • the suspension of rilpivirine is administered by subcutaneous injection at a flow rate of from about 0.5 mL/min to about 3 mL/min of the suspension. In another embodiment, the suspension of rilpivirine is administered by subcutaneous injection at a flow rate of from about 0.5 mL/min to about 2 mL/min of the suspension. In another embodiment, the suspension of rilpivirine is administered by subcutaneous injection at a flow rate of about 9 mL/min of the suspension. In another embodiment, the suspension of rilpivirine is administered by subcutaneous injection at a flow rate of about 6 mL/min of the suspension.
  • the suspension of rilpivirine is administered by subcutaneous injection at a flow rate of about 3 mL/min of the suspension. In another embodiment, the suspension of rilpivirine is administered by subcutaneous injection at a flow rate of about 2 mL/min of the suspension. In another embodiment, the suspension of rilpivirine is administered by subcutaneous injection at a flow rate of about 1 mL/min of the suspension. In another embodiment, the suspension of rilpivirine is administered by subcutaneous injection at a flow rate of about 0.5 mL/min of the suspension.
  • the flow rate is constant throughout administration, for example, the flow rate varies by no more than ⁇ 10%, or by no more than ⁇ 5%, throughout administration.
  • the required flow rate is achieved by administering the suspension of rilpivirine or a pharmaceutically acceptable salt thereof as described herein by subcutaneous injection with the use of a subcutaneous pharmaceutical injection device that provides for a constant flow rate, e.g. an on-body injection device, an off-body injection device or a handheld injection device. Suitable subcutaneous pharmaceutical injection devices are discussed further herein.
  • the suspension of rilpivirine or a pharmaceutically acceptable salt thereof as described herein is administered by the use of a B. Braun Perfusor syringe pump.
  • the suspension of rilpivirine or a pharmaceutically acceptable salt thereof is administered by subcutaneous injection into a single injection site.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 350 mg to about 550 mg/month, the rilpivirine is administered by subcutaneous injection at a flow rate of about 0.5 mL/min to about 6 mL/min of the suspension and the volume of the suspension administered is about 6 mL to 12 ml_.
  • the rilpivirine is administered intermittently at a time interval of six months.
  • the rilpivirine is administered at a constant rate.
  • each administration of the rilpivirine is calculated on the basis of a dose of rilpivirine ranging from about 350 mg to about 550 mg/month, the rilpivirine is administered by subcutaneous injection at a flow rate of about 0.5 mL/min to about 3 mL/min of the suspension and the volume of the suspension administered is about 8 mL to 10 mL.
  • the rilpivirine is administered intermittently at a time interval of six months.
  • the rilpivirine is administered at a constant rate.
  • each administration of the rilpivirine is calculated on the basis of a dose of rilpivirine of about 450 mg/month, the rilpivirine is administered at a time interval of six months by subcutaneous injection at a flow rate of about 0.1 mL/min to about 2 mL/min of the suspension and the volume of suspension administered is about 9 mL.
  • the rilpivirine is administered at a constant rate.
  • each administration of rilpivirine or pharmaceutically acceptable salt thereof may comprise the same dosing as for therapeutic applications as described above.
  • the rilpivirine or pharmaceutically acceptable salt thereof in the pharmaceutical composition is used in an amount such that the blood plasma concentration of rilpivirine in the subject is kept at a level above about 12 ng/ml, preferably ranging from about 12 ng/ml to about 100 ng/ml, more preferably about 12 ng/ml to about 50 ng/ml for at least 3 months after administration, or at least 4 months after administration, or at least 5 months after administration, or at least 6 months after administration, or at least 7 months after administration.
  • the rilpivirine or pharmaceutically acceptable salt thereof in the pharmaceutical composition is used in an amount such that the blood plasma concentration of rilpivirine in the subject is kept at a level of from 12 ng/ml to 100 ng/ml for at least 6 months.
  • the rilpivirine or pharmaceutically acceptable salt thereof is formulated and administered as micro- or nanoparticles in suspension wherein the formulation comprises the following components: rilpivirine or a pharmaceutically acceptable salt thereof, in particular rilpivirine; a surface modifier as defined herein, in particular poloxamer 338; an isotonizing agent, in particular glucose monohydrate; a buffer, in particular sodium dihydrogen phosphate; a chelating agent, in particular citric acid monohydrate; a pH adjusting agent, in particular sodium hydroxide; and water, in particular water for injection.
  • rilpivirine or a pharmaceutically acceptable salt thereof in particular rilpivirine
  • a surface modifier as defined herein, in particular poloxamer 338
  • an isotonizing agent in particular glucose monohydrate
  • a buffer in particular sodium dihydrogen phosphate
  • a chelating agent in particular citric acid monohydrate
  • a pH adjusting agent in particular sodium hydroxide
  • water in particular water for injection.
  • the rilpivirine or pharmaceutically acceptable salt thereof is formulated and administered as micro- or nanoparticles in suspension wherein the formulation comprises the following components: rilpivirine or a pharmaceutically acceptable salt thereof, in particular rilpivirine; poloxamer 338; glucose monohydrate; sodium dihydrogen phosphate; citric acid monohydrate; sodium hydroxide; and water, in particular water for injection.
  • the aqueous suspensions may comprise by weight, based on the total volume of the suspension:
  • rilpivirine from 3% to 50% (w/v), or from 10% to 40% (w/v), or from 10% to 30% (w/v), of rilpivirine or a pharmaceutically acceptable salt thereof; in particular rilpivirine; (b) from 0.5% to 10 % (w/v), or from 0.5% to 5% (w/v), or from 0.5% to 2% (w/v) of a surface modifier; in particular poloxamer 338;
  • the aqueous suspensions may comprise by weight, based on the total volume of the suspension:
  • rilpivirine from 3% to 50% (w/v), or from 10% to 40% (w/v), or from 10% to 30% (w/v), of rilpivirine or a pharmaceutically acceptable salt thereof; in particular rilpivirine;
  • the rilpivirine or pharmaceutically acceptable salt thereof is formulated (and administered) as a suspension of micro- or nanoparticles wherein the suspension comprises the following components:
  • rilpivirine or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of HIV infection in a subject, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of micro- or nanoparticles in suspension, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension and wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered intermittently at a time interval of about three months to about seven months.
  • rilpivirine for treatment or prevention described herein involves administering rilpivirine or a pharmaceutically acceptable salt thereof multiple times, and the time interval between an administration of the rilpivirine or pharmaceutically acceptable salt thereof and a subsequent administration of the rilpivirine or pharmaceutically acceptable salt thereof (i.e. the dosing interval) is about three months to about seven months. That is, the rilpivirine or pharmaceutically acceptable salt thereof according to the invention is administered to a subject as described herein, and then after a period of from three months to seven months the rilpivirine or pharmaceutically acceptable salt thereof according to the invention is administered again to the subject as defined herein.
  • rilpivirine or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of HIV infection in a subject, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of micro- or nanoparticles in suspension, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension and wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered intermittently at a time interval of about three months to about two years. In an embodiment, the time interval is about three months to about eighteen months. In an embodiment, the time interval is about three months to about one year.
  • the time interval is about three months to about seven months. In an embodiment, the time interval is about three months to about six months. In an embodiment, the time interval is about six months to about one year. In an embodiment, the time interval is about one year. In an embodiment, the time interval is about three months. In an embodiment, the time interval is about six months.
  • the subject is a human. More preferably, the subject is an adult infected with HIV. Most preferably, the subject is an adult infected with HIV and who is virologically suppressed (HIV-1 RNA ⁇ 50 copies per mL) that has been on a stable antiretroviral regimen, for instance for at least 20 weeks.
