Liquid composition

Abstract

The present invention relates to an aqueous composition comprising (i) rilpivirine or a pharma- ceutically acceptable salt thereof, (ii) hyaluronidase, and (iii) 0.001-100 mg / mL of at least one excipient selected from the group consisting of (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof, and / or (b) an amino acid. The present invention also relates to further compositions, kits, and uses of the aqueous composition in the treatment or prevention of HIV infection in a subject.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 333,556, filed April 22, 2022, and European Patent Application No. 22173922.0, filed May 17, 2022, the entireties of which are incorporated by reference herein.

[0002] FIELD OF THEINVENTION The present invention relates to storage stable aqueous compositions comprising rilpivirine or a pharma- ceutically acceptable salt thereof, hyaluronidase, and one or more excipients. The present invention also relates to methods for stabilizing such aqueous compositions, the use of the excipients in such methods, and methods for the treatment or prevention of HIV infection. [Background technology]

[0003] The treatment of human immunodeficiency virus (HIV) infection, known as the cause of acquired immune deficiency syndrome (AIDS), remains a major medical challenge. HIV can escape immunological suppression, adapt to different cell types and growth conditions, and develop resistance to anti-HIV drugs. The latter include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), HIV protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and HIV fusion inhibitors.

[0004] Currently available oral therapies require at least one dose per day. Thus, people living with HIV are daily reminders of their HIV-positive status, and daily dosing may reveal their HIV-positive test status. Daily dosing requires the storage and transportation of multiple or large amounts of pills, and there remains a risk that patients will not comply with the prescribed dosing regimen by forgetting to take their daily dose. In addition to reducing the effectiveness of treatment, this also leads to the development of viral resistance.

[0005] One class of HIV drugs often used in highly active antiretroviral therapy (HAART) are NNRTIs. Rilpivirine is an antiretroviral drug of the NNRTI class used to treat HIV infection. Rilpivirine is a second-generation NNRTI with greater efficacy and reduced side effect profile compared to older NNRTIs. Rilpivirine activity is mediated by noncompetitive inhibition of HIV-1 reverse transcriptase.

[0006] Rilpivirine not only exhibits significant activity against wild-type HIV, but also against a number of its mutated variants. Rilpivirine, its pharmacological activity, and some procedures for its preparation are described in WO 2003 / 016306.

[0007] Rilpivirine has been approved for the treatment of HIV infection and is commercially available as a single tablet containing 25 mg of rilpivirine base equivalent per tablet for oral dosing once daily (EDURANT®), and as a single tablet regimen for oral dosing once daily (COMPLERA®, ODEFSEY®, JULUCA®).

[0008] WO 2007 / 147882 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 their surface and a pharma- ceutically acceptable aqueous carrier in which the rilpivirine active ingredient is suspended.

[0009] Rilpivirine extended release suspension for injection, for administration in combination with cabotegravir extended release suspension for injection, has been approved, e.g., in the United States and Canada as CABENUVA® and, e.g., in Europe as REKAMBYS®. These are the first antiretroviral drugs to be offered in a long-acting injectable formulation for administration at intervals of more than one day.

[0010] When rilpivirine is administered by subcutaneous or intramuscular injection, it may be desirable to formulate it or administer it together with hyaluronidase to increase the dispersion and absorption of rilpivirine.Hyaluronidase may also be used to achieve other effects, for example, administration of hyaluronidase may reduce the swelling formed by administration of a high volume of aqueous composition at the injection site.However, storing hyaluronidase in an aqueous composition for weeks, months, or years is a significant challenge.When stored at room temperature for a long period of time, hyaluronidase may not fold rapidly and may degrade. It is therefore also desirable to provide compositions comprising rilpivirine and hyaluronidase, in which the hyaluronidase is stable during storage, particularly at refrigerated temperatures, e.g., 5°C, for weeks, months, or years, without substantially affecting the particle size distribution of the rilpivirine, such that when the rilpivirine is administered after extended periods of storage, particularly at refrigerated temperatures, e.g., 5°C, the bioavailability, efficacy, and sustained release characteristics are maintained over the storage period.

[0011] International Patent / US Patent No. 2021 / 072453 (WO 2022 / 109555) relates to the treatment or prevention of HIV infection using rilpivirine or a pharma- ceutically acceptable salt thereof in the form of microparticles or nanoparticles in suspension in combination with hyaluronidase. Summary of the Invention

[0012] The present inventors have discovered new aqueous compositions of rilpivirine particles and hyaluronidase enzyme that are surprisingly stable for long-term storage, particularly with respect to particle size distribution of the rilpivirine particles and maintenance of enzyme activity over time.

[0013] In a first aspect, the present invention provides a method for treating an inflammatory bowel disease comprising: (i) rilpivirine or a pharma- ceutical acceptable salt thereof; (ii) hyaluronidase; and (iii) 0.001 to 100 mg / mL of hyaluronidase. (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof; and / or (b) at least one excipient selected from the group consisting of amino acids or pharma- ceutically acceptable salts thereof.

[0014] In a related aspect (aspect 1a), the present invention provides a method for producing a composition comprising the steps of: (i) rilpivirine or a pharma- ceutically acceptable salt thereof; (ii) 0.001 to 100 mg / mL, (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof; and / or (b) an aqueous composition comprising at least one excipient selected from the group consisting of amino acids or pharma- ceutically acceptable salts thereof.

[0015] In a related aspect (aspect 1b), the present invention provides a method for producing a composition comprising the steps of: (i) rilpivirine or a pharma- ceutically acceptable salt thereof; (ii) 0.001 to 100 mg / mL, (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof; and / or (b) a first product comprising an aqueous composition comprising at least one excipient selected from the group consisting of an amino acid, or a pharma- ceutically acceptable salt thereof; and a second product comprising an aqueous composition comprising hyaluronidase.

[0016] In a related aspect (aspect 1c), the present invention provides a method for producing a composition comprising the steps of: (i) rilpivirine or a pharma- ceutically acceptable salt thereof; (ii) 0.001 to 100 mg / mL, (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof; and / or (b) a first product comprising an aqueous composition comprising at least one excipient selected from the group consisting of an amino acid, or a pharma- ceutically acceptable salt thereof; (i) hyaluronidase; (ii) 0.001 to 100 mg / mL, (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof; and / or (b) a second product comprising an aqueous composition comprising at least one excipient selected from the group consisting of an amino acid or a pharma- ceutically acceptable salt thereof.

[0017] In a related embodiment (embodiment 1d), the present invention relates to an aqueous composition comprising (i) rilpivirine or a pharma- ceutically acceptable salt thereof, (ii) hyaluronidase, and (iii) 0.1-100 mg / mL of at least one sugar or sugar alcohol, optionally wherein the aqueous composition has a pH of about 5 to about 7, or about 6 to 6.5, e.g., about 6. The aqueous composition in this embodiment (embodiment 1d) can be used to prepare the aqueous composition in the first embodiment.

[0018] In a related embodiment (embodiment 1e), the invention relates to a kit comprising a kit component of embodiment 1b, a kit component of embodiment 1c, or the aqueous composition of embodiment 1d, further comprising one or more other active pharmaceutical agents, in particular one or more other antiretroviral agents, in particular one or more other antiretroviral agents of another class, such as an antiretroviral agent of the INSTI class, such as a composition comprising cabotegravir.

[0019] In a second aspect, the present invention relates to the use of (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof; and / or (b) an amino acid or a pharma- ceutically acceptable salt thereof, in a method for stabilizing an aqueous composition, the method comprising the steps of preparing an aqueous composition comprising (i) rilpivirine or a pharma- ceutically acceptable salt thereof, (ii) hyaluronidase, and (iii) 0.001 to 100 mg / mL of (a) and / or (b).

[0020] In a related aspect (Aspect 2a), the invention relates to the use of (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof; and / or (b) an amino acid or a pharma-ceutically acceptable salt thereof, in a method for stabilizing an aqueous composition, the method comprising the steps of: (i) rilpivirine or a pharma-ceutically acceptable salt thereof; (ii) preparing an aqueous composition containing 0.001 to 100 mg / mL of (a) and / or (b).

[0021] In a related aspect (Aspect 2b), the invention relates to the use of (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof; and / or (b) an amino acid or a pharma- ceutically acceptable salt thereof, in a method for stabilizing an aqueous composition, the method comprising the steps of preparing an aqueous composition comprising (i) rilpivirine or a pharma- ceutically acceptable salt thereof, (ii) hyaluronidase, and (iii) 0.001 to 100 mg / mL of (a) and / or (b).

[0022] In a related aspect (Aspect 2c), the invention relates to the use of at least one sugar or sugar alcohol in a method for stabilizing an aqueous composition, the method comprising the steps of preparing an aqueous composition comprising: (i) rilpivirine or a pharma- ceutically acceptable salt thereof; (ii) hyaluronidase; and (iii) 0.1 to 100 mg / mL of at least one sugar or sugar alcohol; and optionally, the aqueous composition has a pH of about 5 to about 7, or about 6 to 6.5, e.g., about 6.

[0023] In a third aspect, the present invention relates to a method for stabilizing an aqueous composition comprising (i) rilpivirine or a pharma- ceutically acceptable salt thereof, and (ii) hyaluronidase, comprising: The method includes combining components (i) and (ii) with (iii) 0.001 to 100 mg / mL of at least one excipient selected from the group consisting of: (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof; and / or (b) an amino acid or a pharma-ceutically acceptable salt thereof.

[0024] In a related aspect (Aspect 3a), the invention relates to a method for stabilizing an aqueous composition comprising: (i) rilpivirine or a pharma- ceutically acceptable salt thereof, comprising the steps of: The method comprises combining component (i) with (ii) 0.001 to 100 mg / mL of at least one excipient selected from the group consisting of (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof; and / or (b) an amino acid or a pharma-ceutically acceptable salt thereof.

[0025] In a related aspect (Aspect 3b), the invention relates to a method for stabilizing an aqueous composition comprising (i) rilpivirine, or a pharma- ceutically acceptable salt thereof, and (ii) hyaluronidase, comprising: The method comprises combining components (i) and (ii) with (iii) 0.001-100 mg / mL of at least one excipient selected from the group consisting of: a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof; and / or b) an amino acid or a pharma-ceutically acceptable salt thereof.

[0026] In a third aspect (Aspect 3c), the present invention relates to a method for stabilizing an aqueous composition comprising (i) rilpivirine, or a pharma- ceutically acceptable salt thereof, and (ii) hyaluronidase, the method comprising combining components (i) and (ii) with (iii) 0.1 to 100 mg / mL of at least one sugar or sugar alcohol.

[0027] In a fourth aspect, there is provided a method for the treatment or prevention of HIV infection in a subject, the method comprising administering to the subject an aqueous composition of the invention.

[0028] In a related embodiment (embodiment 4a), there is provided a method for the treatment or prevention of HIV infection in a subject, the method comprising administering to a subject a product of a kit of the invention, optionally after combining two or more of the products of the kit.

[0029] In a fifth aspect, there is provided an aqueous composition of the invention for use in treating or preventing HIV infection in a subject. In a related aspect, there is provided a kit of the invention for use in treating or preventing HIV infection in a subject.

[0030] In a sixth aspect there is provided a use of an aqueous composition of the invention for the manufacture of a medicament for treating or preventing HIV infection in a subject. In a related aspect there is provided a kit of the invention for the manufacture of a medicament for treating or preventing HIV infection in a subject. [Brief description of the drawings]

[0031] The present invention will now be described, by way of example only, with reference to the accompanying drawings. [Figure 1-1] Appearance, resuspension and injectability tests under different storage conditions. [Figure 1-2] Appearance, resuspension and injectability tests under different storage conditions. [Figure 1-3] Appearance, resuspension and injectability tests under different storage conditions. [Diagram 2] Hyaluronidase melting temperature test under different storage conditions. [Figure 2A-1] Hyaluronidase melting temperature test under different storage conditions [Figure 2A-2] Hyaluronidase melting temperature test under different storage conditions [Figure 2B-1] Hyaluronidase melting temperature test under different storage conditions. [Figure 2B-2] Hyaluronidase melting temperature test under different storage conditions. [Figure 2C] Hyaluronidase melting temperature test under different storage conditions - pH remeasured. [Diagram 3] Hyaluronidase melting temperature test. [Figure 4] Hyaluronidase melting temperature test under different storage conditions. [Figure 4A] Hyaluronidase melting temperature test under different storage conditions - pH remeasured. [Diagram 5] Hyaluronidase melting temperature test and CMC sodium concentration.

[0032] These figures are further explained in the Examples section.

[0033] Disclosure of the Invention This application is described in several sections for ease of reading. However, this does not mean that each section should be read separately. On the contrary, each section should be read with cross-reference to other sections, i.e., by interpreting the entire application as a whole, unless otherwise specified. No artificial separation of embodiments is intended unless expressly stated. For example, an embodiment refers to all aspects, unless expressly specified otherwise. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Compositions of the Invention Rilpivirine (4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, TMC278, has the following structural formula:

[0035] [ka]

[0036] "Rilpivirine" means rilpivirine having the structural formula above, ie, the free base form.

[0037] In a preferred embodiment, the compositions of the invention comprise rilpivirine.

[0038] A pharmaceutically acceptable salt of rilpivirine means that the counter ion is pharmaceutically acceptable. A pharmaceutically acceptable salt is meant to include the therapeutically active non-toxic acid addition salt forms that rilpivirine can form. These salt forms can be conveniently obtained by treating rilpivirine with a suitable acid, such as an inorganic acid (e.g., hydrohalic acid (e.g., hydrochloric acid, hydrobromic acid, etc.)), sulfuric acid, nitric acid, phosphoric acid, etc.), or an organic acid, such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic 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, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, etc.

[0039] In one embodiment, the rilpivirine or a pharma- ceutically acceptable salt thereof is in the form of particles suspended in the aqueous composition, for example, microparticles or nanoparticles suspended in the aqueous composition.

[0040] Two embodiments having preferred particle sizes are contemplated herein.

[0041] In a first preferred particle size embodiment, the rilpivirine particles have a D v In this embodiment, the particles have a D of about 100 nm to about 2 μm. v In this embodiment, the particles may have a D of about 200 nm to about 2 μm. v In this embodiment, the particles may have a D of 200 nm to about 2 μm. v In this embodiment, the particles may have a D of about 300 nm to about 2 μm. v In this embodiment, the particles may have a D of 300 nm to about 2 μm. v In this embodiment, the particles may have a D of about 400 nm to about 2 μm, for example 400 nm to about 2 μm. vIn this embodiment, the particles may have a D of about 500 nm to about 2 μm, for example 500 nm to about 2 μm. v 90. Preferably, in this embodiment, the particles have a D of about 500 nm to about 1600 nm. v D of 90 or about 500 nm to about 1,000 nm, for example, 500 nm to about 1600 nm or 500 nm to about 1,000 nm v More preferably, in this embodiment, the particles have a D of about 500 nm to about 700 nm, e.g., about 500 nm to about 650 nm, and most preferably, about 525 nm to about 644 nm. v It has 90.

[0042] The term “D v "D 90" as used herein refers to the diameter below which 90% by volume of the particle population is found. v "D 50" as used herein refers to the diameter below which 50% by volume of the particle population is found. v "10" as used herein refers to the diameter below which 10% by volume of the particle population is found.

[0043] In a first preferred particle size embodiment, the particles may have a Dv50 of less than or about 1,000 nm. In this embodiment, the particles have a Dv50 of about 10 nm to about 1000 nm. v 50. In this embodiment, the particles may have a D of about 50 nm to about 700 nm. v 50. In this embodiment, the particles may have a D of about 100 nm to about 600 nm. v 50. In this embodiment, the particles may have a D of about 150 nm to about 500 nm. v 50. Preferably, in this embodiment, the particles have a D of about 200 nm to about 500 nm. v Has 50.

[0044] In a first preferred particle size embodiment, the particles have a D of about 500 nm or less. v In this embodiment, the particles may have a D of about 10 nm to about 500 nm. vIn this embodiment, the particles may have a D of about 25 nm to about 400 nm. v In this embodiment, the particles may have a D of about 50 nm to about 300 nm. v In this embodiment, the particles may have a D of about 50 nm to about 200 nm. v 10. Preferably, in this embodiment, the rilpivirine particles have a D of about 75 nm to about 200 nm. v Has 10.

[0045] Preferably, in this embodiment, the rilpivirine particles have a D of about 500 nm to about 1,600 nm. v 90, D of about 200 nm to about 500 nm v 50, and D of about 75 nm to about 200 nm v Has 10.

[0046] Alternatively, the rilpivirine particles have a D of about 500 nm to about 1,000 nm. v 90, D of about 200 nm to about 500 nm v 50, and D of about 75 nm to about 200 nm v Has 10.

[0047] Alternatively, the rilpivirine particles have a D of about 450 nm to about 700 nm. v 90, D of about 200 nm to about 500 nm v 50, and D of about 75 nm to about 200 nm v Has 10.

