TW202233192A - Treatment or prevention of hiv infection - Google Patents

Abstract

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 in combination with a hyaluronidase. The present invention also relates to rilpivirine or a pharmaceutically acceptable salt thereof in the form of micro- or nanoparticles in suspension.

Description

Treatment or prevention of HIV infection

The present invention pertains to the use of rilpivirine or a pharmaceutically acceptable salt thereof in combination with hyaluronidase in the treatment or prevention of HIV infection in the form of microparticles or nanoparticles in suspension. The present invention also relates to rilpivirine or a pharmaceutically acceptable salt thereof in the form of microparticles or nanoparticles in suspension.

Treatment of human immunodeficiency virus (HIV) infection, known as the cause of acquired immunodeficiency syndrome (AIDS), remains a major medical challenge. HIV is able to evade immune stress, adapt to a variety of cell types and growth conditions and develop resistance to anti-HIV drugs. The latter include nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleotide reverse transcriptase inhibitor (NtRTI), HIV-protease inhibitor (PI), integrase strand transfer ( strand transfer) inhibitors (INSTIs) and HIV fusion inhibitors.

Although effective in inhibiting HIV infection, each of these drugs faces the emergence of resistant mutants when used alone. This has led to the introduction of combination therapy of several anti-HIV agents, often with different activity profiles. In particular, the introduction of "HAART" (highly active antiretroviral therapy) has led to dramatic improvements in anti-HIV therapy, resulting in a substantial reduction in HIV-related morbidity and mortality. Current antiretroviral therapy guidelines recommend dual or triple combination regimens. However, there is currently no drug therapy available that can completely eradicate HIV infection. Even HAART may face the emergence of resistance, often due to non-adherence and non-persistence of antiretroviral therapy. In such cases, HAART can be made effective again by replacing one of its components with another class of components. If applied properly, treatment with a combination of HAART can suppress the virus for many years, up to decades, to levels that can no longer cause an AIDS outbreak.

Because HIV infection cannot currently be completely eradicated, people infected with HIV are potentially at risk of infecting others. A person can survive the infection for years without experiencing any of its effects, thereby unaware of the risk of further transmitting the virus to others. Therefore, preventing HIV transmission is of paramount importance. Currently, prevention focuses on avoiding transmission through sexual contact (especially the use of condoms in people at risk of infection), careful monitoring of blood samples for the presence of HIV, and avoidance of exposure to the blood of potentially infected subjects.

Despite these measures, there is always an imminent risk that individuals come into contact with and become infected with HIV-infected individuals. This is especially the case for those who provide medical care to patients who are infected or who are at risk of becoming infected, such as doctors, nurses or dentists. Another at-risk group is breastfed infants whose mothers are infected or at risk of infection, especially in developing countries where alternatives to breastfeeding are less obvious.

Currently available oral therapies require at least once-daily dosing. Thus, HIV-infected persons are reminded daily of their HIV-positive status, and daily dosing may also lead to disclosure of their HIV-positive status. Daily dosing requires the storage and transport of large or bulky pills, and there is still a risk that the patient forgets to take his daily dose, thereby failing to adhere to the prescribed dosage regimen. In addition to reducing the effectiveness of the treatment, this has led to the emergence of viral resistance.

One class of HIV drugs commonly used in HAART is the NNRTI. Rilpivirine is an antiretroviral drug that is used to treat HIV infection and belongs to the NNRTI class. Rilpivirine is a second-generation NNRTI with higher potency and a reduced side effect profile compared to older NNRTIs. Rilpivirine activity is mediated by non-competitive inhibition of HIV-1 reverse transcriptase.

Rilpivirine showed significant activity not only against wild-type HIV, but also against many of its mutant variants. Rilpivirine, its pharmacological activity and various methods for its preparation have been described in WO 03/16306.

Rilpivirine is approved for the treatment of HIV infection and is available as a single-dose tablet containing 25 mg of rilpivirine base equivalent each for once-daily oral administration (EDURANT®) and for once-daily Single tablet regimens for oral administration ( ^COMPLERA® , ^ODEFSEY® , ^JULUCA® ) are commercially available.

WO 2007147882 discloses intramuscular or subcutaneous injection of a therapeutically effective amount of rilpivirine in the form of microparticles or nanoparticles having a surface modifier adsorbed to its surface; and a pharmaceutically acceptable aqueous carrier; in which the rilpivirine active ingredient is suspended. Products containing rilpivirine are currently being developed to treat HIV infection with monthly or bimonthly injections.

Combination administration of long-release suspension for injection of rilpivirine with long-release suspension for injection of cabotegravir has been approved in Canada as CABENUVA® and the EMA has recommended approval for rilpivirine for injection European marketing authorization for Warin's long-term release suspension (REKAMBYS®). These are the first antiretroviral drugs to be provided in depot injectable formulations for administration at intervals greater than one day.

For drugs administered by subcutaneous or intramuscular injection, such as rilpivirine, patient tolerance is an additional issue, of course when larger volumes are injected. For example, administration by subcutaneous or intramuscular injection may result in irritation, inflammation, swelling, acute pain and/or redness, and bruising at the injection site during and after injection (injection site reactions). Subcutaneous and intramuscular injections may also be associated with raised appearance of the skin surface at the injection site, of course when larger volumes are injected. Such effects are often exacerbated by large injection volumes. Such bumps may indicate that the subject in question has received a large volume injection, and thus may indicate HIV-positive status of the subject.

Therefore, in addition to providing an effective method for preventing HIV transmission or treating HIV infection that does not require frequent dosing (ie, only once every few months or more), it also needs to be well tolerated, Thereby improving patient compliance. The method also needs to be invisible to the outside world.

In a first aspect, there is provided a method for treating or preventing HIV infection in a subject in need thereof, the method comprising administering to the subject by intramuscular injection or subcutaneous injection a therapeutically effective amount of in suspension rilpivirine or a pharmaceutically acceptable salt thereof in microparticle or nanoparticle form, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is combined with hyaluronic acid administered by intramuscular or subcutaneous injection The enzymes are administered in combination, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years.

In a second aspect, there is provided rilpivirine or a pharmaceutically acceptable salt thereof and a hyaluronidase for use in the treatment or prevention of HIV infection in a subject, wherein the rilpivirine or a pharmaceutically acceptable salt thereof The acceptable salt is in the form of microparticles or nanoparticles in suspension, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronan are administered to the subject by intramuscular injection or subcutaneous injection acid enzyme, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years.

In a third aspect, there is provided a product comprising rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase as a combined preparation for use in the treatment or prevention of HIV by intramuscular or subcutaneous injection Simultaneous or sequential use in infection, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of microparticles or nanoparticles in suspension, and wherein intermittently at intervals of about three months to about two years The rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered.

In a fourth aspect, there is provided a kit comprising rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use by intramuscular injection or subcutaneous injection For simultaneous or sequential use in the treatment or prevention of HIV infection, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of microparticles or nanoparticles in suspension, and wherein the The rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at yearly intervals.

In a fifth aspect, there is provided rilpivirine or a pharmaceutically acceptable salt thereof in the form of a suspension of microparticles or nanoparticles for use in the treatment or prevention of HIV infection by intramuscular or subcutaneous injection , wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered in combination with hyaluronidase administered by intramuscular injection or subcutaneous injection, and wherein the administration is intermittently administered at intervals of about three months to about two years The rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase.

In a sixth aspect, there is provided the use of rilpivirine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of HIV infection in a subject, wherein the rilpivirine or a pharmaceutically acceptable salt thereof The accepted salt is in the form of microparticles or nanoparticles in suspension and administered in combination with hyaluronidase, wherein the subject is administered the rilpivirine, or a pharmaceutically acceptable thereof, by intramuscular injection or subcutaneous injection and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years.

In a seventh aspect, there is provided a combination comprising rilpivirine or a pharmaceutically acceptable salt thereof and a hyaluronidase, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in microscopic form in suspension in particle or nanoparticle form.

In an eighth aspect, a kit is provided, the kit comprising rilpivirine or a pharmaceutically acceptable salt thereof and a hyaluronidase, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in suspension in the form of microparticles or nanoparticles in liquid.

Administration of rilpivirine in combination with hyaluronidase by subcutaneous or intramuscular injection may improve patient tolerability compared to administration of rilpivirine alone by subcutaneous or intramuscular injection, especially when larger volumes are injected. Hyaluronidase can facilitate more rapid administration of rilpivirine because it can reduce the resistance of the tissue to which the rilpivirine suspension is delivered. Hyaluronidase reduces leakage of rilpivirine at the injection site by reducing tissue back pressure. Hyaluronidase may also allow delivery of larger volumes in patients with less subcutaneous tissue (or lower body mass index). Hyaluronidase allows the use of shorter needles.

Furthermore, it was surprisingly found that when rilpivirine is administered together with hyaluronidase as defined herein, a suspension of rilpivirine microparticles or nanoparticles by intramuscular or subcutaneous injection can be maintained Achieved prolonged, sustained or long-term release of rilpivirine into plasma. As discussed in more detail below in the section entitled "Hyaluronidase", hyaluronidase is used to increase the dispersion and absorption of injected active pharmaceutical ingredients. Given this, the inventors have surprisingly demonstrated that administration of hyaluronidase with rilpivirine can maintain prolonged, sustained or long-term release of rilpivirine into the bloodstream.

In a ninth aspect, there is provided rilpivirine or a pharmaceutically acceptable salt thereof in the form of microparticles or nanoparticles in suspension, wherein the microparticles or nanoparticles have from about 1 μm to about 10 D _v 90 in µm.

In a tenth aspect, there is provided a pharmaceutical composition comprising rilpivirine or a pharmaceutically acceptable salt thereof as defined in the ninth aspect.

In an eleventh aspect there is provided rilpivirine or a pharmaceutically acceptable salt thereof as defined in the ninth aspect for use in the treatment or prevention of HIV infection in a subject.

In a twelfth aspect, there is provided a method for treating or preventing HIV infection in a subject, the method comprising administering to the subject rilpivirine according to the ninth aspect of the present invention or a pharmaceutically acceptable Acceptable salts (ie, in the form of microparticles or nanoparticles in suspension), wherein the microparticles or nanoparticles have a D _v 90 of from about 1 µm to about 10 µm.

In a thirteenth aspect, there is provided rilpivirine or a pharmaceutically acceptable salt thereof (ie in the form of microparticles or nanoparticles in suspension) according to the ninth aspect of the present invention for use in the manufacture of Use of a medicament for the treatment or prevention of HIV infection in a subject, wherein the microparticles or nanoparticles have a D _v 90 of from about 1 μm to about 10 μm.

Surprisingly, it was found that, compared to rilpivirine in the form of microparticles or nanoparticles, having a lower _Dv 90, a microparticle or nanoparticle having a D _v 90 of from about 1 µm to about 10 µm Forms of rilpivirine reduced the dissolution profile of rilpivirine even though it flattened. Thus, administration of rilpivirine in microparticle or nanoparticle form with a D _v 90 of from about 1 µm to about 10 µm can modulate the exposure of rilpivirine to flatten the pharmacokinetic profile (i.e. decrease the Cmax of this pharmacokinetic profile) while maintaining sustained or long-term release of rilpivirine into plasma. Rilpivirine in the form of microparticles or nanoparticles with a _Dv 90 of from about 1 µm to about 10 µm compared to administration of rilpivirine in the form of microparticles or nanoparticles with a lower D _v 90. Administration of pivaline may result in increased peak-to-trough ratios at multiple doses.

Disclosure of the Invention

This application has been drafted in sections to facilitate reading. However, this does not mean that each section should be read in isolation. Instead, unless otherwise stated, each section should be read with cross-references to the other sections, that is, the entire application as a whole. It is not intended to artificially separate implementations unless explicitly stated.

Accordingly, all embodiments described herein in relation to the first aspect of the invention are equally applicable to the second to eighth aspects described herein (ie, such embodiments are also relevant/combined with the second to eighth aspects described herein exposed). Furthermore, all the embodiments described herein in relation to the ninth aspect of the present invention are equally applicable to the tenth to thirteenth aspects of the present invention (ie, these embodiments also relate to the tenth to thirteenth aspects of the present invention /combinatorially expose). rilpivirine

「利匹韋林」係指具有如上所示結構式（即游離鹼形式）的利匹韋林。 Rilpivirine (4-[[4-[[4-[(1E)-2-cyanovinyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino] benzonitrile; TMC278) has the following structural formula:

"Rilpivirine" refers to rilpivirine having the structural formula shown above (ie, the free base form).

Rilpivirine or a pharmaceutically acceptable salt thereof as used in the first and ninth aspects of the present invention is in the form of microparticles or nanoparticles in suspension, i.e. rilpivirine or rilpivirine in suspension Microparticles or nanoparticles of a pharmaceutically acceptable salt, particularly rilpivirine or a pharmaceutically acceptable salt thereof, suspended in a pharmaceutically acceptable carrier such as, for example, a pharmaceutically acceptable aqueous carrier Microparticles or Nanoparticles.

The pharmaceutically acceptable salts of rilpivirine mean those in which the counterion is pharmaceutically acceptable. A pharmaceutically acceptable salt is meant to comprise the therapeutically active non-toxic acid addition salt form that rilpivirine is capable of forming. Such salt forms can be conveniently obtained by treating rilpivirine with a suitable acid, such as a mineral acid, for example, a hydrohalic acid (eg, hydrochloric acid, hydrobromic acid, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like ; or organic acids such as acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxypropionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-Hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexaneaminosulfonic acid, 2-hydroxybenzoic acid, 4 -Amino-2-hydroxybenzoic acid, etc.

In a preferred embodiment of the first and ninth aspects of the present invention, rilpivirine or a pharmaceutically acceptable salt thereof used in the present invention is rilpivirine, that is, rilpivirine in free base form Forest.

The skilled person will understand that the size of the microparticles or nanoparticles in the first aspect of the invention should be below a maximum size beyond which administration by subcutaneous or intramuscular injection becomes impaired or even no longer possible. The maximum size depends on, for example, the needle diameter or constraints imposed by the body's adverse reaction to large particles, or both.

In a preferred embodiment of the first aspect of the present invention, rilpivirine or a pharmaceutically acceptable salt thereof is in the form of nanoparticles.

In one embodiment of the first aspect of the invention, the microparticles or nanoparticles described herein have an average effective particle size of less than about 20 μm. In one embodiment of the first aspect of the invention, the microparticles or nanoparticles have an average effective particle size of less than about 10 μm. In one embodiment of the first aspect of the invention, the microparticles or nanoparticles have an average effective particle size of less than about 5 μm. In one embodiment of the first aspect of the invention, the microparticles or nanoparticles have an average effective particle size of less than about 1 μm. In one embodiment of the first aspect of the invention, the microparticles or nanoparticles have an average effective particle size of less than about 500 nm.

In another embodiment of the first aspect of the invention, the microparticles or nanoparticles described herein have an average effective particle size of from about 25 nm to about 20 μm. In another embodiment of the first aspect of the invention, the microparticles or nanoparticles have an average effective particle size of from about 25 nm to about 10 μm (eg, about 200 nm to about 10 μm). In another embodiment of the first aspect of the invention, the microparticles or nanoparticles have an average effective particle size of from about 25 nm to about 5 μm (eg, about 200 nm to about 5 μm). In another embodiment of the first aspect of the invention, the microparticles or nanoparticles have an average effective particle size of from about 25 nm to about 1 μm. In another embodiment of the first aspect of the invention, the microparticles or nanoparticles have an average effective particle size of from about 25 nm to about 500 nm.

In a preferred embodiment of the first aspect of the invention, the microparticles or nanoparticles described herein have an average effective particle size of from about 100 nm to about 300 nm. In another preferred embodiment of the first aspect of the invention, the microparticles or nanoparticles have an average effective particle size of from about 150 nm to about 250 nm. In a particularly preferred embodiment of the first aspect of the invention, the microparticles or nanoparticles have an average effective particle size of about 180 nm to about 220 nm (eg, about 200 nm).

In an alternative embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles have an average effective particle size of from about 0.2 μm to about 3 μm. In one embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles have an average effective particle size of from about 0.4 μm to about 3 μm. In one embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles have an average effective particle size of from about 0.6 μm to about 3 μm. In one embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles have an average effective particle size of from about 0.7 μm to about 3 μm. In one embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles have an average effective particle size of from about 0.8 μm to about 3 μm. In one embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles have an average effective particle size of from about 0.9 μm to about 3 μm. In one embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles have an average effective particle size of from about 1 μm to about 3 μm. In one embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles have an average effective particle size of from about 1 μm to about 2.5 μm. In one embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles have an average effective particle size of from about 1 μm to about 2 μm. In one embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles have 0.3 µm, 0.4 µm, 0.5 µm, 0.6 µm, 0.7 µm, 0.8 µm, 0.9 µm, 1 µm, 1.1 µm, 1.2 µm, 1.3 µm, 1.4 µm, 1.5 µm, 1.6 µm, 1.7 µm, 1.8 µm, 1.9 µm, 2 µm, 2.1 µm, 2.2 µm, 2.3 µm, 2.4 µm, 2.5 µm, 2.6 µm, 2.7 µm, 2.8 µm , 2.9 µm or 3 µm, or any sub-range or single value between 0.2 µm and 3 µm, the mean effective particle size.

In one embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles have an average effective particle size of from about 1.5 μm to about 3 μm. In one embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles have an average effective particle size of from about 2 μm to about 3 μm, eg, about 2.5 μm or about 2.7 μm.

As used herein, the term "average effective particle size" refers to the median particle diameter on a volume basis (D _v 50 ), ie the diameter is found to be less than 50% by volume of the particle population.

In an alternative embodiment of the first aspect of the invention, the microparticles or nanoparticles have a _Dv 90 of from about 1 μm to about 10 μm.

The microparticles or nanoparticles of the ninth aspect of the invention have a D _v 90 of from about 1 μm to about 10 μm.

In one embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles have a _Dv 90 of from about 1 μm to about 7 μm. In one embodiment of the first and ninth aspects, the microparticles or nanoparticles have a _Dv 90 of from about 1.5 μm to about 7 μm. In one embodiment of the first and ninth aspects, the microparticles or nanoparticles have a D _v 90 of from about 2 μm to about 7 μm. In one embodiment of the first and ninth aspects, the microparticles or nanoparticles have a D _v 90 of from about 2 μm to about 6 μm. In one embodiment of the first and ninth aspects, the microparticles or nanoparticles have a _Dv 90 of from about 2.5 μm to about 6.5 μm. In one embodiment of the first and ninth aspects, the microparticles or nanoparticles have a _Dv 90 of from about 2.5 μm to about 4 μm. In one embodiment of the first and ninth aspects, the microparticles or nanoparticles have a _Dv 90 of from about 3 μm to about 7 μm. In one embodiment of the first and ninth aspects, the microparticles or nanoparticles have a D _v 90 of from about 4 μm to about 7 μm. In one embodiment of the first and ninth aspects, the microparticles or nanoparticles have a _Dv 90 of from about 3 μm to about 6 μm. In one embodiment, the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 5.5 μm. In one embodiment of the first and ninth aspects, the microparticles or nanoparticles have a _Dv 90 of from about 4.5 μm to about 6.5 μm. In one embodiment of the first and ninth aspects, the microparticles or nanoparticles have a D _v 90 of from about 5 μm to about 6 μm (eg, about 5.5 μm). In one embodiment of the first and ninth aspects, the microparticles or nanoparticles have 2 µm, 2.1 µm, 2.2 µm, 2.3 µm, 2.4 µm, 2.5 µm, 2.6 µm, 2.7 µm, 2.8 µm, 2.9 µm, 3 µm, 3.1 µm, 3.2 µm, 3.3 µm, 3.4 µm, 3.5 µm, 3.6 µm, 3.7 µm, 3.8 µm, 3.9 µm, 4 µm, 4.1 µm, 4.2 µm, 4.3 µm, 4.4 µm, 4.5 µm, 4.6 µm , 4.7 µm, 4.8 µm, 4.9 µm, 5 µm, 5.1 µm, 5.2 µm, 5.3 µm, 5.4 µm, 5.5 µm, 5.6 µm, 5.7 µm, 5.8 µm, 5.9 µm, 6 µm, 6.1 µm, 6.2 µm, 6.3 µm D _v 90 for µm, 6.4 µm, 6.5 µm, 6.6 µm, 6.7 µm, 6.8 µm, 6.9 µm, or 7 µm, or any subrange or single value between 2 µm and 7 µm.