  • HIV-1 RNA ⁇ 50 copies per mL virologically suppressed
  • the time interval is about three months to about two years. In an embodiment, the time interval is about three months to about eighteen months. In an embodiment, the time interval is about three months to about one year. In an embodiment, the time interval is about three months to about six months. In an embodiment, the time interval is about six months to about one year. In an embodiment, the time interval is about one year. In an embodiment, the time interval described herein is about three months to about seven months. In an embodiment, the time interval describe herein is about three months. In an embodiment, the time interval described herein is about four months. In an embodiment, the time interval described herein is about five months. In an embodiment, the time interval described herein is about six months. In an embodiment, the time interval described herein is about seven months.
  • the rilpivirine or pharmaceutically acceptable salt thereof of the invention is for use in the treatment or prevention of HIV infection in a subject.
  • the rilpivirine or pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.
  • therapeutically effective amount it is meant an amount sufficient to provide a therapeutic effect.
  • the rilpivirine or a pharmaceutically acceptable salt thereof used in the invention is rilpivirine, and the rilpivirine is for use in the treatment of HIV infection in a subject as described herein, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which the rilpivirine is suspended in the form of micro- or nanoparticles, preferably wherein the micro- or nanoparticles have a D v 90 of from about 500 nm to about 1 ,600 nm, a D v 50 of from about 200 nm to about 500 nm and a D v 10 of from about 75 nm to about 200 nm, or the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1.5 pm to about 2 pm and a D v 10 of from about 300 nm to about 500 nm, and preferably wherein a surface modifier, e.g. poloxamer 3
  • the rilpivirine or pharmaceutically acceptable salt thereof of the invention is used in a method for the treatment or prevention of HIV type 1 (HIV-1) infection in a subject, i.e. an embodiment described herein relates to the use of rilpivirine or pharmaceutically acceptable salt thereof as defined herein for treating or preventing HIV type 1 (HIV-1) infection in a subject.
  • treatment of HIV infection relates to the treatment of a subject infected with HIV.
  • treatment of HIV infection also relates to the treatment of diseases associated with HIV infection, for example AIDS, or other conditions associated with HIV infection including thrombocytopaenia, Kaposi's sarcoma and infection of the central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as, progressive dysarthria, ataxia and disorientation, and further conditions where HIV infection has also been associated with, such as peripheral neuropathy, progressive generalized lymphadenopathy (PGL), and AIDS-related complex (ARC).
  • PDL progressive generalized lymphadenopathy
  • ARC AIDS-related complex
  • prevention of HIV infection relates to the prevention or avoidance of a subject (who is not infected with HIV) becoming infected with HIV.
  • the source of infection can be various, a material containing HIV, in particular a body fluid that contains HIV such as blood or semen, or another subject who is infected with HIV.
  • Prevention of HIV infection relates to the prevention of the transmission of the virus from the material containing HIV or from the HIV infected individual to an uninfected person, or relates to the prevention of the virus from entering the body of an uninfected person.
  • Transmission of the HIV virus can be by any known cause of HIV transfer such as by sexual transmission or by contact with blood of an infected subject, e.g. medical staff providing care to infected subjects. Transfer of HIV can also occur by contact with HIV infected blood, e.g. when handling blood samples or with blood transfusion. It can also be by contact with infected cells, e.g. when carrying out laboratory experiments with HIV infected cells.
  • treatment of HIV infection refers to a treatment by which the viral load of HIV (represented as the number of copies of viral RNA in a specified volume of serum) is reduced.
  • the viral load should be reduced to as low levels as possible, e.g. below about 200 copies/ml, in particular below about 100 copies/ml, more in particular below 50 copies/ml, if possible below the detection limit of the virus.
  • Reductions of viral load of one, two or even three orders of magnitude are an indication of the effectiveness of the treatment.
  • CD4 count Another parameter to measure effectiveness of HIV treatment is the CD4 count, which in normal adults ranges from 500 to 1500 cells per pl. Lowered CD4 counts are an indication of HIV infection and once below about 200 cells per pl, AIDS may develop. An increase of CD4 count, e.g. with about 50, 100, 200 or more cells per pl, is also an indication of the effectiveness of antiHIV treatment. The CD4 count in particular should be increased to a level above about 200 cells per pl, or above about 350 cells per pl. Viral load or CD4 count, or both, can be used to diagnose the degree of HIV infection.
  • Another parameter to measure effectiveness of HIV treatment is keeping the HIV-infected subject virologically suppressed (HIV-1 RNA ⁇ 50 copies/mL) when on the treatment according to the present invention.
  • treatment of HIV infection refers to that treatment that lowers the viral load, or increases CD4 count, or both, as described above.
  • treatment of HIV infection and similar terms refer to that treatment that lowers the viral load, or increases CD4 count, or keeps the HIV-infected subject virologically suppressed, or two or more of these three, as described above.
  • prevention of HIV infection and similar terms refer to that situation where there is a decrease in the relative number of newly infected subjects in a population in contact with a source of HIV infection such as a material containing HIV, or a HIV infected subject.
  • Effective prevention can be measured, for example, by measuring in a mixed population of HIV infected and non- infected individuals, if there is a decrease of the relative number of newly infected individuals, when comparing non- infected individuals treated with a pharmaceutical composition of the invention, and non-treated non-infected individuals. This decrease can be measured by statistical analysis of the numbers of infected and non- infected individuals in a given population over time.
  • a method for the treatment or prevention of HIV infection in a subject comprising administering to the subject a therapeutically effective amount of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension by subcutaneous injection at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension and wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered intermittently at a time interval of about three months to seven months.
  • rilpivirine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing HIV infection in a subject, wherein the rilpivirine or pharmaceutically acceptable salt thereof is in the form of micro- or nanoparticles in suspension, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered to the subject by subcutaneous injection at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension and wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered intermittently at a time interval of about three months to about seven months.
  • the method or use described herein are used in combination with one or more other active agents, in particular one or more other antiretroviral agents, in particular one or more other antiretroviral agents of another class, such as for example an antiretroviral of the Integrase Strand Transfer Inhibitor (INSTI) class, such as for example cabotegravir.
  • said one or more other antiretroviral agents e.g. cabotegravir
  • said one or more other antiretroviral agents is administered as a subcutaneous injection, in particular as an injectable micro- or nanosuspension, at a time interval of about three months to about seven months.
  • said one or more other antiretroviral agent e.g.
  • cabotegravir is administered at the same intermittent time interval as the rilpivirine or a pharmaceutically acceptable salt thereof as described herein, e.g. the rilpivirine or a pharmaceutically acceptable salt thereof and the other antiretroviral agent are administered intermittently at a time interval of about three months, or of about four months, or of about five months, or of about six months, or of about seven months.
  • the rilpivirine or a pharmaceutically acceptable salt thereof and the one or more other antiretroviral agents, e.g. cabotegravir are administered simultaneously or sequentially by subcutaneous injection.
  • the rilpivirine or a pharmaceutically acceptable salt thereof and the one or more other antiretroviral agents e.g.
  • cabotegravir are administered simultaneously by subcutaneous injection.
  • the rilpivirine or a pharmaceutically acceptable salt thereof and the one or more other antiretroviral agents, e.g. cabotegravir are administered sequentially by subcutaneous injection.
  • the rilpivirine or a pharmaceutically acceptable salt thereof is administered first followed by a cabotegravir injection.
  • the cabotegravir injection is administered first followed by the rilpivirine or a pharmaceutically acceptable salt thereof.
  • the one or more other antiretroviral agents in particular one or more other antiretroviral agents of another class, is an integrase inhibitor. vices accordinq to the invention containinq salt thereof
  • rilpivirine or a pharmaceutically acceptable salt thereof as used in the invention is provided in a subcutaneous pharmaceutical injection device.