[0048] In a second preferred particle size embodiment, the rilpivirine particles have a D v In this embodiment, the particles may have a D of about 2 μm to about 9 μm. v In this embodiment, the particles may have a D of about 3 μm to about 8 μm. v In this embodiment, the particles may have a D of about 3 μm to about 7 μm. v 90. Preferably, in this embodiment, the particles have a D of about 4 μm to about 6 μm. vPreferably, in this embodiment, the particles have a D of about 5 μm to about 6 μm, for example about 5 μm or about 6 μm. v 90. The particles have a D of about 5 μm. v 90. The particles may have a D of about 6 μm. v 90.

[0049] In a second preferred particle size embodiment, the rilpivirine particles have a D v In this embodiment, the particles have a D of less than about 2.5 μm. v In this embodiment, the particles may have a D of about 1 μm to about 2.5 μm. v In this embodiment, the particles may have a D of about 1.2 μm to about 2.2 μm. v 50. Preferably, in this embodiment, the particles have a D of about 1.5 μm to about 2.2 μm. v More preferably, in this embodiment, the particles have a D of about 1.5 μm to about 2 μm. v Has 50.

[0050] In a second preferred particle size embodiment, the rilpivirine particles have a D v In this embodiment, the particles may have a D of about 10 nm to about 1000 nm. v In this embodiment, the particles may have a D of about 100 nm to about 700 nm. v In this embodiment, the particles may have a D of about 200 nm to about 600 nm. v 10. Preferably, in this embodiment, the particles have a D of about 300 nm to about 500 nm. v Has 10.

[0051] Preferably, in this embodiment, the particles have a D of about 4 μm to about 6 μm. v 90, D of about 1.5 μm to about 2 μm v 50, and D of about 300 nm to about 500 nm v Has 10.

[0052] Preferably, in this embodiment, the particles have a D of about 5 μm to about 6 μm.v 90, D of about 1.5 μm to about 2.2 μm v 50, and D of about 300 nm to about 500 nm v Has 10.

[0053] As used herein, D v 10. D v 50, and D v 90 is determined by conventional laser diffraction techniques, for example according to ISO 13320:2009.

[0054] Laser diffraction relies on the principle that particles scatter light at angles that vary with particle size, and a collection of particles produces a pattern of scattered light defined by intensity and angle that can be correlated to particle size distribution. Many laser diffraction instruments are commercially available for fast and reliable measurement of particle size distribution. For example, particle size distribution can be measured by a conventional Malvern Mastersizer™ 3000 particle size analyzer manufactured by Malvern Instruments. The Malvern Mastersizer™ 3000 particle size analyzer works by projecting a helium-neon gas laser beam through a transparent cell that contains particles of interest suspended in an aqueous solution. The light that strikes the particles is scattered at angles that are inversely proportional to the particle size, a photodetector array measures the light intensity at several predefined 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 a wet dispersion of particles in distilled water.

[0055] D v 10. D v 50, and D v Other methods commonly used in the art for measuring 90 include disk centrifugation, scanning electron microscopy (SEM), sedimentation field flow fractionation, and photon correlation spectroscopy.

[0056] In one embodiment, the aqueous composition contains about 100 to about 500 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition contains about 150 to about 450 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition contains about 200 to about 400 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof. In a preferred embodiment, the aqueous composition contains about 250 to about 350 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof, for example about 300 mg / mL, in particular 300 mg / mL of rilpivirine.

[0057] In one embodiment, the amount of rilpivirine or a pharma- ceutically acceptable salt thereof in the aqueous composition is about 900 mg to about 28,800 mg (e.g., about 900 mg to about 14,400 mg, or about 900 mg to about 7,200 mg, or about 900 mg to about 4,500 mg, or about 900 mg to about 3,600 mg), preferably about 1,200 mg to about 14,400 mg, preferably about 1,350 mg to about 13,200 mg, preferably about 1,500 mg to about 12,000 mg (e.g., about 3,000 mg to about 12,000 mg), preferably about 1,800 mg to about 10,800 mg (e.g., about 2,700 mg to about 10,800 mg, or about 1,800 mg to about 3,600 mg), and most preferably about 1,800 mg to about 7,200 mg, or about 2,700 mg to about 4,500 mg. The "mg" indicated corresponds to mg of rilpivirine (i.e., rilpivirine in its free base form). Thus, by way of example, 1 mg of rilpivirine (i.e., rilpivirine in its free base form) is equivalent to 1.1 mg of rilpivirine hydrochloride.

[0058] In one embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (a) in the aqueous composition is from about 200:1 (w / w) to about 400:1 (w / w), or the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (b) in the aqueous composition is from about 2:1 (w / w) to about 30:1 (w / w).

[0059] In one embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (a) in the aqueous composition is from about 250:1 (w / w) to about 350:1 (w / w), or the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (b) in the aqueous composition is from about 3:1 (w / w) to about 20:1 (w / w).

[0060] In one embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (a) in the aqueous composition is from about 20:1 (w / w) to about 4000:1 (w / w), or the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (b) in the aqueous composition is from about 10:1 (w / w) to about 4000:1 (w / w).

[0061] In one embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (a) in the aqueous composition is from about 20:1 (w / w) to about 1000:1 (w / w), or the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (b) in the aqueous composition is from about 10:1 (w / w) to about 500:1 (w / w).

[0062] In a preferred embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (a) in the aqueous composition is from about 50:1 (w / w) to about 400:1 (w / w), or the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (b) in the aqueous composition is from about 10:1 (w / w) to about 20:1 (w / w).

[0063] In some embodiments of the present invention (e.g., embodiments 1-6), the aqueous composition comprises hyaluronidase (in embodiments 1a, 2a, 3a, hyaluronidase is optional). Hyaluronidase is an enzyme that degrades hyaluronic acid (HA) and reduces the viscosity of hyaluronan in the extracellular matrix, for example in the skin. This property allows it to be used to enhance the dispersion and absorption of injected active pharmaceutical ingredients and / or allow for larger subcutaneous doses. The enzymatic activity of hyaluronidase, including rHuPH20, can be defined by units per mL (U / mL) or total enzyme activity (U) in a particular formulation.

[0064] As used herein, the term "hyaluronidase" refers to any enzyme that degrades hyaluronic acid and reduces the viscosity of hyaluronan in the extracellular matrix.

[0065] In one embodiment, the hyaluronidase is a recombinant hyaluronidase. In a preferred embodiment, the hyaluronidase is a recombinant human hyaluronidase, such as rHuPH20. In one embodiment, rHuPH20 is defined by the amino acid sequence available under CAS Registry Number 757971-58-7. Further information regarding rHuPH20 is described in International Patent Publication No. WO 2004 / 078140. In one embodiment, the amino acid sequence of rHuPH20 comprises SEQ ID NO:1. In some embodiments, the hyaluronidase is a variant of rHuPH20 having an amino acid sequence of SEQ ID NO:2, i.e., rHuPH20 comprising residues 36-482 of wild-type human hyaluronidase. In some embodiments, the hyaluronidase is a variant of rHuPH20 having an amino acid sequence comprising SEQ ID NO:3. In some embodiments, the hyaluronidase is a variant of rHuPH20 having an amino acid sequence comprising SEQ ID NO:4. In some embodiments, the hyaluronidase is a variant of rHuPH20 having an amino acid sequence comprising SEQ ID NO:5.

[0066] [Table 1]

[0067] In one embodiment, the concentration of hyaluronidase in the aqueous composition is about 10 to about 10,000 U / mL, or about 100 to about 10,000 U / mL, or about 500 to about 10,000 U / mL, or about 500 to about 5000 U / mL, or about 500 to about 2500 U / mL, or about 1000 to about 2500 U / mL, or about 1500 to about 2500 U / mL. Preferably, the concentration of hyaluronidase in the aqueous composition is about 1800 to about 2200 U / mL (e.g., about 2000 U / mL).

[0068] In one embodiment, the concentration of hyaluronidase in the aqueous composition is about 4.5 to about 90 μg / mL, or about 4.5 to about 45 μg / mL, or about 4.5 to about 22.5 μg / mL, or about 9 to about 22.5 μg / mL, or about 13.5 to about 22.5 μg / mL. Preferably, the concentration of hyaluronidase in the aqueous composition is about 16.2 to about 19.8 μg / mL (e.g., about 18 μg / mL).

[0069] In one embodiment, the aqueous composition further comprises carboxymethylcellulose (CMC) or a derivative thereof, or a pharma- ceutically acceptable salt thereof. In one embodiment, the cellulose or derivative thereof in the aqueous composition is carboxymethylcellulose (CMC) or a derivative thereof, or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition further comprises CMC or a pharma- ceutically acceptable salt thereof, preferably the CMC is not crosslinked. In one embodiment, the cellulose or derivative thereof in the aqueous composition is CMC or a pharma- ceutically acceptable salt thereof, preferably the CMC is not crosslinked. In one embodiment, the CMC or a pharma- ceutically acceptable salt thereof is a pharma- ceutically acceptable salt of CMC. By pharma- ceutically acceptable salt of CMC is meant a salt in which the counterion is pharma- ceutically acceptable. Pharmaceutically acceptable salts are intended to include the therapeutically active non-toxic base addition salt forms that CMC can form. Preferred pharma- ceutically acceptable salts of CMC include sodium CMC and potassium CMC. In a particularly preferred embodiment, CMC or its pharmaceutically acceptable salt is CMC sodium, particularly non-crosslinked CMC sodium.In another embodiment, CMC or its pharmaceutically acceptable salt is CMC.The example of CMC that can be used in the present invention is carmellose sodium, 40MPa.s (parenteral grade), available from Ashland, and Blanose CMC 7 LF PH or Blanose 7 LP EP, available from Ashland.

[0070] CMC or a pharma- ceutically acceptable salt thereof can have any degree of substitution (DS). DS is the average number of carboxymethyl groups per cellulose unit. In a preferred embodiment, the DS is neutralized to a pH of about 0.4 to about 1.5. In one embodiment, CMC or a pharma- ceutically acceptable salt thereof has a DS of about 0.5 to about 1, for example, about 0.65 to about 0.95, for example, about 0.7.

[0071] In one embodiment, CMC or a pharma- ceutically acceptable salt thereof has a viscosity of about 10 mPas to about 100 MPa.s in a 1% (w / v) aqueous solution at room temperature. In one embodiment, CMC or a pharma- ceutically acceptable salt thereof has a viscosity of about 20 mPas to about 60 MPa.s in a 1% (w / v) aqueous solution at room temperature. In one embodiment, CMC or a pharma- ceutically acceptable salt thereof has a viscosity of about 30 mPas to about 50 MPa.s in a 1% (w / v) aqueous solution at room temperature, for example, about 40 MPa.s in a 1% (w / v) aqueous solution at room temperature.

[0072] In one embodiment, CMC or a pharma- ceutically acceptable salt thereof has a viscosity of about 10 MPa.s to about 100 MPa.s in a 2% (w / v) aqueous solution at room temperature. In one embodiment, CMC or a pharma- ceutically acceptable salt thereof has a viscosity of about 20 MPa.s to about 60 MPa.s in a 2% (w / v) aqueous solution at room temperature. In a preferred embodiment, CMC or a pharma- ceutically acceptable salt thereof has a viscosity of about 30 MPa.s to about 50 MPa.s in a 2% (w / v) aqueous solution at room temperature, for example, about 40 MPa.s in a 2% (w / v) aqueous solution at room temperature.

[0073] In one embodiment, the molecular weight of CMC or a pharma- ceutically acceptable salt thereof is about 50 kDa to about 2000 kDa. In one embodiment, the molecular weight of CMC or a pharma- ceutically acceptable salt thereof is about 50 kDa to about 1,000 kDa. In one embodiment, the molecular weight of CMC or a pharma- ceutically acceptable salt thereof is about 70 kDa to about 900 kDa. In a preferred embodiment, the molecular weight of CMC or a pharma- ceutically acceptable salt thereof is about 90 kDa to about 750 kDa. In a most preferred embodiment, the molecular weight of CMC or a pharma- ceutically acceptable salt thereof is about 90 kDa to about 110 kDa, for example about 90 kDa.

[0074] The inventors have surprisingly found that the addition of cellulose or a derivative thereof, such as CMC or a derivative thereof, or a pharma- ceutically acceptable salt thereof, and / or an amino acid or a pharma- ceutically acceptable salt thereof, to the aqueous composition of the present invention comprising hyaluronidase increases the melting temperature (T m ) (Example 6a), which indicates that the storage stability is improved.

[0075] The inventors have surprisingly found that the addition of cellulose or a derivative thereof, such as CMC or a derivative thereof, or a pharma- ceutically acceptable salt thereof, to the aqueous composition of the present invention containing hyaluronidase results in reduced loss of hyaluronidase activity, reduced aggregation of hyaluronidase, and / or reduced oxidation of hyaluronidase after storage under stress test conditions (Example 9), indicating improved storage stability.

[0076] In one embodiment, the aqueous composition of the present invention may be shelf-stable, as defined elsewhere herein, when stored at refrigerated temperatures, e.g., about 2-8°C, e.g., 5°C, for one of the periods defined herein. In one embodiment, the aqueous composition of the present invention may be shelf-stable, as defined elsewhere herein, when stored at about room temperature, e.g., about 25°C, for one of the periods defined herein. In one embodiment, the aqueous composition of the present invention may be shelf-stable, as defined elsewhere herein, when stored at about 30°C, for one of the periods defined herein.

[0077] In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 100 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 75 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 50 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 25 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 10 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 7 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 5 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 0.5 mg / mL to about 5 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In a more preferred embodiment, the aqueous composition comprises about 0.5 mg / mL to about 3 mg / mL, for example about 3 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In a preferred embodiment, the aqueous composition comprises about 0.5 mg / mL to about 1.5 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In a more preferred embodiment, the aqueous composition comprises about 1 mg / mL to about 1.5 mg / mL, for example about 1 mg / mL of CMC or a pharma- ceutically acceptable salt thereof.

[0078] In a preferred embodiment, the CMC or a pharma- ceutically acceptable salt thereof is sodium CMC, and the aqueous composition comprises sodium CMC in any one of the amounts specified in the immediately preceding paragraph. In a preferred embodiment, the CMC or a pharma- ceutically acceptable salt thereof is sodium CMC, and the aqueous composition or the reconstituted aqueous composition has any of the degrees of substitution, viscosities, and molecular weights specified herein.

[0079] In one embodiment, the aqueous composition contains about 0.002 mg to about 5 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase.

[0080] In one embodiment, the aqueous composition comprises about 0.01 mg to about 2 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. In one embodiment, the aqueous composition comprises about 0.02 mg to about 1 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. In one embodiment, the aqueous composition comprises about 0.02 mg to about 0.5 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. In one embodiment, the aqueous composition comprises about 0.02 mg to about 0.1 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. In a preferred embodiment, the aqueous composition comprises about 0.03 mg to about 0.07 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. In another preferred embodiment, the aqueous composition contains about 0.01 mg to about 0.25 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase, for example, about 0.05 mg to about 0.15 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase, for example, 0.05 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase, or for example, about 0.15 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase.

[0081] In a preferred embodiment, the CMC or a pharma- ceutically acceptable salt thereof is CMC sodium, and the aqueous composition comprises any one of the ratios of CMC sodium to hyaluronidase specified in the immediately preceding paragraph.

[0082] In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 100 mg / mL of an amino acid or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 1 mg / mL to about 100 mg / mL of an amino acid or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 5 mg / mL to about 100 mg / mL of an amino acid or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 5 mg / mL to about 80 mg / mL of an amino acid or a pharma- ceutically acceptable salt thereof. In a preferred embodiment, the aqueous composition comprises about 5 mg / mL to about 60 mg / mL of an amino acid or a pharma- ceutically acceptable salt thereof. In another preferred embodiment, the aqueous composition comprises about 15 mg / mL to about 30 mg / mL or about 15 mg / mL to about 25 mg / mL of an amino acid or a pharma- ceutically acceptable salt thereof, for example about 20 mg / mL.

[0083] In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 100 mg / mL of glycine or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 1 mg / mL to about 100 mg / mL of glycine or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 5 mg / mL to about 50 mg / mL of glycine or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 5 mg / mL to about 20 mg / mL of glycine or a pharma- ceutically acceptable salt thereof. In a preferred embodiment, the aqueous composition comprises about 10 mg / mL to about 15 mg / mL of glycine or a pharma- ceutically acceptable salt thereof.

[0084] In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 100 mg / mL of arginine or arginine hydrochloride. In one embodiment, the aqueous composition comprises about 1 mg / mL to about 100 mg / mL of arginine or arginine hydrochloride. In one embodiment, the aqueous composition comprises about 5 mg / mL to about 70 mg / mL of arginine or arginine hydrochloride. In one embodiment, the aqueous composition comprises about 5 mg / mL to about 50 mg / mL of arginine or arginine hydrochloride. In a preferred embodiment, the aqueous composition comprises about 15 mg / mL to about 25 mg / mL of arginine or arginine hydrochloride. In another preferred embodiment, the aqueous composition comprises about 20 mg / mL of arginine or arginine hydrochloride.