As used herein, the term "D _v 90" refers to the diameter found to be less than 90% by volume of the particle population.

In a specific embodiment of the first and ninth aspects, the microparticles or nanoparticles have an average effective particle size (D _v 50 ) of from about 0.2 μm to about 3 μm and a D of from about 1.8 μm to about 7 μm _v 90, or having an average effective particle size (D _v 50) from about 0.6 µm to about 3 µm and a D _v 90 from about 2.5 µm to about 6.5 µm, wherein, for any embodiment, the average effective particle size is less than D _v 90. In an alternative embodiment of the first and ninth aspects, the microparticles or nanoparticles have an average effective particle size (D v 50 ) of from about 0.6 μm to about 1.5 μm and a mean effective particle size (D _v 50 ) of from about 2.5 μm to about 4 μm D _v 90, wherein the average effective particle size is less than D _v 90 for any embodiment. In an alternative embodiment of the first and ninth aspects, the microparticles or nanoparticles have an average effective particle size (D _v 50 ) of from about 1 μm to about 2 μm and a mean particle size of from about 3.5 μm to about 5.5 μm D _v 90, wherein the average effective particle size is less than D _v 90 for any embodiment. In an alternative embodiment of the first and ninth aspects, the microparticles or nanoparticles have an average effective particle size (D _v 50 ) of from about 2 μm to about 3 μm and a mean particle size of from about 5.0 μm to about 6.5 μm D _v 90, wherein the average effective particle size is less than D _v 90 for any embodiment.

As can be seen from Example 3, administration of rilpivirine in the form of microparticles or nanoparticles having a _Dv 90 of from about 1 μm to about 10 μm unexpectedly reduces the dissolution profile of rilpivirine even though it become flat. Thus, particle sizes in this range can modulate rilpivirine exposure to flatten the pharmacokinetic profile (ie, lower the Cmax of that pharmacokinetic profile), while maintaining sustained or long-term rilpivirine delivery into plasma freed.

As used herein, the mean effective particle size (ie, the volume-based median particle diameter (D _v 50 )) and D _v 90 are determined by conventional laser diffraction techniques, eg, according to ISO 13320:2009.

Laser diffraction relies on the principle that particles scatter light at an angle that varies depending on the size of the particles, and that collections of particles produce a scattered light pattern determined by intensity and angle that can be correlated to the particle size distribution . A number of laser diffractometers are commercially available for fast and reliable determination of particle size distribution. For example, particle size distribution can be measured by a conventional Malvern Mastersizer™ 3000 particle size analyzer from Malvern Instruments. The Malvern Mastersizer™ 3000 particle size analyzer operates by projecting a helium-neon gas laser beam into a transparent cell containing target particles suspended in an aqueous solution. Light impinging on the particles is scattered by an angle that is inversely proportional to the particle size, and the light detector array measures the light intensity 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 can be obtained using wet dispersion of particles in distilled water.

Other methods commonly used in the art to measure volume-based median particle diameter (D _v 50 ) and D _v 90 include disk centrifugation, scanning electron microscopy (SEM), sedimentation field flow fractionation, and photon correlation spectroscopy.

In one embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles have one or more surface modifiers adsorbed onto their surface.

Surface modifiers can be selected from known organic and inorganic pharmaceutical excipients, including various polymers, low molecular weight oligomers, natural products and surfactants. Specific surface modifiers useful in the present invention include nonionic and anionic surfactants. Representative examples of surface modifiers include gelatin, casein, lecithin, salts of negatively charged phospholipids, or their acidic forms (eg, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid, and their acid forms). salts, such as alkali metal salts, for example, their sodium salts, such as sodium phosphatidylglycerol of egg, such as the product available under the trade name Lipoid™ EPG), gum arabic, stearic acid, benzalkonium chloride, polyoxyethylene Alkyl ethers (eg, polyethylene glycol ethers such as polycitodol 1000, polyoxyethylene castor oil derivatives); polyoxyethylene stearate, colloidal silica, sodium lauryl sulfate (sodium dodecylsulfate), sodium carboxymethylcellulose, bile salts (eg, sodium taurocholate, sodium deoxytaurocholate, sodium deoxycholate); methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose ethylene oxide, hydroxypropyl methylcellulose, magnesium aluminosilicate, vinyl alcohol (PVA), poloxamers such as Pluronic™ F68, F108 and F127, which are copolymers of ethylene oxide and propylene oxide ); tyloxapol; vitamin E-TGPS (alpha-tocopheryl polyethylene glycol succinate, especially alpha-tocopheryl polyethylene glycol 1000 succinate); poloxamine ), such as Tetronic™ 908 (T908), which is a tetrafunctional block copolymer obtained by the sequential addition of ethylene oxide and propylene oxide to ethylenediamine; dextran; lecithin; dioctyl sodium sulfosuccinate , such as those sold under the trade name Aerosol OT™ (AOT); sodium lauryl sulfate (Duponol™ P); alkyl aryl polyether sulfonates, available under the trade name Triton™ X-200 polyoxyethylene sorbitan fatty acid esters (Tweens™ 20, 40, 60 and 80); sorbitan fatty acid esters (Span™ 20, 40, 60 and 80 or Arlacel™ 20, 40, 60 and 80) 80); polyethylene glycols (such as those sold under the trade names Carbowax™ 3550 and 934); mixtures of sucrose stearate and sucrose distearate, such as Crodesta™ F110 or Crodesta™ SL-40 The products obtained; hexyldecyltrimethylammonium chloride (CTAC); polyvinylpyrrolidone (PVP). If desired, two or more surface modifiers may be used in combination.

In one embodiment of the first and ninth aspects of the present invention, the surface modifier is selected from the group consisting of poloxamers, alpha-tocopherol polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid ester, and salts of negatively charged phospholipids or their acidic forms. In a preferred embodiment of the first and ninth aspects of the present invention, the surface modifier is selected from Pluronic™ F108, Vitamin E TGPS, Tween™ 80 and Lipoid™ EPG.

In one embodiment of the first and ninth aspects of the invention, the surface modifier is a poloxamer, in particular Pluronic™ F108. Pluronic™ F108 corresponds to Poloxamer 338 and is a polyoxyethylene, polyoxypropylene block copolymer generally conforming to the formula HO-[ _CH2CH2O ] _x- [ _CH ( _{CH3 )} CH2O] _y -[ _CH2CH2O ] _{z -} H, where the mean values of x, y and z are 128, 54 and 128, respectively. Other trade names for Poloxamer 338 are Hodag Nonionic™ 1108-F and Synperonic™ PE/F108. In one embodiment of the first and ninth aspects of the invention, the surface modifier comprises a combination of a polyoxyethylene sorbitan fatty acid ester and a phosphatidylglycerol salt, particularly sodium phosphatidylglycerol of egg.

In one embodiment of the first and ninth aspects of the present invention, the relative amount (w/w) of rilpivirine or a pharmaceutically acceptable salt thereof and the surface modifier is from about 1:2 to about 20 : 1, specifically from about 1: 1 to about 10: 1, such as from about 4: 1 to about 6: 1, preferably about 6: 1.

In one embodiment of the first and ninth aspects of the invention, the microparticles or nanoparticles of the invention comprise rilpivirine as defined herein or a pharmaceutically acceptable salt thereof and one or more of the as defined herein A surface modifier as defined, wherein the amount of rilpivirine or a pharmaceutically acceptable salt thereof is at least about 50% by weight of the microparticles or nanoparticles, by weight of the microparticles or nanoparticles At least about 80% by weight, at least about 85% by weight of the microparticles or nanoparticles, at least about 90% by weight of the microparticles or nanoparticles, at least about 90% by weight of the microparticles or nanoparticles at least about 95% by weight of the microparticles or nanoparticles, or at least about 99% by weight of the microparticles or nanoparticles, particularly in the range between 80% and 90% by weight of the microparticles or nanoparticles Or in the range between 85% and 90% by weight of the microparticles or nanoparticles.

In one embodiment of the first and ninth aspects of the present invention, the suspension comprises a pharmaceutically acceptable aqueous carrier in which rilpivirine or a pharmaceutically acceptable salt thereof is suspended of microparticles or nanoparticles. Pharmaceutically acceptable aqueous carriers include sterile water, such as water for injection, optionally mixed with other pharmaceutically acceptable ingredients. The latter include any ingredients for use in injectable formulations. Such ingredients may be selected from one or more of the following: suspending agents, buffers, pH adjusting agents, preservatives, isotonizing agents, surface modifiers, chelating agents and the like. In one embodiment of the first and ninth aspects of the present invention, the ingredients are selected from one or more of the following: suspending agents, buffers, pH adjusting agents, and optionally, preservatives and isotonic agents. Certain ingredients may act simultaneously as two or more of these agents, eg, as preservatives and buffers, or as buffers and isotonicity agents. In one embodiment of the first and ninth aspects of the present invention, the ingredients are selected from one or more of the following: buffers, pH adjusters, isotonicity agents, chelating agents and surface modifiers. In one embodiment of the first and ninth aspects of the present invention, the ingredients are selected from one or more of the following: buffering agents, pH adjusting agents, isotonicity agents and chelating agents.

In one embodiment of the first and ninth aspects of the present invention, the suspension additionally comprises buffering agents and/or pH adjusting agents. Suitable buffers and pH adjusters should be used in amounts sufficient to neutralize the dispersion to slightly alkaline (up to pH 8.5), preferably in the pH range of 7 to 7.5. Certain buffers are weak acid salts. Buffers and pH adjusters that can be added can be selected from tartaric acid, maleic acid, glycine, sodium lactate/lactic acid, ascorbic acid, sodium citrate/citric acid, sodium acetate/acetic acid, sodium bicarbonate/carbonic acid, sodium succinate/ Succinic acid, sodium benzoate/benzoic acid, sodium phosphate, tris(hydroxymethyl)aminomethane, sodium bicarbonate/sodium carbonate, ammonium hydroxide, benzenesulfonic acid, sodium benzoate/benzoic acid, diethanolamine, gluconic acid delta Esters, hydrochloric acid, hydrobromic acid, lysine, methanesulfonic acid, monoethanolamine, sodium hydroxide, tromethamine, gluconic acid, glyceric acid, glutaric acid (gluratic), glutamic acid, EDTA Acetic acid (EDTA), triethanolamine, including mixtures thereof. In one embodiment of the first and ninth aspects of the invention, the buffer is a sodium phosphate buffer, such as sodium dihydrogen phosphate monohydrate. In one embodiment, the pH adjusting agent is sodium hydroxide.

In one embodiment of the first and ninth aspects of the invention, the suspension additionally comprises a preservative. Preservatives include antimicrobials and antioxidants that can be selected from the group consisting of: benzoic acid, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), chlorobutanol, gallic acid Salt, hydroxybenzoate, EDTA, phenol, chlorocresol, m-cresol, bensonin chloride, myristyl-gamma-picoline chloride, phenylmercuric acetate and thimerosal. Free 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, sodium acetone bisulfite, isoascorbic acid, hydroxypropyl cyclodextrin. Chelating agents include sodium citrate, sodium EDTA, citric acid and malic acid. In one embodiment of the first and ninth aspects of the invention, the chelating agent is citric acid, such as citric acid monohydrate.

In one embodiment of the first and ninth aspects of the invention, the suspension additionally comprises an isotonicity agent. Isotonic agents or isotonifiers may be present to ensure isotonicity of the pharmaceutical compositions of the present invention, and include sugars such as glucose, dextrose, sucrose, fructose, trehalose, lactose; polysaccharide alcohols, relatively Preferred are trihydric or higher sugar alcohols such as glycerol, erythritol, arabitol, xylitol, sorbitol and mannitol. Alternatively, sodium chloride, sodium sulfate, or other suitable inorganic salts can be used to make the solution isotonic. The isotonicity agents can be used alone or in combination. The suspension conveniently contains from 0 to 10% (w/v), in particular 0 to 6% (w/v), of isotonicity agent. Of interest are nonionic isotonic agents, such as glucose, mannitol, because electrolytes may affect colloidal stability.

In one embodiment of the first aspect of the present invention, each administration comprises up to about 600 mL of a suspension as described herein, ie, comprising rilpivirine or a pharmaceutically acceptable form thereof in the form of microparticles or nanoparticles The volume of the accepted salt suspension can have a volume of up to 600 mL. In one embodiment of the first aspect of the invention, each administration comprises from about 5 mL to about 600 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises from about 5 mL to about 300 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises from about 5 mL to about 150 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises from about 5 mL to about 25 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises from about 6 mL to about 20 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises from about 6 mL to about 18 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises from about 6 mL to about 15 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises from about 6 mL to about 12 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises from about 9 mL to about 18 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises from about 9 mL to about 15 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises from about 9 mL to about 12 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises about 6 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises about 9 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises about 12 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises about 15 mL of the suspension. In another embodiment of the first aspect of the invention, each administration comprises about 18 mL of the suspension. In one embodiment of the first aspect of the invention, the rilpivirine suspension contains 300 mg rilpivirine/mL.

In one embodiment, the rilpivirine of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, in the form of microparticles or nanoparticles in suspension, is in a separate form from hyaluronidase. provided in the pharmaceutical composition. As discussed further herein (eg, in the section entitled "Use of rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase in the present invention"), the separate pharmaceutical composition may be combined with a composition comprising The pharmaceutical composition of the hyaluronidase of the first aspect of the present invention is administered sequentially, or the separate pharmaceutical composition may be mixed with a pharmaceutical composition comprising the hyaluronidase of the present invention, followed by administration of the resulting mixed pharmaceutical composition thing.

In another embodiment, the rilpivirine of the first aspect of the invention, or a pharmaceutically acceptable salt thereof (in the form of microparticles or nanoparticles in suspension), is administered in the same drug as hyaluronidase Provided in a composition, ie, the rilpivirine or a pharmaceutically acceptable salt thereof, and the hyaluronidase are formulated in a combined pharmaceutical composition.

In one embodiment of the first aspect of the invention, for the treatment of HIV infection, it may be based on about 300 mg to about 1200 mg/month, or about 450 mg to about 1200 mg/month, or about 450 mg to about 900 mg /month, or about 600 mg to about 900 mg/month, or about 450 mg to about 750 mg/month, or 450 mg/month, or 600 mg/month, or 750 mg/month, or 900 mg/month dose administered. Dosages for other dosing regimens can be easily calculated by multiplying the monthly dose by the number of months between each administration. For example, if the dose is 450 mg/month, and if the time interval between each administration is 6 months, the dose to be administered in each administration is 2700 mg. The "mg" shown corresponds to mg of rilpivirine (ie, rilpivirine in its free base form). Thus, for example, 1 mg of rilpivirine (ie, rilpivirine in its free base form) corresponds to 1.1 mg of rilpivirine hydrochloride.

In one embodiment of the first aspect of the invention, for the treatment of HIV infection, it may be based on about 300 mg to about 1200 mg/4 weeks (28 days), or about 450 mg to about 1200 mg/4 weeks (28 days) ), or about 450 mg to about 900 mg/4 weeks (28 days), or about 600 mg to about 900 mg/4 weeks (28 days), or about 450 mg to about 750 mg/4 weeks (28 days), Either 450 mg/4 weeks (28 days), or 600 mg/4 weeks (28 days), or 750 mg/4 weeks (28 days) or 900 mg/4 weeks (28 days) to calculate the dose to be administered. Dosages for other dosing regimens can be easily calculated by multiplying the weekly or daily dose by the number of weeks between each administration. For example, if the dose is 450 mg/4 weeks (28 days), and if the time interval between each administration is 24 weeks, the dose to be administered in each administration is 2700 mg. Or for example, if the dose is 750 mg/4 weeks (28 days), and if the time interval between each administration is 24 weeks, the dose to be administered in each administration is 4500 mg. The "mg" shown corresponds to mg of rilpivirine (ie, rilpivirine in its free base form). Thus, for example, 1 mg of rilpivirine (ie, rilpivirine in its free base form) corresponds to 1.1 mg of rilpivirine hydrochloride.

In one embodiment of the first aspect of the invention, for the treatment of HIV infection, each administration of rilpivirine or a pharmaceutically acceptable salt thereof may comprise from about 900 mg to about 28800 mg (eg from about 900 mg) mg to about 14400 mg, or from about 900 mg to about 7200 mg, or from about 900 mg to about 3600 mg), preferably from about 1200 mg to about 14400 mg, preferably from about 1350 mg to about 13200 mg, preferably from about 1500 mg to about 12000 mg (eg from about 3000 mg to about 12000 mg), preferably from about 1800 mg to about 10800 mg (eg from about 2700 mg to about 10800 mg, or from about 1800 mg to about 3600 mg), most preferably from about 1800 mg to about 7200 mg or from about 2700 mg to about 4500 mg of the rilpivirine or a pharmaceutically acceptable salt thereof.

Thus, the amount of rilpivirine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition (ie the pharmaceutical composition as defined herein, alone or in combination in relation to the first aspect of the invention) may be from about 900 mg to about 28800 mg (eg from about 900 mg to about 14400 mg, or from about 900 mg to about 7200 mg, or from about 900 mg to about 3600 mg), preferably from about 1200 mg to about 14400 mg, Preferably from about 1350 mg to about 13200 mg, preferably from about 1500 mg to about 12000 mg (eg from about 3000 mg to about 12000 mg), preferably from about 1800 mg to about 10800 mg ( For example from about 2700 mg to about 10800 mg, or from about 1800 mg to about 3600 mg), most preferably from about 1800 mg to about 7200 mg or from about 2700 mg to about 4500 mg. The "mg" shown corresponds to mg of rilpivirine (ie, rilpivirine in its free base form). Thus, for example, 1 mg of rilpivirine (ie, rilpivirine in its free base form) corresponds to 1.1 mg of rilpivirine hydrochloride.

In the case of prevention of HIV infection, each administration of rilpivirine or a pharmaceutically acceptable salt thereof may comprise the same administration as described above for therapeutic use.

In one embodiment of the first aspect of the present invention, rilpivirine, or a pharmaceutically acceptable salt thereof, is used in a pharmaceutical composition (ie, a single or combined pharmaceutical composition as defined herein) in the following amounts, This amount maintains the plasma concentration of rilpivirine in the subject after administration at a level above about 12 ng/ml, preferably ranging from about 12 ng/ml to about 100 ng/ml, more preferably It is about 12 ng/ml to about 50 ng/ml for at least three months, or at least 6 months, or at least 9 months, or at least 1 year, or for at least 2 years after each administration. In a preferred embodiment of the first aspect of the present invention, rilpivirine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is such that the plasma concentration of rilpivirine in the subject is maintained from 12 ng Use at levels of /ml to 100 ng/ml for at least 6 months.

In a specific embodiment of the first aspect of the invention, rilpivirine or a pharmaceutically acceptable salt thereof is formulated into microparticles or nanoparticles in suspension and administered, wherein the formulation comprises the following group Minute: rilpivirine or a pharmaceutically acceptable salt thereof, in particular rilpivirine; A surface modifier as defined herein, in particular Poloxamer 338; isotonicity agents, especially glucose monohydrate; Buffers, especially sodium dihydrogen phosphate; Chelating agents, especially citric acid monohydrate; pH adjusters, in particular sodium hydroxide; and Water, especially water for injection.

In another specific embodiment of the first aspect of the present invention, rilpivirine or a pharmaceutically acceptable salt thereof is formulated into microparticles or nanoparticles in suspension and administered, 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, especially water for injection.