  • the subcutaneous pharmaceutical injection device is of a form such that the rilpivirine or a pharmaceutically acceptable salt thereof, as used in the invention, can be dispensed from the subcutaneous pharmaceutical injection device when required.
  • subcutaneous pharmaceutical injection device includes a container and a discharge nozzle associated with a driver, the discharge nozzle being sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously.
  • the container is capable of containing the rilpivirine or a pharmaceutically acceptable salt thereof as used in the invention and the driver is configured to drive the rilpivirine or a pharmaceutically acceptable salt thereof from the container and out of the discharge nozzle at a flow rate of 0.1 mL/min to about 15 mL/min of the suspension.
  • the container can be removably coupleable to a housing of the subcutaneous injection device.
  • the container contains a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months.
  • the container contains a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1 .5 pm to about 2 pm and a D V 10 of from about 300 nm to about 500 nm, the volume being 2ml_ or greater and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months.
  • the subcutaneous pharmaceutical injection device can be an on-body device, an off-body device or a handheld device.
  • On-body devices also called ‘wearable devices’ and ‘patch pumps’ comprise a container and driver which are both adhered to the injection site. Examples of on-body devices are described herein with respect to Figures 3A and 3B.
  • Off-body devices comprise drivers which are not adhered to the injection site, such as infusion pumps and syringe pumps. Examples of off-body devices are described herein with respect to Figures 5 and 6.
  • Handheld devices comprise injection devices which must be manually held against the injection site, such as syringes and autoinjectors. Examples of handheld devices are described with referenced to Figures 1 and 2.
  • subcutaneous pharmaceutical injection devices which form embodiments of the invention including: syringes, autoinjectors, syringe pumps, infusion pumps and patch pumps.
  • These subcutaneous pharmaceutical injection devices may be provided with the rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension in the container of the subcutaneous pharmaceutical injection device.
  • these subcutaneous pharmaceutical injection devices may be combined with a drug provision device, such that the drug provision device provides the drug via an introducer to the subcutaneous pharmaceutical injection device.
  • a vial can be used to provide the rilpivirine or a pharmaceutically acceptable salt thereof into the container of an autoinjector via a discharge nozzle.
  • the subcutaneous pharmaceutical injection device comprises rilpivirine or a pharmaceutically acceptable salt thereof in its container.
  • the discharge nozzle may comprise an injection needle or catheter.
  • the discharge nozzle may have a gauge of 23 gauge to 25 gauge (internal diameter from about 0.330mm to 0.250mm), such as 23 gauge, 24 gauge or 25 gauge.
  • the discharge nozzle may have a length of about 12.7mm to about 19.1 mm long.
  • the discharge nozzle may comprise an injection needle or catheter.
  • the discharge nozzle may have a gauge of 21 gauge to 25 gauge (internal diameter from about 0.514mm to about 0.250mm), such as 21 gauge, 22 gauge, 23 gauge, 24 gauge or 25 gauge.
  • the discharge nozzle may have a length of about 12.7mm to about 19.1 mm long.
  • the subcutaneous pharmaceutical injection device is a syringe or syringe pump that may comprise a discharge nozzle that may comprise an injection needle, catheter, or infusion set.
  • the discharge nozzle may have a gauge of 23 gauge to 25 gauge (internal diameter from about 0.330mm to 0.250mm), such as 23 gauge,
  • the discharge nozzle may have a length of about 12.7mm to about 19.1 mm long.
  • the subcutaneous pharmaceutical injection device is a syringe or syringe pump that may comprise a discharge nozzle that may comprise an injection needle, catheter, or infusion set.
  • the discharge nozzle may have a gauge of 21 gauge to
  • the discharge nozzle may have a length of about 12.7mm to about 19.1 mm long.
  • the subcutaneous pharmaceutical injection device may have a housing which accommodates the container and driver.
  • the subcutaneous pharmaceutical injection device may comprise a container in the form of one of a vial, a cartridge, a syringe body and an expandable member.
  • the container can be removably coupleable to a housing of the subcutaneous injection device or can be fixedly attached to or integral with the housing.
  • the container of the subcutaneous pharmaceutical injection device may contain a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension which is greater than 4ml_, 5ml_, 6ml_, 7 ml_, 8 ml_, 9 ml_, 10ml_, 11 ml_, 12ml_, 13ml_, 14ml_ or 15ml_.
  • the container of the subcutaneous pharmaceutical injection device may contain a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension which is greater than 20 ml_, 25 ml_, 30 ml_, 35 ml_, 40 ml_, 45 ml_, 50 ml_, 55 ml_, or 60 ml_.
  • the release of rilpivirine or a pharmaceutically acceptable salt thereof from the container may be instigated by a user.
  • an embodiment of the subcutaneous pharmaceutical injection device may be provided with a trigger for initiating the release of the rilpivirine or a pharmaceutically acceptable salt thereof from the container by the driver. This allows controlled administration of the rilpivirine or a pharmaceutically acceptable salt thereof to the patient.
  • An embodiment of the subcutaneous pharmaceutical injection device may include a metering mechanism which measures out a dose to be released from the container by the driver. In this manner the subcutaneous pharmaceutical injection device can provide a known dose size.
  • a dosage selector may be provided. The dosage selector enables a user to select a dose of drug to be measured out by the metering mechanism. This allows control over the size of the dose.
  • the subcutaneous pharmaceutical injection device may have at least one environment sensor, which is configured to sense information relating to the environment in which the device is present, such as the temperature of the environment.
  • the subcutaneous pharmaceutical injection device may include at least one drug sensor, which is configured to sense information relating to the rilpivirine or a pharmaceutically acceptable salt thereof contained in the subcutaneous pharmaceutical injection device.
  • the subcutaneous pharmaceutical injection device may include a device indicator which is configured to present information about the status of the subcutaneous pharmaceutical injection device and/or the rilpivirine or a pharmaceutically acceptable salt thereof contained therein.
  • the subcutaneous pharmaceutical injection device may be enclosed in packaging.
  • the packaging may include an environment sensor and/or device indicator as described herein.
  • the subcutaneous pharmaceutical injection device may include a device operation prevention mechanism which can prevent and/or stop the driver releasing rilpivirine or a pharmaceutically acceptable salt thereof from the container. This can prevent accidental delivery of the rilpivirine or a pharmaceutically acceptable salt thereof.
  • the subcutaneous pharmaceutical injection device may include a user interface which can be configured to present a user of the subcutaneous pharmaceutical injection device with information about the subcutaneous pharmaceutical injection device and/or to enable the user to control certain aspects of the subcutaneous pharmaceutical injection device, including profiles of drug administration and dosage sizes.
  • the subcutaneous pharmaceutical injection device may include at least one device sensor which senses information about the device.
  • the subcutaneous pharmaceutical injection device may have a sensor configured to sense the dose actually delivered by the driver.
  • an embodiment of the subcutaneous pharmaceutical injection device may comprise a power supply in order to provide power to one or more components of the subcutaneous pharmaceutical injection device.
  • the power supply can be a source of power which is integral to device and/or a mechanism for connecting the subcutaneous pharmaceutical injection device to an external source of power.
  • a method of administering a pharmaceutical composition using a subcutaneous injection device comprising: inserting a discharge nozzle of the subcutaneous injection device into a subcutaneous layer of a patient; and causing a driver of the subcutaneous injection device to drive a volume of rilpivirine or pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension from a container of the injection device and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt thereof in a patient for at least three months.
  • this method may be repeated over an interval of at least three months.