[0085] In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 100 mg / mL of arginine hydrochloride. In one embodiment, the aqueous composition comprises about 1 mg / mL to about 100 mg / mL of arginine hydrochloride. In one embodiment, the aqueous composition comprises about 5 mg / mL to about 70 mg / mL of arginine hydrochloride. In one embodiment, the aqueous composition comprises about 5 mg / mL to about 50 mg / mL of arginine hydrochloride. In a preferred embodiment, the aqueous composition comprises about 15 mg / mL to about 25 mg / mL of arginine hydrochloride, for example, about 20 mg / mL of arginine hydrochloride.

[0086] In a preferred embodiment, the aqueous composition comprises arginine or arginine hydrochloride (as an amino acid) and CMC or a pharma- ceutically acceptable salt thereof. In a more preferred embodiment, the aqueous composition comprises arginine hydrochloride (as an amino acid) and CMC sodium.

[0087] In one embodiment, the aqueous composition further comprises a sugar or sugar alcohol. Suitable sugars and sugar alcohols include mannitol, lactose, glucose, sucrose, trehalose, sorbitol, dextrose, fructose, maltose, xylitol and raffinose. Preferably, the sugar or sugar alcohol is selected from glucose and sucrose. More preferably, the sugar or sugar alcohol is sucrose. In one embodiment, the aqueous composition further comprises a sugar or sugar alcohol and an amino acid or a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable salt of a sugar, sugar alcohol or amino acid means that the counter ion is pharmaceutically acceptable. A pharmaceutically acceptable salt is meant to include the therapeutically active non-toxic acid and base addition salt forms that a particular sugar, sugar alcohol, or amino acid can form. Suitable amino acids or pharmaceutically acceptable salts thereof include arginine, glycine and histidine or a pharmaceutically acceptable salt thereof. In one embodiment, the amino acid or its pharmaceutically acceptable salt is selected from arginine and glycine or its pharmaceutically acceptable salt. In a preferred embodiment, the amino acid or its pharmaceutically acceptable salt is arginine (e.g., arginine hydrochloride). In one embodiment, the aqueous composition further comprises a sugar or sugar alcohol and CMC or its pharmaceutically acceptable salt.

[0088] In a preferred embodiment, the aqueous composition further comprises sucrose (as a sugar or sugar alcohol) and CMC or a pharma- ceutically acceptable salt thereof. In a more preferred embodiment, the aqueous composition further comprises sucrose (as a sugar or sugar alcohol) and CMC sodium.

[0089] In one embodiment, the aqueous composition does not include glucose, eg, it does not include glucose monohydrate.

[0090] In one embodiment, the aqueous composition comprises from about 0.1 mg / mL to about 100 mg / mL of a sugar or sugar alcohol. In one embodiment, the aqueous composition comprises from about 1 mg / mL to about 100 mg / mL of a sugar or sugar alcohol. In one embodiment, the aqueous composition comprises from about 5 mg / mL to about 100 mg / mL of a sugar or sugar alcohol. In a preferred embodiment, the aqueous composition comprises from about 10 mg / mL to about 100 mg / mL of a sugar or sugar alcohol. In a more preferred embodiment, the aqueous composition comprises from about 45 mg / mL to about 55 mg / mL of a sugar or sugar alcohol, for example about 50 mg / mL of a sugar or sugar alcohol.

[0091] In one embodiment, the aqueous composition comprises, for example, glucose and / or glucose monohydrate as the sugar or sugar alcohol.

[0092] In one embodiment, the aqueous composition comprises from about 0.1 mg / mL to about 100 mg / mL of glucose monohydrate. In one embodiment, the aqueous composition comprises from about 1 mg / mL to about 100 mg / mL of glucose monohydrate. In one embodiment, the aqueous composition comprises from about 5 mg / mL to about 50 mg / mL of glucose monohydrate. In a preferred embodiment, the aqueous composition comprises from about 10 mg / mL to about 30 mg / mL of glucose monohydrate.

[0093] In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 100 mg / mL of sucrose. In one embodiment, the aqueous composition comprises about 1 mg / mL to about 100 mg / mL of sucrose. In one embodiment, the aqueous composition comprises about 10 mg / mL to about 100 mg / mL of sucrose. In a preferred embodiment, the aqueous composition comprises about 40 mg / mL to about 70 mg / mL of sucrose. In a more preferred embodiment, the aqueous composition comprises about 45 mg / mL to about 55 mg / mL, for example about 50 mg / mL of sucrose. In one embodiment, the ratio of cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof to a sugar or sugar alcohol is about 1:2 (w / w) to about 1:1000 (w / w). In one embodiment, the ratio of cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof to a sugar or sugar alcohol is about 1:2 (w / w) to about 1:500 (w / w). In one embodiment, the ratio of cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof to a sugar or sugar alcohol is about 1:2 (w / w) to about 1:200 (w / w). In one embodiment, the ratio of cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof to a sugar or sugar alcohol is about 1:2 (w / w) to about 1:100 (w / w). In one embodiment, the ratio of cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof to a sugar or sugar alcohol is about 1:10 (w / w) to about 1:100 (w / w). In a preferred embodiment, the ratio of cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof to a sugar or sugar alcohol is about 1:15 (w / w) to about 1:60 (w / w), for example, 1:16 (w / w) or 1:50 (w / w).

[0094] In one embodiment, the ratio of sodium CMC to sucrose is about 1:2 (w / w) to about 1:1000 (w / w). In one embodiment, the ratio of sodium CMC to sucrose is about 1:2 (w / w) to about 1:500 (w / w). In one embodiment, the ratio of sodium CMC to sucrose is about 1:2 (w / w) to about 1:200 (w / w). In one embodiment, the ratio of sodium CMC to sucrose is about 1:2 (w / w) to about 1:100 (w / w). In one embodiment, the ratio of sodium CMC to sucrose is about 1:10 (w / w) to about 1:100 (w / w). In a preferred embodiment, the ratio of sodium CMC to sucrose is about 1:15 (w / w) to about 1:60 (w / w), for example, 1:16 (w / w) or 1:50 (w / w).

[0095] In one embodiment, the aqueous composition further comprises one or more surface modifiers. When the rilpivirine or a pharma- ceutically acceptable salt thereof is in the form of a particle as defined herein, the one or more surface modifiers are adsorbed to the surface of the particle.

[0096] The surface modifier may be selected from known organic and inorganic pharmaceutical excipients, including various polymers, low molecular weight oligomers, natural products, and surfactants. Specific surface modifiers that may be used in the present invention may include non-ionic surfactants and anionic surfactants. Representative examples of surface modifiers include gelatin, casein, lecithin, salts or acid forms of negatively charged phospholipids (phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphoric acid, and salts thereof, such as alkali metal salts, e.g., their sodium salts, e.g., sodium egg phosphatidylglycerol, such as products available under the trade name Lipoid™ EPG), gum acacia, stearic acid, benzalkonium chloride, polyoxyethylene alkyl ethers, e.g., macrogol ethers, such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, colloidal silicon dioxide, dodecyl sulfate, bile salts, such as sodium taurocholate, sodium desoxytaurocholate, sodium desoxycholate, methylcellulose ... tylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminosilicate, polyvinyl alcohol (PVA), poloxamers such as Pluronic® F68, F108 and F127, which are block copolymers of ethylene oxide and propylene oxide, tyloxapol, vitamin E-TGPS (α-tocopheryl polyethylene glycol, in particular α-tocopheryl polyethylene glycol 1000), poloxamines such as Tetronic® 908 (T908), which is a tetrafunctional block copolymer derived from the sequential addition of ethylene oxide and propylene oxide to ethylenediamine, dextran, lecithin, dioctyl esters of sodium sulfosuccinate, such as those sold under the trade name AerosolExamples of suitable surface modifiers include those sold under the tradenames Crodesta™ F110 or Crodesta™ SL-40, hexyldecyltrimethylammonium chloride (CTAC), polyvinylpyrrolidone (PVP), and the like. If desired, two or more surface modifiers may be used in combination.

[0097] In one embodiment, the surface modifier is selected from poloxamers, α-tocopheryl polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid esters, and salts of negatively charged phospholipids or their acid forms. In one embodiment, the surface modifier is selected from polyoxyethylene sorbitan fatty acid esters such as Pluronic™ F108, Vitamin E TGPS (α-tocopheryl polyethylene glycol succinate, particularly α-tocopheryl polyethylene glycol 1000 succinate), Tween™ 80, and phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphoric acid, and salts thereof such as alkali metal salts, for example, their sodium salts, for example, egg phosphatidylglycerol sodium, such as the product available under the trade name Lipoid™ EPG.

[0098] In a preferred embodiment, the surface modifier is a poloxamer, in particular Pluronic™ F108. Pluronic™ F108 corresponds to poloxamer 338 and has the formula HO-[CH2CH2O] x-[CH(CH3)CH2O] y -[CH2CH2O] z -H, where the average 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 / F 108. In one embodiment, the surface modifier comprises a combination of a polyoxyethylene sorbitan fatty acid ester and a phosphatidylglycerol salt, particularly sodium egg phosphatidylglycerol.

[0099] In one embodiment, the aqueous composition comprises from about 0.1 mg / mL to about 100 mg / mL of poloxamer. In one embodiment, the aqueous composition comprises from about 5 mg / mL to about 100 mg / mL of poloxamer. In one embodiment, the aqueous composition comprises from about 5 mg / mL to about 70 mg / mL of poloxamer. In one embodiment, the aqueous composition comprises from about 5 mg / mL to about 60 mg / mL of poloxamer.

[0100] In one embodiment, the aqueous composition comprises about 15 mg / mL to about 35 mg / mL, for example about 20 mg / mL to about 30 mg / mL of the poloxamer. In one embodiment, the aqueous composition comprises about 15 mg / mL to about 25 mg / mL, for example about 20 mg / mL of the poloxamer. In one embodiment, the aqueous composition comprises about 25 mg / mL to about 35 mg / mL, for example about 30 mg / mL of the poloxamer.

[0101] In one embodiment, the aqueous composition contains from about 20 mg / mL to about 60 mg / mL of the poloxamer. In one embodiment, the aqueous composition contains from about 25 mg / mL to about 60 mg / mL of the poloxamer. In a preferred embodiment, the aqueous composition contains from about 40 mg / mL to about 60 mg / mL of the poloxamer, for example about 50 mg / mL.

[0102] In one embodiment, the aqueous composition comprises a poloxamer and rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, where the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to the poloxamer is about 10:1 or greater when the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less.In one embodiment, the aqueous composition comprises a poloxamer and rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, where the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to the poloxamer is about 10:1 to about 60:1 when the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. In one embodiment, the aqueous composition comprises a poloxamer and rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, where the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to the poloxamer is about 10:1 to about 30:1 when the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. In one embodiment, the aqueous composition comprises a poloxamer and rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, where the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to the poloxamer is about 10:1 to about 20:1 when the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. In one embodiment, the aqueous composition comprises a poloxamer and rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, where the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 10:1 to about 15:1 when the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. In a preferred embodiment, the aqueous composition comprises a poloxamer and rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, where the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 15:1 when the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less.In a preferred embodiment, the aqueous composition comprises a poloxamer and rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, where the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 10:1, where the ratio is by weight, and where the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less.

[0103] In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is less than about 10:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1 μm to about 10 μm, about 2 μm to about 9 μm, about 3 μm to about 8 μm, or about 3 μm to about 7 μm. In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is from about 10:1 to about 3:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of from about 1 μm to about 10 μm, from about 2 μm to about 9 μm, from about 3 μm to about 8 μm, or from about 3 μm to about 7 μm. In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is from about 10:1 to about 4:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of from about 1 μm to about 10 μm, from about 2 μm to about 9 μm, from about 3 μm to about 8 μm, or from about 3 μm to about 7 μm. In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is from about 10:1 to about 6:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of from about 1 μm to about 10 μm, from about 2 μm to about 9 μm, from about 3 μm to about 8 μm, or from about 3 μm to about 7 μm. In a preferred embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 6:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1 μm to about 10 μm, about 2 μm to about 9 μm, about 3 μm to about 8 μm, or about 3 μm to about 7 μm, e.g., about 4 μm to about 6 μm, e.g., about 4 μm or about 5 μm or about 6 μm. This ratio is by weight.

[0104] In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to the poloxamer is about 10:1 or less, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to the poloxamer is about 10:1 to about 3:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 10:1 to about 4:1, and the rilpivirine or a pharma-ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. In one embodiment, the aqueous composition comprises rilpivirine or a pharma-ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition and a poloxamer, wherein the ratio of rilpivirine or a pharma-ceutically acceptable salt thereof to poloxamer is about 10:1 to about 6:1, and the rilpivirine or a pharma-ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. In a preferred embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 6:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less, said ratio being by weight.

[0105] In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to the poloxamer is about 10:1 or greater, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to the poloxamer is about 10:1 to about 60:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to the poloxamer is about 10:1 to about 30:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to the poloxamer is about 10:1 to about 20:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 10:1 to about 15:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm. In a preferred embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 15:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm, e.g., about 500 nm to about 700 nm.In a preferred embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 10:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm, e.g., about 500 nm to about 700 nm, this ratio being by weight.

[0106] In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 10:1 or less, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 10:1 to about 3:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to the poloxamer is about 10:1 to about 4:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to the poloxamer is about 10:1 to about 6:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm. In a preferred embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 6:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm, e.g., about 500 nm to about 700 nm, this ratio being by weight.

[0107] In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and the surface modifier is about 1:1 to about 40:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and the surface modifier is about 1:1 to about 30:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and the surface modifier is about 1:1 to about 20:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and the surface modifier is about 5:1 to about 15:1, for example, about 10:1. The surface modifier is preferably a poloxamer, for example, poloxamer 338.

[0108] In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and the surface modifier is about 5:1 to about 25:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and the surface modifier is about 10:1 to about 20:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and the surface modifier is about 13:1 to about 17:1, for example, about 15:1. The surface modifier is preferably a poloxamer, for example, poloxamer 338.

[0109] In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof to the surface modifier is from about 1:2 to about 20:1, in particular from about 1:1 to about 10:1, such as from about 4:1 to about 8:1, for example from about 4:1 to about 6:1, preferably about 6:1. The surface modifier is preferably a poloxamer, for example poloxamer 338.

[0110] In one embodiment, the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof as defined herein in the form of particles suspended in the aqueous composition, and comprises one or more surface modifiers as defined herein, wherein the amount of rilpivirine or a pharma- ceutically acceptable salt thereof is at least about 50% by weight of the particles, at least about 80% by weight of the particles, at least about 85% by weight of the particles, at least about 90% by weight of the particles, at least about 95% by weight of the particles, or at least about 99% by weight of the particles, particularly in the range of 80%-90% by weight of the particles, or in the range of 85%-90% by weight of the particles.

[0111] Aqueous compositions include water, for example, sterile water for injection.

[0112] In one embodiment, the aqueous composition further comprises a buffering agent and / or a pH adjusting agent. A particular buffering agent is a salt of a weak acid. The buffering agents and pH adjusting agents 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 / acid, diethanolamine, glucono delta lactone, hydrochloric acid, hydrogen bromide, lysine, methanesulfonic acid, monoethanolamine, sodium hydroxide, tromethamine, gluconic acid, glyceric acid, glutaric acid, glutamic acid, ethylenediaminetetraacetic acid (EDTA), triethanolamine, and mixtures thereof. In one embodiment, the buffering agent is a sodium phosphate buffer, such as sodium dihydrogen phosphate monohydrate. In one embodiment, the pH adjusting agent is sodium hydroxide. In a preferred embodiment, the aqueous composition comprises a buffering agent and a pH adjusting agent, wherein the buffering agent is sodium dihydrogen phosphate monohydrate and the pH adjusting agent is sodium hydroxide.

[0113] In one embodiment, the pH of the aqueous composition is about 5 to about 7. In one embodiment, the pH of the aqueous composition is about 6 to about 7. In one embodiment, the pH of the aqueous composition is about 6 to about 6.5. In a preferred embodiment, the pH of the aqueous composition is about 6. The pH of the aqueous composition can be adjusted, for example, by varying the type and / or amount of a buffer and / or pH adjusting agent present in the aqueous composition.

[0114] In one embodiment, the aqueous composition further comprises a chelating agent. In one embodiment, the chelating agent is selected from sodium citrate, sodium EDTA, citric acid and malic acid. In a preferred embodiment, the chelating agent is citric acid, e.g., citric acid monohydrate.

[0115] In one embodiment, the aqueous composition further comprises an antioxidant. In one embodiment, the antioxidant is methionine. In one embodiment, the aqueous composition comprises about 1.0 mg / mL to about 2.0 mg / mL, e.g., about 1.5 mg / mL, of an antioxidant (e.g., methionine).

[0116] In one embodiment, the aqueous composition is isotonic.

[0117] In one embodiment, the aqueous composition does not include a tonicity agent.

[0118] In one embodiment, the aqueous composition does not include polyvinylpyrrolidone (PVP).

[0119] In one embodiment, the aqueous composition is substantially free of glucose, for example, containing less than about 10% w / w glucose, or less than about 5% w / w glucose, or preferably less than about 1% w / w glucose.