In one embodiment of the first and ninth aspects of the present invention, the aqueous suspension may comprise by weight, based on the total volume of the suspension: (a) 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 Accepted salts; 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) surface modifier; in particular poise Losham 338; (c) from 0% to 10% (w/v), or from 0% to 5% (w/v), or from 0% to 2% (w/v), or from 0% to 1% (w/v) /v) one or more buffers; in particular sodium dihydrogen phosphate; (d) from 0% to 10% (w/v), or from 0% to 6% (w/v), or from 0% to 5% (w/v), or from 0% to 3% (w/v) /v), or an isotonicity agent from 0% to 2% (w/v); in particular glucose monohydrate; (e) from 0% to 2% (w/v), or from 0% to 1% (w/v), or from 0% to 0.5% (w/v), or from 0% to 0.1% (w/v) /v) pH regulator; in particular sodium hydroxide; (f) from 0% to 2% (w/v), or from 0% to 1% (w/v), or from 0% to 0.5% (w/v), or from 0% to 0.1% (w/v) /v) chelating agents; in particular citric acid monohydrate; (g) from 0% to 2% (w/v) of preservatives; and (h) Water for injection, add appropriate amount to 100%.

In one embodiment of the first and ninth aspects of the present invention, the aqueous suspension may comprise by weight, based on the total volume of the suspension: (a) 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 Accepted salts; 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) surface modifier; in particular poise Losham 338; (c) from 0% to 10% (w/v), or from 0% to 5% (w/v), or from 0% to 2% (w/v), or from 0% to 1% (w/v) /v) one or more buffers; in particular sodium dihydrogen phosphate; (d) from 0% to 10% (w/v), or from 0% to 6% (w/v), or from 0% to 5% (w/v), or from 0% to 3% (w/v) /v), or an isotonicity agent from 0% to 2% (w/v); in particular glucose monohydrate; (e) from 0% to 2% (w/v), or from 0% to 1% (w/v), or from 0% to 0.5% (w/v), or from 0% to 0.1% (w/v) /v) pH regulator; in particular sodium hydroxide; (f) from 0% to 2% (w/v), or from 0% to 1% (w/v), or from 0% to 0.5% (w/v), or from 0% to 0.1% (w/v) /v) chelating agents; in particular citric acid monohydrate; and (g) Water for injection, add appropriate amount to 100%.

In a specific embodiment of the first aspect of the invention, rilpivirine or a pharmaceutically acceptable salt thereof is formulated into a suspension of micro- or nanoparticles (and administered), wherein the suspension is as follows The amount contains the following components: (a) rilpivirine (300 mg); (b) Poloxamer 338 (50 mg); and (c) Water for injection (add to 1 ml).

Alternatively, the components can be used in different amounts, but the weight ratios between the components are the same, and the total volume (consisting of water for injection) is scaled by the same value.

In a specific embodiment of the first aspect of the invention, rilpivirine or a pharmaceutically acceptable salt thereof is formulated into a suspension of micro- or nanoparticles (and administered), wherein the suspension is as follows The amount contains the following components: a. Rilpivirine (300 mg); b. Poloxamer 338 (50 mg); c. Glucose monohydrate (19.25 mg); d. Sodium dihydrogen phosphate (2.00 mg); e. Citric acid monohydrate (1.00 mg); f. Sodium hydroxide (0.866 mg); and g. Water for injection (add to 1 ml).

Alternatively, the components can be used in different amounts, but the weight ratios between the components are the same, and the total volume (consisting of water for injection) is scaled by the same value.

In one embodiment of the first aspect of the invention, the suspension of rilpivirine or a pharmaceutically acceptable salt thereof as described herein is administered by manual injection method.

In one embodiment of the ninth aspect of the present invention, the amount of rilpivirine or a pharmaceutically acceptable salt thereof in the suspension or pharmaceutical composition of the present invention is from about 900 mg to about 28800 mg (eg from about 900 mg to about 14400 mg, or from about 900 mg to about 7200 mg, or from about 900 mg to about 3600 mg), preferably from about 1200 mg to about 14400 mg, preferably from about 1350 mg to about 13200 mg, preferably from about 1500 mg to about 12000 mg (eg from about 3000 mg to about 12000 mg), preferably from about 1800 mg to about 10800 mg (eg from about 2700 mg to about 10800 mg) , or from about 1800 mg to about 3600 mg), most preferably from about 1800 mg to about 7200 mg, or from about 2700 mg to about 4500 mg. The "mg" shown corresponds to mg of rilpivirine (ie, rilpivirine in its free base form). Thus, for example, 1 mg of rilpivirine (ie, rilpivirine in its free base form) corresponds to 1.1 mg of rilpivirine hydrochloride.

In one embodiment, the suspension of the ninth aspect of the invention is formulated for administration by subcutaneous or intramuscular injection. In a preferred embodiment of the ninth aspect of the present invention, the suspension of the present invention is formulated for administration by subcutaneous injection.

In a specific embodiment, rilpivirine or a pharmaceutically acceptable salt thereof of the ninth aspect of the present invention is formulated in a formulation comprising: rilpivirine or a pharmaceutically acceptable salt thereof, in particular rilpivirine, in suspension as defined herein; A surface modifier as defined herein, in particular Poloxamer 338; isotonicity agents, especially glucose monohydrate; Buffers, especially sodium dihydrogen phosphate; Chelating agents, especially citric acid monohydrate; pH adjusters, in particular sodium hydroxide; and Water, especially water for injection.

In a specific embodiment, rilpivirine or a pharmaceutically acceptable salt thereof of the ninth aspect of the present invention is formulated in a formulation comprising: rilpivirine or a pharmaceutically acceptable salt thereof, in particular rilpivirine, in suspension as defined herein; Poloxamer 338; Glucose monohydrate; Sodium dihydrogen phosphate; Citric acid monohydrate; sodium hydroxide; and Water, especially water for injection.

In a specific embodiment of the ninth aspect of the invention, rilpivirine or a pharmaceutically acceptable salt thereof is formulated as a suspension of microparticles or nanoparticles, wherein the suspension comprises the following groups in the following amounts Minute: (a) rilpivirine (300 mg); (b) Poloxamer 338 (50 mg); and (c) Water for injection (add to 1 ml). Alternatively, the components can be used in different amounts, but the weight ratios between the components are the same, and the total volume (consisting of water for injection) is scaled by the same value.

In a specific embodiment, rilpivirine or a pharmaceutically acceptable salt thereof of the ninth aspect of the invention is formulated in a formulation comprising the following components in the following amounts: (a) rilpivirine (300 mg) as defined herein in the form of microparticles or nanoparticles in suspension; (b) Poloxamer 338 (50 mg); (c) Glucose monohydrate (19.25 mg); (d) sodium dihydrogen phosphate (2.00 mg); (e) citric acid monohydrate (1.00 mg); (f) sodium hydroxide (0.866 mg); and (g) Water for injection (add to 1 ml).

Alternatively, the components can be used in different amounts, but the weight ratios between the components are the same, and the total volume (consisting of water for injection) is scaled by the same value.

For the avoidance of doubt, each of the embodiments described in this section in relation to the first aspect of the present invention is equally applicable to the second to eighth aspects of the present invention (ie, each of the embodiments is also applicable to the second to eighth aspects of the present invention). The eighth aspect is disclosed in combination). In addition, each of the embodiments described in this section in relation to the ninth aspect of the present invention is equally applicable to the tenth to thirteenth aspects of the present invention (ie, each of the embodiments is also applicable to the tenth to thirteenth aspects of the present invention). Thirteen aspects are disclosed in combination). Hyaluronidase

Hyaluronidase is an enzyme that degrades hyaluronic acid (HA) and reduces the viscosity of hyaluronan in the extracellular matrix. Due to this property, the hyaluronidase can be used to increase the dispersion and absorption of injected active pharmaceutical ingredients. The enzymatic activity of hyaluronidases, including rHuPH20, can be defined by units per mL (U/mL) or total enzymatic activity (U) in a particular formulation.

It is generally known that delivery of hyaluronidase (E.C. 3.2.1.35/36) into tissue can improve drug permeability. Thus, administration of hyaluronidase represents a means of increasing drug dispersion and improving drug absorption.

Administration of large volumes of rilpivirine or a pharmaceutically acceptable salt thereof may cause bulges at the injection site. Administration of the hyaluronidase according to the first aspect of the invention together with rilpivirine or a pharmaceutically acceptable salt thereof may result in a reduction in the formation of such bumps.

As used herein, the term "hyaluronidase" means any enzyme that degrades hyaluronic acid and reduces the viscosity of hyaluronan in the extracellular matrix.

In a preferred embodiment of the first aspect of the present invention, the hyaluronidase is a recombinant hyaluronidase. In a particularly preferred embodiment of the first aspect of the present invention, the hyaluronidase is a recombinant human hyaluronidase, such as rHuPH20. In one embodiment of the first aspect of the invention, rHuPH20 is defined by the amino acid sequence available under CAS Registry No. 757971-58-7. More information on rHuPH20 is provided in International Patent Publication No. WO 2004/078140. In one embodiment of the first aspect of the invention, the amino acid sequence of rHuPH20 comprises SEQ ID NO:1. In some embodiments of the first aspect of the invention, the hyaluronidase is a variant of rHuPH20, the variant having the amino acid sequence of rHuPH20 comprising SEQ ID NO: 2, i.e. the wild-type human hyaluronidase Residues 36-482. In some embodiments of the first aspect of the invention, the hyaluronidase is a variant of rHuPH20, the variant having an amino acid sequence comprising SEQ ID NO:3. In some embodiments of the first aspect of the invention, the hyaluronidase is a variant of rHuPH20, the variant having an amino acid sequence comprising SEQ ID NO:4. In some embodiments of the first aspect of the invention, the hyaluronidase is a variant of rHuPH20, the variant having an amino acid sequence comprising SEQ ID NO:5. SEQ ID NO: 1: rHuPH20 LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRIN ATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDKAK KDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNRSIEL VQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRPNHLW GYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLWNESTALY PSIYLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPLPVFAYTRIV FTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLSIMRSMKSCLL LDNYMETILNPYIINVTLAAKMCSQVLCQEQGVCIRKNWNSSDYL HLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCK EKADVKDTDAVDVCIADGVCIDAFLKPPMETEEP SEQ ID NO: 2: rHuPH20 variant 1 LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRIN ATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDKAK KDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNRSIEL VQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRPNHLW GYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLWNESTALY PSIYLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPLPVFAYTRIV FTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLSIMRSMKSCLL LDNYMETILNPYIINVTLAAKMCSQVLCQEQGVCIRKNWNSSDYL HLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCK EKADVKDTDAVDVCIADGVCIDAFLKPPMETEEPQIFY SEQ ID NO: 3: rHuPH20 variant 2 LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRIN ATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDKAK KDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNRSIEL VQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRPNHLW GYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLWNESTALY PSIYLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPLPVFAYTRIV FTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLSIMRSMKSCLL LDNYMETILNPYIINVTLAAKMCSQVLCQEQGVCIRKNWNSSDYL HLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCK EKADVKDTDAVDVCIADGVCIDAFLKPPMETEEPQIF SEQ ID NO: 4: rHuPH20 variant 3 LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRIN ATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDKAK KDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNRSIEL VQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRPNHLW GYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLWNESTALY PSIYLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPLPVFAYTRIV FTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLSIMRSMKSCLL LDNYMETILNPYIINVTLAAKMCSQVLCQEQGVCIRKNWNSSDYL HLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCK EKADVKDTDAVDVCIADGVCIDAFLKPPMETEEPQI SEQ ID NO: 5: rHuPH20 variant 4 LNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRIN ATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDKAK KDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNRSIEL VQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRPNHLW GYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLWNESTALY PSIYLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPLPVFAYTRIV FTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLSIMRSMKSCLL LDNYMETILNPYIINVTLAAKMCSQVLCQEQGVCIRKNWNSSDYL HLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCK EKADVKDTDAVDVCIADGVCIDAFLKPPMETEEPQ

In one embodiment of the first aspect of the invention, the hyaluronidase of the invention is formulated in a separate pharmaceutical composition. As discussed further herein (e.g., rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase in the first to eighth aspects of the invention and the ninth to thirteenth aspects of the invention Use of rilpivirine or a pharmaceutically acceptable salt thereof in the aspect"), the separate pharmaceutical composition may be sequentially combined with a pharmaceutical composition comprising rilpivirine or a pharmaceutically acceptable salt thereof Administration, or the separate pharmaceutical composition may be admixed extemporaneously with a pharmaceutical composition comprising rilpivirine or a pharmaceutically acceptable salt thereof, followed by administration of the resulting mixed pharmaceutical composition.

In another embodiment, the hyaluronidase of the first aspect of the invention is formulated in the same pharmaceutical composition as rilpivirine or a pharmaceutically acceptable salt thereof, ie the hyaluronidase is formulated A combined pharmaceutical composition (with rilpivirine or a pharmaceutically acceptable salt thereof) is made.

In one embodiment of the first aspect of the invention, the hyaluronidase is in the form of a solution, preferably wherein the concentration of the hyaluronidase in the solution is from about 50 to about 20,000 U/mL, preferably It is about 50 to about 10,000 U/mL, from about 50 to about 5000 U/mL, from about 500 to about 2000 U/mL. In one embodiment of the first aspect of the invention, the hyaluronidase is in the form of a solution, preferably wherein the concentration of the hyaluronidase in the solution is about 500 U/mL. In one embodiment of the first aspect of the invention, the hyaluronidase is in the form of a solution, preferably wherein the concentration of the hyaluronidase in the solution is about 750 U/mL. In one embodiment of the first aspect of the invention, the hyaluronidase is in the form of a solution, preferably wherein the concentration of the hyaluronidase in the solution is about 1000 U/mL. In one embodiment of the first aspect of the invention, the hyaluronidase is in the form of a solution, preferably wherein the concentration of the hyaluronidase in the solution is about 1250 U/mL. In one embodiment of the first aspect of the invention, the hyaluronidase is in the form of a solution, preferably wherein the concentration of the hyaluronidase in the solution is about 1500 U/mL. In one embodiment of the first aspect of the invention, the hyaluronidase is in the form of a solution, preferably wherein the concentration of the hyaluronidase in the solution is about 1750 U/mL. In one embodiment of the first aspect of the invention, the hyaluronidase is in the form of a solution, preferably wherein the concentration of the hyaluronidase in the solution is about 2000 U/mL.

In some embodiments of the first aspect of the invention, the hyaluronidase-containing composition comprises the following doses of hyaluronidase: about 1,000 U, 2,000 U, 3,000 U, 4,000 U, about 5,000 U, about 6,000 U , approximately 7,000 U, approximately 8,000 U, approximately 9,000 U, approximately 10,000 U, approximately 11,000 U, approximately 12,000 U, approximately 13,000 U, approximately 14,000 U, approximately 15,000 U, approximately 16,000 U, approximately 17,000 U, approximately 18,000 U, approximately 19,000 U, approximately 20,000 U, approximately 21,000 U, approximately 22,000 U, approximately 23,000 U, approximately 24,000 U, approximately 25,000 U, approximately 26,000 U, approximately 27,000 U, approximately 30,000 U, approximately 31,000 U, approximately 32,000 U, approximately 33,000 U , about 34,000 U, about 35,000 U, about 36,000 U, about 37,000 U, about 38,000 U, about 39,000 U, about 40,000 U, or any value in between. In some embodiments of the first aspect of the invention, wherein the hyaluronidase is administered sequentially with a pharmaceutical composition comprising rilpivirine or a pharmaceutically acceptable salt thereof, the hyaluronidase-containing composition comprises the following Dosage of hyaluronidase: about 1,000 U, 2,000 U, 3,000 U, 4,000 U, about 5,000 U, about 6,000 U, about 7,000 U, about 8,000 U, about 9,000 U, about 10,000 U, or any value in between. In a preferred embodiment of the first aspect of the present invention, the hyaluronidase-containing composition comprises a dose of about 2,000 U of hyaluronidase. In some embodiments of the first aspect of the invention, wherein the hyaluronidase is admixed extemporaneously with a pharmaceutical composition comprising rilpivirine or a pharmaceutically acceptable salt thereof, followed by administration of the resulting mixed pharmaceutical composition, The mixed composition comprises the following doses of hyaluronidase: about 11,000 U, about 12,000 U, about 13,000 U, about 14,000 U, about 15,000 U, about 16,000 U, about 17,000 U, about 18,000 U, about 19,000 U, About 20,000 U, about 21,000 U, about 22,000 U, about 23,000 U, about 24,000 U, about 25,000 U, about 26,000 U, about 27,000 U, about 30,000 U, about 31,000 U, about 32,000 U, about 33,000 U, about 34,000 U, about 35,000 U, about 36,000 U, about 37,000 U, about 38,000 U, about 39,000 U, about 40,000 U, or any value in between. In a preferred embodiment of the first aspect of the present invention, the mixed composition comprises a dose of about 18,000 U or 30,000 U of hyaluronidase.

In a specific embodiment of the first aspect of the present invention, the hyaluronidase is formulated as a solution of a separate pharmaceutical composition, i.e., as a solution without rilpivirine or a pharmaceutically acceptable salt thereof, And the separate pharmaceutical composition comprises the following components: rHuPH20 from about 50 U/mL to about 10,000 U/mL; from about 5 mM to about 50 mM histidine; from about 50 mM to about 400 mM sorbitol; from about 0.1 mg/mL to about 2.5 mg/mL methionine; and From about 0.01% (w/v) to about 0.1% (w/v) polysorbate 20 buffer.

For the avoidance of doubt, each of the embodiments described in this section in relation to the first aspect of the present invention is equally applicable to the second to eighth aspects of the present invention (ie, each of the embodiments is also applicable to the second to eighth aspects of the present invention). The eighth aspect is disclosed in combination). Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase in the first to eighth aspects of the present invention and rilpivirine or a pharmaceutically acceptable salt thereof in the ninth to thirteenth aspects of the present invention Accepted uses of salt

In a first aspect of the present invention there is provided a method for treating or preventing HIV infection in a subject in need thereof, the method comprising administering to the subject by intramuscular injection or subcutaneous injection a therapeutically effective amount of a Rilpivirine or a pharmaceutically acceptable salt thereof in microparticle or nanoparticle form in suspension, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered by intramuscular or subcutaneous injection. The hyaluronidase is administered in combination, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years.

Accordingly, the methods for treatment or prevention of the first aspect of the invention described herein relate to multiple administrations of rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase, and administration of rilpivirine or a pharmaceutically acceptable salt thereof The time interval between the above acceptable salt and hyaluronidase and subsequent administration of rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase is about three months to about two years, i.e. Said subject is administered rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase according to the first aspect of the invention, and then re-applied to as described herein after a period of three months to two years. A defined subject is administered rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase according to the present invention.

In an eleventh aspect of the present invention, there is provided rilpivirine or a pharmaceutically acceptable salt thereof (that is, in the form of microparticles or nanoparticles in suspension) according to the ninth aspect of the present invention, using For use in the treatment or prevention of HIV infection in a subject, wherein the microparticles or nanoparticles have a D _v 90 of from about 1 μm to about 10 μm.

As used herein, the term "is/are administered" in relation to a method for treatment or prevention and the uses described herein may encompass the term "is/are to be administered," respectively.

In a preferred embodiment of the first or eleventh aspect of the present invention, the subject is a human.

Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase of the first aspect of the invention may be administered simultaneously or sequentially. In one embodiment of the first aspect of the invention, rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase are administered sequentially, ie one after the other, preferably within 24 hours of each other, Preferably within 1 hour of each other, preferably within 30 minutes of each other, preferably within 10 minutes of each other, more preferably within 5 minutes of each other. Preferably, the hyaluronidase is administered prior to the administration of rilpivirine or a pharmaceutically acceptable salt thereof. In another embodiment of the first aspect of the invention, rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase are administered simultaneously.

When rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase of the first aspect of the invention are administered sequentially, they are formulated in separate pharmaceutical compositions. These individual pharmaceutical compositions are further described herein in the sections entitled "Rilpivirine" and "Hyaluronidase".

When rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase of the first aspect of the invention are administered sequentially, they are all administered by the same method, ie subcutaneous or intramuscular injection. Furthermore, they are all administered at the same site. The same site means that the injection sites are within 15 cm of each other, within 12 cm of each other, or within 8 cm of each other. Preferably, the injection sites are within 10 cm of each other, more preferably within 5 cm of each other, even more preferably within 1 cm of each other. This allows hyaluronidase to exert its role in increasing the injection tolerance of rilpivirine or a pharmaceutically acceptable salt thereof.

When rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase of the first aspect of the invention are administered simultaneously, they are both administered simultaneously at the same site, ie via the same syringe/needle. When rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase of the first aspect of the present invention are administered simultaneously, the rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase may Provided in a combined pharmaceutical composition (ie, a pharmaceutical composition comprising both the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase). The pharmaceutical composition of the combination is further described herein in the sections entitled "Rilpivirine" and "Hyaluronidase". When rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase of the first aspect of the present invention are administered simultaneously, the rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase also It may be provided as separate pharmaceutical compositions which are mixed (ie, the mixed pharmaceutical formulation is provided extemporaneously prior to administration).

The combined pharmaceutical composition of the first aspect of the invention is surprisingly stable on storage (ie hyaluronidase is active even in temporary combination with rilpivirine or a pharmaceutically acceptable salt thereof prior to administration), eg, Store at room temperature for at least 4 hours, or 24 hours or longer, especially when stored at 2-8°C.

In one embodiment, the rilpivirine of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, and Hyaluronidase.

Rilpivirine, or a pharmaceutically acceptable salt thereof, and hyaluronidase of the first aspect of the invention are administered such that the time interval between administrations (ie, the dosing interval) is from about three months to about two years. That is, administering (eg, simultaneously or sequentially) rilpivirine, or a pharmaceutically acceptable salt thereof, and hyaluronidase, and then after an interval of about three months to about one year, administering again (eg, simultaneously) or sequentially) rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase.

It has been found that when administered by intramuscular or subcutaneous injection in the form of microparticles or nanoparticles in suspension, rilpivirine of the first aspect of the invention or a pharmaceutically acceptable thereof is administered as defined herein Prolonged, sustained, or long-term release of rilpivirine can be maintained in the presence of salts and hyaluronidase. This unexpected effect is discussed in detail in Examples 1 and 2.

In one embodiment, the treatment or prevention of the eleventh aspect of the present invention involves multiple (ie intermittent) administration of rilpivirine or a pharmaceutically acceptable salt thereof, and administration of rilpivirine or a pharmaceutically acceptable salt thereof The time interval between receipt of the salt and subsequent administration of rilpivirine or a pharmaceutically acceptable salt thereof (ie, the dosing interval) is from about three months to about two years, ie administration to a subject as described herein Rilpivirine or a pharmaceutically acceptable salt thereof according to the eleventh aspect of the present invention is then administered again to a subject as defined herein after a period of from about three months to about two years The rilpivirine or a pharmaceutically acceptable salt thereof according to the eleventh aspect of the present invention.

In one embodiment of the first and eleventh aspects of the invention, the time interval described herein is about 1.5 years. In one embodiment of the first and eleventh aspects of the invention, the time interval described herein is about two years. In a preferred embodiment of the first and eleventh aspects of the present invention, the time interval described herein is from about three months to about 1.5 years. In another preferred embodiment of the first and eleventh aspects of the present invention, the time interval described herein is from about three months to about one year. In another preferred embodiment of the first and eleventh aspects of the present invention, the time interval described herein is from about three months to about six months. In another preferred embodiment of the first and eleventh aspects of the present invention, the time interval described herein is from about six months to about one year. In another preferred embodiment of the first and eleventh aspects of the present invention, the time interval described herein is about three months. In another preferred embodiment of the first and eleventh aspects of the present invention, the time interval described herein is about six months. In another preferred embodiment of the first and eleventh aspects of the present invention, the time interval described herein is about 1 year.

Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase of the first aspect of the invention are administered by subcutaneous injection or intramuscular injection. Preferably, the rilpivirine and hyaluronidase of the first aspect of the invention are administered by subcutaneous injection (either via the same combined pharmaceutical composition or via separate pharmaceutical compositions).

In one embodiment of the eleventh aspect of the present invention, rilpivirine or a pharmaceutically acceptable salt thereof is administered by subcutaneous injection or intramuscular injection. Preferably, rilpivirine or a pharmaceutically acceptable salt thereof is administered by subcutaneous injection.

In one embodiment of the eleventh aspect of the present invention, rilpivirine or a pharmaceutically acceptable salt thereof is administered by a manual injection method.

Use of rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase of the first aspect of the present invention and rilpivirine or a pharmaceutically acceptable salt thereof of the eleventh aspect of the present invention for treatment or In a method of preventing HIV infection in a subject, i.e. adding rilpivirine or a pharmaceutically acceptable salt thereof of the first aspect of the invention as defined herein and a hyaluronidase and the invention as defined herein The rilpivirine of the eleventh aspect or a pharmaceutically acceptable salt thereof is for use in the treatment or prevention of HIV infection. Rilpivirine or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount. A "therapeutically effective amount" means an amount sufficient to provide a therapeutic effect.

In a specific embodiment, the rilpivirine or a pharmaceutically acceptable salt thereof used in the first aspect of the invention is rilpivirine, and the rilpivirine and hyaluronidase are used in therapy In the method of HIV infection in a subject in need thereof as described herein, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which the suspension is suspended in the form of microparticles or nanoparticles rilpivirine, and wherein the rilpivirine and hyaluronidase are administered by subcutaneous injection, preferably wherein the microparticles or nanoparticles have an average effective particle size of from about 100 nm to about 300 nm nm, and preferably where a surface modifier (eg, Poloxamer 338) is adsorbed to the surface of the microparticles or nanoparticles.

In a specific embodiment, the rilpivirine or a pharmaceutically acceptable salt thereof used in the first aspect of the invention is rilpivirine, and the rilpivirine and hyaluronidase are used in therapy In the method of HIV infection in a subject in need thereof as described herein, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which the suspension is suspended in the form of microparticles or nanoparticles rilpivirine, and wherein the rilpivirine and hyaluronidase are administered by subcutaneous injection, preferably wherein the microparticles or nanoparticles have a _Dv ranging from about 0.2 µm to about 3 µm 50 or have a _Dv 50 as described herein, and preferably wherein a surface modifier (eg, Poloxamer 338) is adsorbed to the surface of the microparticles or nanoparticles.

In a specific embodiment, the rilpivirine or a pharmaceutically acceptable salt thereof used in the first aspect of the invention is rilpivirine, and the rilpivirine and hyaluronidase are used in therapy In the method of HIV infection in a subject in need thereof as described herein, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which is suspended in the form of microparticles or nanoparticles rilpivirine, and wherein the rilpivirine and hyaluronidase are administered by subcutaneous injection, preferably wherein the microparticles or nanoparticles have a _Dv90 ranging from about 1 µm to about 10 µm Or have a _Dv 90 as described herein, and preferably wherein a surface modifier (eg, Poloxamer 338) is adsorbed to the surface of the microparticles or nanoparticles.

In a specific embodiment, the rilpivirine or a pharmaceutically acceptable salt thereof used in the eleventh aspect of the present invention is rilpivirine, and the rilpivirine is used in therapy as described herein A method for HIV infection in a subject in need thereof, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which rilpivir is suspended in the form of microparticles or nanoparticles Lin, and wherein the _rilpivirine is administered by subcutaneous injection, preferably wherein the microparticles or nanoparticles have a Dv50 ranging from about 0.2 μm to about 3 μm and from about 1 μm to about 10 A combination of D _v 90 in the µm range or with a combination of D _v 50 and D _v 90 as described herein, and preferably wherein a surface modifier (eg poloxamer 338) is adsorbed to the microparticles or the surface of nanoparticles.

In a specific embodiment, the rilpivirine of the eleventh aspect of the present invention or a pharmaceutically acceptable salt thereof is rilpivirine, and the rilpivirine is used in the presence of Treatment of HIV infection in a subject in need thereof, wherein a suspension comprises a pharmaceutically acceptable aqueous carrier in which rilpivirine in the form of microparticles or nanoparticles is suspended, and the like The microparticle or nanoparticle has a D _v 90 of from about 1 µm to about 7 µm, and wherein the rilpivirine is administered by subcutaneous injection, preferably wherein a surface modifier (eg, poloxamer 338) adsorbed to the surface of these microparticles or nanoparticles.

In one embodiment, rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase according to the first aspect of the present invention and rilpivirine or a pharmaceutically acceptable salt thereof according to the eleventh aspect of the present invention are combined A salt of rilpivirine for use in a method of treating or preventing HIV type 1 (HIV-1) infection in a subject, i.e., rilpivirine or a pharmaceutically acceptable form thereof of one embodiment described herein in relation to the first aspect of the present invention. Accepted salts and hyaluronidase and rilpivirine or a pharmaceutically acceptable salt thereof according to the eleventh aspect of the invention as defined herein for use in the treatment or prevention of HIV type 1 (HIV-1 ) infection use.

In one embodiment of the eleventh aspect of the present invention, each administration comprises up to about 600 mL of the suspension described herein, ie the volume of the suspension comprising rilpivirine or a pharmaceutically acceptable salt thereof may be Available in volumes up to 600 mL. In one embodiment of the eleventh aspect of the invention, each administration comprises from about 5 mL to about 600 mL of the suspension. In another embodiment of the eleventh aspect of the present invention, each administration comprises from about 5 mL to about 300 mL of the suspension. In another embodiment of the eleventh aspect of the present invention, each administration comprises from about 5 mL to about 150 mL of the suspension. In another embodiment of the eleventh aspect of the invention, each administration comprises from about 5 mL to about 25 mL of the suspension. In another embodiment of the eleventh aspect of the present invention, each administration comprises from about 6 mL to about 20 mL of the suspension. In another embodiment of the eleventh aspect of the present invention, each administration comprises from about 6 mL to about 18 mL of the suspension. In another embodiment of the eleventh aspect of the present invention, each administration comprises from about 6 mL to about 15 mL of the suspension. In another embodiment of the eleventh aspect of the invention, each administration comprises from about 6 mL to about 12 mL of the suspension. In another embodiment of the eleventh aspect of the invention, each administration comprises from about 9 mL to about 18 mL of the suspension. In another embodiment of the eleventh aspect of the present invention, each administration comprises from about 9 mL to about 15 mL of the suspension. In another embodiment of the eleventh aspect of the invention, each administration comprises from about 9 mL to about 12 mL of the suspension. In another embodiment of the eleventh aspect of the invention, each administration comprises about 6 mL of the suspension. In another embodiment of the eleventh aspect of the present invention, each administration comprises about 9 mL of the suspension. In another embodiment of the eleventh aspect of the present invention, each administration comprises about 12 mL of the suspension. In another embodiment of the eleventh aspect of the present invention, each administration comprises about 15 mL of the suspension. In another embodiment of the eleventh aspect of the present invention, each administration comprises about 18 mL of the suspension. In one embodiment of the eleventh aspect of the present invention, the rilpivirine suspension contains 300 mg rilpivirine/mL.

In one embodiment of the eleventh aspect of the present invention, for the treatment of HIV infection, it may be based on about 300 mg to about 1200 mg/month, or about 450 mg to about 1200 mg/month, or about 450 mg to about 900 mg/month mg/month, or about 450 mg to about 750 mg/month, or about 600 mg to about 900 mg/month, or 450 mg/month, or 600 mg/month, or 750 mg/month, or 900 mg/month calculated the dose to be administered. Dosages for other dosing regimens can be easily calculated by multiplying the monthly dose by the number of months between each administration. For example, if the dose is 450 mg/month, and if the time interval between each administration is 6 months, the dose to be administered in each administration is 2700 mg. Or for example, if the dose is 750 mg/month, and if the time interval between each administration is 6 months, the dose to be administered in each administration is 4500 mg. The "mg" shown corresponds to mg of rilpivirine (ie, rilpivirine in its free base form). Thus, for example, 1 mg of rilpivirine (ie, rilpivirine in its free base form) corresponds to 1.1 mg of rilpivirine hydrochloride.

In one embodiment of the eleventh aspect of the present invention, for the treatment of HIV infection, it may be based on about 300 mg to about 1200 mg/4 weeks (28 days), or about 450 mg to about 1200 mg/4 weeks (28 days) days), or about 450 mg to about 900 mg/4 weeks (28 days), or about 450 mg to about 750 mg/4 weeks (28 days), or about 600 mg to about 900 mg/4 weeks (28 days) , or 450 mg/4 weeks (28 days), or 600 mg/4 weeks (28 days), or 750 mg/4 weeks (28 days), or 900 mg/4 weeks (28 days) to calculate the dose to be administered. Dosages for other dosing regimens can be easily calculated by multiplying the weekly or daily dose by the number of weeks between each administration. For example, if the dose is 450 mg/4 weeks (28 days), and if the time interval between each administration is 24 weeks, the dose to be administered in each administration is 2700 mg. Or for example, if the dose is 750 mg/4 weeks (28 days), and if the time interval between each administration is 24 weeks, the dose to be administered in each administration is 4500 mg. The "mg" shown corresponds to mg of rilpivirine (ie, rilpivirine in its free base form). Thus, for example, 1 mg of rilpivirine (ie, rilpivirine in its free base form) corresponds to 1.1 mg of rilpivirine hydrochloride.

In one embodiment of the eleventh aspect of the present invention, for the treatment of HIV infection, each administration of rilpivirine or a pharmaceutically acceptable salt thereof may comprise from about 900 mg to about 28800 mg (eg, from about 900 mg to about 14400 mg, or from about 900 mg to about 7200 mg, or from about 900 mg to about 3600 mg), preferably from about 1200 mg to about 14400 mg, preferably from about 1350 mg to about 13200 mg, preferably from about 1500 mg to about 12000 mg (eg from about 3000 mg to about 12000 mg), preferably from about 1800 mg to about 10800 mg (eg from about 2700 mg to about 10800 mg) , or from about 1800 mg to about 3600 mg), most preferably from about 1800 mg to about 7200 mg, or from about 2700 mg to about 4500 mg of the rilpivirine or a pharmaceutically acceptable salt thereof.

In the case of preventing HIV infection, each administration of rilpivirine or a pharmaceutically acceptable salt thereof according to the eleventh aspect of the present invention may comprise the same administration as described above for therapeutic applications.

In one embodiment of the eleventh aspect of the present invention, rilpivirine or a pharmaceutically acceptable salt thereof is used in an amount such that the plasma concentration of rilpivirine in the subject after administration remains high at a level of 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 three months, or For at least 6 months, or at least 9 months, or at least 1 year, or for at least 2 years after each administration. In a preferred embodiment of the eleventh aspect of the present invention, rilpivirine or a pharmaceutically acceptable salt thereof is such that the plasma concentration of rilpivirine in the subject is maintained from 12 ng/ml to Use at a level of 100 ng/ml for at least 6 months.

As used herein, the term "treating HIV infection" refers to treating a subject infected with HIV. The term "treating HIV infection" also relates to the treatment of diseases associated with HIV infection, such as AIDS; or other conditions associated with HIV infection, including thrombocytopenia, Kaposi's sarcoma, and central nervous system characterized by progressive demyelination infection, which leads to dementia and symptoms such as progressive dysarthria, ataxia, and disorientation; and additional conditions in which HIV infection has been associated with, for example, peripheral neuropathy, progressive generalized lymphadenopathy (PGL), and AIDS Symptoms (ARC) related.

As used herein, the term "preventing HIV infection" refers to preventing or avoiding HIV infection in a subject (uninfected with HIV). The source of infection can be various materials containing HIV, particularly HIV-containing bodily fluids (eg, blood or semen), or another subject infected with HIV. Prevention of HIV infection is about preventing the transmission of the virus from HIV-containing material or from an HIV-infected individual to an uninfected person, or about preventing the virus from entering 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 the blood of an infected subject, such as medical personnel providing care to an infected subject. HIV transfer can also occur through exposure to HIV-infected blood, such as when processing a blood sample or when performing a blood transfusion. It can also be achieved by contact with infected cells, such as when using HIV-infected cells for laboratory experiments.

The term "treatment of HIV infection" refers to treatment that reduces the viral load of HIV (expressed as the number of copies of viral RNA in a defined volume of serum). The more effective the treatment, the lower the viral load. Preferably, the viral load should be reduced to as low a level as possible, for example below 200 copies/ml, particularly below about 100 copies/ml, more particularly below 50 copies/ml, and if possible below The detection limit of the virus. A reduction in viral load of one, two, or even three orders of magnitude (eg, a reduction in the order of about 10 to about 10 ² or greater (eg, about 10 ³ )) is indicative of the effectiveness of the treatment. Another parameter that measures the effectiveness of HIV treatment is the CD4 count, which in normal adults ranges from 500 to 1500 cells/µl. Decreased CD4 counts are indicative of HIV infection, and once below about 200 cells/µl, AIDS may occur. An increase in CD4 count, eg by about 50, 100, 200 or more cells/µl, is also indicative of the effectiveness of anti-HIV therapy. In particular, CD4 counts should increase to levels above about 200 cells/µl, or above about 350 cells/µl. Viral load or CD4 count, or both, can be used to diagnose the extent of HIV infection.

The term "treating HIV infection" and similar terms refers to treatments that reduce viral load, or increase CD4 counts, or both, as described above. The term "preventing HIV infection" and similar terms refers to a situation in which the relative number of newly infected subjects decreases in a population exposed to a source of HIV infection (eg, HIV-containing material, or HIV-infected subjects). Effective prevention can be measured, for example, by measuring in a mixed population of HIV-infected and uninfected individuals, as long as uninfected individuals treated with the pharmaceutical compositions of the invention are compared with untreated uninfected individuals. When compared, the relative number of newly infected individuals decreased. This decrease can be measured by statistical analysis of infected and uninfected individuals over time in a given population.

In a second aspect, there is provided rilpivirine or a pharmaceutically acceptable salt thereof and a hyaluronidase for use in the treatment or prevention of HIV infection in a subject, wherein the rilpivirine or a pharmaceutically acceptable salt thereof The acceptable salts above are in the form of microparticles or nanoparticles in suspension, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronic acid are administered to the subject by intramuscular or subcutaneous injection enzyme, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years.

It should be understood that all embodiments described herein in relation to the first aspect, such as rilpivirine in the first aspect of the invention, hyaluronidase in the invention and rilpivirine in the first aspect of the invention Embodiments relating to the use of hyaluronidase are also applicable to the second aspect of the invention, ie they are also disclosed herein in relation to the second aspect of the invention.

In a third aspect, there is provided a product comprising rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase as a combined preparation for use in the treatment or prevention of HIV by intramuscular or subcutaneous injection Simultaneous or sequential use in infection, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of microparticles or nanoparticles in suspension, and wherein intermittently at intervals of about three months to about two years The rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered.

It should be understood that all embodiments described herein in relation to the first aspect, such as rilpivirine in the first aspect of the invention, hyaluronidase in the invention and rilpivirine in the first aspect of the invention Embodiments relating to the use of hyaluronidase are also applicable to the third aspect of the invention, ie they are also disclosed herein in relation to the third aspect of the invention.

In a fourth aspect, a kit is provided, the kit comprising rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use in intramuscular injection or subcutaneous injection Simultaneous or sequential use in the treatment or prevention of HIV infection, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of microparticles or nanoparticles in suspension, and wherein the The rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at time intervals.

It should be understood that all embodiments described herein in relation to the first aspect, such as rilpivirine in the first aspect of the invention, hyaluronidase in the invention and rilpivirine in the first aspect of the invention Embodiments related to the use of hyaluronidase are also applicable to the fourth aspect of the present invention, ie they are also disclosed herein in relation to the fourth aspect of the present invention.

In a fifth aspect, there is provided rilpivirine or a pharmaceutically acceptable salt thereof in the form of microparticles or nanoparticles in suspension for use in the treatment or prevention of HIV infection by intramuscular or subcutaneous injection use, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered in combination with hyaluronidase administered by intramuscular injection or subcutaneous injection, and wherein intermittently at intervals of about three months to about two years The rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered.

It should be understood that all embodiments described herein in relation to the first aspect, such as rilpivirine in the first aspect of the invention, hyaluronidase in the invention and rilpivirine in the first aspect of the invention Embodiments related to the use of hyaluronidase are also applicable to the fifth aspect of the present invention, ie they are also disclosed herein in relation to the fifth aspect of the present invention.

In a sixth aspect, there is provided the use of rilpivirine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of HIV infection in a subject, wherein the rilpivirine or a pharmaceutically acceptable salt thereof The accepted salt is in the form of microparticles or nanoparticles in suspension and administered in combination with hyaluronidase, wherein the subject is administered the rilpivirine, or a pharmaceutically acceptable thereof, by intramuscular injection or subcutaneous injection and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years.