  • the method may comprise enabling fluid flow between the discharge nozzle and the container of the injection device after inserting a discharge nozzle of the subcutaneous injection device into a subcutaneous layer of a patient, and before causing the driver of the subcutaneous injection device to drive the volume of rilpivirine or pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension from the container of the injection device and out of the discharge nozzle.
  • the method may comprise enabling fluid flow between the discharge nozzle and the container of the injection device before inserting a discharge nozzle of the subcutaneous injection device into a subcutaneous layer of a patient, and before causing the driver of the subcutaneous injection device to drive the volume of rilpivirine or pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension from the container of the injection device and out of the discharge nozzle.
  • a method of preparing a subcutaneous injection device for injection comprising: introducing a volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device, the rilpivirine or a pharmaceutically acceptable salt thereof being in the form of micro- or nanoparticles in suspension, and the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt thereof in a patient for at least three months.
  • introducing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device comprises drawing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into a container of the subcutaneous injection device.
  • introducing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device comprises injecting the volume of rilpivirine or a pharmaceutically acceptable salt thereof into a container of the subcutaneous injection device.
  • introducing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device comprises inserting a container into the subcutaneous injection device, the container containing the volume of rilpivirine or a pharmaceutically acceptable salt thereof.
  • the subcutaneous injection device comprises a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously.
  • the subcutaneous injection device comprises a container containing the volume of rilpivirine or a pharmaceutically acceptable salt thereof.
  • a kit comprising: a subcutaneous pharmaceutical injection device, comprising: a container configured to contain a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously; and a driver configured to drive the rilpivirine or pharmaceutically acceptable salt from the container and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension; and the kit comprising a drug provision device containing a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the r
  • the kit may comprise an introducer for introducing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into the container of the subcutaneous pharmaceutical injection device or the container may be prefilled with the volume.
  • a kit comprising: a subcutaneous pharmaceutical injection device, comprising: a container configured to contain a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously; and a driver configured to drive the rilpivirine or pharmaceutically acceptable salt from the container and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension; and the kit comprising a drug provision device containing a volume of ril
  • a method of administering a pharmaceutical using a subcutaneous injection device comprising: inserting a discharge nozzle of the subcutaneous injection device into a subcutaneous layer of a patient; and causing a driver of the subcutaneous injection device to drive a volume of rilpivirine or pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension from a container of the injection device and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension, wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1.5 pm to about 2 pm and a D v 10 of from about 300 nm to about 500 nm, the volume being 2mL or greater and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months
  • a method of preparing a subcutaneous injection device for injection comprising: introducing a volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device, the rilpivirine or a pharmaceutically acceptable salt thereof being in the form of micro- or nanoparticles in suspension, wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1 .5 pm to about 2 pm and a D V 10 of from about 300 nm to about 500 nm, and the volume being 2mL or greater and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months.
  • a kit comprising: a subcutaneous pharmaceutical injection device, comprising: a container configured to contain a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1 .5 pm to about 2 pm and a D V 10 of from about 300 nm to about 500 nm, the volume being 2ml_ or greater and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously; and a driver configured to drive the rilpivirine or pharmaceutically acceptable salt from the container and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension; and
  • the kit may comprise an introducer for introducing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into the container of the subcutaneous pharmaceutical injection device or the container may be prefilled with the volume.
  • a kit comprising: a subcutaneous pharmaceutical injection device, comprising: a container configured to contain a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1 .5 pm to about 2 pm and a D V 10 of from about 300 nm to about 500 nm, the volume being 2ml_ or greater and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously; and a driver configured to drive the r
  • the ‘drug’ is: a) a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; or b) a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1 .5 pm to about
  • Figure 1 shows a subcutaneous pharmaceutical injection device in the form of a syringe 100.
  • the syringe 100 is of conventional type, including a container in the form of the syringe body 110 terminating at one end in a discharge nozzle in the form of an injection needle 112.
  • the syringe body 110 contains the drug according to the invention.
  • the syringe 100 further comprises a driver in the form of a plunger 114.
  • the plunger can be used to manually drive the contents of the syringe 100 from the syringe body 110 and out of the injection needle 112 at a flow rate of about 0.1 mL/min to about 15 mL/min.
  • the contents of the syringe can be discharged automatically at a flow rate of about 0.1 mL/min to about 15 mL/min, as will be described with reference to the autoinjector and syringe pump set out below.
  • fluid flow between the discharge nozzle in the form of an injection needle 112 and the container in the form of a syringe body 110 can be enabled by removing a cap from the injection needle 112. After the cap has been removed from the injection needle, the injection needle can be inserted to a subcutaneous layer of a patient and the plunger 114 can be used to drive the contents of the syringe from the syringe body 110 and out of the injection needle 112.
  • a user can introduce a volume of the drug into the syringe body by inserting the injection needle 112 into a drug provision device containing the drug according to the invention, and withdrawing the plunger 114 to draw the drug from the drug provision device, through the injection needle 112 and into the syringe body 110.
  • FIG. 2 shows an example of a subcutaneous pharmaceutical injection device in the form of an autoinjector 200 in which a housing 230 contains a syringe.
  • the syringe is of conventional type, including a container in the form of the syringe body 210 terminating at one end in an injection needle 212.
  • the injection needle 212 is sized to deliver the drug, namely rilpivirine or pharmaceutically acceptable salt thereof in accordance with the present invention, from the container to a patient subcutaneously.
  • the syringe body 210 contains a drug in accordance with the present invention.
  • the conventional plunger that would normally be used to discharge the contents of the syringe manually has been removed and replaced with a driver 220 which is configured to drive the contents of the syringe body from the syringe body 210 and out of the injection needle 212 at a flow rate of about 0.1 mL/min to about 15 mL/min.
  • the driver comprises a drive element 214 as will be described below, terminating in a bung 222. This drive element 214 constrains the drug to be administered within the syringe body 210.
  • the housing includes a return spring 242 that biases the syringe from an extended position in which the injection needle 212 extends from an aperture in the housing 230 to a retracted position in which the injection needle 212 is contained within the housing 230.
  • the return spring 242 acts on the syringe via a sleeve 241 .
  • a trigger 251 is provided and, when operated, serves to decouple a drive sleeve 226 from the housing 230, allowing it to move relative to the housing 230 under the influence of the drive spring 227.
  • Drive from the drive spring 227 is transmitted via a drive sleeve 226 and the drive element 214 to the syringe 210 to advance it from its retracted position to its extended position and discharge its contents through the needle 212 and thus acts as the driver.
  • the drive accomplishes this task by acting directly on the drug and the syringe.
  • the drive element 214 When the drive element 214 reaches the end of its travel within the syringe body 210, the drive element 214 unlatches from the drive sleeve 226 so that the force developed by the drive spring 227 is no longer being transmitted to the syringe 210. At this point, the only force acting on the syringe 210 will be the return force from the return spring 242. Thus, the syringe 210 now returns to its retracted position and the injection cycle is complete. All this takes place only once a cap has been removed from the end of the housing 230 and a needle boot from the syringe 210. Removing the cap may enable fluid flow between the discharge nozzle in the form of the injection needle and the container in the form of a syringe body 210.
  • a user can introduce a volume of the drug into the syringe body by inserting the syringe 210 into the subcutaneous injection device, the syringe 210 containing the volume of rilpivirine or a pharmaceutically acceptable salt thereof according to the invention.
  • the present invention is not limited to such an autoinjector.
  • the autoinjector may be gas powered, electrically powered, or powered by a torsion spring.
  • Figure 3A shows an example of a subcutaneous pharmaceutical injection device in the form of a patch pump 300.
  • the patch pump 300 comprises a housing 330 with underside 332 and an injection button 351 with return spring 342.
  • the patch pump 300 also comprises a container in the form of an expandable member 310, such as a balloon or bladder.