[0120] In one embodiment, the aqueous composition of the present invention may be packaged with an inert gas, which may be, for example, nitrogen.

[0121] In certain embodiments of the first aspect, the present invention relates to an aqueous composition comprising: (i) rilpivirine or a pharma- ceutically acceptable salt thereof; (ii) hyaluronidase; and (iii) 0.001 to 100 mg / mL of cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof.

[0122] In certain embodiments of the first aspect, the present invention relates to an aqueous composition comprising: (i) rilpivirine or a pharma- ceutically acceptable salt thereof; (ii) hyaluronidase; (iii) 0.001-100 mg / mL of cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof; and (iv) a sugar.

[0123] In a particular embodiment of the first aspect, the present invention provides a method for treating rheumatoid arthritis comprising administering to the patient a therapeutically effective amount of rilpivirine or a pharma- ceutical agent comprising: (i) rilpivirine or a pharma- ceutical acceptable salt thereof; (ii) hyaluronidase; and (iii) 0.001 to 100 mg / mL of hyaluronidase. (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof, and (b) An aqueous composition comprising an amino acid or a pharma- ceutically acceptable salt thereof.

[0124] In certain embodiments, the aqueous composition comprises: Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof; CMC or a pharma- ceutical acceptable salt thereof; The pH of the aqueous composition is about 6 to about 7. Optionally, the aqueous composition further comprises one or more components selected from a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide, and optionally, the aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0125] In certain embodiments, the aqueous composition comprises: Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof; Glucose monohydrate; CMC or a pharma- ceutical acceptable salt thereof; The pH of the aqueous composition is about 6 to about 7. Optionally, the aqueous composition further comprises one or more components selected from a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide, and optionally, the aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0126] In certain embodiments, the aqueous composition comprises: Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof; an amino acid or a pharma- ceutically acceptable salt thereof; The pH of the aqueous composition is about 6 to about 7. Optionally, the aqueous composition further comprises one or more components selected from a surfactant, such as a poloxamer, a buffer, such as sodium dihydrogen phosphate, a chelating agent, such as citric acid, and a pH adjuster, such as sodium hydroxide, and further optionally, the aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0127] In certain embodiments, the aqueous composition comprises: Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof; Glycine, The pH of the aqueous composition is about 6 to about 7. Optionally, the aqueous composition further comprises one or more components selected from a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide, and further optionally, the aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0128] In certain embodiments, the aqueous composition comprises: Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof; glycine or a pharma- ceutically acceptable salt thereof; The pH of the aqueous composition is about 6 to about 7. Optionally, the aqueous composition further comprises one or more components selected from a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide, and further optionally, the aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0129] In certain embodiments, the aqueous composition comprises: Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof; Contains arginine, The pH of the aqueous composition is about 6 to about 7. Optionally, the aqueous composition further comprises one or more components selected from a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide, and further optionally, the aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0130] In certain embodiments, the aqueous composition comprises: Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof; arginine hydrochloride, The pH of the aqueous composition is about 6 to about 7. Optionally, the aqueous composition further comprises one or more components selected from a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide, and further optionally, the aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0131] In certain embodiments, the aqueous composition comprises: Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof; arginine or a pharma- ceutical acceptable salt thereof; The pH of the aqueous composition is about 6 to about 7. Optionally, the aqueous composition further comprises one or more components selected from a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide, and further optionally, the aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0132] In certain embodiments, the aqueous composition comprises: Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof; Sucrose, CMC or a pharma- ceutical acceptable salt thereof; The pH of the aqueous composition is about 6 to about 7. Optionally, the aqueous composition further comprises one or more components selected from a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide, and further optionally, the aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0133] In certain embodiments, the aqueous composition comprises: Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof; Sucrose, Contains sodium CMC, The pH of the aqueous composition is about 6 to about 7. Optionally, the aqueous composition further comprises one or more ingredients selected from a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0134] In certain embodiments, the aqueous composition comprises: Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof; arginine or a pharma- ceutically acceptable salt thereof; CMC or a pharma- ceutical acceptable salt thereof; The pH of the aqueous composition is about 6 to about 7. Optionally, the aqueous composition further comprises one or more ingredients selected from a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0135] In certain embodiments, the aqueous composition comprises: Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof; arginine or a pharma- ceutically acceptable salt thereof; Contains sodium CMC, The pH of the aqueous composition is about 6 to about 7. Optionally, the aqueous composition further comprises one or more ingredients selected from a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0136] In certain embodiments, the aqueous composition comprises: Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof; Arginine hydrochloride, CMC or a pharma- ceutical acceptable salt thereof; The pH of the aqueous composition is about 6 to about 7. Optionally, the aqueous composition further comprises one or more ingredients selected from a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0137] In certain embodiments, the aqueous composition comprises: Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof; Arginine hydrochloride, Contains sodium CMC, The pH of the aqueous composition is about 6 to about 7. Optionally, the aqueous composition further comprises one or more ingredients selected from a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0138] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, Contains sodium CMC, The pH of the aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0139] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, Contains sodium CMC, The pH of the aqueous composition is from about 6 to about 6.5. the aqueous composition comprising from about 0.002 mg of CMC sodium per 100 U of rHuPH20 to about 5 mg of CMC sodium per 100 U of rHuPH20; Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0140] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, Contains sodium CMC, The pH of the aqueous composition is about 6 to about 6.5. the aqueous composition comprising from about 0.01 mg of CMC sodium per 100 U of rHuPH20 to about 0.25 mg of CMC sodium per 100 U of rHuPH20; Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0141] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, Sodium CMC, and and a sugar or sugar alcohol, The pH of the aqueous composition is about 6 to about 6.5. Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0142] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, Sodium CMC, and glucose monohydrate and / or sucrose, The pH of the aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0143] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, Sodium CMC, and and sucrose, The pH of the aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0144] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, Sodium CMC, and arginine or a pharma- ceutical acceptable salt thereof; The pH of the aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0145] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, Sodium CMC, and arginine hydrochloride, The pH of the aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0146] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, Sodium CMC, and glucose monohydrate and / or sucrose, The pH of the aqueous composition is from about 6 to about 6.5. the aqueous composition comprising from about 0.0025 mg of CMC sodium per 100 U of rHuPH20 to about 5 mg of CMC sodium per 100 U of rHuPH20; Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0147] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, Sodium CMC, and glucose monohydrate and / or sucrose, The pH of the aqueous composition is from about 6 to about 6.5. the aqueous composition comprises about 0.01 mg of CMC sodium per 100 U of rHuPH20 to about 0.25 mg of CMC sodium per 100 U of rHuPH20, e.g., 0.05 mg of CMC sodium per 100 U of rHuPH20 or 0.15 mg of CMC sodium per 100 U of rHuPH20; Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0148] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, Sodium CMC, and and sucrose, The pH of the aqueous composition is from about 6 to about 6.5. the aqueous composition comprises about 0.01 mg of CMC sodium per 100 U of rHuPH20 to about 0.25 mg of CMC sodium per 100 U of rHuPH20, e.g., 0.05 mg of CMC sodium per 100 U of rHuPH20 or 0.15 mg of CMC sodium per 100 U of rHuPH20; Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0149] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, Sodium CMC, and arginine or a pharma- ceutical acceptable salt thereof; The pH of the aqueous composition is from about 6 to about 6.5. the aqueous composition comprises about 0.01 mg of CMC sodium per 100 U of rHuPH20 to about 0.25 mg of CMC sodium per 100 U of rHuPH20, e.g., 0.05 mg of CMC sodium per 100 U of rHuPH20 or 0.15 mg of CMC sodium per 100 U of rHuPH20; Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0150] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, Sodium CMC, and arginine hydrochloride, The pH of the aqueous composition is from about 6 to about 6.5. the aqueous composition comprises about 0.01 mg of CMC sodium per 100 U of rHuPH20 to about 0.25 mg of CMC sodium per 100 U of rHuPH20, e.g., 0.05 mg of CMC sodium per 100 U of rHuPH20 or 0.15 mg of CMC sodium per 100 U of rHuPH20; Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0151] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, and an amino acid or a pharma- ceutically acceptable salt thereof; The pH of the aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0152] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, and Arginine HCl, The pH of the aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0153] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, and an amino acid or a pharma- ceutically acceptable salt thereof, and a sugar or a sugar alcohol; The pH of the aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0154] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, and an amino acid or a pharma- ceutically acceptable salt thereof, and a sugar or a sugar alcohol; The pH of the aqueous composition is from about 6 to about 6.5. the ratio of rilpivirine to sugar or sugar alcohol and amino acid or a pharma- ceutically acceptable salt thereof is about 2:1 (w / w) to about 30:1 (w / w); Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0155] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine, and an amino acid or a pharma- ceutically acceptable salt thereof and a sugar or a sugar alcohol; The pH of the aqueous composition is from about 6 to about 6.5. the ratio of rilpivirine to sugar or sugar alcohol and amino acid or a pharma- ceutically acceptable salt thereof is about 5:1 (w / w) to about 16:1 (w / w); Optionally, the aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0156] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine in the form of particles suspended in an aqueous composition; Sodium CMC, Sucrose, and Poloxamer 338, Optionally, when rilpivirine has a Dv90 of about 1600 nm or less, the ratio of rilpivirine to poloxamer 338 is about 10:1 or more.

[0157] In certain embodiments, the aqueous composition comprises: Approximately 1800U / mL to approximately 2200U / mL of rHuPH20, about 250 to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition; About 0.5 mg / mL to about 5 mg / mL of CMC sodium; About 45 mg / mL to about 55 mg / mL of sucrose, and and about 10 mg / mL to about 60 mg / mL of poloxamer 338; Optionally, when the aqueous composition comprises about 40 mg / mL to about 60 mg / mL, e.g., about 50 mg / mL, of poloxamer 338, the rilpivirine has a Dv90 of about 3 μm to about 7 μm, e.g., about 6 μm. In another particular embodiment, the Dv90 is about 5 μm.

[0158] In certain embodiments, the aqueous composition comprises: Approximately 1800U / mL to approximately 2200U / mL of rHuPH20, about 250 to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition; About 0.5 mg / mL to about 5 mg / mL of CMC sodium; About 45 mg / mL to about 55 mg / mL of sucrose, and and about 10 mg / mL to about 60 mg / mL of poloxamer 338; Optionally, the aqueous composition comprises about 40 mg / mL to about 60 mg / mL, for example about 50 mg / mL, of poloxamer 338, and the rilpivirine has a Dv90 of about 500 nm to 1600 nm.

[0159] In certain embodiments, the aqueous composition comprises: Approximately 1800U / mL to approximately 2200U / mL of rHuPH20, about 250 to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition; About 0.5 mg / mL to about 5 mg / mL of CMC sodium; About 45 mg / mL to about 55 mg / mL of sucrose, and and about 10 mg / mL to about 60 mg / mL of poloxamer 338, Optionally, when the aqueous composition comprises about 20 mg / mL to about 30 mg / mL of poloxamer 338, the rilpivirine has a Dv90 of about 500 nm to 1600 nm.

[0160] In certain embodiments, the aqueous composition comprises: Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition; About 1 mg / mL to about 3 mg / mL of CMC sodium; About 50 mg / mL sucrose, and and about 50 mg / mL of poloxamer 338; Rilpivirine has a Dv90 of about 4 μm to about 6 μm, for example about 6 μm, hi another particular embodiment, the Dv90 is about 5 μm.

[0161] In certain embodiments, the aqueous composition comprises: Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition; About 1 mg / mL to about 3 mg / mL of CMC sodium; About 50 mg / mL sucrose, and and about 50 mg / mL of poloxamer 338; Rilpivirine has a Dv90 of about 500 nm to about 1600 μm.

[0162] In certain embodiments, the aqueous composition comprises: Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition; About 1 mg / mL to about 3 mg / mL of CMC sodium; About 50 mg / mL sucrose, and and about 20 mg / mL to about 30 mg / mL of poloxamer 338, Rilpivirine has a Dv90 of about 500 nm to about 1600 μm.

[0163] In certain embodiments, the aqueous composition comprises: rHuPH20 and Rilpivirine in the form of particles suspended in an aqueous composition; Sodium CMC, Arginine HCl, and Poloxamer 338, Optionally, when rilpivirine has a Dv90 of about 1600 nm or less, the weight ratio of rilpivirine to poloxamer 338 is about 10:1 or more.

[0164] In certain embodiments, the aqueous composition comprises: Approximately 1800U / mL to approximately 2200U / mL of rHuPH20, about 250 to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition; About 0.5 mg / mL to about 5 mg / mL of CMC sodium; Arginine HCl at about 15 mg / mL to about 25 mg / mL, and and about 10 mg / mL to about 60 mg / mL of poloxamer 338, Optionally, when rilpivirine has a Dv90 of about 1600 nm or less, the weight ratio of rilpivirine to poloxamer 338 is about 10:1 or more.

[0165] In certain embodiments, the aqueous composition comprises: Approximately 1800U / mL to approximately 2200U / mL of rHuPH20, about 250 to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition; About 0.5 mg / mL to about 5 mg / mL of CMC sodium; Arginine HCl at about 15 mg / mL to about 25 mg / mL, and and about 10 mg / mL to about 60 mg / mL of poloxamer 338, Optionally, when rilpivirine has a Dv90 of about 1600 nm or less, the weight ratio of rilpivirine to poloxamer 338 is about 10:1 or less.

[0166] In certain embodiments, the aqueous composition comprises: Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition; About 1 mg / mL to about 3 mg / mL of CMC sodium; Arginine HCl at about 20 mg / mL, and and about 50 mg / mL of poloxamer 338; Rilpivirine has a Dv90 of about 4 μm to about 6 μm, for example about 6 μm, hi another particular embodiment, the Dv90 is about 5 μm.

[0167] In certain embodiments, the aqueous composition comprises: Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition; About 1 mg / mL to about 3 mg / mL of CMC sodium; Arginine HCl at about 20 mg / mL, and and about 50 mg / mL of poloxamer 338; Rilpivirine has a Dv90 of about 500 nm to 1600 μm.

[0168] In certain embodiments, the aqueous composition comprises: Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition; About 1 mg / mL to about 3 mg / mL of CMC sodium; Arginine HCl at about 20 mg / mL, and and about 20 mg / mL to about 30 mg / mL of poloxamer 338, Rilpivirine has a Dv90 of approximately 500 nm to 1600 nm.

[0169] In certain embodiments, the aqueous composition comprises: Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition; About 1 mg / mL to about 3 mg / mL of CMC sodium; Arginine HCl at about 20 mg / mL, and Approximately 50 mg / mL of poloxamer 338; Approximately 2 mg / mL NaH2PO4·H2O, Approximately 1 mg / mL citric acid·H2O, Sodium hydroxide (appropriate amount for pH 6), and Includes water (1mL) Rilpivirine has a Dv90 of about 4 μm to about 6 μm, for example about 6 μm, hi another particular embodiment, the Dv90 is about 5 μm.

[0170] In certain embodiments, the aqueous composition comprises: Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition; About 1 mg / mL to about 3 mg / mL of CMC sodium; Arginine HCl at about 20 mg / mL, and Approximately 50 mg / mL of poloxamer 338; Approximately 2 mg / mL NaH2PO4·H2O, Approximately 1 mg / mL citric acid·H2O, Sodium hydroxide (appropriate amount for pH 6), and Water (1mL) is included. Rilpivirine has a Dv90 of about 500 nm to 1600 μm.

[0171] In certain embodiments, the aqueous composition comprises: Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition; About 1 mg / mL to about 3 mg / mL of CMC sodium; Arginine HCl at about 20 mg / mL, and About 20 mg / mL to about 30 mg / mL of poloxamer 338; Approximately 2 mg / mL NaH2PO4·H2O, Approximately 1 mg / mL citric acid·H2O, Sodium hydroxide (appropriate amount for pH 6), and Includes water (1mL) Rilpivirine has a Dv90 of approximately 500 nm to 1600 nm.

[0172] In any of these particular embodiments, the aqueous composition may optionally further comprise an antioxidant (e.g., methionine) in an amount of about 1.0 mg / mL to about 2.0 mg / mL (e.g., 1.5 mg / mL).

[0173] In a preferred embodiment, an aqueous composition is provided having a pH of about 5 to about 7 (preferably about 6) and comprising: (i) rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in an aqueous composition; (ii) hyaluronidase; (iii) 0.1 to 100 mg / mL of glucose or glucose monohydrate (e.g., glucose); (iv) a blanket of inert gas (e.g., nitrogen); and (v) An antioxidant (e.g., methionine), for example, from about 1 mg / mL to about 2 mg / mL, for example, 1.5 mg / mL.

[0174] In one embodiment, an aqueous composition is provided having a pH of about 6 to about 6.5, preferably 6; (i) rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in an aqueous composition; and (ii) hyaluronidase.

[0175] In one embodiment, an aqueous composition is provided having a pH of about 6 to about 6.5, preferably 6; (i) rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in an aqueous composition; (ii) hyaluronidase, and (iii) An antioxidant (e.g., methionine), for example, from about 1 mg / mL to about 2 mg / mL, for example, 1.5 mg / mL.

