WO2023222754A1 - Rilpivirine destinée à être utilisée dans le traitement ou la prévention d'une infection par le vih - Google Patents

Rilpivirine destinée à être utilisée dans le traitement ou la prévention d'une infection par le vih Download PDF

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Publication number
WO2023222754A1
WO2023222754A1 PCT/EP2023/063238 EP2023063238W WO2023222754A1 WO 2023222754 A1 WO2023222754 A1 WO 2023222754A1 EP 2023063238 W EP2023063238 W EP 2023063238W WO 2023222754 A1 WO2023222754 A1 WO 2023222754A1
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Prior art keywords
rilpivirine
pharmaceutically acceptable
acceptable salt
use according
suspension
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PCT/EP2023/063238
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English (en)
Inventor
Steven M. VESOLE
Guenter Karl Wilhelm KRAUS
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Janssen Sciences Ireland Unlimited Company
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Publication of WO2023222754A1 publication Critical patent/WO2023222754A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

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, and to a method of administering rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension.
  • 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.
  • 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.
  • Rilpivirine (4-[[4-[[4-[(1 E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]- amino]benzonitrile; TMC278) has the following structural formula: By “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.
  • hydrochloric, hydrobromic and the like sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2- hydroxy- 1 ,2,3- propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methyl- benzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.
  • organic acids for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2- hydroxy- 1 ,2,3
  • 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. In this embodiment, the micro- or nanoparticles may have a D v 90 of from 500 nm to about 2 pm. Preferably in this embodiment, the micro- or nanoparticles have a D v 90 of from 500 nm to about 1 ,600 nm or a D v 90 of from 500 nm to about 1 ,000 nm, for example about 800 nm.
  • the particles have a D v 90 of about 500 nm to about 700 nm, even more preferably from about 500 nm to about 650 nm, and most preferably from about 525 nm to about 644 nm.
  • 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.
  • 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, phosphatidy
  • 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-[CH 2 CH 2 O] X - [CH(CH3)CH 2 O]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
  • the suspensions conveniently comprise from 0 to 10% (w/v), in particular 0 to 6% of isotonizing agent.
  • isotonizing agent e.g. glucose, mannitol
  • electrolytes may affect colloidal stability.
  • 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. In another embodiment, 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.
  • 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. In another embodiment, each administration comprises about 3 mL of the reconstituted aqueous composition. In another embodiment, each administration comprises about 4 mL of the reconstituted aqueous composition. In another embodiment, each administration comprises about 5 mL of the reconstituted aqueous composition.
  • each administration comprises about 6 mL of the suspension. In another embodiment, each administration comprises about 7 mL of the reconstituted aqueous composition. In another embodiment, each administration comprises about 8 mL of the reconstituted aqueous composition. 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 is 1800 mg
  • the dose to be administered in each administration in the case of a time interval of 4 months between 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
  • the dose to be administered in each administration 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.
  • dose to be administered in each administration 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.
  • the indicated “mg” corresponds to mg of 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 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;
  • 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.
  • 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 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 0.3 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 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 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 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 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 from 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.
  • 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 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 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.
  • 110. The use according to any one of embodiments 95 to 109, 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.
  • 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.
  • surface modifier is a poloxamer.
  • 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.
  • 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.

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  • AIDS & HIV (AREA)
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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, ainsi qu'une méthode d'administration de rilpivirine ou d'un sel pharmaceutiquement acceptable de celle-ci sous la forme de micro- ou nanoparticules en suspension par injection sous-cutanée.
PCT/EP2023/063238 2022-05-17 2023-05-17 Rilpivirine destinée à être utilisée dans le traitement ou la prévention d'une infection par le vih WO2023222754A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003016306A1 (fr) 2001-08-13 2003-02-27 Janssen Pharmaceutica N.V. Derives de pyrimidines inhibiteurs de vih
WO2007147882A2 (fr) 2006-06-23 2007-12-27 Tibotec Pharmaceuticals Ltd. Suspensions aqueuses de tmc278
WO2021064618A1 (fr) * 2019-10-01 2021-04-08 Viiv Healthcare Company Procédé de traitement du vih à l'aide de cabotégravir et de rilpivirine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003016306A1 (fr) 2001-08-13 2003-02-27 Janssen Pharmaceutica N.V. Derives de pyrimidines inhibiteurs de vih
WO2007147882A2 (fr) 2006-06-23 2007-12-27 Tibotec Pharmaceuticals Ltd. Suspensions aqueuses de tmc278
WO2021064618A1 (fr) * 2019-10-01 2021-04-08 Viiv Healthcare Company Procédé de traitement du vih à l'aide de cabotégravir et de rilpivirine

Non-Patent Citations (3)

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Title
BAERT L ET AL: "Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVIER SCIENCE PUBLISHERS B.V., AMSTERDAM, NL, vol. 72, no. 3, 1 August 2009 (2009-08-01), pages 502 - 508, XP026218287, ISSN: 0939-6411, [retrieved on 20090327], DOI: 10.1016/J.EJPB.2009.03.006 *
G. VAN 'T KLOOSTER ET AL: "Pharmacokinetics and Disposition of Rilpivirine (TMC278) Nanosuspension as a Long-Acting Injectable Antiretroviral Formulation", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 54, no. 5, 16 February 2010 (2010-02-16), pages 2042 - 2050, XP055190760, ISSN: 0066-4804, DOI: 10.1128/AAC.01529-09 *
MARGOLIS D A ET AL: "Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial", THE LANCET, ELSEVIER, AMSTERDAM, NL, vol. 390, no. 10101, 23 September 2017 (2017-09-23), pages 1499 - 1510, XP009508252, ISSN: 0140-6736, DOI: 10.1016/S0140-6736(17)31917-7 *

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