  • the expandable member 310 is formed from an elastomeric material such that it is configured to hold a volume of the drug under pressure and provide elastic force to expel the drug from the expandable member 310.
  • the patch pump 300 also comprises a discharge nozzle in the form of an injection needle 312, the injection needle 312 further comprising a side hole 313.
  • the patch pump 300 further comprises internal tubing 314 configured to provide fluid communication between expandable member 310 and injection needle 312, as will be described below. In use, the patch pump 300 is placed on a patient such that the underside 332 is in contact with the patient’s skin.
  • the underside 332 may comprise an adhesive configured to releasably attach the patch pump 300 to the patient’s skin.
  • the injection button 351 is then depressed to insert needle 312 into the injection site to a subcutaneous layer of the patient. Depressing injection button 351 also aligns the internal tubing 314 with side hole 313 so that the expandable member 310 is in fluid communication with the injection needle 312. In this way, a user enables fluid flow between the discharge nozzle in the form of the injection needle 312 and the container in the form of the expandable member 310. The user can enable fluid flow after inserting the injection needle 312 into a subcutaneous layer of a patient, or before inserting the injection needle into a subcutaneous layer of a patient.
  • a stop (not shown) can be provided to limit the injection depth reached by the injection needle 312.
  • the drug is driven out of the injection needle 312 due to the pressure from expandable member 310.
  • the elastomeric material of the expandable member 310 provides the driver configured to drive the drug from the expandable member 310 and out of the injection needle 312 at a flow rate of about 0.1 mL/min to about 15 mL/min.
  • a user can introduce a volume of the drug into the expandable member 310 by injecting the volume of rilpivirine or a pharmaceutically acceptable salt thereof into a container of the subcutaneous injection device.
  • the present invention is not limited to such a patch pump.
  • the container may comprise a syringe or vial.
  • FIG. 3B shows another example of a patch pump 400.
  • the patch pump 400 comprises a housing 430 with underside 432 and injection button 451.
  • a user can introduce a volume of the drug into the syringe body by inserting the container into the subcutaneous injection device, the container containing the volume of rilpivirine or a pharmaceutically acceptable salt thereof.
  • the present invention is not limited to such a patch pump.
  • the driver may be gas powered, or electrically powered.
  • FIG. 4 shows a subcutaneous pharmaceutical injection device in the form of a subcutaneous infusion set 500.
  • the subcutaneous infusion set 500 comprises a housing 530, a discharge nozzle in the form of an injection needle 512 and tubing 513 configured to provide fluid communication between a container containing the drug and the injection needle 512.
  • the arrow indicates the connection between the injection needle 512 and the container containing the drug.
  • the subcutaneous infusion set 512 comprises wings 515, 516 which are configured to limit the injection depth reached by the injection needle 512.
  • Tubing 513 comprises a connection feature (e.g. a Y-connector or luer connection) configured to place the tubing 513 in fluid communication with a container containing a drug and a driver configured to drive the drug from the container and out of the injection needle 512.
  • the container and driver may comprise one or more of: a syringe such as the syringe 100 described with reference to Figure 1 ; a syringe pump such as the syringe pump 600 described with reference to Figure 5; and an infusion pump such as the infusion pump described with reference to Figure 6.
  • the subcutaneous infusion set 500 is placed on the skin of the patient such that the injection needle 512 is inserted into the injection site into a subcutaneous layer of the patient.
  • a user may enable fluid flow between injection needle 512 and container via tubing 513 after inserting the injection needle 512 into a subcutaneous layer of a patient, or before inserting the injection needle 512 into a subcutaneous layer of a patient.
  • a driver is used to drive the drug from a container and out of the injection needle 512 at a flow rate of about 0.1 mL/min to about 15 mL/min.
  • a plunger 114 may be used to drive a drug from a syringe body 100 through tubing 513 and out of the injection needle 512.
  • a syringe pump 600 may be used to drive a drug from a syringe 610 through tubing 613 and out of the injection needle 512.
  • an infusion pump 700 may be used to drive a drug from a reservoir 710 through an infusion line 712 and out of the injection needle 512.
  • Syringe pumps provide controlled drug infusion, by facilitating the administering of the drug at a precise rate that keeps the drug concentration within a therapeutic margin, without requiring frequent attention. Syringe pumps can be non-pulsatile.
  • FIG. 5 shows an example of a subcutaneous pharmaceutical injection device in the form of a syringe pump 600.
  • the syringe pump 600 comprises a container in the form of a syringe 610, which is configured to hold a volume of the drug, and a syringe holder 630 configured to hold said syringe.
  • the syringe 610 is in fluid communication with tubing 613 and a discharge nozzle (indicated by the arrow in Figure 5).
  • the syringe pump 600 further comprises a driver in the form of a plunger 614 and a motor driven actuator 616 which pushes the plunger 614 into the syringe 610 to drive the drug from the syringe 610.
  • the syringe pump 600 further comprises a housing 696 which contains a motor for driving the actuator 616 and a processor and memory for controlling the motor.
  • the housing 696 may also comprise a user interface 680, 681 which can be used to set use parameters of the syringe pump 600.
  • the syringe pump 600 may be powered by battery or mains power.
  • the syringe 610 is placed into the syringe holder 630.
  • the syringe pump may comprise a sensor configured to sense if a syringe is properly placed within the syringe holder 630 and prevent use of the syringe pump unless a syringe is properly placed within the syringe holder 630.
  • a user can introduce a volume of the drug into the syringe 610 by inserting the tubing 613 into a drug provision device containing the drug according to the invention and withdrawing the plunger 614 to draw the drug from the drug provision device, through the tubing 613 and into the syringe body 610.
  • the user interface 680, 681 can then be used to operate the syringe pump 600.
  • the user interface can be used to select the speed and duration at which the motor should operate.
  • the user interface can be used to indicate which drug is within the syringe and the syringe pump 600 will then operate according to a predetermined setting.
  • the motor then drives actuator 616 which pushes the plunger 614 into the syringe 610 to drive the drug from the syringe 610 and through tubing 613.
  • the tubing 613 is connected to a discharge nozzle which is configured to deliver a drug to a patient subcutaneously at a flow rate of about 0.1 mL/min to about 15 mL/min.
  • the tubing 613 may be connected to a subcutaneous infusion set, such as the subcutaneous infusion set described with reference to Figure 4.
  • the syringe pump 600 can also comprise safety features.
  • the syringe pump 600 can be configured to provide visual or audible alarms in the event that: pressure in the tubing 613 is too high or too low, the syringe pump 600 battery is empty or nearly empty, the syringe 610 is nearly empty and/or the syringe holder 630 detects that the syringe 610 is not properly fitted.
  • the present invention is not limited to such a syringe pump.
  • the processor may be pre-programmed, such that it is not necessary for the syringe pump to include a user interface.
  • infusion pumps provide controlled drug infusion, by facilitating the administering of the drug at a precise rate that keeps the drug concentration within a therapeutic margin, without requiring frequent attention.
  • FIG 6 shows a subcutaneous pharmaceutical injection device in the form of an infusion pump 700.
  • the infusion pump 700 includes a container in the form of a reservoir 710 for containing a drug to be delivered, and a driver comprising a pump 716 adapted to dispense a drug contained in the reservoir, such that it can be delivered to a patient.
  • the drug is delivered from the reservoir upon actuation of the pump 716 via an infusion line 712, which may take the form of a cannula or a subcutaneous infusion set, such as the infusion set described with reference to Figure 4.
  • the pump 716 may take the form of an elastomeric pump, a peristaltic pump or an osmotic pump.
  • the pump 716 is configured to drive the drug from the reservoir 716 and out of a discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min.