[0176] In one embodiment, an aqueous composition is provided having a pH of about 6 to about 6.5, preferably 6; (i) rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in an aqueous composition; (ii) hyaluronidase; (iii) an antioxidant (e.g., methionine), for example, from about 1 mg / mL to about 2 mg / mL, for example, 1.5 mg / mL; and (iv) 0.1 to 100 mg / mL of glucose or glucose monohydrate (e.g., glucose).

[0177] In a preferred embodiment, the compositions of the invention reduce the change in particle size distribution of rilpivirine microparticles or nanoparticles over time, optionally compared to a composition in which excipients (a) and / or (b) are not added to the composition.

[0178] In a preferred embodiment, the compositions of the present invention reduce the change in particle size distribution of rilpivirine microparticles or nanoparticles over time, optionally compared to a composition in which excipient (a) is not added to the composition.

[0179] In a preferred embodiment, the compositions of the present invention reduce the change in particle size distribution of rilpivirine microparticles or nanoparticles over time, optionally compared to a composition in which excipient (b) is not added to the composition.

[0180] In a preferred embodiment, the compositions of the present invention reduce the change in particle size distribution of rilpivirine microparticles or nanoparticles over time, optionally compared to a composition in which excipients (a) and (b) are not added to the composition.

[0181] In the use of the present invention (use in a method for stabilizing an aqueous composition), the stabilization may be a reduction in the change in particle size distribution of the rilpivirine microparticles or nanoparticles over time, which reduction may be compared to a composition in which the excipients (a) and / or (b) are not added to the composition.

[0182] In the use of the present invention (use in a method for stabilizing an aqueous composition), the stabilization may be a reduction in the change in particle size distribution of the rilpivirine microparticles or nanoparticles over time, which reduction may be compared to a composition in which the excipient (a) is not added to the composition.

[0183] In the use of the present invention (use in a method for stabilizing an aqueous composition), the stabilization may be a reduction in the change in particle size distribution of the rilpivirine microparticles or nanoparticles over time, which reduction may be compared to a composition in which the excipient (b) is not added to the composition.

[0184] In the use of the present invention (use in a method for stabilizing an aqueous composition), the stabilization may be a reduction in the change in particle size distribution of the rilpivirine microparticles or nanoparticles over time, which reduction may be compared to a composition in which the excipients (a) and (b) are not added to the composition.

[0185] For example, the Dv10, Dv50, and Dv90 values ​​of the particles may be maintained within about 20% of the original values ​​after storage of the aqueous composition at about 5° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months.

[0186] As a further example, the Dv10, Dv50, and Dv90 values ​​of the particles may be maintained within about 10% of the original values ​​after storage of the aqueous composition at about 5° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months.

[0187] For example, the Dv10, Dv50, and Dv90 values ​​of the particles may be maintained within about 20% of the original values ​​after storing the aqueous composition at about 5° C. for about 1, about 2, about 4, about 8, about 16, or about 32 weeks.

[0188] As a further example, the Dv10, Dv50, and Dv90 values ​​of the particles may be maintained within about 10% of the original values ​​after storage of the aqueous composition at about 5° C. for about 1, about 2, about 4, about 8, about 16, or about 32 weeks.

[0189] For example, the Dv10, Dv50, and Dv90 values ​​of the particles may be maintained within about 20% of the original values ​​after storing the aqueous composition at about 25° C. for about 1, about 2, about 4, about 8, about 16, or about 32 weeks.

[0190] As a further example, the Dv10, Dv50, and Dv90 values ​​of the particles may be maintained within about 10% of the original values ​​after the aqueous composition is stored at about 25° C. for about 1, about 2, about 4, about 8, about 16, or about 32 weeks.

[0191] For example, the Dv10, Dv50, and Dv90 values ​​of the particles may be maintained within about 20% of the original values ​​after the aqueous composition is stored at about 25° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months.

[0192] As a further example, the Dv10, Dv50, and Dv90 values ​​of the particles may be maintained within about 30% of the original values ​​after the aqueous composition is stored at about 25° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months.

[0193] In preferred embodiments, the compositions of the invention maintain hyaluronidase activity for a period of time, for example, about 1, about 3, about 6, about 12, about 18, or about 24 months, which may be compared to a composition in which excipients (a) and / or (b) are not added to the composition.

[0194] In preferred embodiments, the compositions of the invention maintain hyaluronidase activity for a period of time, for example, about 1, about 3, about 6, about 12, about 18, or about 24 months, which may be compared to a composition in which excipient (a) is not added to the composition.

[0195] In preferred embodiments, the compositions of the invention maintain hyaluronidase activity for a period of time, for example, about 1, about 3, about 6, about 12, about 18, or about 24 months, which may be compared to a composition in which excipient (b) is not added to the composition.

[0196] In preferred embodiments, the compositions of the invention maintain hyaluronidase activity for a period of time, for example, about 1, about 3, about 6, about 12, about 18, or about 24 months, which may be compared to a composition in which excipients (a) and (b) are not added to the composition.

[0197] In the uses of the invention (use in methods of stabilizing an aqueous composition), the stabilization can be the maintenance of hyaluronidase activity over time, which may be compared to a composition in which excipients (a) and / or (b) are not added to the composition.

[0198] In the uses of the present invention (use in a method of stabilizing an aqueous composition), the stabilization can be the maintenance of hyaluronidase activity over time, which may be compared to a composition in which excipient (a) is not added to the composition.

[0199] In the uses of the present invention (use in a method of stabilizing an aqueous composition), the stabilization can be the maintenance of hyaluronidase activity over time, which may be compared to a composition in which excipient (b) is not added to the composition.

[0200] In the uses of the present invention (use in a method of stabilizing an aqueous composition), the stabilization can be the maintenance of hyaluronidase activity over time, which may be compared to a composition in which excipients (a) and (b) are not added to the composition.

[0201] For example, the composition can maintain hyaluronidase activity for a period of time, such as about 1, about 3, about 6, about 12, about 18, or about 24 months, which may be when storage is at about 5°C or about 25°C.

[0202] As a further example, the hyaluronidase activity may maintain at least 50% of the original activity after the aqueous composition is stored at about 5° C. or about 25° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months.

[0203] As a further example, the hyaluronidase activity may maintain at least 50% of the original activity after the aqueous composition is stored at about 5° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months.

[0204] As a further example, the hyaluronidase activity may maintain at least 25% of the original activity after the aqueous composition is stored at about 5° C. or about 25° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months.

[0205] In preferred embodiments, the compositions of the invention maintain hyaluronidase concentrations (e.g., as determined by size exclusion chromatography) for a period of time, such as about 1, about 3, about 6, about 12, about 18, or about 24 months.

[0206] This maintenance may be compared to a composition in which excipients (a) and / or (b) are not added to the composition.

[0207] This maintenance may be compared to a composition in which excipient (a) is not added to the composition.

[0208] This maintenance may be compared to a composition in which excipient (b) is not added to the composition.

[0209] This maintenance may be compared to a composition in which excipients (a) and (b) are not added to the composition.

[0210] In the uses of the invention (use in methods of stabilizing an aqueous composition), the stabilization can be the maintenance of hyaluronidase concentration (e.g., as determined by size exclusion chromatography) over time, which may be compared to a composition in which excipients (a) and / or (b) are not added to the composition.

[0211] In the uses of the present invention (use in a method of stabilizing an aqueous composition), the stabilization can be the maintenance of hyaluronidase concentration (e.g., as determined by size exclusion chromatography) over time, which may be compared to a composition in which excipient (a) is not added to the composition.

[0212] In the uses of the present invention (use in a method of stabilizing an aqueous composition), the stabilization can be the maintenance of hyaluronidase concentration (e.g., as determined by size exclusion chromatography) over time, which may be compared to a composition in which excipient (b) is not added to the composition.

[0213] In the uses of the invention (use in methods of stabilizing an aqueous composition), the stabilization can be the maintenance of hyaluronidase concentration (e.g., as determined by size exclusion chromatography) over time, which may be compared to a composition in which excipients (a) and (b) are not added to the composition.

[0214] For example, the composition can maintain a hyaluronidase concentration (e.g., as determined by size exclusion chromatography) for a period of time, such as about 1 week, about 2 weeks, about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months, when storage is at about 5°C or about 25°C.

[0215] By way of further example, at least 25% of the original concentration of hyaluronidase may remain after storage of the aqueous composition at about 5° C. or about 25° C. for about 1 week, about 2 weeks, about 6 months, about 12 months, about 18 months, or about 24 months.

[0216] By way of further example, after storage of the aqueous composition at about 5° C. or about 25° C. for about 6 months, about 12 months, about 18 months, or about 24 months, at least 50% of the original concentration of hyaluronidase may remain.

[0217] By way of further example, after storage of the aqueous composition at about 5° C. or about 25° C. for about 6 months, about 12 months, about 18 months, or about 24 months, at least 95% of the original concentration of hyaluronidase may remain.

[0218] In preferred embodiments, the compositions of the invention maintain hyaluronidase purity for a period of time, such as, for example, about 1 week, about 2 weeks, about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months.

[0219] This maintenance may be compared to a composition in which excipients (a) and / or b) are not added to the composition.

[0220] This maintenance may be compared to a composition in which excipient (a) is not added to the composition.

[0221] This maintenance may be compared to a composition in which excipient (b) is not added to the composition.

[0222] This maintenance may be compared to a composition in which excipients (a) and (b) are not added to the composition.

[0223] In the uses of the invention (use in a method of stabilizing an aqueous composition), the stabilization can be the maintenance of hyaluronidase purity over time, which may be compared to a composition in which excipients (a) and / or (b) are not added to the composition.

[0224] In the uses of the present invention (use in a method for stabilizing an aqueous composition), the stabilization can be the maintenance of hyaluronidase purity over time, which may be compared to a composition in which excipient (a) is not added to the composition.

[0225] In the uses of the present invention (use in a method for stabilizing an aqueous composition), the stabilization can be the maintenance of hyaluronidase purity over time, which may be compared to a composition in which excipient (b) is not added to the composition.

[0226] In the uses of the present invention (use in a method of stabilizing an aqueous composition), the stabilization can be the maintenance of hyaluronidase purity over time, which may be compared to a composition in which excipients (a) and (b) are not added to the composition.

[0227] For example, the composition can maintain hyaluronidase purity (i.e., reduce the presence of degradants) over a period of time, such as about 1 week, about 2 weeks, about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months, which may be when storage is at about 5°C or about 25°C.

[0228] By way of further example, after storage of the aqueous composition at about 5° C. or about 25° C. for about 1 week, about 2 weeks, about 6 months, about 12 months, about 18 months, or about 24 months, less than 50% of the original hyaluronidase is degraded into degradants.

[0229] By way of further example, after storage of the aqueous composition at about 5° C. or about 25° C. (e.g., about 5° C.) for about 6, about 12, about 18, or about 24 months, less than 25% of the original hyaluronidase is degraded into degradants.

[0230] By way of further example, after storage of the aqueous composition at about 5° C. or about 25° C. (e.g., about 5° C.) for about 6, about 12, about 18, or about 24 months, less than 20% of the original hyaluronidase is degraded into degradants.

[0231] By way of further example, after storage of the aqueous composition at about 5° C. or about 25° C. (e.g., about 5° C.) for about 6, about 12, about 18, or about 24 months, less than 5% of the original hyaluronidase is degraded into degradants.

[0232] In one embodiment, the degradation product measured is an oxidized species of hyaluronidase. In a particular embodiment, the degradation product measured is an oxidized species of hyaluronidase with reduced enzymatic activity.

[0233] Use of the composition of the present invention The aqueous composition can be used to treat or prevent an HIV infection in a subject.

[0234] Thus, in one aspect, the present invention relates to a method for the treatment or prevention of HIV infection in a subject, the method comprising administering to the subject an aqueous composition as defined herein. In a fifth aspect, the present invention relates to an aqueous composition as defined herein for use in the treatment or prevention of HIV infection in a subject. In a sixth aspect, the present invention relates to the use of an aqueous composition as defined herein for the manufacture of a medicament for the treatment or prevention of HIV infection in a subject.

[0235] In a preferred embodiment, the subject is a human.

[0236] In one embodiment, the aqueous composition is administered such that the time interval between administrations (i.e., the administration interval) is from about 3 months to about 2 years. In one embodiment, the time interval is from about 3 months to about 1.5 years. In one embodiment, the time interval is from about 3 months to about 1 year. In one embodiment, the time interval is from about 3 months to about 6 months. In one embodiment, the time interval is from about 6 months to about 1 year. In one embodiment, the time interval is about 1 year. In one embodiment, the time interval is about 3 months. In one embodiment, the time interval is about 4 months. In one embodiment, the time interval is about 5 months. In one embodiment, the time interval is about 6 months. In one embodiment, the time interval is about 7 months. In one embodiment, the time interval is about 8 months. In one embodiment, the time interval is about 9 months. In one embodiment, the time interval is about 10 months. In one embodiment, the time interval is about 11 months.

[0237] In one embodiment, the aqueous composition is administered by subcutaneous or intramuscular injection. In one embodiment, the aqueous composition is administered by intramuscular injection. In a preferred embodiment, the aqueous composition is administered by subcutaneous injection.

[0238] In another embodiment, the aqueous composition is administered by a manual injection process.

[0239] The aqueous composition may usefully have an osmolality suitable for reducing pain during subcutaneous injection. For example, in one embodiment, the aqueous composition has an osmolality of about 280 mOsm / kg to about 600 mOsm / kg. In another embodiment, the aqueous composition has an osmolality of about 280 mOsm / kg to about 300 mOsm / kg. In a more preferred embodiment, the aqueous composition has an osmolality of about 290 mOsm / kg.

[0240] The rilpivirine or a pharma- ceutically acceptable salt thereof is present in the aqueous composition (and administered to the subject) in a therapeutically effective amount. By "therapeutically effective amount" is meant an amount sufficient to provide a therapeutic effect.

[0241] In one embodiment, each dose contains up to about 150 mL of the aqueous composition described herein. In another embodiment, each dose contains about 3 mL to about 150 mL of the aqueous composition. In another embodiment, each dose contains about 3 mL to about 100 mL of the aqueous composition. In another embodiment, each dose contains about 3 mL to about 15 mL of the aqueous composition. In another embodiment, each dose contains about 5 mL to about 25 mL of the aqueous composition. In another embodiment, each dose contains about 6 mL to about 20 mL of the aqueous composition. In another embodiment, each dose contains about 6 mL to about 18 mL of the aqueous composition. In another embodiment, each dose contains about 6 mL to about 15 mL of the aqueous composition. In another embodiment, each dose contains about 6 mL to about 12 mL of the aqueous composition. In another embodiment, each dose contains about 9 mL to about 18 mL of the aqueous composition. In another embodiment, each dose contains about 9 mL to about 15 mL of the aqueous composition. In another embodiment, each dose contains about 9 mL to about 12 mL of the aqueous composition. In another embodiment, each dose comprises about 3 mL of the aqueous composition. In another embodiment, each dose comprises about 4 mL of the aqueous composition. In another embodiment, each dose comprises about 5 mL of the aqueous composition. In another embodiment, each dose comprises about 6 mL of the aqueous composition. In another embodiment, each dose comprises about 7 mL of the aqueous composition. In another embodiment, each dose comprises about 8 mL of the aqueous composition. In another embodiment, each dose comprises about 9 mL of the aqueous composition. In another embodiment, each dose comprises about 10 mL of the aqueous composition. In another embodiment, each dose comprises about 11 mL of the aqueous composition. In another embodiment, each dose comprises about 12 mL of the aqueous composition. In another embodiment, each dose comprises about 13 mL of the aqueous composition. In another embodiment, each dose comprises about 14 mL of the aqueous composition. In another embodiment, each dose comprises about 15 mL of the aqueous composition. In another embodiment, each dose comprises about 18 mL of the aqueous composition. In a preferred embodiment, each dose comprises about 3 mL, about 7 mL, or about 15 mL of the aqueous composition.

[0242] In one embodiment, for the treatment of HIV infection, the dose of rilpivirine administered can be calculated 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. Doses for other dosing regimens can be easily calculated by multiplying the monthly dose by the number of months between each administration. For example, for a dose of 450 mg / month and a time interval of 6 months between each administration, the dose of rilpivirine administered in each administration is 2700 mg. The "mg" indicated corresponds to mg of rilpivirine (i.e., rilpivirine in its free base form). Thus, by way of example, 1 mg of rilpivirine (ie, rilpivirine in its free base form) is equivalent to 1.1 mg of rilpivirine hydrochloride.

[0243] In one embodiment, for the treatment of HIV infection, the dose of rilpivirine administered at time intervals can be calculated 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) 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). Doses 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, in the case of a dose of 450 mg / 4 weeks (28 days), and when the time interval between each administration is 24 weeks, the dose of rilpivirine administered in each administration is 2700 mg. Alternatively, for example, in the case of a dose of 750 mg / 4 weeks (28 days), and when the time interval between each administration is 24 weeks, the dose of rilpivirine administered in each administration is 4500 mg. The "mg" shown corresponds to mg of rilpivirine (i.e., rilpivirine in its free base form). Thus, for example, 1 mg of rilpivirine (i.e., rilpivirine in its free base form) is equivalent to 1.1 mg of rilpivirine hydrochloride.