It should be understood that all embodiments described herein in relation to the first aspect, such as rilpivirine in the first aspect of the invention, hyaluronidase in the first aspect of the invention, and rilpivirine in the invention Embodiments related to the use of hyaluronidase are also applicable to the sixth aspect of the present invention, ie they are also disclosed herein in relation to the sixth aspect of the present invention.

In a seventh aspect, there is provided a combination comprising rilpivirine or a pharmaceutically acceptable salt thereof and a hyaluronidase, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in microscopic form in suspension in particle or nanoparticle form.

It should be understood that all embodiments described herein in relation to the first aspect, eg in relation to rilpivirine in the first aspect of the invention and hyaluronidase in the first aspect of the invention, are equally applicable to the present invention. A seventh aspect of the invention, ie the embodiments are also disclosed herein in relation to the seventh aspect of the invention.

In some embodiments, there is provided a combination of the seventh aspect of the invention for use in the treatment or prevention of HIV infection, wherein intermittently by intramuscular or subcutaneous injection at intervals of about three months to about two years administer the combination.

In an eighth aspect, a kit is provided, the kit comprising rilpivirine or a pharmaceutically acceptable salt thereof and a hyaluronidase, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in suspension in the form of microparticles or nanoparticles in liquid.

It should be understood that all embodiments described herein in relation to the first aspect, eg in relation to the rilpivirine of the first aspect of the invention and the hyaluronidase of the first aspect of the invention, are equally applicable to the present invention The eighth aspect of the invention, ie the embodiments are also disclosed herein in relation to the eighth aspect of the invention.

In a twelfth aspect, there is provided a method for treating or preventing HIV infection in a subject, the method comprising administering to the subject rilpivirine according to the ninth aspect of the present invention or a pharmaceutically acceptable Acceptable salts (ie, in the form of microparticles or nanoparticles in suspension), wherein the microparticles or nanoparticles have a D _v 90 of from about 1 µm to about 10 µm.

It should be understood that all the embodiments described herein related to the eleventh aspect, such as the embodiments related to rilpivirine in the eleventh aspect of the present invention, are also applicable to the twelfth aspect of the present invention, that is, these Embodiments are also disclosed herein in relation to the twelfth aspect of the invention.

In a thirteenth aspect, there is provided rilpivirine or a pharmaceutically acceptable salt thereof (ie in the form of microparticles or nanoparticles in suspension) according to the ninth aspect of the present invention for use in the manufacture of Use of a medicament for the treatment or prevention of HIV infection in a subject, wherein the microparticles or nanoparticles have a D _v 90 of from about 1 μm to about 10 μm.

It should be understood that all the embodiments described herein related to the eleventh aspect, such as the embodiments related to rilpivirine in the eleventh aspect of the present invention, are also applicable to the thirteenth aspect of the present invention, that is, these Embodiments are also disclosed herein in relation to the thirteenth aspect of the invention.

In one embodiment of the first to eighth aspects of the invention, a method or use or combination or product or kit as described herein is combined with one or more other active agents, in particular one or more other antiretroviral agents agents, in particular one or more other antiretroviral agents of another type (eg, antiretroviral agents like INSTIs, eg, cabotevir). In one embodiment of the first to eighth aspects of the invention, as an intramuscular or subcutaneous injection, particularly as an injectable microsuspension or nanosuspension, at intervals of about three months to about two years solution, administer the one or more other antiretroviral agents (eg, cabotevir). In one embodiment of the first to eighth aspects of the invention, as described herein, rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase of the first to eighth aspects of the invention The one or more other antiretroviral agents (eg, cabotevir) are administered at intermittent intervals of, for example, about three months, or about four months, or about five months, or about six months , or about seven months, or about eight months, or about ten months, or about eleven months, or about one year, or about one year to about 2 years. Intermittent administration of rilpivirine or Pharmaceutically acceptable salts thereof, hyaluronidase and other antiretroviral agents. In one embodiment of the first to eighth aspects of the present invention, rilpivirine, or a pharmaceutically acceptable salt thereof, hyaluronic acid, is administered simultaneously or sequentially by intramuscular or subcutaneous injection, in particular subcutaneous injection acidase and one or more other antiretroviral agents (eg, cabotevir). In one embodiment of the first to eighth aspects of the present invention, rilpivirine or a pharmaceutically acceptable salt thereof, hyaluronidase and one or more other antistresses are administered simultaneously, particularly by subcutaneous injection Transcriptoviral agents (eg, cabotevir). In one embodiment of the first to eighth aspects of the present invention, rilpivirine or a pharmaceutically acceptable salt thereof, hyaluronidase and one or more other antistresses are administered sequentially, particularly by subcutaneous injection Transcriptoviral agents (eg, cabotevir). In one embodiment of the first to eighth aspects of the present invention, hyaluronidase is administered first, followed by rilpivirine or a pharmaceutically acceptable salt thereof, and then cabotevir injection. In one embodiment of the first to eighth aspects of the present invention, hyaluronidase is administered first, followed by cabotevir injection, and then rilpivirine or a pharmaceutically acceptable salt thereof.

In one embodiment of the eleventh to thirteenth aspects of the invention, the treatment/prophylaxis of the invention is combined with one or more other active agents, in particular one or more other antiretroviral agents, in particular another type of One or more other antiretroviral agents (eg, antiretrovirals like INSTIs, eg, cabotevir) are used in combination. In one embodiment of the eleventh to thirteenth aspects of the invention, at intervals of about three months to about two years, as an intramuscular or subcutaneous injection, particularly as an injectable microsuspension or nanosuspension rice suspension, administering the one or more other antiretroviral agents (eg, cabotevir). In one embodiment of the eleventh to thirteenth aspects of the present invention, the one or more other other An antiretroviral agent (eg, cabotevir), for example, for about three months, or about four months, or about five months, or about six months, or about seven months, or about eight months , or about ten months, or about eleven months, or about one year, or about one year to about 2 years, intermittently administering rilpivirine or a pharmaceutically acceptable salt thereof and other antiretroviral viral agent. In one embodiment of the eleventh to thirteenth aspects of the present invention, rilpivirine or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially by intramuscular or subcutaneous injection, particularly subcutaneous injection One or more other antiretroviral agents (such as cabotevir). In one embodiment of the eleventh to thirteenth aspects of the invention, rilpivirine, or a pharmaceutically acceptable salt thereof, and one or more other antiretroviral agents are administered concurrently, particularly by subcutaneous injection (eg Cabotvir). In one embodiment of the eleventh to thirteenth aspects of the invention, rilpivirine or a pharmaceutically acceptable salt thereof and one or more other antiretroviral agents are administered sequentially, particularly by subcutaneous injection (eg Cabotvir). In one embodiment of the eleventh to thirteenth aspects of the present invention, rilpivirine or a pharmaceutically acceptable salt thereof is administered first, followed by cabotevir injection. In one embodiment of the eleventh to thirteenth aspects of the present invention, cabotevir injection is administered first, followed by rilpivirine or a pharmaceutically acceptable salt thereof.

For the avoidance of doubt, the pharmaceutical composition according to the tenth aspect of the present invention can also be used in the treatment or prevention according to the eleventh to thirteenth aspects of the present invention. common definition

The term "comprising" encompasses "including" as well as "consisting," eg, a composition "comprising" X may consist of X only, or may include something else, such as X+Y. The term "comprising" as used herein also encompasses "consisting essentially of", eg, a composition "comprising" X may consist of X and any other that does not substantially affect the essential characteristics of the composition component composition.

The term "about" in relation to a numerical value Y is optional and means, for example, Y ± 10%.

When a time interval is expressed as a specified number of months, it is from the given numbered day of the given month to the same numbered day of the month after the specified number of months. In the case where the same numbered day does not exist in the month after the specified number of months, the interval will run to the next month for the same number of days as if the same numbered day exists in the month after the specified number of months.

When an interval is expressed as a number of years, it is from the given date in the given year to the same date in the year after the specified number of years. In the case where the same day does not exist in the year following the specified number of years, the interval runs for the same number of days as if the same numbered day exists in the month following the specified number of months. In other words, if a time interval starts on February 29 in a given year, but ends in a year without February 29, the time period ends on March 1 of that year.

The term "about" in relation to this definition means that a time interval may end on a date ± 10% of the time interval.

In one embodiment, a time interval may begin up to 7 days before or after the time interval begins and end up to 7 days before or after the time interval ends.

All references cited herein are incorporated by reference in their entirety.

The invention will now be described with reference to the following examples. For the avoidance of doubt, these examples do not limit the scope of the invention. Modifications may be made while remaining within the scope and spirit of the invention. EXAMPLES Example 1 - Administration of rilpivirine with hyaluronidase

This example compares the plasma kinetics following administration of a suspension of rilpivirine with the plasma kinetics following administration of a hyaluronidase solution followed by a suspension of rilpivirine sequentially. Preparation of rilpivirine and hyaluronidase composition (a) Suspension of rilpivirine

A 3.380 mL total suspension of 300 mg/mL rilpivirine (D _v 50 = about 200 nm) was prepared in a 4R glass vial with the following excipients: Poloxamer 338 (50 mg/ml ) • Glucose monohydrate (19.25 mg/ml) • Sodium dihydrogen phosphate monohydrate (2.00 mg/ml) • Citric acid monohydrate (1.00 mg/ml) • Sodium hydroxide (0.866 mg/ml) • Injection Prepare a suspension with water (add qs. to 3 mL) as follows:

Buffer solutions were prepared by dissolving citric acid monohydrate, sodium dihydrogen phosphate monohydrate, sodium hydroxide and glucose monohydrate in water for injection in a stainless steel container. Poloxamer 338 was added to the buffer solution and mixed until dissolved. The first fraction of Poloxamer 338 buffer solution was passed sequentially through a pre-filter and 2 sterile filters connected in series into a sterile stainless steel vessel. The sterile drug substance (micronized, irradiated) is aseptically dispersed into a sterile solution via a charged isolator. The remaining fractions of the Poloxamer 338 buffer solution were passed sequentially through a pre-filter and 2 sterile filters connected in series into a grinding vessel to form a suspension concentrate. During and after addition of the drug substance, the suspension concentrate is mixed to wet and disperse the drug substance. Grinding of suspension concentrates

The suspension concentrate in the grinding vessel was aseptically ground by circulation in a sterile stainless steel grinding chamber, using sterile zirconia beads as the grinding medium. During milling, the suspension is circulated by means of a peristaltic pump between the milling chamber and the milling vessel until the target particle size is reached. Suspension concentrate diluted to final concentration

The suspension concentrate in the holding vessel was diluted with water for injection, sterile filtered through a pre-filter and 2 sterile filters connected in series into this vessel leading to the grinding chamber and a 70 µm stainless steel filter. After final dilution, the vessel headspace was blanketed with nitrogen and the suspension mixed until homogeneous. Containment and filling of the final suspension

While mixing, the suspension is aseptically transferred from the holding vessel to a time/pressure (t/p) dosing vessel from which the suspension is filled into vials that are nitrogen flushed, stoppered, And capped with an aluminum seal with flip-off button. (b) Solution of Hyaluronidase (rHuPH20)

by adding 10 mM histidine, 300 mM sorbitol, 1 mg/mL methionine (pH 5.6), 0.04% polysorbate 20 buffer, by diluting rHuPH20 concentrate ( ^1x106 ) to 10,000 U/mL to prepare a solution of rHuPH20.

The solution was sterile filtered and supplied in 1 mL aliquots of 10,000 U/mL filled into 2R sterile glass vials. program

Six minipigs weighing 20 to 25 kg were used at the start of the study. The minipigs were fasted overnight before dosing. Three minipigs were administered 0.19 mL of hyaluronidase solution (10,000 U/mL) subcutaneously at the waist followed by 900 mg/3 mL of rilpivirine nanosuspension at the same injection site (treatment group A) . Three minipigs were administered 900 mg/3 mL of control rilpivirine suspension subcutaneously at the waist (Treatment B - Control). In both treatment groups, the injection volume was 3 mL of rilpivirine suspension. Method - Sequential Administration

1. Flip the rHuPH20 solution vial cap and wipe with isopropyl alcohol wipes. Let it dry. Attach an 18G inoculation needle to a 1 mL syringe.

2. Draw 0.35 mL into a syringe.

3. Push the syringe and set the level in the syringe to 0.25 mL.

4. Remove the inoculation needle and attach the syringe cap to the 1 mL syringe.

5. Mix rilpivirine by shaking the container horizontally 30 times (arm movement = 2 times) horizontally within about 25 cm in about 10 s. Ensure thorough mixing/complete resuspension.

6. Flip the lid of the rilpivirine vial and wipe with an isopropyl alcohol wipe. Let it dry.

7. Connect the 18G inoculation needle to the 5 mL syringe.

8. Invert the vial and draw >3.2 mL into a 5 mL syringe (mL) (or remove as much suspension as possible from the vial). Injecting 1-2 mL of air will aid in aspiration.

9. Remove the needle and attach the syringe cap to the 5 mL syringe.

10. Invert the syringe. Wait 5 minutes for the bubbles to settle.

11. Attach the Winged Infusion Set to the rHuPH20 1 mL Syringe. Invert the syringe and expel the air, allowing liquid to form at the tip of the needle. (0.19 mL of rHuPH20 should be in the tube)

12. Insert the airfoil infusion set into the subcutaneous tissue of the target injection site by pinching the skin and inserting the needle at a 30-45 degree angle.

13. Release the pinched skin.

14. Withdraw the rHuPH20 syringe from the infusion set, keeping the needle in the skin. When preparing the rilpivirine syringe, keep the luer end (open end) facing up to prevent fluid from flowing out of the infusion tube. It is recommended that the syringe be prepared when the technician inserts the rHuPH20 infusion line.

15. Remove the syringe cap of the 5 mL syringe with rilpivirine. Expel air and set the dose to 3.2 mL.

16. Attach the rilpivirine-filled syringe to the open end of the infusion set.

17. Inject at a constant rate over 1 minute until the syringe plunger bottoms out (this will leave approximately 0.19 mL of rilpivirine in the infusion tube)

18. Remove the airfoil infusion set and dispose of it.

19. Document any leaks. Take pictures of the injection site

• Visually assess the injection site for bulges. blood sampling

• Over the next 2160 hours, 2 mL blood samples were drawn from the jugular veins of all minipigs at regular intervals. Blood samples were placed on EDTA. Within 1 hour of blood sampling, centrifuge the samples at approximately 1900 x g for ±10 min at 5 °C to allow plasma separation. The plasma was immediately transferred to a second tube and stored in the refrigerator within 1 hour of starting centrifugation. Plasma samples were individually analyzed by a validated LC-MS/MS method. Pharmacokinetic data analysis

• Use of non-compartmental pharmacokinetic analysis (using individual C _p versus time curves) to evaluate the pharmacokinetic profile of plasma samples. Mean plasma concentrations and PK parameters ( _Cmax , _Tmax , t1 _/2 and AUC values) were measured and the results are provided in Table 1. Results and discussion parameter rHuPH20 + rilpivirine according to the present invention (treatment group A ) Rilpivirine (Treatment Group B ) Control N 3 3 _Cmax (ng/mL) 52.2 ± 24.1 28.5 ± 9.56 T _max ^a (h) 312 (24-312) 744 (312-1248) T _last ^a (h) 2160 (2160-2160) 2160 (2160-2160) AUC _last (ng*h/mL) 24900 ± 7840 22330 ± 2930 AUC _∞ (ng*h/mL) ^31200b 27000 ± 3200 λ _z (1/h) 0.0008 ± 0.0002 0.0009 ± 0.00009 a: median (min-max) b: N = 2, subject 0005 was not included in the calculation of summary statistics

[Table 1]: Pharmacokinetic parameters

Table 1 and Figure 1 show that administration of a nanosuspension of hyaluronidase and rilpivirine according to the present invention and administration of a nanosuspension of rilpivirine alone resulted in a period of at least 3 months rilpivirine plasma levels. Surprisingly, the long-term, prolonged, sustained release profile of rilpivirine was maintained when administered with hyaluronidase. Example 2 - Effect of Sequential and Mixed Administration of Rilpivirine and Hyaluronidase within 6 Months of a Single Administration

This embodiment compares the plasma kinetics over a 6-month period: (i) rilpivirine suspension (control), (ii) hyaluronidase solution administered sequentially first, followed by rilpivirine suspension, and (iii) mixed administration of hyaluronidase solution and rilpivirine suspension. Preparation of rilpivirine and hyaluronidase composition

(a) Suspension of rilpivirine A suspension of rilpivirine was prepared as described in Example 1.

(b) Solution of Hyaluronidase (rHuPH20) Solutions of hyaluronidase were prepared as described in Example 1. program

Nine minipigs weighing 17 to 21 kg were used at the start of the study. The minipigs were fasted overnight before dosing. The minipigs were anesthetized with propofol before dosing. Three minipigs were administered 0.44 mL of hyaluronidase solution (10,000 U/mL) subcutaneously at the waist followed by 1818 mg/6.06 mL of rilpivirine nano-suspension at the same injection site (treatment groups A - in order). Three minipigs were subcutaneously administered 1816 mg/6.5 mL of mixed hyaluronidase solution (10,000 U/mL) + rilpivirine suspension (treatment group B - mixed). Three minipigs were subcutaneously administered 1830 mg/6.1 mL of a control rilpivirine suspension (treatment group C - control) at the waist. If necessary, seal the injection site with Vetbond 3M Surgical Sealant to limit any leakage. Method - rilpivirine control

A control rilpivirine suspension was prepared and administered by the following method.

1. Mix rilpivirine by shaking the container horizontally 30 times within about 25 cm in about 10 s (arm movement = 2 times). Ensure thorough mixing/complete resuspension.

2. Flip the lid of the rilpivirine vial and wipe with an isopropyl alcohol wipe. Let it dry.

3. Repeat steps 1-2 with the second vial of rilpivirine. If the draw volume is low, or an unexpected amount of air/sediment appears after draw, a 3rd vial may need to be prepared to ensure the proper dose level can be filled into the syringe.

4. Connect the 18G inoculation needle to the 10 mL syringe

5. Invert the vial and draw >3.2 mL into a 10 mL syringe (or remove as much suspension as possible from the vial). Injecting 1-2 mL of air will aid in aspiration. Repeat step 5 with the second vial so that the 10 mL syringe contains approximately 6.5 mL of drug product. IMPORTANT: See note in (step 3) about preparing a 3rd vial in case of low volume draw.

6. Remove the needle and attach the syringe cap to the 10 mL syringe.

7. Invert the syringe and wait 5 minutes for the air bubbles to settle.

8. Remove the syringe cap, invert the syringe, and expel the air.

9. Connect the airfoil infusion set.

10. After filling the infusion set tube, set the dose to 6.1 mL until fluid forms at the needle tip (there will be 0.44 mL of undeliverable/dead volume in the infusion set).

11. Insert the airfoil infusion set into the subcutaneous tissue of the target injection site by pinching the skin and inserting the needle at a 30-45 degree angle.

12. Release the pinched skin.

13. Inject at a constant rate over 2 minutes until the syringe plunger bottoms out

14. Remove and dispose of the airfoil infusion set.

15. Document any leaks. Method - (i) Sequential Administration

The sequential administration of the hyaluronidase solution and the rilpivirine suspension was performed according to the following method.

1. Flip the rHuPH20 solution vial cap and wipe with isopropyl alcohol wipes. Swirl the vial. Allow the stopper of the vial to dry. Attach an 18G inoculation needle to a 1 mL syringe.

2. Draw 0.70 mL into a syringe.

3. Push the syringe and set the level in the syringe to 0.60 mL.

4. Remove the inoculation needle and attach the syringe cap to the 1 mL syringe.

5. Mix rilpivirine by shaking the container horizontally 30 times (arm movement = 2 times) horizontally within about 25 cm in about 10 s. Ensure thorough mixing/complete resuspension.

6. Flip the lid of the rilpivirine vial and wipe with an isopropyl alcohol wipe. Let it dry.

7. Repeat steps 5-6 with the second vial of rilpivirine. If the draw volume is low, or an unexpected amount of air/sediment appears after draw, a 3rd vial may need to be prepared to ensure the proper dose level can be filled into the syringe.