  • Actuation of the pump 716 is controlled by a processor 796 electrically coupled to the pump.
  • the processor may be programmed by a user, via a user interface 780, such that the infusion pump 700 can provide the drug to a patient in a controlled manner.
  • the user can enter parameters, such as infusion duration and delivery rate according to the invention.
  • the programmed parameters for controlling the pump 716 are stored in and retrieved from a memory 797 in communication with the processor 796.
  • the user interface 780 may take the form of a touch screen or a keypad.
  • Power supply 795 provides power to the infusion pump 700, and may take the form of a source of power which is integral to infusion pump 700 and/or a mechanism for connecting the infusion pump 700 to an external source of power.
  • Infusion pumps may take a variety of forms, including stationary bedside devices, as well as ambulatory infusion pumps which are designed to be portable or wearable.
  • An integral power supply 795 is particularly beneficial for ambulatory infusion pumps.
  • introducing the drug according the present invention into the infusion pump 700 can comprise inserting a reservoir 710 into the subcutaneous injection device, the reservoir 710 containing the volume of rilpivirine or a pharmaceutically acceptable salt thereof.
  • the present invention is not limited to such an infusion pump.
  • the processor may be pre-programmed, such that it is not necessary for the infusion pump to include a user interface.
  • composition “comprising” encompasses “including” as well as “consisting”, e.g. a composition “comprising” X may consist exclusively of X or may include something additional, e.g. X + Y.
  • composition “comprising” used herein also encompasses “consisting essentially of’, e.g. a composition “comprising” X may consist of X and any other components that do not materially affect the essential characteristics of the composition.
  • Y is optional and means, for example, Y ⁇ 10%.
  • a time interval When a time interval is expressed as a specified number of months, it runs from a given numbered day of a given month to the same numbered day of the month that falls the specified number of months later. Where the same numbered day does not exist in the month that falls the specified number of months later, the time interval runs into the following month for the same number of days it would have run if the same numbered day would exist in the month that falls the specified number of months later.
  • a time interval When a time interval is expressed as a number of years, it runs from a given date of a given year to the same date in the year that falls the specified number of years later. Where the same date does not exist in the year that falls the specified number of years later, the time interval runs for the same number of days it would have run if the same numbered day would exist in the month that falls the specified number of years later. In other words, if the time interval starts on 29th February of a given year but ends in a year where there is no 29th February, the time period ends instead on 1st March in that year.
  • the term “about” in relation to such a definition means that the time interval may end on a date that is ⁇ 10% of the time interval.
  • the time interval may start up to 7 days before or after the start of the time interval and end up to 7 days before or after the end of the time interval.
  • Rilpivirine or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of HIV infection in a subject, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of micro- or nanoparticles in suspension, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension and wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered intermittently at a time interval of about three months to about seven months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 350 mg to about 900 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 350 mg to about 550 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 400 mg to about 500 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine of about 450 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 500 mg to about 700 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 550 mg to about 650 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 1350 mg in each administration and wherein the time interval is about three months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 1800 mg in each administration and wherein the time interval is about four months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 2250 mg in each administration and wherein the time interval is about five months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 2700 mg in each administration and wherein the time interval is about six months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 3150 mg in each administration and wherein the time interval is about seven months.
  • rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of the preceding embodiments, wherein rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.25 mL/min to about 9 mL/min of the suspension.
  • rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of the preceding embodiments, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.3 mL/min to about 6 mL/min of the suspension.
  • rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of the preceding embodiments, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.5 mL/min to about 3 mL/min of the suspension.
  • rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of the preceding embodiments, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.5 mL/min to about 2 mL/min of the suspension.
  • rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 16, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 9 mL/min of the suspension.
  • rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 19, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 2 mL/min of the suspension.
  • rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 19, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 1 mL/min of the suspension.
  • rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 19, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.5 mL/min of the suspension.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 350 mg to about 550 mg/month, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.5 mL/min to about 3 mL/min of the suspension and wherein the volume of the suspension administered is about 8 mL to 10 mL.
  • micro- or nanoparticles have a Dv10 of from about 75 nm to about 200 nm, and/or wherein the micro- or nanoparticles have a Dv50 of from about 200 nm to about 500 nm.
  • micro- or nanoparticles have a Dv10 of from about 300 nm to about 500 nm, and/or wherein the particles have a Dv50 of from about 1.5 pm to about 2 pm.
  • rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of the preceding embodiments, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which the rilpivirine or a pharmaceutically acceptable salt thereof is suspended.
  • HIV infection is HIV type 1 (HIV-1) infection.
  • rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of the preceding embodiments, wherein the subject is a human.
  • 44. The rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of the preceding embodiments, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is rilpivirine.
  • a method of treating or preventing a HIV infection in a subject comprising administering to the subject rilpivirine or a pharmaceutically acceptable salt thereof, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of micro- or nanoparticles in suspension, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension and wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered intermittently at a time interval of about three months to about seven months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 350 mg to about 900 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 350 mg to about 550 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 400 mg to about 500 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine of about 450 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 500 mg to about 700 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 550 mg to about 650 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine of about 600 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 1350 mg in each administration and wherein the time interval is about three months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 1800 mg in each administration and wherein the time interval is about four months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 2250 mg in each administration and wherein the time interval is about five months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 2700 mg in each administration and wherein the time interval is about six months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 3150 mg in each administration and wherein the time interval is about seven months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 350 mg to about 550 mg/month, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.3 mL/min to about 6 mL/min of the suspension and wherein the volume of the suspension administered is about 6 mL to 12 mL.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 350 mg to about 550 mg/month, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.5 mL/min to about 3 mL/min of the suspension and wherein the volume of the suspension administered is about 8 mL to 10 mL.
  • micro- or nanoparticles have a surface modifier adsorbed to their surface.
  • micro- or nanoparticles have a Dv90 of from about 100 nm to about 10 pm.
  • micro- or nanoparticles have a Dv90 of from about 500 nm to about 6 pm, optionally wherein the micro- or nanoparticles have a Dv90 of from about 500 nm to about 1 ,600 nm.
  • micro- or nanoparticles have a Dv10 of from about 75 nm to about 200 nm, and/or wherein the micro- or nanoparticles have a Dv50 of from about 200 nm to about 500 nm.
  • micro- or nanoparticles have a Dv90 of from about 4 pm to about 6 pm.
  • 87. The method according to any one of embodiments 83 to 84 and 86, wherein the micro- or nanoparticles have a Dv10 of from about 300 nm to about 500 nm, and/or wherein the particles have a Dv50 of from about 1.5 pm to about 2 pm.
  • the suspension comprises a pharmaceutically acceptable aqueous carrier in which the rilpivirine or a pharmaceutically acceptable salt thereof is suspended.
  • HIV infection is HIV type 1 (HIV-1) infection.
  • rilpivirine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment or prevention of HIV infection in a subject, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of micro- or nanoparticles in suspension, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension and wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered intermittently at a time interval of about three months to about seven months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 300 mg to about 1200 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 350 mg to about 900 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 400 mg to about 500 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine of about 600 mg/month.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 1350 mg in each administration and wherein the time interval is about three months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 1800 mg in each administration and wherein the time interval is about four months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 2250 mg in each administration and wherein the time interval is about five months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 2700 mg in each administration and wherein the time interval is about six months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises about 3150 mg in each administration and wherein the time interval is about seven months.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 350 mg to about 550 mg/month, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.3 mL/min to about 6 mL/min of the suspension and wherein the volume of the suspension administered is about 6 mL to 12 mL.