[0244] In one embodiment, rilpivirine or a pharma- ceutically acceptable salt thereof is used in an amount such that the plasma concentration of rilpivirine in the subject is maintained at a level of greater than about 12 ng / ml, preferably in the range of about 12 ng / ml to about 100 ng / ml, more preferably about 12 ng / ml to about 50 ng / ml, for at least 3 months after administration, or at least 6 months after administration, or at least 9 months after administration, or at least 1 year after administration, or at least 2 years after each administration. In a preferred embodiment, rilpivirine or a pharma- ceutically acceptable salt thereof in the aqueous composition is used in an amount such that the plasma concentration of rilpivirine in the subject is maintained at a level of about 12 ng / ml to 100 ng / ml for at least 6 months.

[0245] In the case of prevention of HIV infection, each administration of rilpivirine or a pharma- ceutically acceptable salt thereof may contain the same dose as for therapeutic applications as described above.

[0246] In one embodiment, the aqueous composition is used in combination with one or more other active agents, particularly one or more other antiretroviral agents, particularly one or more other antiretroviral agents of another class, for example an antiretroviral agent of the INSTI class, such as cabotegravir. In a particular embodiment, the invention is a kit comprising a) a composition or kit of the invention, and b) a second composition comprising one or more other antiretroviral agents.

[0247] In one embodiment, the one or more other antiretroviral agents, e.g., cabotegravir, are administered as an intramuscular or subcutaneous injection, particularly as an injectable micro- or nanosuspension, at a time interval of about 3 months to about 2 years. In one embodiment, the one or more other antiretroviral agents, e.g., cabotegravir, are administered at the same intermittent time intervals as the aqueous compositions described herein, e.g., the aqueous composition and the other antiretroviral agents are administered intermittently at a time interval of about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 10 months, about 11 months, about 1 year, or about 1 year to about 2 years. In one embodiment, the aqueous composition and the one or more other antiretroviral agents, e.g., cabotegravir, are administered simultaneously or sequentially by intramuscular or subcutaneous injection, particularly subcutaneous injection. In one embodiment, the aqueous composition and the one or more other antiretroviral agents, e.g., cabotegravir, are administered simultaneously, particularly by subcutaneous injection. In one embodiment, the aqueous composition and one or more other antiretroviral agents, such as cabotegravir, are administered sequentially, particularly by subcutaneous injection, hi one embodiment, the aqueous composition is administered first, followed by the cabotegravir injection.

[0248] As used herein, the term "treatment of HIV infection" refers to the treatment of subjects infected with HIV. The term "treatment of HIV infection" also refers to the treatment of diseases associated with HIV infection (e.g., AIDS) or other symptoms associated with HIV infection (including thrombocytopenia, Kaposi's sarcoma, and infection of the central nervous system characterized by progressive demyelination resulting in dementia and symptoms (e.g., progressive dysarthria, ataxia, and disorientation)), as well as further symptoms with which HIV infection is also associated (e.g., peripheral neuropathy, progressive generalized lymphadenopathy GL, and AIDS-related syndrome (RC)).

[0249] As used herein, the term "prevention of HIV infection" refers to preventing or avoiding a subject (not infected with HIV) from becoming infected with HIV. The source of infection can be various HIV-containing materials, particularly HIV-containing body fluids, such as blood or semen, or another subject infected with HIV. Prevention of HIV infection refers to preventing the transmission of the virus from HIV-containing materials or HIV-infected individuals to uninfected individuals, or to preventing the virus from entering the body of an uninfected individual. Transmission of the HIV virus can be by any of the known causes of HIV transfer, such as by sexual transmission or by contact with the blood of an infected subject (e.g., medical staff providing care to an infected subject). Transfer of HIV can also occur by contact with HIV-infected blood, for example, when handling blood samples or using blood transfusions. It can also be by contact with infected cells, for example, when performing laboratory experiments with HIV-infected cells.

[0250] The term "treatment of HIV infection" refers to a treatment in which the HIV viral load (expressed as the number of copies of viral RNA in a specific volume of serum) is reduced. The more effective the treatment, the lower the viral load. Preferably, the viral load should be reduced to the lowest possible level, for example below about 200 copies / mL, in particular below about 100 copies / mL, more in particular 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 (for example, from about 10 to about 10 2 , or more, for example, about 10 3 A decrease in the CD4 count (of the order of magnitude of a decrease in the CD4 count) is an indication of the effectiveness of the treatment. Another parameter for measuring the effectiveness of HIV treatment is the CD4 count, which ranges from 500 to 1500 cells per μL in healthy adults. A decrease in the CD4 count is an indication of HIV infection, and when it falls below about 200 cells / μL, AIDS may develop. An increase in the CD4 count (e.g., about 50, 100, 200, or more cells per μL) is also an indication of the effectiveness of anti-HIV treatment. In particular, the CD4 count should increase to a level of more than about 200 cells per μL, or to a level of more than about 350 cells per μL. The viral load or the CD4 count, or both, can be used to diagnose the extent of HIV infection. Another parameter for measuring the effectiveness of HIV treatment is the maintenance of an HIV-infected subject in a virologically suppressed state (HIV-1 RNA<50 copies / mL) when undergoing treatment according to the invention.

[0251] The term "treatment of HIV infection" and similar terms refer to that treatment that reduces viral load, increases CD4 count, or both, or keeps HIV-infected subjects in a virologically suppressed state, as described above. The term "prevention of HIV infection" and similar terms refer to a situation in which there is a reduction in the relative number of newly infected subjects in a population that is in contact with a source of HIV infection (e.g., a material containing HIV) or an HIV-infected subject. Effective prevention can be measured, for example, by measuring in a mixed population of HIV-infected and uninfected individuals, when there is a reduction in the relative number of newly infected individuals when comparing uninfected individuals treated with the aqueous composition of the present invention with uninfected individuals that are not treated. This reduction can be measured by statistical analysis of the number of infected and uninfected individuals in a given population over time.

[0252] general definition The term "comprising" encompasses "including" as well as "consisting," e.g., a composition "comprising" X may consist only of X, or may include something additional, e.g., X+Y. As used herein, the term "comprising" also encompasses "consisting essentially of," e.g., a composition "comprising" X may consist of X plus any other components that do not substantially affect the essential characteristics of the composition.

[0253] The term "about" in reference to a numerical value Y is optional and means, for example, Y±10%.

[0254] When a time interval is expressed as a specified number of months, the time interval extends from a given numbered day in a given month to the same numbered day in the month that falls the specified number of months later. If the same numbered day does not exist in the month that falls the specified number of months later, the time interval extends the same number of days into the next month, if the same numbered day does exist in the month that falls the specified number of months later.

[0255] When a time interval is expressed as a number of years, the time interval lasts from a given date in a given year to the same date in the year that falls the specified number of years later. If the same date does not exist in the year that falls the specified number of years later, the time interval lasts for the same number of days, if there is an identically numbered day in the month that falls the specified number of months later. In other words, if the time interval begins on February 29th of a given year but ends in a year that does not have February 29th, the period ends on March 1st of that year.

[0256] The term "about" in connection with such a definition means that the time interval may end on a date that is ±10% of the time interval.

[0257] In one embodiment, the time interval may begin up to 7 days before or after the start of the time interval and end up to 7 days before or after the end of the time interval.

[0258] All publications cited herein are incorporated by reference in their entirety.

[0259] The present invention will now be described with reference to the following examples. For the avoidance of doubt, these examples are not intended to limit the scope of the present invention. Modifications may be made within the scope and spirit of the present invention. EXAMPLES

[0260] Example 1 - Appearance test under stress test conditions This example compares the appearance of various compositions, each having a different combination of excipients, after storage under different conditions.

[0261] An aqueous composition of rilpivirine nanoparticles was prepared containing the following excipients: Rilpivirine (300 mg / mL) rHuPH20 (2000U / mL) Sodium dihydrogen phosphate monohydrate (2mg / ml) Citric acid monohydrate (1 mg), Poloxamer 338 (50 mg), · Sodium hydroxide 5N aqueous solution (appropriate amount for pH 6.0). ·Water for injection (appropriate amount 1mL)

[0262] Compositions A to E were prepared by adding or adjusting the above components as summarized below in Table 1. For compositions A to E, the pH was adjusted to 6.0 using 5N aqueous sodium hydroxide solution.

[0263] [Table 2]

[0264] Compositions A and B were prepared using rilpivirine nanoparticles (Dv10=95 nm, Dv50=220 nm, and Dv90=494 nm).

[0265] Compositions C through E were prepared using rilpivirine nanoparticles (having Dv10=102 nm, Dv50=234 nm, and Dv90=512 nm).

[0266] The results are shown in Figure 1. Injectability was tested using a 25G x 3 / 4" needle.

[0267] Example 2 - Particle size This example investigates the effect of various compositions, each having a different combination of excipients, on particle size of rilpivirine in suspension after storage conditions of 1 month, 3 months, and 6 months at 5°C.

[0268] Rilpivirine nanoparticle compositions A to E (having the same Dv10, Dv50, and Dv90 as in Example 1) were prepared in a similar manner to Example 1.

[0269] The composition was stored for one month at 5° C. The particle size of rilpivirine was measured according to the following method.

[0270] Particle size distribution measurement Volumetric particle size distribution of the rilpivirine suspension was determined by wet dispersion laser diffraction using a Malvern Mastersizer3000 laser diffraction (Malvern Instruments) and a HydroMV wet dispersion module.

[0271] The results are shown in Table 2 and FIG. 2A.

[0272] [Table 3]

[0273] [Table 4]

[0274] Example 3 - Purity Assay This example compares rilpivirine assay data for various compositions, each having a different combination of excipients, after storage under different conditions.

[0275] Rilpivirine nanoparticle compositions A to E were prepared as in Example 1.

[0276] The compositions were then stored in a refrigerator at 5° C. for 2 days to 2 weeks. Rilpivirine assay measurements of the compositions were performed immediately and after 1 month of storage at 5, 25, and 40° C. The amount of rilpivirine was determined according to the following method.

[0277] Rilpivirine assay measurement Measurement of the amount of rilpivirine present in the composition was based on a gradient ultra-high performance liquid chromatography (UHPLC) method with UV detection at 280 nm. The same method was also used to determine the amount of a specific impurity in the composition, hereafter referred to as Impurity 1.

[0278] The results are shown in Table 3.

[0279] [Table 5]

[0280] Example 4 - pH This example compares the pH of various rilpivirine compositions, each having a different combination of excipients, after storage under different conditions.

[0281] Rilpivirine nanoparticle compositions A to E were prepared as in Example 1.

[0282] The compositions were stored for one month under conditions of 5, 25, and 40° C. The pH was determined according to the following method.

[0283] pH measurement The pH of the compositions was measured using a benchtop pH meter. The pH meter was pre-calibrated with a two-point calibration to 4.0 and 7.0 and corrected for temperature. The pH was measured by submerging the probe in the aqueous composition.

[0284] The results are shown in Table 4.

[0285] [Table 6]

[0286] The pH value measured for composition A after one month storage at 25° C. was anomalous.

[0287] Example 5 - Melting temperature test under different storage conditions This example shows the T of rHuPH20 in various compositions, each having a different combination of excipients and / or pH, under different storage conditions. m Compare the higher T m To provide optimal thermodynamic stability of hyaluronidase, the T is set to about 25 to about 30° C. higher than the intended long-term storage conditions. m The goal is to

[0288] Compositions 1-21 were prepared by adding the components shown in Table 5 below to the following composition (Composition F). Glucose monohydrate (19.25 mg), rHuPH20 (2000U / mL) Sodium dihydrogen phosphate monohydrate (2mg / ml) Citric acid monohydrate (1 mg), Poloxamer 338 (50 mg), · Sodium hydroxide (varied to provide target pH). ·Water for injection (appropriate amount 1mL)

[0289] By varying the amount of sodium hydroxide, the pH of the composition was adjusted to 5.0, 6.0, 6.5, or 7.0 as needed.

[0290] [Table 7]

[0291] In this embodiment, T m Values ​​were measured using a nano-differential scanning fluorimetry (nDSF) assay, which uses intrinsic tryptophan and tyrosine fluorescence to monitor protein unfolding. The nDSF assay was performed as follows.

[0292] All nDSF assays were performed using a Prometheus NT.Plex instrument controlled by PR.ThermControl-CFR software. A temperature range of 20-95°C with a temperature gradient of 1°C / min was used when measuring samples. In all cases, 95% excitation power was used. The instrument determined the fluorescence ratio at 350 nm (tryptophan) and 330 nm (tyrosine) of the protein during a heating ramp to 95°C. The unfolding onset temperature (T on ) and the inflection point of this unfolding transition (T m ) was calculated from the unfolding curve.

[0293] To enable high-throughput sample testing, the nanoDSF instrument was operated in conjunction with a robotic autosampler. The autosampler performs the loading and transfer of capillary tips from 384-well plates for nanoDSF measurements. Preparation of the 384-well plates was automated using a Tecan Fluent 760 liquid handling system in conjunction with a custom-made sample holder for the 2R vials typically provided for sample testing.

[0294] Compositions 1 to 21 were prepared as described above and then stored in a refrigerator at 5° C. for 2 days to 2 weeks. m The T was measured immediately, stored at 25°C for 1 week, stored at 40°C for 1 week, and then stored under extreme storage conditions, i.e., 2 weeks at 25°C and 2 weeks at 40°C. m Immediately prior to measuring the values, the pH of the aqueous composition was remeasured.

[0295] The results are shown in Figures 2, 2A, 2B, and 2C.

[0296] Example 6a - Melting Temperature Test This example shows the T of rHuPH20 in various compositions, each having a different combination of excipients and / or pH. m Compare.

[0297] A composition (Composition G) was prepared containing the following excipients: Sodium dihydrogen phosphate monohydrate (2mg / ml) Citric acid monohydrate (1 mg), rHuPH20 (2000U / mL) · Sodium hydroxide (varied to provide the required pH). ·Water for injection (appropriate amount 1mL)

[0298] Compositions 22 to 44 were prepared by adding the components shown in Table 6 below to composition G, and the pH was adjusted to 6.0, 6.5, or 7.0 by varying the amount of sodium hydroxide in the composition.

[0299] [Table 8]

[0300] Compositions 22-44 were prepared as described above and then stored in a refrigerator at 5°C for 2 days to 2 weeks. m was immediately measured for each composition using the method described in Example 5.

[0301] The results are shown in Table 6 and FIG.

[0302] Example 6b - Melting temperature test under different storage conditions This example compares the fluorescence emission spectra of rHuPH20 compositions after storage under different conditions. Fluorescence emission spectroscopy uses light that is absorbed by an enzyme (rHuPH20) and a ground state fluorophore is excited to a higher energy state, thereby resulting in light emission. For an enzyme such as rHuPH20, tryptophan fluorescence can be used to measure changes in tertiary enzyme structure during or after storage under different conditions, thus quantifying the thermal stability of rHuPH20. The maximum emission wavelengths for folded and unfolded rHuPH20 are 330 nm and 350 nm, respectively.

[0303] Spectra of the compositions were collected immediately after storage at 5° C. and after 1 and 2 weeks of storage at 40° C. The peak maxima and minima as well as the intensity ratio 350 / 330 nm were calculated and plotted as a function of time. The slope of the curves was used to perform semi-quantitative thermal stability assessments and comparisons between compositions.

[0304] Preparation of the Composition 200 μl of each composition was manually dispensed into a UV-STAR®, COC, 96-well flat-bottom microplate.

[0305] Fluorescence emission spectra of the samples were measured before and after stress via a Tecan plate reader (Infinite 200). The following method parameters were used:

[0306] temperature: Parameter (on), Temperature = 25.0℃

[0307] Wait for temperature: Parameter Min=24.5℃; Max=25.5℃

[0308] Fluorescence Intensity Scanning: Scanning selection (light emission scanning) Mode (top) Excitation wavelength: 280nm~; Bandwidth: 230~315: 5nm; 316~850: 9nm Emission wavelength: 310nm~;~420nm; scale=1nm; bandwidth: 280~850:20nm; 111 measured values Integration: Delay time = 0μs; Integration time = 20μs Read: Flash count = 25; Settling time = 0 ms Gain (Manual = 95) ·Label:name=Label1

[0309] The results are shown in Table 7 below.

[0310] [Table 9]

[0311] Example 7 - Melting temperature test under different storage conditions This example compares the melting temperatures of rHuPH20 in various compositions under different storage conditions.

[0312] Composition F was prepared in the same manner as in Example 5. Compositions 45 to 57 were then prepared by omitting glucose monohydrate (19.25 mg / mL) and adding the components shown in Table 8 to Composition F, and adjusting the pH to 6.0 by varying the amount of sodium hydroxide in the composition.

[0313] [Table 10]

[0314] Compositions 45-57 were prepared as above and then stored in a refrigerator at 5° C. for 2 days to 2 weeks. m Values ​​were measured immediately (ie, "t=0") and after storage at 40° C. for 1 week using the methods described in Example 5.