8. Connect the 18G inoculation needle to the 10 mL syringe

9. Invert the vial and draw >3.2 mL into a 10 mL syringe (or remove as much suspension as possible from the vial). Injecting 1-2 mL of air will aid in aspiration.

10. Repeat step 9 with the second vial so that the 10 mL syringe contains approximately 6.5 mL of drug product. IMPORTANT: See note in (step 7) about preparing a 3rd vial in case of low volume draw.

11. Remove the needle and attach the syringe cap to the 10 mL syringe

12. Invert the syringe. Wait 5 minutes for the bubbles to settle.

13. Attach the Winged Infusion Set to the rHuPH20 1 mL Syringe. Invert the syringe and expel the air, allowing liquid to form at the tip of the needle. (0.44 mL of rHuPH20 should be in the tube)

14. Insert the airfoil infusion set into the subcutaneous tissue of the target injection site by pinching the skin and inserting the needle at a 30-45 degree angle.

15. Release the pinched skin.

16. Withdraw the rHuPH20 syringe from the infusion set, keeping the needle in the skin. When preparing the rilpivirine syringe, keep the open end facing up to prevent fluid from flowing out of the infusion tube. It is recommended that the syringe be prepared when the technician inserts the rHuPH20 infusion line.

17. Remove the syringe cap of the 10 mL syringe with rilpivirine. Expel air and set dose to approximately 6.5 mL.

18. Attach the rilpivirine-filled syringe to the open end of the infusion set.

19. Inject at a constant rate over 1 minute until the syringe plunger bottoms out (this will leave approximately 0.44 mL of rilpivirine in the infusion tube)

20. Remove and dispose of the airfoil infusion set.

21. Document any leaks. Method - (ii) Mixed application

The mixed administration of the hyaluronidase solution and the rilpivirine suspension was carried out according to the following method.

1. Flip the rHuPH20 solution vial cap and wipe with isopropyl alcohol wipes. Let it dry. Attach an 18G inoculation needle to a 1 mL syringe.

2. Draw 0.40 mL into a syringe.

3. Push the syringe and set the level in the syringe to 0.35 mL.

4. Remove the inoculation needle and attach the syringe cap to the 1 mL syringe.

5. Mix rilpivirine by shaking the container horizontally 30 times (arm movement = 2 times) horizontally within about 25 cm in about 10 s. Ensure thorough mixing/complete resuspension.

6. Flip the lid of the rilpivirine vial and wipe with an isopropyl alcohol wipe. Let it dry.

7. Remove the syringe cap of the 1 mL syringe filled with PH20 and attach a 25G needle.

8. Push the syringe to form liquid at the tip and set the syringe to approximately 0.25 mL

9. Insert a 25 G needle/rHuPH20 solution syringe into the vial so that the needle is in the liquid.

10. Transfer 0.25 mL of the rHuPH20 solution (2500 U) into the rilpivirine vial.

11. Shake the vial gently.

12. Repeat steps 1-10 to prepare a second vial of rilpivirine and rHuPH20. If the draw volume is low, or an unexpected amount of air/sediment appears after draw, a 3rd vial may need to be prepared to ensure the proper dose level can be filled into the syringe.

13. Connect the 18G needle to the 10 mL syringe

14. Invert the vial and draw >3.4 mL (or as much suspension as possible from the vial) into a 10 mL syringe. Injecting 1-2 mL of air will aid in aspiration.

15. Repeat step 14 with the second prepared vial so that the 10 mL syringe contains approximately 7.0 mL of drug product. IMPORTANT: See note in (step 12) about preparing a 3rd vial in case of low volume draw.

16. Remove the needle and attach the syringe cap to the 10 mL syringe.

17. Invert the syringe and wait 5 minutes for the air bubbles to settle.

18. Remove the syringe cap and expel the air to form a droplet at the needle, push to set the dose to 6.5 mL.

19. Attach the wing infusion set to the 10 mL syringe. Invert the syringe and expel the air, allowing liquid to form at the tip of the needle.

20. Insert the airfoil infusion set into the subcutaneous tissue of the target injection site by pinching the skin and inserting the needle at a 30-45 degree angle.

21. Inject at a constant rate over 1 minute until the syringe plunger bottoms out (this will leave approximately 0.44 mL of rilpivirine in the infusion tube)

22. Remove the airfoil infusion set and dispose of it.

23. Document any leaks. Take pictures of the injection site

• Visually assess the injection site for bulges. blood sampling

• During the next 6 months, 2 mL blood samples were drawn from the jugular veins of all minipigs at regular intervals. Blood samples were placed on EDTA. Within 1 hour of blood sampling, centrifuge the samples at approximately 1900 x g for ±10 min at 5 °C to allow plasma separation. The plasma was immediately transferred to a second tube and stored in the refrigerator within 1 hour of starting centrifugation. Plasma samples were individually analyzed by a validated LC-MS/MS method. Pharmacokinetic data analysis

• Use of non-compartmental pharmacokinetic analysis (using individual C _p versus time curves) to assess PK profiles of plasma samples. Mean plasma concentrations and PK parameters ( _Cmax and AUC values) were measured and the results are provided in Table 2. Results and discussion

Table 2 shows the PK parameters following a single subcutaneous administration of 6 mL of rilpivirine nanosuspension with rHuPH20 solution (sequential and mixed administration) and rilpivirine nanosuspension without rHuPH20 solution. Sequential administration of rHuPH20 + rilpivirine according to the invention (treatment group A ) Mixed administration of rHuPH20 + rilpivirine according to the present invention (treatment group B ) Rilpivirine (Treatment Group C ) Control N 3 3 3 Mean _Cmax (ng/mL) 146 94 ^49a Mean AUC _{0-1 month} (ng*h/mL) 38400 21000 22000 Mean AUC _{0-6 months} (ng*h/mL) 136000 107000 78300

[Table 2]: Pharmacokinetic parameters

^a Abnormal minipigs ( _Cmax of 563 ng/mL 7 hours after administration) were excluded.

Table 2 and Figure 2 show that both sequential and mixed administration of a nanosuspension of hyaluronidase and rilpivirine according to the present invention as well as administration of a nanosuspension of rilpivirine alone resulted in measurable benefit Pevirine plasma levels are slowly released from the injection site over a period of at least 6 months. Surprisingly, the long-term, prolonged, sustained release profile of rilpivirine was maintained when administered sequentially as well as in admixture with hyaluronidase. Example 3 - Dissolution Studies at Different Particle Sizes

This example compares the dissolution profiles of three rilpivirine suspensions, each with a different particle size. Preparation of rilpivirine suspension and measurement of particle size

A suspension of rilpivirine (Suspension 1) was prepared according to the method described in Example 1. Two other suspensions (Suspensions 2 and 3) having the same composition as Example 1 but different particle sizes were prepared by compounding and grinding as described below. Preparation of Suspensions 2 and 3

1. Add 586.62 g of water for injection to a 2 L glass beaker containing a magnetic stir bar.

2. Add the correct amounts of citric acid monohydrate, sodium dihydrogen phosphate monohydrate, sodium hydroxide and stir until dissolved.

3. Add the correct amounts of Poloxamer 338 and Dextrose Monohydrate and stir until dissolved.

4. Filter the diluent through a 0.22 µm filter, rinse the beaker with the remaining 100 mL of water for injection and filter.

5. Add rilpivirine micropowder and stir until a homogeneous suspension is obtained.

6. Transfer 500 mL of the suspension to a sterile beaker and place in a double-walled cooled glass beaker with a magnetic stir bar.

7. Start grinding on the Netzsch Labstar until the target particle size distribution is achieved. For Suspension 2, the milling time was about 180 minutes. For Suspension 3, the milling time was about 35 minutes.

8. Measure the particle size distribution during milling.

9. Dilute each suspension to 300 mg/mL. Particle size distribution measurement

Volume-based particle size distribution of rilpivirine suspensions was determined by wet dispersion laser diffraction using a Malvern Mastersizer 3000 Laser Diffraction (Malvern Instruments) and a Hydro MV Wet Dispersion Module.

The particle sizes of the three rilpivirine suspensions were determined in Table 3. suspension D _v 50 ( µm ) D _v 90 ( µm ) 1 0.29 0.69 2 0.39 1.91 3 2.46 5.55

[Table 3]: Particle size In vitro dissolution measurement

6.0% w/v polysorbate in 0.05 M sodium phosphate buffer in 900 mL at 5.0 ± 0.5°C using a paddle apparatus (USP Type 2, Ph. Eur. [European Pharmacopoeia], Japan) at 50 rpm Dissolution of these three rilpivirine suspensions in water was performed in Ester 20 (pH 7.4). Add an amount of 64.98 mg (= 0.06 mL x 1.083 g/mL (theoretical density of the suspension)) ± 5% of the homogeneous rilpivirine suspension (corresponding to 18 ± 0.9 mg of rilpivirine).

The amount of rilpivirine present in the dissolution samples was determined based on a gradient ultra-high performance liquid chromatography (UHPLC) method with UV detection at 280 nm. The results are shown in Figure 3. Results and discussion

Figure 3 shows that administration of rilpivirine in the form of microparticles or nanoparticles with larger particle sizes as shown in Table 3 unexpectedly reduces the dissolution profile of rilpivirine, even if it becomes flat. Example 4 - Further Dissolution Studies at Different Particle Sizes

This example compares the dissolution profiles of five rilpivirine suspensions, each with a different particle size. Preparation of rilpivirine suspension and measurement of particle size

Five suspensions of rilpivirine were prepared according to methods corresponding to those described for Suspensions 2 and 3 in Example 3. The volume-based particle size distribution of the rilpivirine microparticles or nanoparticles in suspension was determined according to methods corresponding to those indicated in Example 3. suspension D _v 50 ( µm ) D _v 90 ( µm ) 1 0.42 2.12 2 0.63 2.85 3 1.29 3.69 4 1.99 5.00 5 2.72 6.46

[Table 4]: Particle size In vitro dissolution measurement

Dissolution of these five rilpivirine suspensions in water was performed according to the method specified in Example 3. Results and discussion

Figure 4 and Table 4 show that as the particle size of rilpivirine in the form of microparticles or nanoparticles increases, the dissolution profile of rilpivirine decreases, ie becomes flat. This article also describes the following numbered clauses.

1. A rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase 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 microparticles or nanoparticles in suspension, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase are administered to the subject by subcutaneous or intramuscular injection, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years.

2. Rilpivirine or a pharmaceutically acceptable salt thereof and a hyaluronidase for use according to clause 1, wherein the hyaluronidase is a recombinant human hyaluronidase (e.g., rHuPH20 enzyme), e.g. , comprising the amino acid sequence of SEQ ID NO: 1.

3. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any of the preceding clauses, wherein the time interval is from about three months to about one year.

4. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to clause 3, wherein the time interval is from about three months to about six months.

5. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to clause 3, wherein the time interval is from about six months to about one year, particularly wherein the time interval is about six months.

6. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any one of the preceding clauses, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially Accepted salt and hyaluronidase.

7. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any one of the preceding clauses, wherein the microparticles or nanoparticles have surfaces adsorbed onto their surfaces modifier.

8. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to clause 7, wherein the surface modifier is a poloxamer.

9. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to clause 8, wherein the poloxamer is Poloxamer 338.

10. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any one of the preceding clauses, wherein the microparticles or nanoparticles have an average effective particle size of less than about 1 µm.

11. Rilpivirine, or a pharmaceutically acceptable salt thereof, and hyaluronidase for use according to clause 10, wherein the microparticles or nanoparticles have an average effective particle size of less than about 500 nm.

12. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to clause 11, wherein the microparticles or nanoparticles have an average effective particle size of from about 100 nm to about 300 nm.

13. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to clause 12, wherein the microparticles or nanoparticles have an average effective particle size of from about 150 nm to about 250 nm.

14. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to clause 13, wherein the microparticles or nanoparticles have an average effective particle size of from about 180 nm to about 220 nm.

15. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any one of the preceding clauses, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered sequentially and the hyaluronidase.

16. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any of the preceding clauses, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered as a separate pharmaceutical composition Acceptable salts and hyaluronidase.

17. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to clause 16, wherein the pharmaceutical composition comprising the hyaluronidase is a solution, and hyaluronic acid in the solution The concentration of the enzyme is from about 50 to about 10,000 U/mL, particularly about 2,000 U/mL.

18. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any one of clauses 1-14, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and The hyaluronidase is administered as a combined pharmaceutical composition.

19. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any one of the preceding clauses, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered by subcutaneous injection of salts and the hyaluronidase.

20. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any one of the preceding clauses, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which The rilpivirine or a pharmaceutically acceptable salt thereof is suspended in an acceptable aqueous carrier.

21. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any one of the preceding clauses, wherein the treatment or prevention of HIV infection is treatment of HIV infection.

22. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to clause 21, wherein each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises from about 2700 mg to about 5400 mg of rilpivirine or a pharmaceutically acceptable salt thereof, particularly from about 2700 mg to about 4500 mg of rilpivirine or a pharmaceutically acceptable salt thereof.

23. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any one of the preceding clauses, wherein the HIV infection is HIV type 1 (HIV-1) infection.

24. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any of the preceding clauses, wherein the subject is a human.

25. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any one of the preceding clauses, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is rilpivirine Waring.

26. A combination for use in the treatment or prevention of HIV infection, wherein the combination comprises rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of microparticles or nanoparticles in suspension, and wherein the combination is administered intermittently by subcutaneous or intramuscular injection at intervals of about three months to about two years.

27. The combination for use according to clause 26, wherein the hyaluronidase is a recombinant human hyaluronidase (eg, rHuPH20), eg, comprising the amino acid sequence of SEQ ID NO: 1.

28. A combination for use according to any of clauses 26-27, wherein the time interval is from about three months to about one year.

29. Combinations for use according to clause 28, wherein the time interval is from about three months to about six months.

30. The combination for use according to clause 28, wherein the time interval is from about six months to about one year, particularly wherein the time interval is about six months.

31. A combination for use according to any one of clauses 26-30, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered simultaneously or sequentially.

32. A combination for use according to any of clauses 26-31, wherein the micro- or nanoparticles have a surface modifier adsorbed onto their surface.

33. A combination for use according to clause 32, wherein the surface modifier is a poloxamer.

34. The combination for use according to clause 33, wherein the poloxamer is Poloxamer 338.

35. The combination for use according to any one of clauses 26-34, wherein the microparticles or nanoparticles have an average effective particle size of less than about 1 μm.

36. The combination for use according to clause 35, wherein the microparticles or nanoparticles have an average effective particle size of less than about 500 nm.

37. The combination for use according to clause 36, wherein the microparticles or nanoparticles have an average effective particle size of from about 100 nm to about 300 nm.

38. The combination for use according to clause 37, wherein the average effective particle size of the microparticles or nanoparticles is from about 150 nm to about 250 nm.

39. The combination for use according to clause 38, wherein the average effective particle size of the microparticles or nanoparticles is from about 180 nm to about 220 nm.

40. A combination for use according to any one of clauses 26-39, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered sequentially.

41. A combination for use according to any one of clauses 26-40, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase are administered as separate pharmaceutical compositions.

42. A combination for use according to clause 41, wherein the pharmaceutical composition comprising the hyaluronidase is a solution, and the concentration of the hyaluronidase in the solution is from about 50 to about 10,000 U/mL, in particular is about 2,000 U/mL.

43. The combination for use according to any one of clauses 26-39, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered as a combined pharmaceutical composition.

44. The combination for use according to any one of clauses 26-43, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered by subcutaneous injection.

45. A combination for use according to any one of clauses 26-44, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which the rilpivirine or rilpivirine is suspended its pharmaceutically acceptable salts.

46. The combination for use according to any one of clauses 26-45, wherein the treatment or prevention of HIV infection is treatment of HIV infection.

47. The combination for use according to clause 46, wherein each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises from about 2700 mg to about 5400 mg of rilpivirine or a pharmaceutically acceptable salt thereof. Accepted salts, particularly from about 2700 mg to about 4500 mg of rilpivirine or a pharmaceutically acceptable salt thereof.

48. The combination for use according to any one of clauses 26-47, wherein the HIV infection is HIV type 1 (HIV-1) infection.

49. The combination for use according to any one of clauses 26-48, wherein the subject is a human.

50. The combination for use according to any one of clauses 26-49, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is rilpivirine.

51. A product comprising rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase as a combined preparation for simultaneous or sequential use in the treatment or prevention of HIV infection by subcutaneous or intramuscular injection use, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of microparticles or nanoparticles in suspension, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years.

52. A product for simultaneous or sequential use according to clause 51, wherein the hyaluronidase is a recombinant human hyaluronidase (e.g., rHuPH20), e.g., comprising the amino acid sequence of SEQ ID NO: 1.

53. For a product for simultaneous or sequential use according to any of clauses 51-52, wherein the time interval is from about three months to about one year.

54. For products for simultaneous or sequential use according to clause 53, wherein the time interval is from about three months to about six months.

55. A product for simultaneous or sequential use according to clause 53, wherein the time interval is about six months to about one year, particularly wherein the time interval is about six months.

56. A product for simultaneous or sequential use according to any one of clauses 51-55, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered sequentially.

57. For a product for simultaneous or sequential use according to any of clauses 51-56, wherein the micro- or nano-particles have a surface modifier adsorbed onto their surface.

58. For a product for simultaneous or sequential use according to clause 57, wherein the surface modifier is a poloxamer.

59. A product for simultaneous or sequential use according to clause 58, wherein the poloxamer is Poloxamer 338.

60. For a product for simultaneous or sequential use according to any of clauses 51-59, wherein the microparticles or nanoparticles have an average effective particle size of less than about 1 µm.

61. For a product for simultaneous or sequential use according to clause 60, wherein the average effective particle size of the microparticles or nanoparticles is less than about 500 nm.

62. For a product for simultaneous or sequential use according to clause 61, wherein the microparticles or nanoparticles have an average effective particle size of from about 100 nm to about 300 nm.

63. For a product for simultaneous or sequential use according to clause 62, wherein the microparticles or nanoparticles have an average effective particle size of from about 150 nm to about 250 nm.

64. For a product for simultaneous or sequential use according to clause 63, wherein the average effective particle size of the microparticles or nanoparticles is from about 180 nm to about 220 nm.

65. A product for simultaneous or sequential use according to any one of clauses 51-64, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered sequentially by subcutaneous injection.

66. A product for simultaneous or sequential use according to any one of clauses 51-65, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase are administered as separate pharmaceutical compositions.

67. A product for simultaneous or sequential use according to clause 66, wherein the pharmaceutical composition comprising the hyaluronidase is a solution and the concentration of the hyaluronidase in the solution is from about 50 to about 10,000 U/mL , in particular about 2,000 U/mL.

68. A product for simultaneous or sequential use according to any one of clauses 51-64, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered as a combined pharmaceutical composition.

69. A product for simultaneous or sequential use according to any one of clauses 51-68, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered by subcutaneous injection.

70. A product for simultaneous or sequential use according to any one of clauses 51-69, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which the Lipid is suspended Warin or a pharmaceutically acceptable salt thereof.

71. A product for simultaneous or sequential use according to any of clauses 51-70, wherein the treatment or prevention of HIV infection is treatment of HIV infection.

72. A product for simultaneous or sequential use according to clause 71, wherein each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises from about 2700 mg to about 5400 mg of rilpivirine or A pharmaceutically acceptable salt, particularly from about 2700 mg to about 4500 mg of rilpivirine or a pharmaceutically acceptable salt thereof.

73. A product for simultaneous or sequential use according to any of clauses 51-72, wherein the HIV infection is HIV type 1 (HIV-1) infection.

74. A product for simultaneous or sequential use according to any one of clauses 51-73, wherein the subject is a human.

75. A product for simultaneous or sequential use according to any one of clauses 51-74, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is rilpivirine.

76. A kit of parts comprising rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use in the treatment or prevention of HIV infection by subcutaneous or intramuscular injection Simultaneous or sequential use, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of microparticles or nanoparticles in suspension, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years.

77. A kit for simultaneous or sequential use according to clause 76, wherein the hyaluronidase is a recombinant human hyaluronidase (e.g., rHuPH20), e.g., comprising the amino acid sequence of SEQ ID NO: 1 .