  • each administration of the rilpivirine or a pharmaceutically acceptable salt thereof is calculated on the basis of a dose of rilpivirine ranging from about 350 mg to about 550 mg/month, wherein the rilpivirine or pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a flow rate of about 0.5 mL/min to about 3 mL/min of the suspension and wherein the volume of the suspension administered is about 8 mL to 10 mL.
  • micro- or nanoparticles have a Dv90 of from about 500 nm to about 6 pm, optionally wherein the micro- or nanoparticles have a Dv90 of from about 500 nm to about 1 ,600 nm.
  • micro- or nanoparticles have a Dv10 of from about 75 nm to about 200 nm, and/or wherein the micro- or nanoparticles have a Dv50 of from about 200 nm to about 500 nm.
  • micro- or nanoparticles have a Dv90 of from about 4 pm to about 6 pm.
  • micro- or nanoparticles have a Dv10 of from about 300 nm to about 500 nm, and/or wherein the particles have a Dv50 of from about 1.5 pm to about 2 pm.
  • HIV infection is HIV type 1 (HIV-1) infection.
  • a subcutaneous pharmaceutical injection device comprising: a container containing a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously; and a driver configured to drive the rilpivirine or pharmaceutically acceptable salt from the container and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension.
  • the discharge nozzle is an injection needle or a catheter.
  • the container comprises one of a vial, a cartridge, a syringe body and an expandable member.
  • micro- or nanoparticles have a Dv90 of from about 500 nm to about 6 pm, optionally wherein the micro- or nanoparticles have a Dv90 of from about 500 nm to about 1 ,600 nm.
  • micro- or nanoparticles have a Dv10 of from about 75 nm to about 200 nm, and/or wherein the micro- or nanoparticles have a Dv50 of from about 200 nm to about
  • micro- or nanoparticles have a Dv10 of from about 300 nm to about 500 nm, and/or wherein the particles have a Dv50 of from about 1 .5 pm to about 2 pm.
  • a method of administering a pharmaceutical composition using a subcutaneous injection device comprising: inserting a discharge nozzle of the subcutaneous injection device into a subcutaneous layer of a patient; and causing a driver of the subcutaneous injection device to drive a volume of rilpivirine or pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension from a container of the injection device and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt thereof in the patient for at least three months.
  • invention 160 comprising enabling fluid flow between the discharge nozzle and the container of the injection device after inserting a discharge nozzle of the subcutaneous injection device into a subcutaneous layer of the patient and before causing the driver of the subcutaneous injection device to drive the volume of rilpivirine or pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension from the container of the injection device and out of the discharge nozzle.
  • the method of embodiment 160 comprising enabling fluid flow between the discharge nozzle and the container of the injection device before inserting a discharge nozzle of the subcutaneous injection device into a subcutaneous layer of the patient and before causing the driver of the subcutaneous injection device to drive the volume of rilpivirine or pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension from the container of the injection device and out of the discharge nozzle. 163.
  • the method of any one of embodiments 160 to 162, wherein the method comprises repeating the method of embodiment 160 over an interval of at least three months.
  • subcutaneous injection device is an on-body injection device, an off-body injection device or a handheld injection device.
  • the subcutaneous pharmaceutical injection device comprises one or more of: a syringe, a subcutaneous pharmaceutical infusion set, a syringe pump and an infusion pump.
  • volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension is greater than 4ml_, 5ml_, 6ml_, 7 ml_, 8 ml_, 9 ml_, 10ml_, 11 ml_, 12ml_, 13ml_, 14ml_ or 15mL
  • the rilpivirine suspension further contains one or more of a buffer, a pH adjusting agent, an isotonizing agent, a chelating agent and a surface modifier.
  • micro- or nanoparticles have a Dv90 of from about 500 nm to about 6 pm, optionally wherein the micro- or nanoparticles have a Dv90 of from about 500 nm to about 1 ,600 nm.
  • micro- or nanoparticles have a Dv10 of from about 75 nm to about 200 nm, and/or wherein the micro- or nanoparticles have a Dv50 of from about 200 nm to about 500 nm.
  • micro- or nanoparticles have a Dv90 of from about 4 pm to about 6 pm.
  • micro- or nanoparticles have a Dv10 of from about 300 nm to about 500 nm, and/or wherein the particles have a Dv50 of from about 1 .5 pm to about 2 pm.
  • a method of preparing a subcutaneous injection device for injection comprising: introducing a volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device, the rilpivirine or a pharmaceutically acceptable salt thereof being in the form of micro- or nanoparticles in suspension, and the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months.
  • introducing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device comprises drawing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into a container of the subcutaneous injection device.
  • introducing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device comprises injecting the volume of rilpivirine or a pharmaceutically acceptable salt thereof into a container of the subcutaneous injection device.
  • introducing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device comprises inserting a container into the subcutaneous injection device, the container containing the volume of rilpivirine or a pharmaceutically acceptable salt thereof.
  • the subcutaneous injection device comprises a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt thereof to a patient subcutaneously.
  • the subcutaneous injection device comprises a container containing the volume of rilpivirine or a pharmaceutically acceptable salt thereof.
  • the container comprises one of a vial, a cartridge, a syringe body and an expandable member.
  • subcutaneous injection device is an on-body injection device, an off-body injection device or a handheld injection device.
  • subcutaneous pharmaceutical injection device is a syringe, an autoinjector, or a patch pump.
  • the subcutaneous pharmaceutical injection device comprises one or more of: a syringe, a subcutaneous pharmaceutical infusion set, a syringe pump and an infusion pump.
  • volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension is greater than 4ml_, 5ml_, 6ml_, 7 ml_, 8 ml_, 9 ml_, 10ml_, 11 ml_, 12ml_, 13ml_, 14ml_ or 15ml_.
  • the rilpivirine suspension further contains one or more of a buffer, a pH adjusting agent, an isotonizing agent, a chelating agent and a surface modifier.
  • micro- or nanoparticles have a Dv90 of from about 500 nm to about 6 pm, optionally wherein the micro- or nanoparticles have a Dv90 of from about 500 nm to about 1 ,600 nm.
  • micro- or nanoparticles have a Dv10 of from about 75 nm to about 200 nm, and/or wherein the micro- or nanoparticles have a Dv50 of from about 200 nm to about 500 nm.
  • micro- or nanoparticles have a Dv10 of from about 300 nm to about 500 nm, and/or wherein the particles have a Dv50 of from about 1 .5 pm to about 2 pm. 199.
  • a kit comprising: a subcutaneous pharmaceutical injection device, comprising: a container configured to contain a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt thereof to a patient subcutaneously; and a driver configured to drive the rilpivirine or pharmaceutically acceptable salt from the container and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension; and a drug provision device containing a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension, the volume being greater than 3 mL and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in
  • the subcutaneous pharmaceutical injection device is a syringe, an autoinjector, or a patch pump.
  • the subcutaneous pharmaceutical injection device comprises one or more of: a syringe, a subcutaneous pharmaceutical infusion set, a syringe pump and an infusion pump.
  • kits of any one of embodiments 199 to 206, wherein the volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension is greater than 4ml_, 5ml_, 6ml_, 7 ml_, 8 ml_, 9 ml_, 10ml_, 1 1 ml_, 12ml_, 13ml_, 14ml_ or 15ml_.
  • kits of embodiment 209 wherein the micro- or nanoparticles have a Dv90 of from about 500 nm to about 6 pm, optionally wherein the micro- or nanoparticles have a Dv90 of from about 500 nm to about 1 ,600 nm.
  • a subcutaneous pharmaceutical injection device comprising: a container containing a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1 .5 pm to about 2 pm and a D v 10 of from about 300 nm to about 500 nm, the volume being 2ml_ or greater and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously; and a driver configured to drive the rilpivirine or pharmaceutically acceptable salt from the container and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension.