[0315] T m Immediately prior to measuring the values, the pH of the aqueous composition was remeasured.

[0316] The results are shown in Table 8 and Figures 4 and 4A, where rHuPH20 was degraded when the Tm value at 40°C for t = 1 week was not shown (i.e., when Tm and its SD are "-").

[0317] Example 8 - CMC sodium concentration In this example, the T m Check the dependency of.

[0318] Composition H was prepared containing the following excipients: rHuPH20 (2000U / mL) Sodium dihydrogen phosphate monohydrate (2mg / ml) Citric acid monohydrate (1 mg), Poloxamer 338 (50 mg), ·Sodium hydroxide (appropriate amount for pH 6.0). Mannitol (50mg / mL) or sucrose (100mg / mL) ·Water for injection (appropriate amount 1mL)

[0319] Next, compositions 58 to 63 were prepared by adding the sodium CMC shown in Table 9 below to composition H, and the pH was adjusted to 6.0 by changing the amount of sodium hydroxide in the composition.

[0320] [Table 11]

[0321] Compositions 58-63 were prepared as above and then stored in a refrigerator at 5° C. for 2 days to 2 weeks. m The values ​​were measured.

[0322] The results are shown in Figure 5.

[0323] Example 9 - Enzyme stability This example compares the stability of rHuPH20 in various compositions under stress test conditions.

[0324] Compositions A to E containing rilpivirine nanoparticles were prepared as in Example 1.

[0325] The compositions were stored for 6 months under conditions of 5° C. or 25° C. / 60% RH. Enzyme stability was assessed by one or more of the following: (i) activity (bioassay); (ii) quantification / aggregation (size exclusion chromatography / SEC) and (iii) purity (reversed phase liquid chromatography / RP-LC).

[0326] SEC: A size-exclusion chromatography separation technique that uses a column to distribute molecules in a flowing solution according to their broad size range. Monomers, aggregates and fragments elute from the column at different times, so that their relative proportions in a sample can be quantified using a standard UV detector.

[0327] The results are shown in Table 10.

[0328] [Table 12] * Ox2 is the oxidized form of rHuPH20. Ox2 is less active than rHuPH20.

[0329] Example 10 - Enzyme stability test under different storage conditions This example compares the fluorescence emission spectra of rHuPH20 compositions after storage under different conditions.

[0330] Aqueous compositions 45-57 were prepared as described in Example 7 above. Spectra of the compositions were collected immediately after storage at 5° C. and after storage at 50° C. for 1 day. The peak maxima and minima as well as the intensity ratios 350 / 330 nm were calculated for each time point and plotted as a function of storage time. The slopes of the curves were used to perform semi-quantitative thermal stability assessments and comparisons between compositions.

[0331] Preparation of the Composition 200 μl of each composition was manually dispensed into a UV-STAR®, COC, 96-well flat-bottom microplate.

[0332] Fluorescence emission spectra of the samples were measured before and after stress via a Tecan plate reader (Infinite 200). The following method parameters were used:

[0333] temperature: Parameter (on), Temperature = 25.0℃ Wait for the temperature.

[0334] Parameter Min=24.5℃; Max=25.5℃

[0335] Fluorescence Intensity Scanning: Scanning selection (light emission scanning) Mode (top) Excitation wavelength: 280nm~; Bandwidth: 230~315: 5nm; 316~850: 9nm Emission wavelength: 310nm~;to=420nm;scale=1nm;bandwidth:280~850:20nm;111 measured values Integration: Delay time = 0μs; Integration time = 20μs Read: Flash count = 25; Settling time = 0 ms Gain (Manual = 95) ·Label:name=Label1

[0336] The results are shown in Table 11 below.

[0337] [Table 13]

[0338] Example 11 - Melting temperature test under different storage conditions This example compares the melting temperatures of rHuPH20 in various compositions under different storage conditions.

[0339] Aqueous compositions of rilpivirine nanoparticles (having a Dv10 of 75-200 nm, a Dv50 of 200-500 nm, and a Dv90 of 500-1600 nm) were prepared containing the following excipients: rHuPH20 (2000U / mL) Sodium dihydrogen phosphate monohydrate (2mg / ml) Citric acid monohydrate (1 mg) Poloxamer 338 (50 mg) Sodium hydroxide (appropriate amount for pH 6) ·Water for injection (appropriate amount 1mL)

[0340] Next, compositions 64 to 149 were prepared by adding the components shown in Table 12, and the pH was adjusted to 6.0 by varying the amount of sodium hydroxide in the composition.

[0341] [Table 14-1]

[0342] [Table 14-2]

[0343] [Table 14-3]

[0344] [Table 14-4]

[0345] Compositions 64-149 were prepared as above and then stored in a refrigerator at 5° C. for 2 days to 2 weeks. m Values ​​were measured immediately (ie, "t=0") and after storage at 40° C. for 1 week using the methods described in Example 5.

[0346] The results are shown in Table 12.

[0347] The following numbered clauses are also set forth herein: 1. (i) rilpivirine or a pharma- ceutically acceptable salt thereof; (ii) hyaluronidase; (iii) 0.001 to 100 mg / mL, (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof; and / or (b) an aqueous composition comprising at least one excipient selected from the group consisting of an amino acid or a pharma- ceutically acceptable salt thereof. 2. The aqueous composition according to clause 1, wherein the rilpivirine is in the form of particles suspended in the aqueous composition. 3. The aqueous composition of clause 2, wherein the rilpivirine is in the form of microparticles or nanoparticles suspended in the aqueous composition. 4. The aqueous composition of clause 2 or 3, wherein the particles have a Dv90 of from about 100 nm to about 10 μm. 5. The aqueous composition of clause 4, wherein the particles have a Dv90 of from about 300 nm to about 6 μm. 6. The aqueous composition of clause 5, wherein the particles have a Dv90 of from about 300 nm to about 1600 nm. 7. The aqueous composition of clause 6, wherein the particles have a Dv90 of about 450 nm to about 700 nm. 8. The aqueous composition according to clause 7, wherein the particles have a Dv90 of from about 475 nm to about 650 nm, for example from about 525 to about 644 nm. 9. The aqueous composition of any one of clauses 2 to 8, wherein the particles have a Dv10 of from about 75 nm to about 200 nm. 10. The aqueous composition of any one of clauses 2 to 9, wherein the particles have a Dv50 of from about 200 nm to about 500 nm. 11. The aqueous composition of any one of clauses 2 to 4, wherein the particles have a Dv90 of from about 4 μm to about 6 μm. 12. The aqueous composition of clause 11, wherein the particles have a Dv90 of about 5 μm to about 6 μm. 13. The aqueous composition of any one of clauses 2-5 or 11 or 12, wherein the particles have a Dv10 of from about 300 nm to about 500 nm, and / or the particles have a Dv50 of from about 1.5 μm to about 2 μm. 14. The aqueous composition according to any one of clauses 1 to 13, wherein the aqueous composition comprises from about 200 mg / mL to about 400 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof. 15. The aqueous composition according to clause 14, wherein the aqueous composition comprises from about 250 mg / mL to about 350 mg / mL, for example 300 mg / mL, of rilpivirine or a pharma- ceutically acceptable salt thereof. 16. The aqueous composition according to any one of clauses 1 to 15, wherein the aqueous composition comprises rilpivirine. 17. The aqueous composition of any one of clauses 1-16, wherein the hyaluronidase is recombinant human hyaluronidase. 18. The aqueous composition of any one of clauses 1-17, wherein the hyaluronidase is rHuPH20. 19. The aqueous composition of any one of clauses 1-18, wherein the aqueous composition comprises from about 1500 U / mL to about 2500 U / mL of hyaluronidase. 20. The aqueous composition of any one of clauses 1-19, wherein the aqueous composition comprises from about 1750 U / mL to about 2250 U / mL of hyaluronidase. 21. The aqueous composition of clause 20, wherein the aqueous composition comprises about 2000 U / mL of hyaluronidase. 22. The aqueous composition of any one of clauses 1-21, wherein at least one excipient comprises cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof. 23. The aqueous composition according to clause 22, wherein the cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof is carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 24. The aqueous composition according to clause 23, wherein the carboxymethylcellulose or a pharma- ceutically acceptable salt thereof is sodium carboxymethylcellulose. 25. The aqueous composition of clause 23 or 24, wherein the aqueous composition comprises from about 0.1 mg / mL to about 50 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 26. The aqueous composition according to clause 25, wherein the aqueous composition comprises from about 0.1 mg / mL to about 10 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 27. The aqueous composition according to clause 26, wherein the aqueous composition comprises from about 1 mg / mL to about 5 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 28. The aqueous composition according to clause 27, wherein the aqueous composition comprises from about 1 mg / mL to about 3 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 29. The aqueous composition according to clause 26, wherein the aqueous composition comprises about 1 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 30. The aqueous composition of clause 28, wherein the aqueous composition comprises about 3 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 31. The aqueous composition of any one of clauses 22-30, wherein the aqueous composition comprises from about 0.01 mg per 100 U of hyaluronidase to about 0.25 mg per 100 U of hyaluronidase of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 32. The aqueous composition of clause 31, wherein the aqueous composition comprises from about 0.05 mg per 100 U of hyaluronidase to about 0.15 mg per 100 U of hyaluronidase of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 33. The aqueous composition of clause 31, wherein the aqueous composition comprises from about 0.02 mg per 100 U of hyaluronidase to about 0.1 mg per 100 U of hyaluronidase of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 34. The aqueous composition of clause 33, wherein the aqueous composition comprises from about 0.03 mg per 100 U of hyaluronidase to about 0.07 mg per 100 U of hyaluronidase of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 35. The aqueous composition of any one of clauses 1-34, wherein at least one excipient comprises an amino acid or a pharma- ceutically acceptable salt thereof. 36. The aqueous composition according to clause 33, wherein the aqueous composition comprises about 5 to about 60 mg / mL of an amino acid or a pharma- ceutically acceptable salt thereof. 37. The aqueous composition according to clause 36, wherein the aqueous composition comprises about 15 to about 25 mg / mL of the amino acid or a pharma- ceutically acceptable salt thereof. 38. The aqueous composition according to any one of clauses 35 to 37, wherein the amino acid is selected from glycine and arginine, pharma- ceutically acceptable salts thereof, and combinations thereof. 39. The aqueous composition according to clause 38, wherein the amino acid is glycine. 40. The aqueous composition of any one of clauses 39, wherein the aqueous composition comprises about 5 to about 20 mg / mL of glycine. 41. The aqueous composition of clause 38, wherein the aqueous composition comprises about 10 to about 15 mg / mL of glycine. 42. The aqueous composition of clause 41, wherein the aqueous composition comprises about 13 mg / mL of glycine. 43. The aqueous composition of any one of clauses 35 to 38, wherein the amino acid is arginine or arginine hydrochloride. 44. The aqueous composition of clause 43, wherein the aqueous composition comprises about 5 to about 50 mg / mL of arginine or arginine hydrochloride. 45. The aqueous composition of clause 44, wherein the aqueous composition comprises about 15 to about 25 mg / mL of arginine or arginine hydrochloride. 46. ​​The aqueous composition according to clause 45, wherein the aqueous composition comprises about 21 mg / mL of arginine or arginine hydrochloride. 47. The aqueous composition according to clause 43, wherein the amino acid is arginine hydrochloride. 48. The aqueous composition of clause 47, wherein the aqueous composition comprises about 5 to about 50 mg / mL of arginine hydrochloride. 49. The aqueous composition of clause 48, wherein the aqueous composition comprises about 15 to about 25 mg / mL of arginine hydrochloride. 50. The aqueous composition of clause 49, wherein the aqueous composition comprises about 20 mg / mL of arginine hydrochloride. 51. The aqueous composition of any of clauses 1-50, wherein at least one excipient further comprises a sugar or sugar alcohol. 52. The aqueous composition according to clause 51, wherein the aqueous composition comprises from about 10 to about 100 mg / mL of sugar or sugar alcohol. 53. The aqueous composition according to clause 52, wherein the aqueous composition comprises about 45 to about 55 mg / mL of sugar or sugar alcohol. 54. The aqueous composition according to clause 53, wherein the aqueous composition comprises about 50 mg / mL of sugar or sugar alcohol. 55. The aqueous composition of any one of clauses 51-54, wherein the sugar or sugar alcohol is selected from glucose and sucrose, and combinations thereof. 56. The aqueous composition according to clause 55, wherein the sugar or sugar alcohol is sucrose. 57. The aqueous composition of clause 56, wherein the aqueous composition comprises about 10 to about 100 mg / mL of sucrose. 58. The aqueous composition of clause 57, wherein the aqueous composition comprises about 40 to about 70 mg / mL of sucrose. 59. The aqueous composition of clause 58, wherein the aqueous composition comprises about 57 mg / mL of sucrose. 60. The aqueous composition of clause 58, wherein the aqueous composition comprises about 50 mg / mL of sucrose. 61. The aqueous composition according to clause 55, wherein the sugar or sugar alcohol is glucose. 62. The aqueous composition of clause 61, wherein the aqueous composition comprises about 1 to about 100 mg / mL of glucose. 63. The aqueous composition according to clause 62, wherein the aqueous composition comprises about 10 to about 30 mg / mL of glucose. 64. The aqueous composition according to clause 63, wherein the aqueous composition comprises about 17 mg / mL of glucose. 65. An aqueous composition according to any one of clauses 1 to 54 and 56 to 60, wherein the aqueous composition is substantially free of glucose, for example containing less than 10% w / w glucose, preferably less than 1% w / w glucose. 66. The aqueous composition according to any one of clauses 1 to 65, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (a) in the aqueous composition is from about 50:1 (w / w) to about 400:1 (w / w), or the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (b) in the aqueous composition is from about 10:1 (w / w) to about 20:1 (w / w). 67. The aqueous composition according to any one of clauses 1 to 65, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (a) in the aqueous composition is from about 200:1 (w / w) to about 400:1 (w / w), or the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (b) in the aqueous composition is from about 2:1 (w / w) to about 30:1 (w / w). 68. The aqueous composition according to clause 67, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (a) in the aqueous composition is from about 250:1 (w / w) to about 350:1 (w / w), or the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (b) in the aqueous composition is from about 3:1 (w / w) to about 20:1 (w / w). 69. The aqueous composition according to any one of clauses 1 to 65, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (a) or (b) in the aqueous composition is from about 5:1 (w / w) to about 16:1 (w / w). 70. The aqueous composition according to any one of clauses 1 to 65, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to excipient (a) or (b) in the aqueous composition is from about 10:1 (w / w) to about 400:1 (w / w). 71. An aqueous composition according to any one of clauses 52 to 65 when subject to any one of clauses 22 to 34, wherein the ratio of cellulose or a derivative thereof or a pharma- ceutically acceptable salt thereof to sugar or sugar alcohol is from about 1:2 (w / w) to about 1:1000 (w / w). 72. An aqueous composition according to any one of clauses 52 to 65 when subject to any one of clauses 22 to 34, wherein the ratio of cellulose or a derivative thereof or a pharma- ceutically acceptable salt thereof to sugar or sugar alcohol is from about 1:2 (w / w) to about 1:200 (w / w). 73. The aqueous composition according to clause 72, wherein the ratio of cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof to sugar or sugar alcohol is from about 1:2 (w / w) to about 1:100 (w / w). 74. The aqueous composition according to clause 73, wherein the ratio of cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof to sugar or sugar alcohol is from about 1:10 (w / w) to about 1:100 (w / w). 75. The aqueous composition according to clause 74, wherein the ratio of cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof to sugar or sugar alcohol is from about 1:15 (w / w) to about 1:60 (w / w). 76. The aqueous composition according to any one of clauses 1 to 75, wherein the aqueous composition further comprises a poloxamer, for example poloxamer 338. 77. The aqueous composition according to clause 76 when dependent on clause 2, wherein when rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less, the weight ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 10:1 or more, for example about 10:1 to about 20:1. 78. The aqueous composition according to clause 76, when dependent on clause 2, wherein the weight ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 15:1, when rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. 79. The aqueous composition according to clause 76 when dependent on clause 2, wherein the weight ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 10:1 when rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. 80. The aqueous composition according to clause 76 when dependent on clause 2, wherein the weight ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 10:1 or less when rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. 81. The aqueous composition according to clause 76 when dependent on clause 2, wherein the weight ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is less than about 10:1 when rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1 μm to about 10 μm, about 2 μm to about 9 μm, about 3 μm to about 8 μm, or about 3 μm to about 7 μm. 82. The aqueous composition of any one of clauses 1-81, wherein the aqueous composition further comprises one or more of poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide. 83. The aqueous composition of any one of clauses 1-81, wherein the aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide. 84. The aqueous composition of any one of clauses 1-81, wherein the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide. 85. The aqueous composition of any one of clauses 76-84, wherein the aqueous composition comprises from about 15 mg / mL to about 35 mg / mL of poloxamer. 86. The aqueous composition of any one of clauses 76-84, wherein the aqueous composition comprises from about 20 mg / mL to about 30 mg / mL of poloxamer. 87. The aqueous composition of any one of clauses 76-84, wherein the aqueous composition comprises from about 40 mg / mL to about 60 mg / mL of poloxamer. 88. The aqueous composition of any one of clauses 1-87, wherein the aqueous composition further comprises an antioxidant, and optionally the antioxidant is methionine. 89. The aqueous composition according to clause 88, wherein the aqueous composition comprises from about 1.0 mg / mL to about 2.0 mg / mL, for example about 1.5 mg / mL, of the antioxidant. 90. A solid composition according to any one of clauses 1 to 89, wherein the aqueous composition does not contain glucose, e.g. it does not contain glucose monohydrate. 91. The aqueous composition of any one of clauses 1-90, wherein the aqueous composition has a pH of about 5 to about 7. 92. The process of clause 91, wherein the aqueous composition has a pH in the range of about 6 to about 7. 93. The process of clause 92, wherein the aqueous composition has a pH in the range of about 6 to about 6.5. 94. The aqueous composition according to clause 93, wherein the aqueous composition has a pH of about 6. 95. The aqueous composition of any one of clauses 2-94, wherein the Dv10, Dv50, and Dv90 of the particles do not increase by more than about 30% after storing the aqueous composition at about 5° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months. 96. The aqueous composition of clause 95, wherein the Dv10, Dv50, and Dv90 of the particles do not increase by more than about 20% after storing the aqueous composition at about 5° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months. 97. The aqueous composition of clause 95, wherein the Dv10, Dv50, and Dv90 of the particles do not increase by more than about 10% after storing the aqueous composition at about 5° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months. 98. The aqueous composition of clause 95, wherein the Dv10, Dv50, and Dv90 of the particles do not increase by more than about 50% after storing the aqueous composition at about 25° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months. 99. The aqueous composition of clause 95, wherein the Dv10, Dv50, and Dv90 of the particles do not increase by more than about 20% after storing the aqueous composition at about 25° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months. 100. The aqueous composition of any one of clauses 1-99, wherein the hyaluronidase activity maintains at least 25% of its original activity after storing the aqueous composition at about 5° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months. 101. The aqueous composition of clause 100, wherein the hyaluronidase activity maintains at least 25% of the original activity after storing the aqueous composition at about 5° C. for about 24 months. 102. The aqueous composition of clause 100, wherein the hyaluronidase activity maintains at least 25% of the original activity after storing the aqueous composition at about 5° C. for about 18 months. 103. The aqueous composition of any one of clauses 1-102, wherein the hyaluronidase activity maintains at least 50% of the original activity after storing the aqueous composition at about 5°C or about 25°C for about 1, about 3, about 6, about 12, about 18, or about 24 months. 104. The aqueous composition of clause 103, wherein the hyaluronidase activity maintains at least 50% of the original activity after storage of the aqueous composition at about 5°C or about 25°C for about 24 months. 105. The aqueous composition of clause 104, wherein the hyaluronidase activity maintains at least 50% of the original activity after the aqueous composition is stored at about 5° C. for about 24 months. 106. The aqueous composition of clause 103, wherein the hyaluronidase activity maintains at least 50% of the original activity after storage of the aqueous composition at about 5° C. for about 18 months. 107. The aqueous composition of clause 103, wherein the hyaluronidase activity maintains at least 75% of the original activity after storing the aqueous composition at about 5° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months. 108. The aqueous composition of clause 103, wherein the hyaluronidase activity maintains at least 75% of the original activity after the aqueous composition is stored at about 5° C. for about 24 months. 109. The aqueous composition of clause 103, wherein the hyaluronidase activity maintains at least 75% of the original activity after the aqueous composition is stored at about 5° C. for about 18 months. 110. The aqueous composition of any one of clauses 1-109, wherein the hyaluronidase concentration maintains at least 25% of the original concentration after storing the aqueous composition at about 5° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months, and the concentration is determined by size exclusion chromatography. 111. The aqueous composition of claim 110, wherein the hyaluronidase concentration maintains at least 50% of the original concentration after storage of the aqueous composition at about 5° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months, wherein the concentration is determined by size exclusion chromatography. 112. The aqueous composition of any one of clauses 1-111, wherein less than 50% of the original hyaluronidase is degraded into degradation products after storage of the aqueous composition at about 5° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months. 113. The aqueous composition of clause 112, wherein less than 20% of the original hyaluronidase is degraded into degradants after storing the aqueous composition at about 5° C. for about 1, about 3, about 6, about 12, about 18, or about 24 months. 114. A method for stabilizing an aqueous composition, comprising: (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof, and / or (b) Use of an amino acid or a pharma- ceutically acceptable salt thereof, The method (i) rilpivirine or a pharma- ceutically acceptable salt thereof, (ii) hyaluronidase, and (iii) Use comprising the step of preparing an aqueous composition comprising 0.001 to 100 mg / mL of (a) and / or (b). 115. The use according to clause 114, wherein the aqueous composition is as described in any one of clauses 1 to 113. 116. The use according to clause 114 or clause 115, wherein the stabilization is maintaining hyaluronidase activity over time, for example, for about 6 months, about 12 months, about 18 months, or about 24 months. 117. The use according to clause 114 or clause 115, wherein the stabilization is maintaining the hyaluronidase concentration over time, for example for about 6, about 12, about 18, or about 24 months. 118. The use according to clause 114 or clause 115, wherein the stabilization reduces the presence of hyaluronidase degradation products, for example, for about 6 months, about 12 months, about 18 months, or about 24 months. 119. The use according to any one of clauses 114 to 118, wherein the stabilization is to reduce the change in the particle size distribution of the rilpivirine microparticles or nanoparticles over time, for example over about 6 months, about 12 months, about 18 months, or about 24 months. 120. (i) rilpivirine or a pharma- ceutically acceptable salt thereof; (ii) A method for stabilizing an aqueous composition comprising hyaluronidase, comprising: A method comprising combining components (i) and (ii) with 0.001 to 100 mg / mL of at least one excipient selected from the group consisting of: (a) cellulose or a derivative thereof, or a pharma- ceutically acceptable salt thereof; and / or (b) an amino acid or a pharma-ceutically acceptable salt thereof. 121. A method for the treatment or prevention of HIV infection in a subject, in particular for the treatment of HIV infection in a subject, comprising administering to the subject an aqueous composition according to any one of clauses 1 to 113. 122. An aqueous composition according to any one of clauses 1 to 113 for use in the treatment or prevention of HIV infection in a subject, in particular for the treatment of HIV infection in a subject. 123. Use of an aqueous composition according to any one of clauses 1 to 113 for the manufacture of a medicament for treating or preventing HIV infection in a subject, in particular for treating HIV infection in a subject. 124. The method, aqueous composition for use or use according to clause 121, 122 or 123, wherein the aqueous composition is administered to the subject by intramuscular or subcutaneous injection. 125. The method, aqueous composition for use or use according to clause 124, wherein the aqueous composition is administered to the subject by intramuscular injection. 126. The method, aqueous composition for use or use according to clause 124, wherein the aqueous composition is administered to the subject by subcutaneous injection. 127. The method, aqueous composition for use or use according to any one of clauses 121 to 126, wherein the aqueous composition is administered to the subject intermittently at time intervals of from about 3 months to about 2 years. 128. The method, aqueous composition for use or use according to claim 127, wherein the time interval is from about 3 months to about 1 year. 129. The method, aqueous composition for use, or use according to clause 110, wherein the time interval is from about 3 months to about 6 months. 130. The method, aqueous composition for use, or use according to claim 113, wherein the time interval is from about 6 months to about 1 year. 131. The method, aqueous composition for use or use according to clause 129 or 130, wherein the time interval is about 6 months. 132. The method, the aqueous composition for use, or the use according to any one of clauses 121 to 131, wherein the HIV infection is HIV type 1 (HIV-1) infection. 133. The method, aqueous composition for use, or use according to any one of clauses 121 to 132, wherein the subject is a human.