78. A kit for simultaneous or sequential use according to any of clauses 76-77, wherein the time interval is from about three months to about one year.

79. A kit for simultaneous or sequential use as described in clause 78, wherein the time interval is from about three months to about six months.

80. A kit for simultaneous or sequential use according to clause 78, wherein the time interval is about six months to about one year, particularly wherein the time interval is about six months.

81. A kit for simultaneous or sequential use according to any one of clauses 76-80, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered sequentially.

82. A kit for simultaneous or sequential use according to any of clauses 76-81, wherein the microparticles or nanoparticles have a surface modifier adsorbed onto their surface.

83. A kit for simultaneous or sequential use according to clause 82, wherein the surface modifier is a poloxamer.

84. A kit for simultaneous or sequential use according to clause 83, wherein the poloxamer is Poloxamer 338.

85. A kit for simultaneous or sequential use according to any of clauses 76-84, wherein the microparticles or nanoparticles have an average effective particle size of less than about 1 µm.

86. A kit for simultaneous or sequential use according to clause 85, wherein the microparticles or nanoparticles have an average effective particle size of less than about 500 nm.

87. A kit for simultaneous or sequential use according to clause 86, wherein the microparticles or nanoparticles have an average effective particle size of from about 100 nm to about 300 nm.

88. A kit for simultaneous or sequential use according to clause 87, wherein the microparticles or nanoparticles have an average effective particle size of from about 150 nm to about 250 nm.

89. A kit for simultaneous or sequential use according to clause 88, wherein the microparticles or nanoparticles have an average effective particle size of from about 180 nm to about 220 nm.

90. A kit for simultaneous or sequential use according to any one of clauses 76-89, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronic acid are administered sequentially by subcutaneous injection enzymes.

91. A kit for simultaneous or sequential use according to any one of clauses 76-90, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase are administered as separate pharmaceutical compositions .

92. A kit for simultaneous or sequential use according to clause 91, wherein the pharmaceutical composition comprising the hyaluronidase is a solution, and the concentration of the hyaluronidase in the solution is from about 50 to about 10,000 U /mL, in particular about 2,000 U/mL.

93. A kit for simultaneous or sequential use according to any one of clauses 76-89, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are as a combined pharmaceutical composition apply.

94. A kit for simultaneous or sequential use according to any one of clauses 76-93, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered by subcutaneous injection.

95. A kit for simultaneous or sequential use according to any one of clauses 76-94, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which the pharmaceutically acceptable aqueous carrier is suspended. Rilpivirine or a pharmaceutically acceptable salt thereof.

96. A kit for simultaneous or sequential use according to any one of clauses 76-95, wherein the treatment or prevention of HIV infection is treatment of HIV infection.

97. A kit for simultaneous or sequential use according to clause 96, wherein each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises from about 2700 mg to about 5400 mg of rilpivirine or a pharmaceutically acceptable salt thereof, particularly from about 2700 mg to about 4500 mg of rilpivirine or a pharmaceutically acceptable salt thereof.

98. A kit for simultaneous or sequential use according to any one of clauses 76-97, wherein the HIV infection is HIV type 1 (HIV-1) infection.

99. A kit for simultaneous or sequential use according to any one of clauses 76-98, wherein the subject is a human.

100. A kit for simultaneous or sequential use according to any of clauses 76-99, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is rilpivirine.

101. A rilpivirine or a pharmaceutically acceptable salt thereof in the form of microparticles or nanoparticles in suspension for use in the treatment or prevention of HIV infection by subcutaneous or intramuscular injection, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered in combination with hyaluronidase administered by subcutaneous or intramuscular injection, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years.

102. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 101, wherein the hyaluronidase is a recombinant human hyaluronidase (e.g., rHuPH20), e.g., comprising SEQ ID NO: The amino acid sequence of 1.

103. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of clauses 101-102, wherein the time interval is from about three months to about one year.

104. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 103, wherein the time interval is about three months to about six months, particularly wherein the time interval is about six months .

105. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 103, wherein the time interval is from about six months to about one year.

106. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of clauses 101-105, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially and hyaluronidase.

107. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of clauses 101-106, wherein the microparticles or nanoparticles have a surface modifier adsorbed onto their surface .

108. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 107, wherein the surface modifier is a poloxamer.

109. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 108, wherein the poloxamer is Poloxamer 338.

110. Rilpivirine, or a pharmaceutically acceptable salt thereof, for use according to any one of clauses 101-109, wherein the average effective particle size of the microparticles or nanoparticles is less than about 1 μm.

111. Rilpivirine, or a pharmaceutically acceptable salt thereof, for use according to clause 110, wherein the microparticles or nanoparticles have an average effective particle size of less than about 500 nm.

112. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 111, wherein the average effective particle size of the microparticles or nanoparticles is from about 100 nm to about 300 nm.

113. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 112, wherein the average effective particle size of the microparticles or nanoparticles is from about 150 nm to about 250 nm.

114. Rilpivirine, or a pharmaceutically acceptable salt thereof, for use according to clause 113, wherein the microparticles or nanoparticles have an average effective particle size of from about 180 nm to about 220 nm.

115. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of clauses 101-114, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the transparent Ronidase.

116. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of clauses 101-115, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered as a separate pharmaceutical composition Salt and Hyaluronidase.

117. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 116, wherein the pharmaceutical composition comprising the hyaluronidase is a solution and the concentration of the hyaluronidase in the solution is from About 50 to about 10,000 U/mL, especially about 2,000 U/mL.

118. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of clauses 101-114, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase Administered as a combined pharmaceutical composition.

119. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of clauses 101-118, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered by subcutaneous injection and the hyaluronidase.

120. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of clauses 101-119, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which the pharmaceutically acceptable The rilpivirine or a pharmaceutically acceptable salt thereof is suspended in an aqueous carrier.

121. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of clauses 101-120, wherein the treatment or prevention of HIV infection is treatment of HIV infection.

122. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 121, wherein each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises from about 2700 mg to about 5400 mg. mg of rilpivirine or a pharmaceutically acceptable salt thereof, particularly from about 2700 mg to about 4500 mg of rilpivirine or a pharmaceutically acceptable salt thereof.

123. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of clauses 101-122, wherein the HIV infection is HIV type 1 (HIV-1) infection.

124. Rilpivirine, or a pharmaceutically acceptable salt thereof, for use according to any one of clauses 101-123, wherein the subject is a human.

125. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any one of clauses 101-124, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is rilpivirine.

126. Use of rilpivirine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of HIV infection in a subject, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of microparticles or nanoparticles in suspension and administered in combination with hyaluronidase, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered to the subject by subcutaneous or intramuscular injection, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years.

127. The use according to clause 126, wherein the hyaluronidase is a recombinant human hyaluronidase (eg, rHuPH20), eg, comprising the amino acid sequence of SEQ ID NO: 1.

128. The use according to any of clauses 126-127, wherein the time interval is from about three months to about one year.

129. Use according to clause 128, wherein the time interval is from about three months to about six months.

130. Use according to clause 129, wherein the time interval is about six months to about one year, in particular wherein the time interval is about six months.

131. The use according to any one of clauses 126-130, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered simultaneously or sequentially.

132. The use according to any of clauses 126-131, wherein the micro- or nanoparticles have a surface modifier adsorbed onto their surface.

133. The use according to clause 132, wherein the surface modifier is a poloxamer.

134. The use according to clause 133, wherein the poloxamer is Poloxamer 338.

135. The use according to any of clauses 126-134, wherein the average effective particle size of the micro- or nanoparticles is less than about 1 μm.

136. The use according to clause 135, wherein the average effective particle size of the micro- or nanoparticles is less than about 500 nm.

137. The use according to clause 136, wherein the average effective particle size of the micro- or nanoparticles is from about 100 nm to about 300 nm.

138. The use according to clause 137, wherein the average effective particle size of the micro- or nanoparticles is from about 150 nm to about 250 nm.

139. The use according to clause 138, wherein the average effective particle size of the micro- or nanoparticles is from about 180 nm to about 220 nm.

140. The use according to any one of clauses 126-139, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered sequentially.

141. The use according to any of clauses 126-140, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase are administered as separate pharmaceutical compositions.

142. Use according to clause 141, wherein the pharmaceutical composition comprising the hyaluronidase is a solution, and the concentration of the hyaluronidase in the solution is from about 50 to about 10,000 U/mL, in particular about 2,000 U/mL.

143. The use according to any one of clauses 126-139, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered as a combined pharmaceutical composition.

144. The use according to any one of clauses 126-143, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered by subcutaneous injection.

145. The use according to any one of clauses 126-144, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which the rilpivirine or a pharmaceutically acceptable carrier is suspended. acceptable salt.

146. The use according to any one of clauses 126-145, wherein the use is for the manufacture of a medicament for the treatment of HIV infection in a subject.

147. The use according to clause 146, wherein each administration of the rilpivirine or a pharmaceutically acceptable salt thereof comprises from about 2700 mg to about 5400 mg of rilpivirine or a pharmaceutically acceptable salt thereof , in particular from about 2700 mg to about 4500 mg of rilpivirine or a pharmaceutically acceptable salt thereof.

148. The use according to any of clauses 126-147, wherein the HIV infection is HIV type 1 (HIV-1) infection.

149. The use according to any one of clauses 126-148, wherein the subject is human.

150. The use according to any one of clauses 126-149, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is rilpivirine.

151. A combination comprising rilpivirine or a pharmaceutically acceptable salt thereof and a hyaluronidase, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is a microparticle or nanoparticle in suspension Granular form.

152. The combination according to clause 151, wherein the hyaluronidase is a recombinant human hyaluronidase (eg, rHuPH20), eg, comprising the amino acid sequence of SEQ ID NO: 1.

153. The combination according to any one of clauses 151-152, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are formulated for simultaneous or sequential administration.

154. The combination according to any of clauses 151-153, wherein the microparticles or nanoparticles have a surface modifier adsorbed onto their surface.

155. The combination according to clause 154, wherein the surface modifier is a poloxamer.

156. The combination according to clause 155, wherein the poloxamer is Poloxamer 338.

157. The combination according to any of clauses 151-156, wherein the average effective particle size of the micro- or nanoparticles is less than about 1 μm.

158. The combination according to clause 157, wherein the average effective particle size of the microparticles or nanoparticles is less than about 500 nm.

159. The combination according to clause 158, wherein the average effective particle size of the microparticles or nanoparticles is from about 100 nm to about 300 nm.

160. The combination according to clause 159, wherein the average effective particle size of the microparticles or nanoparticles is from about 150 nm to about 250 nm.

161. The combination according to clause 160, wherein the average effective particle size of the micro- or nanoparticles is from about 180 nm to about 220 nm.

162. The combination according to any one of clauses 151-161, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are formulated to be administered sequentially.

163. The combination according to any one of clauses 151-162, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and/or hyaluronidase is formulated for administration in separate pharmaceutical compositions.

164. The combination according to clause 163, wherein the pharmaceutical composition comprising the hyaluronidase is a solution, and the concentration of the hyaluronidase in the solution is from about 50 to about 10,000 U/mL, particularly about 2,000 U/mL.

165. The combination according to any one of clauses 151-161, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are formulated for administration as a combined pharmaceutical composition.

166. The combination according to any one of clauses 151-165, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are formulated for administration by subcutaneous injection.

167. The combination according to any one of clauses 151-166, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which the rilpivirine or a pharmaceutically acceptable carrier thereof is suspended. acceptable salt.

168. The combination according to any one of clauses 151-167, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is rilpivirine.

169. A complete set of kits comprising rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of microparticles in suspension. in particle or nanoparticle form.

170. The kit of clause 169, wherein the hyaluronidase is a recombinant human hyaluronidase (eg, rHuPH20), eg, comprising the amino acid sequence of SEQ ID NO: 1.

171. The kit of any one of clauses 169-170, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are formulated for simultaneous or sequential administration.

172. The kit of any one of clauses 169-171, wherein the micro- or nanoparticles have surface modifiers adsorbed onto their surfaces.

173. The kit according to clause 172, wherein the surface modifier is a poloxamer.

174. The kit according to clause 173, wherein the poloxamer is Poloxamer 338.

175. The kit of any one of clauses 169-174, wherein the microparticles or nanoparticles have an average effective particle size of less than about 1 μm.

176. The kit of clause 175, wherein the microparticles or nanoparticles have an average effective particle size of less than about 500 nm.

177. The kit of clause 176, wherein the microparticles or nanoparticles have an average effective particle size of from about 100 nm to about 300 nm.

178. The kit of clause 177, wherein the microparticles or nanoparticles have an average effective particle size of from about 150 nm to about 250 nm.

179. The kit of clause 178, wherein the microparticles or nanoparticles have an average effective particle size of from about 180 nm to about 220 nm.

180. The kit of any one of clauses 169-179, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are formulated for sequential administration.

181. The kit of any one of clauses 169-180, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and/or hyaluronidase is formulated for administration in separate pharmaceutical compositions.

182. The kit according to clause 181, wherein the pharmaceutical composition comprising the hyaluronidase is a solution, and the concentration of the hyaluronidase in the solution is from about 50 to about 10,000 U/mL, particularly About 2,000 U/mL.

183. The kit of any one of clauses 169-179, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are formulated for administration as a combined pharmaceutical composition.

184. The kit of any one of clauses 169-183, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are formulated for administration by subcutaneous injection.

185. The kit of any one of clauses 169-184, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which the rilpivirine or its rilpivirine is suspended. Pharmaceutically acceptable salts.

186. The kit of any one of clauses 169-185, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is rilpivirine.

187. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any of clauses 1-9 and 15-25 not subordinate to any of clauses 10-14 , wherein the microparticles or nanoparticles have an average effective particle size of from about 0.2 µm to about 3 µm.

188. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to clause 187, wherein the microparticles or nanoparticles have from about 1 µm to about 3 µm, preferably is about 1.5 µm to about 3 µm, more preferably about 2 µm to about 3 µm average effective particle size.

189. Rilpivirine, or a pharmaceutically acceptable salt thereof, and hyaluronidase for use according to clause 187, wherein the microparticles or nanoparticles have an average potency of from about 1 µm to about 2.5 µm particle size.

190. Rilpivirine, or a pharmaceutically acceptable salt thereof, and hyaluronidase for use according to clause 189, wherein the microparticles or nanoparticles have an average effective particle size of about 2.5 μm.

191. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any of clauses 1-9 and 15-25 not subordinate to any of clauses 10-14 , wherein the microparticles or nanoparticles have a D _v 90 of from about 2 μm to about 7 μm.

192. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to clause 191, wherein the microparticles or nanoparticles have a D _v of from about 3 µm to about 6 µm 90.

193. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to clause 192, wherein the microparticles or nanoparticles have a D _v of from about 3 µm to about 5.5 µm 90.

194. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to clause 193, wherein the microparticles or nanoparticles have a D _v 90 of about 5.5 μm.

195. Rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for use according to any of clauses 1-9 and 15-25 not subordinate to any of clauses 10-14 , wherein the microparticles or nanoparticles have an average effective particle size of from about 0.2 μm to about 3 μm and a D _v 90 of from about 1.8 μm to about 7 μm.

196. Combinations for use according to any of clauses 26-34 and 40-50 not subordinate to any of clauses 35-39, wherein the microparticles or nanoparticles have from about 0.2 µm to Average effective particle size of about 3 µm.

197. A combination for use according to clause 196, wherein the microparticles or nanoparticles have from about 1 μm to about 3 μm, preferably about 1.5 μm to about 3 μm, more preferably about Average effective particle size from 2 µm to about 3 µm.

198. A combination for use according to clause 196, wherein the microparticles or nanoparticles have an average effective particle size of from about 1 µm to about 2.5 µm.

199. A combination for use according to clause 198, wherein the microparticles or nanoparticles have an average effective particle size of about 2.5 μm.

200. A combination for use according to any one of clauses 26-34 and 40-50 not subordinate to any one of clauses 35-39, wherein the microparticles or nanoparticles have from about 2 µm to D _v 90 of about 7 µm.

201. The combination for use according to clause 200, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 6 μm.

202. The combination for use according to clause 201, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 5.5 μm.

203. The combination for use according to clause 202, wherein the microparticles or nanoparticles have a D _v 90 of about 5.5 μm.

204. A combination for use according to any one of clauses 26-34 and 40-50 not subordinate to any one of clauses 35-39, wherein the microparticles or nanoparticles have from about 0.2 µm to Average effective particle size of about 3 µm and D _v 90 from about 1.8 µm to about 7 µm.

205. A product for simultaneous or sequential use according to any of clauses 51-59 and 65-75 not subordinate to any of clauses 60-64, wherein the microparticles or nanoparticles have from about Average effective particle size from 0.2 µm to about 3 µm.

206. Products for simultaneous or sequential use according to clause 205, wherein the microparticles or nanoparticles have from about 1 µm to about 3 µm, preferably about 1.5 µm to about 3 µm, more preferably is an average effective particle size of about 2 µm to about 3 µm.

207. A product for simultaneous or sequential use according to clause 205, wherein the microparticles or nanoparticles have an average effective particle size of from about 1 µm to about 2.5 µm.

208. A product for simultaneous or sequential use according to clause 207, wherein the microparticles or nanoparticles have an average effective particle size of about 2.5 µm.

209. A product for simultaneous or sequential use according to any of clauses 51-59 and 65-75 not subordinate to any of clauses 60-64, wherein the microparticles or nanoparticles have from about D _v 90 from 2 µm to about 7 µm.

210. A product for simultaneous or sequential use according to clause 209, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 6 μm.

211. A product for simultaneous or sequential use according to clause 210, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 5.5 μm.

212. A product for simultaneous or sequential use according to clause 211, wherein the micro- or nanoparticles have a D _v 90 of about 5.5 µm.

213. Products for simultaneous or sequential use according to any of clauses 51-59 and 65-75 not subordinate to any of clauses 60-64, wherein the microparticles or nanoparticles have from about Average effective particle size from 0.2 µm to about 3 µm and D _v 90 from about 1.8 µm to about 7 µm.

214. A kit for simultaneous or sequential use according to any of clauses 76-84 and 90-100 not subordinate to any of clauses 85-89, wherein the microparticles or nanoparticles have Average effective particle size from about 0.2 µm to about 3 µm.

215. A kit for simultaneous or sequential use according to clause 214, wherein the microparticles or nanoparticles have from about 1 µm to about 3 µm, preferably about 1.5 µm to about 3 µm, more Preferred is an average effective particle size of about 2 µm to about 3 µm.

216. A kit for simultaneous or sequential use according to clause 214, wherein the microparticles or nanoparticles have an average effective particle size of from about 1 µm to about 2.5 µm.

217. A kit for simultaneous or sequential use according to clause 216, wherein the microparticles or nanoparticles have an average effective particle size of about 2.5 µm.

218. A kit for simultaneous or sequential use according to any of clauses 76-84 and 90-100 not subordinate to any of clauses 85-89, wherein the microparticles or nanoparticles have D _v 90 from about 2 µm to about 7 µm.

219. A kit for simultaneous or sequential use according to clause 218, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 6 μm.

220. A kit for simultaneous or sequential use according to clause 219, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 5.5 μm.

221. A kit for simultaneous or sequential use according to clause 210, wherein the microparticles or nanoparticles have a D _v 90 of about 5.5 µm.

222. A kit for simultaneous or sequential use according to any of clauses 76-84 and 90-100 not subordinate to any of clauses 85-89, wherein the microparticles or nanoparticles have Average effective particle size from about 0.2 µm to about 3 µm and D _v 90 from about 1.8 µm to about 7 µm.

223. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any of clauses 101-109 and 115-125 not subordinate to any of clauses 110-114, wherein the micro The particles or nanoparticles have an average effective particle size of from about 0.2 μm to about 3 μm.

224. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 223, wherein the microparticles or nanoparticles have from about 1 µm to about 3 µm, preferably about 1.5 µm to about 3 µm, more preferably about 2 µm to about 3 µm average effective particle size.

225. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 223, wherein the microparticles or nanoparticles have an average effective particle size of from about 1 μm to about 2.5 μm.

226. Rilpivirine, or a pharmaceutically acceptable salt thereof, for use according to clause 225, wherein the microparticles or nanoparticles have an average effective particle size of about 2.5 μm.

227. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any of clauses 101-109 and 115-125 not subordinate to any of clauses 110-114, wherein the micro The particles or nanoparticles have a D _v 90 of from about 2 μm to about 7 μm.

228. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 227, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 6 μm.

229. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 228, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 5.5 μm.

230. Rilpivirine, or a pharmaceutically acceptable salt thereof, for use according to clause 229, wherein the microparticles or nanoparticles have a D _v 90 of about 5.5 μm.

231. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any of clauses 101-109 and 115-125 not subordinate to any of clauses 110-114, wherein the micro The particles or nanoparticles have an average effective particle size of from about 0.2 μm to about 3 μm and a D _v 90 of from about 1.8 μm to about 7 μm.

232. The use according to any of clauses 126-134 and 140-150 not subordinate to any of clauses 135-139, wherein the micro- or nano-particles have from about 0.2 µm to about 3 µm average effective particle size.

233. The use according to clause 232, wherein the microparticles or nanoparticles have from about 1 μm to about 3 μm, preferably about 1.5 μm to about 3 μm, more preferably about 2 μm to about 3 μm. Average effective particle size of about 3 µm.

234. The use according to clause 232, wherein the micro- or nanoparticles have an average effective particle size of from about 1 μm to about 2.5 μm.

235. The use according to clause 234, wherein the microparticles or nanoparticles have an average effective particle size of about 2.5 μm.

236. The use according to any of clauses 126-134 and 140-150 not subordinate to any of clauses 135-139, wherein the micro- or nanoparticles have from about 2 µm to about 7 µm D _v 90.

237. The use according to clause 236, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 6 μm.

238. The use according to clause 237, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 5.5 μm.

239. The use according to clause 238, wherein the microparticles or nanoparticles have a D _v 90 of about 5.5 μm.

240. The use according to any of clauses 126-134 and 140-150 not subordinate to any of clauses 135-139, wherein the micro- or nanoparticles have from about 0.2 µm to about 3 µm average effective particle size and D _v 90 from about 1.8 µm to about 7 µm.

241. The combination according to any one of clauses 151-156 and 162-169 not subordinate to any one of clauses 157-161, wherein the micro- or nanoparticles have from about 0.2 μm to about 3 μm average effective particle size.

242. The combination according to clause 241, wherein the microparticles or nanoparticles have from about 1 μm to about 3 μm, preferably about 1.5 μm to about 3 μm, more preferably about 2 μm to about 3 μm. Average effective particle size of about 3 µm.

243. The combination according to clause 241, wherein the microparticles or nanoparticles have an average effective particle size of from about 1 μm to about 2.5 μm.

244. The combination according to clause 243, wherein the microparticles or nanoparticles have an average effective particle size of about 2.5 μm.

245. A combination according to any one of clauses 151-156 and 162-168 not subordinate to any one of clauses 157-161, wherein the microparticles or nanoparticles have from about 2 µm to about 7 µm. D _v 90.

246. The combination according to clause 245, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 6 μm.

247. The combination according to clause 246, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 5.5 μm.

248. The combination according to clause 247, wherein the microparticles or nanoparticles have a D _v 90 of about 5.5 μm.

249. A combination according to any one of clauses 151-156 and 162-168 not subordinate to any one of clauses 157-161, wherein the microparticles or nanoparticles have from about 0.2 μm to about 3 μm average effective particle size and D _v 90 from about 1.8 µm to about 7 µm.

250. The kit of any one of clauses 169-174 and 180-186 not subordinate to any of clauses 175-179, wherein the microparticles or nanoparticles have from about 0.2 μm to about Average effective particle size of 3 µm.

251. The kit according to clause 250, wherein the microparticles or nanoparticles have from about 1 μm to about 3 μm, preferably about 1.5 μm to about 3 μm, more preferably about 2 μm. Average effective particle size from µm to about 3 µm.

252. The kit of clause 250, wherein the microparticles or nanoparticles have an average effective particle size of from about 1 µm to about 2.5 µm.

253. The kit of clause 252, wherein the microparticles or nanoparticles have an average effective fineness of about 2.5 μm.

254. The kit of any one of clauses 169-174 and 180-86 not subordinate to any one of clauses 175-179, wherein the microparticles or nanoparticles have from about 2 μm to about D _v 90 of 7 µm.

255. The kit of clause 254, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 6 μm.

256. The kit of clause 255, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 5.5 μm.

257. The kit of clause 256, wherein the microparticles or nanoparticles have a D _v 90 of about 5.5 μm.

258. The kit of any one of clauses 169-174 and 180-186 not subordinate to any of clauses 175-179, wherein the microparticles or nanoparticles have from about 0.2 μm to about Average effective particle size of 3 µm and D _v 90 from about 1.8 µm to about 7 µm.

259. A rilpivirine or a pharmaceutically acceptable salt thereof in the form of microparticles or nanoparticles in suspension, wherein the microparticles or nanoparticles have a D _v of from about 1 μm to about 10 μm 90.

260. Rilpivirine or a pharmaceutically acceptable salt thereof according to clause 259, wherein the microparticles or nanoparticles have from about 1 μm to about 7 μm, preferably from about 2 μm to about D _v 90 of 7 µm.

261. Rilpivirine or a pharmaceutically acceptable salt thereof according to clause 260, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 6 μm.

262. Rilpivirine or a pharmaceutically acceptable salt thereof according to clause 261, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 5.5 μm.

263. Rilpivirine or a pharmaceutically acceptable salt thereof according to clause 259, wherein the microparticles or nanoparticles have a D _v 90 of from about 1.8 μm to about 7 μm and from about 0.2 μm to about Average effective particle size (D _v 50) of 3 µm.

264. Rilpivirine or a pharmaceutically acceptable salt thereof according to clause 262 or clause 263, wherein the D _v 90 is about 5.5 μm.

265. Rilpivirine or a pharmaceutically acceptable salt thereof according to clause 263 or clause 264, wherein the mean effective particle size is about 2.5 μm.

266. Rilpivirine, or a pharmaceutically acceptable salt thereof, according to any one of clauses 259-265, wherein the microparticles or nanoparticles have a surface modifier adsorbed onto their surface.

267. Rilpivirine or a pharmaceutically acceptable salt thereof according to clause 266, wherein the surface modifier is a poloxamer.

268. Rilpivirine or a pharmaceutically acceptable salt thereof according to clause 267, wherein the poloxamer is Poloxamer 338.

269. Rilpivirine or a pharmaceutically acceptable salt thereof according to any one of clauses 259-268, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which The rilpivirine or a pharmaceutically acceptable salt thereof is suspended.

270. Rilpivirine or a pharmaceutically acceptable salt thereof according to any one of clauses 259-269, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is rilpivirine (i.e. warin free base).

271. A pharmaceutical composition comprising rilpivirine, or a pharmaceutically acceptable salt thereof, as defined in any one of clauses 259-270, in the form of microparticles or nanoparticles in suspension.

272. The pharmaceutical composition according to clause 271, wherein the pharmaceutical composition is formulated for administration by subcutaneous or intramuscular injection.

273. The pharmaceutical composition according to clause 271, wherein the pharmaceutical composition is formulated for administration by subcutaneous injection.

274. Rilpivirine as defined in any of clauses 259-270, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of HIV infection in a subject.

275. A method for treating or preventing HIV infection in a subject, the method comprising administering to the subject rilpivirine as defined in any one of clauses 259-270 or a pharmaceutically acceptable form thereof Salt.

276. Use of rilpivirine as defined in any of clauses 259-270, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of HIV infection in a subject.

277. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 274, in a method according to clause 275 or for use according to clause 276, for a period of about three months to about two years The subject is administered the rilpivirine or a pharmaceutically acceptable salt thereof at a time interval.

278. Rilpivirine or a pharmaceutically acceptable salt thereof for the use according to clause 277, the method according to clause 277 or the use according to clause 277, wherein the time interval is about three months to about six months.

279. Rilpivirine or a pharmaceutically acceptable salt thereof for the use according to clause 277, the method according to clause 277 or the use according to clause 277, wherein the time interval is about six months to about two years.

280. Rilpivirine or a pharmaceutically acceptable salt thereof for the use according to clause 279, the method according to clause 279 or the use according to clause 279, wherein the time interval is about six months to About one year, in particular about 6 months.

281. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any of clauses 274-280, according to the method of any of clauses 274-280 or according to any of clauses 274-280 The use of any one, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered to the subject by subcutaneous or intramuscular injection.

282. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 281, method according to clause 281 or use according to clause 281, wherein the subject is administered by subcutaneous injection The rilpivirine or a pharmaceutically acceptable salt thereof is administered.

283. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any of clauses 274-282, according to the method of any of clauses 274-282 or according to any of clauses 274-282 The use of any one, wherein the treating or preventing HIV infection is treating HIV infection.

284. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to clause 283, a method according to clause 283 or a use according to clause 283, wherein the rilpivirine or a pharmaceutically acceptable salt thereof Each administration of an acceptable salt includes from about 2700 mg to about 5400 mg of rilpivirine or a pharmaceutically acceptable salt thereof.

285. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any of clauses 274-284, according to the method of any of clauses 274-284 or according to any of clauses 274-284 The use of any one, wherein the HIV infection is HIV type 1 (HIV-1) infection.

286. Rilpivirine or a pharmaceutically acceptable salt thereof for use according to any of clauses 274-285, according to the method of any of clauses 274-285 or according to any of clauses 274-285 The use of any one, wherein the subject is human.

The invention will be described, by way of example only, with reference to the accompanying drawings.

[ Fig. 1 ]: Mean plasma concentrations over time after administration of rilpivirine nano-suspension and hyaluronidase according to the present invention and administration of rilpivirine nano-suspension alone.

[ Fig. 2 ]: Mean plasma concentrations six months after administration of rilpivirine suspension and hyaluronidase according to the present invention and administration of rilpivirine suspension alone.

[ Figure 3 ]: Dissolution study of rilpivirine suspensions with different particle sizes

[ Figure 4 ]: Further dissolution studies of rilpivirine suspensions with different particle sizes

These figures are further explained in the "Examples" section.

Claims (66)

A method for treating or preventing HIV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a microparticle or nanoparticle in suspension by intramuscular injection or subcutaneous injection rilpivirine or a pharmaceutically acceptable salt thereof in granular form, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered in combination with hyaluronidase administered by intramuscular injection or subcutaneous injection, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years. The method of claim 1, wherein the hyaluronidase is a recombinant human hyaluronidase (eg, rHuPH20), eg, comprising the amino acid sequence of SEQ ID NO: 1. The method of any of the preceding claims, wherein the time interval is from about three months to about one year. The method of claim 3, wherein the time interval is from about three months to about six months. The method of claim 3, wherein the time interval is about six months to about one year, preferably wherein the time interval is about six months. The method of any one of the preceding claims, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered simultaneously or sequentially. A method as claimed in any preceding claim, wherein the micro- or nanoparticles have surface modifiers adsorbed onto their surfaces. The method of claim 7, wherein the surface modifier is a poloxamer. The method of claim 8, wherein the poloxamer is Poloxamer 338. The method of any one of the preceding claims, wherein the microparticles or nanoparticles have an average effective particle size of less than about 1 μm. The method of claim 10, wherein the microparticles or nanoparticles have an average effective particle size of less than about 500 nm. The method of claim 11, wherein the microparticles or nanoparticles have an average effective particle size of from about 100 nm to about 300 nm. The method of claim 12, wherein the microparticles or nanoparticles have an average effective particle size of from about 150 nm to about 250 nm. The method of claim 13, wherein the microparticles or nanoparticles have an average effective particle size of from about 180 nm to about 220 nm. The method of any one of claims 1-9, wherein the microparticles or nanoparticles have an average effective particle size of from about 0.2 μm to about 3 μm. The method of claim 15, wherein the microparticles or nanoparticles have from about 1 µm to about 3 µm, preferably from about 1.5 µm to about 3 µm, more preferably from about 2 µm to about Average effective particle size of 3 µm. The method of claim 15, wherein the microparticles or nanoparticles have an average effective particle size of from about 1 μm to about 2.5 μm. The method of claim 17, wherein the microparticles or nanoparticles have an average effective particle size of about 2.5 μm. The method of any of clauses 1-9, wherein the microparticles or nanoparticles have a _Dv 90 of from about 2 μm to about 7 μm. The method of claim 19, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 6 μm. The method of claim 20, wherein the microparticles or nanoparticles have a D _v 90 of from about 3 μm to about 5.5 μm. The method of claim 21, wherein the microparticles or nanoparticles have a D _v 90 of about 5.5 μm. The method of any one of the preceding claims, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered sequentially. The method of any of the preceding claims, wherein the rilpivirine, or a pharmaceutically acceptable salt thereof, and hyaluronidase are administered as separate pharmaceutical compositions. The method of claim 24, wherein the pharmaceutical composition comprising the hyaluronidase is a solution, and the concentration of the hyaluronidase in the solution is from about 50 to about 10,000 U/mL, preferably about 2,000 U/mL. The method of any one of claims 1-22, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered as a combined pharmaceutical composition. The method of any one of the preceding claims, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered by subcutaneous injection. The method of any one of the preceding claims, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which the rilpivirine or a pharmaceutically acceptable form thereof is suspended Salt. The method of any one of the preceding claims, wherein the method is a method of treating HIV infection. The method of claim 29, wherein each administration of rilpivirine or a pharmaceutically acceptable salt thereof comprises from about 2700 mg to about 5400 mg of rilpivirine or a pharmaceutically acceptable salt thereof, Preferred is from about 2700 mg to about 4500 mg of rilpivirine or a pharmaceutically acceptable salt thereof. The method of any one of the preceding claims, wherein the HIV infection is HIV type 1 (HIV-1) infection. The method of any one of the preceding claims, wherein the subject is a human. The method of any one of the preceding claims, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is rilpivirine. A rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase 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 microparticles or nanoparticles in suspension, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase are administered to the subject by intramuscular or subcutaneous injection, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years. A product comprising rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase as a combined preparation for simultaneous or sequential use in the treatment or prevention of HIV infection by intramuscular or subcutaneous injection , wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of microparticles or nanoparticles in suspension, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years. A kit comprising rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase for simultaneous treatment or prevention of HIV infection by intramuscular or subcutaneous injection or use sequentially, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of microparticles or nanoparticles in suspension, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years. A rilpivirine or a pharmaceutically acceptable salt thereof in the form of microparticles or nanoparticles in suspension for use in the treatment or prevention of HIV infection by intramuscular or subcutaneous injection, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered in combination with hyaluronidase administered by intramuscular injection or subcutaneous injection, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years. Use of rilpivirine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of HIV infection in a subject, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of microparticles or nanoparticles in suspension and administered in combination with hyaluronidase, wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered to the subject by intramuscular injection or subcutaneous injection, and wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at intervals of about three months to about two years. A combination comprising rilpivirine or a pharmaceutically acceptable salt thereof and a hyaluronidase, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is in the form of microparticles or nanoparticles in suspension . A kit of parts comprising rilpivirine or a pharmaceutically acceptable salt thereof and a hyaluronidase, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is microparticles in suspension or Nanoparticle form. A rilpivirine or a pharmaceutically acceptable salt thereof in the form of microparticles or nanoparticles in suspension, wherein the microparticles or nanoparticles have a D _v 90 of from about 1 μm to about 10 μm. The rilpivirine or a pharmaceutically acceptable salt thereof of claim 41, wherein the microparticles or nanoparticles have from about 1 µm to about 7 µm, preferably from about 2 µm to about 7 µm D _v 90 in µm. The rilpivirine or a pharmaceutically acceptable salt thereof of claim 42, wherein the microparticles or nanoparticles have from about 3 µm to about 6 µm, preferably from about 3 µm to about 5.5 µm D _v 90 in µm. The rilpivirine or a pharmaceutically acceptable salt thereof of claim 41, wherein the microparticles or nanoparticles have a D v 90 of from about 1.8 μm to about 7 μm and a D _v 90 of from about 0.2 μm to about 3 μm Average effective particle size in µm. The rilpivirine or a pharmaceutically acceptable salt thereof of claim 43 or claim 44, wherein the D _v 90 is about 5.5 μm. The rilpivirine or a pharmaceutically acceptable salt thereof of claim 44 or claim 45, wherein the average effective particle size is about 2.5 µm. The rilpivirine or a pharmaceutically acceptable salt thereof of any one of claims 41-46, wherein the microparticles or nanoparticles have a surface modifier adsorbed onto their surface. The rilpivirine or a pharmaceutically acceptable salt thereof according to claim 47, wherein the surface modifier is a poloxamer. The rilpivirine or a pharmaceutically acceptable salt thereof according to claim 48, wherein the poloxamer is Poloxamer 338. The rilpivirine or a pharmaceutically acceptable salt thereof according to any one of claims 41-49, wherein the suspension comprises a pharmaceutically acceptable aqueous carrier in which it is suspended There is the rilpivirine or a pharmaceutically acceptable salt thereof. The rilpivirine or a pharmaceutically acceptable salt thereof according to any one of claims 41-50, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is rilpivirine. A pharmaceutical composition comprising rilpivirine, or a pharmaceutically acceptable salt thereof, as defined in any of claims 41-51, in the form of microparticles or nanoparticles in suspension. The pharmaceutical composition of claim 52, wherein the pharmaceutical composition is formulated for administration by subcutaneous or intramuscular injection. The pharmaceutical composition of claim 53, wherein the pharmaceutical composition is formulated for administration by subcutaneous injection. Rilpivirine, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 41-51, for use in the treatment or prevention of HIV infection in a subject. A method for treating or preventing HIV infection in a subject, the method comprising administering to the subject rilpivirine or a pharmaceutically acceptable salt thereof as defined in any one of claims 41-51 . Use of rilpivirine or a pharmaceutically acceptable salt thereof as defined in any one of claims 41-51 for the manufacture of a medicament for the treatment or prevention of HIV infection in a subject. Rilpivirine or a pharmaceutically acceptable salt thereof for use as claimed in claim 55, the method as claimed in claim 56, or the use as claimed in claim 57, wherein for about three months to about two The rilpivirine, or a pharmaceutically acceptable salt thereof, is administered to the subject at yearly intervals. Rilpivirine or a pharmaceutically acceptable salt thereof for use as claimed in claim 58, the method as claimed in claim 58 or the use as claimed in claim 58, wherein the time interval is about three months to about six months. Rilpivirine or a pharmaceutically acceptable salt thereof for use as claimed in claim 58, the method as claimed in claim 58 or the use as claimed in claim 58, wherein the time interval is about six months To about one year, preferably wherein the time interval is about 6 months. Rilpivirine or a pharmaceutically acceptable salt thereof for use as claimed in any of claims 55-60, the method of any of claims 55-60 or as claimed in claims 55-60 The use of any one, wherein the rilpivirine or a pharmaceutically acceptable salt thereof is administered to the subject by subcutaneous or intramuscular injection. Rilpivirine or a pharmaceutically acceptable salt thereof for use as claimed in claim 61, the method as claimed in claim 61 or the use as claimed in claim 61, wherein the subject is administered by subcutaneous injection to administer the rilpivirine or a pharmaceutically acceptable salt thereof. Rilpivirine or a pharmaceutically acceptable salt thereof for use as claimed in any of claims 55-62, the method of any of claims 55-62 or as claimed in claims 55-62 The use of any one, wherein the treating or preventing HIV infection is treating HIV infection. Rilpivirine or a pharmaceutically acceptable salt thereof for use as claimed in claim 63, the method as claimed in claim 63 or the use as claimed in claim 63, wherein the rilpivirine or a pharmaceutically acceptable salt thereof Each administration of the above acceptable salt includes from about 2700 mg to about 5400 mg of rilpivirine or a pharmaceutically acceptable salt thereof, preferably from about 2700 mg to about 4500 mg of rilpivirine or its pharmaceutically acceptable salts. Rilpivirine or a pharmaceutically acceptable salt thereof for use as claimed in any of claims 55-64, the method of any of claims 55-64 or as claimed in claims 55-64 The use of any one, wherein the HIV infection is type 1 HIV (HIV-1) infection. Rilpivirine or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 55-65, the method of any one of claims 55-65 or as claimed in claims 55-65 The use of any one, wherein the subject is a human.

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