  • the subcutaneous pharmaceutical injection device of embodiment 214, wherein the discharge nozzle has an inner diameter of 23 gauge to 25 gauge, such as 23 gauge, 24 gauge or 25 gauge.
  • subcutaneous pharmaceutical injection device of any one of embodiments 214 to 218, wherein the subcutaneous injection device is an on-body injection device, an off-body injection device or a handheld injection device.
  • the subcutaneous pharmaceutical injection device comprises one or more of: a syringe, a subcutaneous pharmaceutical infusion set, a syringe pump and an infusion pump.
  • the subcutaneous pharmaceutical injection device of any one of embodiments 214 to 221 wherein the volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension is greater than 4ml_, 5ml_, 6ml_, 7 ml_, 8 ml_, 9 ml_, 10ml_, 11 ml_, 12ml_, 13ml_, 14ml_ or 15ml_.
  • micro- or nanoparticles have a Dv90 of from about 500 nm to about 6 pm, optionally wherein the micro- or nanoparticles have a Dv90 of from about 500 nm to about 1 ,600 nm.
  • a method of administering a pharmaceutical using a subcutaneous injection device comprising: inserting a discharge nozzle of the subcutaneous injection device into a subcutaneous layer of a patient; and causing a driver of the subcutaneous injection device to drive a volume of rilpivirine or pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension from a container of the injection device and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension, wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1 .5 pm to about 2 pm and a D v 10 of from about 300 nm to about 500 nm, the volume being 2ml_ or greater and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months.
  • invention 229 comprising enabling fluid flow between the discharge nozzle and the container of the injection device after inserting a discharge nozzle of the subcutaneous injection device into a subcutaneous layer of a patient and before causing the driver of the subcutaneous injection device to drive the volume of rilpivirine or pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension from the container of the injection device and out of the discharge nozzle.
  • invention 229 comprising enabling fluid flow between the discharge nozzle and the container of the injection device before inserting a discharge nozzle of the subcutaneous injection device into a subcutaneous layer of a patient and before causing the driver of the subcutaneous injection device to drive the volume of rilpivirine or pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension from the container of the injection device and out of the discharge nozzle.
  • the subcutaneous pharmaceutical injection device comprises one or more of: a syringe, a subcutaneous pharmaceutical infusion set, a syringe pump and an infusion pump.
  • rilpivirine suspension further contains one or more of a buffer, a pH adjusting agent, an isotonizing agent, a chelating agent and a surface modifier.
  • micro- or nanoparticles have a Dv90 of from about 500 nm to about 6 pm, optionally wherein the micro- or nanoparticles have a Dv90 of from about 500 nm to about 1 ,600 nm. 245.
  • the micro- or nanoparticles have a Dv10 of from about 75 nm to about 200 nm, and/or wherein the micro- or nanoparticles have a Dv50 of from about 200 nm to about 500 nm.
  • micro- or nanoparticles have a Dv10 of from about 300 nm to about 500 nm, and/or wherein the particles have a Dv50 of from about 1 .5 pm to about 2 pm.
  • a method of preparing a subcutaneous injection device for injection comprising: introducing a volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device, the rilpivirine or a pharmaceutically acceptable salt thereof being in the form of micro- or nanoparticles in suspension, wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1 .5 pm to about 2 pm and a D v 10 of from about 300 nm to about 500 nm, and the volume being 2ml_ or greater and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months.
  • introducing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device comprises drawing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into a container of the subcutaneous injection device.
  • introducing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device comprises injecting the volume of rilpivirine or a pharmaceutically acceptable salt thereof into a container of the subcutaneous injection device.
  • introducing the volume of rilpivirine or a pharmaceutically acceptable salt thereof into the subcutaneous injection device comprises inserting a container into the subcutaneous injection device, the container containing the volume of rilpivirine or a pharmaceutically acceptable salt thereof. 252.
  • the subcutaneous injection device comprises a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously.
  • the subcutaneous injection device comprises a container containing the volume of rilpivirine or a pharmaceutically acceptable salt thereof.
  • the subcutaneous pharmaceutical injection device comprises one or more of: a syringe, a subcutaneous pharmaceutical infusion set, a syringe pump and an infusion pump.
  • micro- or nanoparticles have a Dv90 of from about 500 nm to about 6 pm, optionally wherein the micro- or nanoparticles have a Dv90 of from about 500 nm to about 1 ,600 nm.
  • micro- or nanoparticles have a Dv10 of from about 75 nm to about 200 nm, and/or wherein the micro- or nanoparticles have a Dv50 of from about 200 nm to about 500 nm.
  • micro- or nanoparticles have a Dv10 of from about 300 nm to about 500 nm, and/or wherein the particles have a Dv50 of from about 1 .5 pm to about 2 pm.
  • a kit comprising: a subcutaneous pharmaceutical injection device, comprising: a container configured to contain a volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension, wherein the micro- or nanoparticles have a D v 90 of from about 4 pm to about 6 pm, a D v 50 of from about 1 .5 pm to about 2 pm and a D V 10 of from about 300 nm to about 500 nm, the volume being 2ml_ or greater and sufficient to maintain a therapeutic level of the rilpivirine or a pharmaceutically acceptable salt in a patient for at least three months; a discharge nozzle sized to deliver the rilpivirine or pharmaceutically acceptable salt to a patient subcutaneously; and a driver configured to drive the rilpivirine or pharmaceutically acceptable salt from the container and out of the discharge nozzle at a flow rate of about 0.1 mL/min to about 15 mL/min of the suspension; and a drug provision device
  • kit of any one of embodiments 268 to 271 wherein the container comprises one of a vial, a cartridge, a syringe body and an expandable member.
  • kit of any one of embodiments 268 to 273 wherein the subcutaneous pharmaceutical injection device is a syringe, an autoinjector, or a patch pump.
  • the subcutaneous pharmaceutical injection device comprises one or more of: a syringe, a subcutaneous pharmaceutical infusion set, a syringe pump and an infusion pump.
  • kit of any one of embodiments 268 to 275, wherein the volume of rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension is greater than 4ml_, 5ml_, 6ml_, 7 ml_, 8 ml_, 9 ml_, 10ml_, 1 1 ml_, 12ml_, 13ml_, 14ml_ or 15ml_.
  • kits of embodiment 278 or 281 wherein the micro- or nanoparticles have a Dv10 of from about 300 nm to about 500 nm, and/or wherein the particles have a Dv50 of from about 1 .5 pm to about 2 pm.

Abstract

La présente invention concerne le traitement ou la prévention d'une infection par le VIH à l'aide de rilpivirine ou d'un sel pharmaceutiquement acceptable de celle-ci sous la forme de micro- ou nanoparticules en suspension, un dispositif d'injection sous-cutanée, et une méthode d'administration de rilpivirine ou d'un sel pharmaceutiquement acceptable de celle-ci sous la forme de micro- ou nanoparticules en suspension faisant appel à un dispositif d'injection sous-cutanée.
PCT/EP2023/063239 2022-05-17 2023-05-17 Traitement ou prévention d'une infection par le vih WO2023222755A1 (fr)

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US20030109829A1 (en) * 2001-09-28 2003-06-12 Mogensen Lasse Wesseltoft Injector device for placing a subcutaneous infusion set
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US20080177234A1 (en) * 2006-11-21 2008-07-24 Candace Keaton Safety subcutaneous infusion set
US20210162117A1 (en) * 2015-05-18 2021-06-03 Tandem Diabetes Care, Inc. Patch pump cartridge attachment
US20160361491A1 (en) * 2015-06-11 2016-12-15 Steadymed Ltd. Infusion set
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