Claims

1. (i) rilpivirine or a pharmaceutically acceptable salt thereof, (ii) hyaluronidase, optionally wherein the hyaluronidase may be rHuPH20, and (iii) 0.001 to 100 mg / mL (a) Cellulose or its derivatives, or pharmaceutically acceptable salts thereof, and / or (b) an aqueous composition comprising at least one excipient selected from the group consisting of amino acids or pharmaceutically acceptable salts thereof.

2. The aqueous composition according to claim 1, wherein the rilpivirine is in the form of particles suspended in the aqueous composition.

3. The aqueous composition according to claim 1, wherein the at least one excipient comprises cellulose or a derivative thereof, or a pharmaceutically acceptable salt thereof, optionally wherein the cellulose or a derivative thereof, or a pharmaceutically acceptable salt thereof, is carboxymethylcellulose or a pharmaceutically acceptable salt thereof, and optionally wherein the carboxymethylcellulose or a pharmaceutically acceptable salt thereof is sodium carboxymethylcellulose.

4. The aqueous composition according to claim 3, wherein the aqueous composition comprises about 1 mg / mL to about 5 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

5. The aqueous composition according to claim 3, wherein the aqueous composition comprises carboxymethylcellulose or a pharmaceutically acceptable salt thereof in an amount from about 0.01 mg to about 0.25 mg per 100 U of hyaluronidase, or carboxymethylcellulose or a pharmaceutically acceptable salt thereof in an amount from about 0.05 mg to about 0.15 mg per 100 U of hyaluronidase, or carboxymethylcellulose or a pharmaceutically acceptable salt thereof in an amount from about 0.02 mg to about 0.1 mg per 100 U of hyaluronidase, or carboxymethylcellulose or a pharmaceutically acceptable salt thereof in an amount from about 0.03 mg to about 0.07 mg per 100 U of hyaluronidase.

6. The aqueous composition according to claim 1, wherein the at least one excipient comprises an amino acid or a pharmaceutically acceptable salt thereof, and optionally the amino acid is selected from glycine, arginine, a pharmaceutically acceptable salt thereof, and combinations thereof.

7. The aqueous composition according to claim 6, wherein the aqueous composition comprises about 5 to about 20 mg / mL of glycine, or about 10 to about 15 mg / mL of glycine, or about 13 mg / mL of glycine.

8. The aqueous composition according to claim 6, wherein the aqueous composition comprises about 5 to about 50 mg / mL of arginine or arginine hydrochloride, or about 15 to about 25 mg / mL of arginine or arginine hydrochloride, or about 20 mg / mL of arginine or arginine hydrochloride, wherein the arginine or arginine hydrochloride is optionally arginine hydrochloride.

9. The aqueous composition according to claim 1, wherein the at least one excipient further comprises a sugar or a sugar alcohol, optionally selected from glucose, for example glucose monohydrate, and sucrose, and combinations thereof, and optionally selected from sucrose.

10. The aqueous composition according to claim 9, wherein the aqueous composition contains about 10 to about 100 mg / mL of sucrose, or about 40 to about 70 mg / mL of sucrose, or about 57 mg / mL of sucrose, or about 50 mg / mL of sucrose.

11. The aqueous composition according to claim 9, wherein the ratio of cellulose or a derivative thereof, or a pharmaceutically acceptable salt thereof, to sugar or sugar alcohol is about 1:2 (w / w) to about 1:200 (w / w), or about 1:2 (w / w) to about 1:100 (w / w), or about 1:10 (w / w) to about 1:100 (w / w), or about 1:15 (w / w) to about 1:60 (w / w).

12. The aqueous composition according to claim 1, wherein the aqueous composition further comprises an antioxidant.

13. The aqueous composition according to claim 1, wherein the aqueous composition has a pH of about 6.

14. The aqueous composition according to claim 1, wherein the Dv10, Dv50, and Dv90 values ​​of the particles are maintained within approximately 20% of their original values ​​after storage of the aqueous composition for approximately 1, approximately 3, approximately 6, approximately 12, approximately 18, or approximately 24 months at approximately 5°C, and optionally, the Dv10, Dv50, and Dv90 values ​​of the particles are maintained within approximately 10% of their original values ​​after storage of the aqueous composition for approximately 1, approximately 3, approximately 6, approximately 12, approximately 18, or approximately 24 months at approximately 5°C.

15. The aqueous composition according to claim 1, wherein hyaluronidase activity is maintained for a certain period of time, for example, about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months, and the storage temperature is about 5°C or about 25°C.

16. Aqueous composition, (i) rilpivirine or a pharmaceutically acceptable salt thereof, and (ii) 0.001 to 100 mg / mL (a) Cellulose or its derivatives, or pharmaceutically acceptable salts thereof, and / or (b) an aqueous composition comprising at least one excipient selected from the group consisting of amino acids or pharmaceutically acceptable salts thereof.

17. A pharmaceutical composition according to claim 16, comprising rilpivirine or a pharmaceutically acceptable salt thereof, sucrose, and sodium carboxymethylcellulose, optionally further comprising poloxamer, or comprising rilpivirine or a pharmaceutically acceptable salt thereof, arginine hydrochloride, and sodium carboxymethylcellulose, optionally further comprising poloxamer.

18. rHuPH20 and, Rilpivirine in the form of particles suspended in the aqueous composition, CMC sodium and, Including sucrose, Or, rHuPH20 and, Rilpivirine in the form of particles suspended in the aqueous composition, Sodium CMC and, Sucrose and, Contains poloxamer 338, Or, rHuPH20 and, Rilpivirine in the form of particles suspended in the aqueous composition, CMC sodium and, It contains arginine HCl, Or, rHuPH20 and, Rilpivirine in the form of particles suspended in the aqueous composition, Sodium CMC and, Arginine HCl and, The aqueous composition according to claim 1, comprising poloxamer 338.

19. Approximately 2,000 U / mL of rHuPH20, Approximately 300 mg / mL of rilpivirine in the form of particles suspended in the aqueous composition, CMC sodium in a concentration of approximately 1 mg / mL to approximately 3 mg / mL, Approximately 50 mg / mL of sucrose, and It contains approximately 50 mg / mL of poloxamer 338, The rilpivirine is in the form of particles suspended in the aqueous composition, having a Dv90 of about 4 μm to about 6 μm. Or, Approximately 2,000 U / mL of rHuPH20, Approximately 300 mg / mL of rilpivirine in the form of particles suspended in the aqueous composition, CMC sodium in a concentration of approximately 1 mg / mL to approximately 3 mg / mL, Approximately 50 mg / mL of sucrose, and It contains approximately 50 mg / mL of poloxamer 338, The rilpivirine is in the form of particles suspended in the aqueous composition, having a Dv90 of approximately 500 nm to 1 μm. Or, Approximately 2,000 U / mL of rHuPH20, Approximately 300 mg / mL of rilpivirine in the form of particles suspended in the aqueous composition, CMC sodium in a concentration of approximately 1 mg / mL to approximately 3 mg / mL, Approximately 50 mg / mL of sucrose, and It contains poloxamer 338 in a concentration of approximately 20 mg / mL to approximately 30 mg / mL, The rilpivirine is in the form of particles suspended in the aqueous composition, having a Dv90 of approximately 500 nm to 1 μm. Or, Approximately 2,000 U / mL of rHuPH20, Approximately 300 mg / mL of rilpivirine in the form of particles suspended in the aqueous composition, CMC sodium in a concentration of approximately 1 mg / mL to approximately 3 mg / mL, Approximately 20 mg / mL of arginine HCl, and It contains approximately 50 mg / mL of poloxamer 338, The rilpivirine is in the form of particles suspended in the aqueous composition, having a Dv90 of about 4 μm to about 6 μm, for example, about 6 μm. Or, Approximately 2,000 U / mL of rHuPH20, Approximately 300 mg / mL of rilpivirine in the form of particles suspended in the aqueous composition, CMC sodium in a concentration of approximately 1 mg / mL to approximately 3 mg / mL, Approximately 20 mg / mL of arginine HCl, and It contains approximately 50 mg / mL of poloxamer 338, The rilpivirine is in the form of particles suspended in the aqueous composition, having a Dv90 of approximately 500 nm to 1 μm. Or, Approximately 2,000 U / mL of rHuPH20, Approximately 300 mg / mL of rilpivirine in the form of particles suspended in the aqueous composition, CMC sodium in a concentration of approximately 1 mg / mL to approximately 3 mg / mL, Approximately 20 mg / mL of arginine HCl, and It contains poloxamer 338 in a concentration of approximately 20 mg / mL to approximately 30 mg / mL, The aqueous composition according to claim 1, wherein the rilpivirine is in the form of particles suspended in the aqueous composition and has a Dv90 of about 500 nm to 1 μm.

20. A method for stabilizing an aqueous composition, comprising the use of (a) cellulose or a derivative thereof, or a pharmaceutically acceptable salt thereof, and / or (b) an amino acid or a pharmaceutically acceptable salt thereof, wherein the method Use comprising the step of preparing an aqueous composition comprising (i) rilpivirine or a pharmaceutically acceptable salt thereof, (ii) hyaluronidase, and (iii) 0.001 to 100 mg / mL of (a) and / or (b), wherein the aqueous composition is optionally as defined in any of claims 1 to 19.

21. A method for treating or preventing HIV infection in a subject, the method comprising administering an aqueous composition defined in any one of claims 1 to 19 to the subject.

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