Liquid composition

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 333,556 filed on April 22, 2022 and European Patent Application No. EP22173922.0 filed on May 17, 2022, the entire contents of which are expressly incorporated herein by reference. Technical Field

[0003] The present invention relates to a storage-stable aqueous composition comprising rilpivirine or a pharmaceutically acceptable salt thereof, hyaluronidase and one or more excipients. The present invention also relates to a method for stabilizing such an aqueous composition, the use of an excipient in such a method, and a method for treating or preventing HIV infection. Background Art

[0004] Human immunodeficiency virus (HIV) infection is considered the etiology of acquired immunodeficiency syndrome (AIDS), and its treatment remains a major medical challenge. HIV is able to evade immune pressure, adapt to a variety of 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.

[0005] Currently available oral therapies require dosing at least once a day. As a result, people living with HIV are reminded of their HIV-positive status every day, and daily dosing may also result in their HIV-positive status being disclosed. Daily dosing requires the storage and transportation of a larger number or volume of pills, and there is still a risk that patients will forget to take their daily dose, thereby failing to adhere to the prescribed dosing regimen. In addition to reducing the effectiveness of the treatment, this can also lead to the emergence of viral resistance.

[0006] One class of HIV drugs commonly used in highly active antiretroviral therapy (HAART) is the NNRTIs. Rilpivirine is an antiretroviral drug from the NNRTI class used to treat HIV infection. Rilpivirine is a second-generation NNRTI with increased potency and a reduced side effect profile compared to older NNRTIs. Rilpivirine activity is mediated by noncompetitive inhibition of HIV-1 reverse transcriptase.

[0007] Rilpivirine exhibits significant activity not only against wild-type HIV, but also against many of its mutant variants. Rilpivirine, its pharmacological activities and its various preparation procedures have been described in WO2003 / 016306.

[0008] Rilpivirine is approved for the treatment of HIV infection and is available as a single-dose tablet for once-daily oral administration. (each tablet contains 25 mg of rilpivirine-based equivalents) and a single-tablet regimen for once-daily oral administration Commercially available.

[0009] WO2007 / 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 the surface thereof; and a pharmaceutically acceptable aqueous carrier; wherein the active ingredient of rilpivirine is suspended.

[0010] Rilpivirine extended-release suspension for injection for administration in combination with cabotegravir extended-release suspension for injection is available as a Approved and used in the EU, for example These are the first antiretroviral drugs available in a long-acting injectable formulation for administration at intervals greater than one day.

[0011] When rilpivirine is administered by subcutaneous or intramuscular injection, it may be desirable to prepare or administer it with hyaluronidase to increase the dispersion and absorption of rilpivirine. Hyaluronidase can also be used to achieve other effects-for example, the administration of hyaluronidase can reduce the mass formed by administering a high volume of pharmaceutical composition at the injection site. However, storing hyaluronidase in a pharmaceutical composition for weeks, months or years presents a major challenge. When storing an extended period of time at room temperature, hyaluronidase can be rapidly unfolded and degraded. Therefore, it is also desirable to provide a composition comprising rilpivirine and hyaluronidase, wherein the hyaluronidase is particularly stable during storage for weeks, months or years at refrigerated temperatures (e.g., at 5°C), and does not substantially affect the particle size distribution of rilpivirine, so that when rilpivirine is administered after a long period of time, particularly at refrigerated temperatures (e.g., at 5°C), bioavailability, efficacy and extended release characteristics are maintained during storage.

[0012] PCT / US2021 / 072453 (WO2022 / 109555) discloses the use of rilpivirine or a pharmaceutically acceptable salt thereof in the form of microparticles or nanoparticles in suspension in combination with hyaluronidase to treat or prevent HIV infection. Summary of the invention

[0013] The present inventors have discovered novel aqueous compositions of rilpivirine particles and hyaluronidase that are surprisingly long term storage stable, particularly with respect to maintaining the particle size distribution and enzyme activity of the rilpivirine particles over time.

[0014] In a first aspect, the present invention relates to an aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; (ii) hyaluronidase; and (iii) 0.001 mg / mL-100 mg / mL of at least one excipient selected from the group consisting of:

[0015] (a) cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof; and / or

[0016] (b) an amino acid or a pharmaceutically acceptable salt thereof.

[0017] In a related aspect (Aspect 1a), the present invention relates to an aqueous composition comprising:

[0018] (i) rilpivirine or a pharmaceutically acceptable salt thereof; and

[0019] (ii) 0.001 mg / mL to 100 mg / mL of at least one excipient selected from the group consisting of:

[0020] (a) cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof; and / or

[0021] (b) an amino acid or a pharmaceutically acceptable salt thereof.

[0022] In a related aspect (Aspect 1b), the present invention relates to a kit comprising:

[0023] A first product comprising an aqueous composition comprising:

[0024] (i) rilpivirine or a pharmaceutically acceptable salt thereof; and

[0025] (ii) 0.001 mg / mL to 100 mg / mL of at least one excipient selected from the group consisting of:

[0026] (a) cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof; and / or

[0027] (b) an amino acid or a pharmaceutically acceptable salt thereof; and

[0028] A second product comprises an aqueous composition including a hyaluronidase.

[0029] In a related aspect (Aspect 1c), the present invention relates to a kit comprising:

[0030] A first product comprising an aqueous composition comprising:

[0031] (i) rilpivirine or a pharmaceutically acceptable salt thereof; and

[0032] (ii) 0.001 mg / mL to 100 mg / mL of at least one excipient selected from the group consisting of:

[0033] (a) cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof; and / or

[0034] (b) an amino acid or a pharmaceutically acceptable salt thereof; and

[0035] A second product comprising an aqueous composition comprising:

[0036] (i) hyaluronidase; and

[0037] (ii) 0.001 mg / mL to 100 mg / mL of at least one excipient selected from the group consisting of:

[0038] (a) cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof; and / or

[0039] (b) an amino acid or a pharmaceutically acceptable salt thereof.

[0040] In a related aspect (Aspect 1d), the invention relates to an aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; (ii) hyaluronidase; and (iii) 0.1 mg / mL-100 mg / mL of at least one sugar or sugar alcohol, optionally wherein the pH of the aqueous composition is from about 5 to about 7, or from about 6 to 6.5, for example about 6. The aqueous composition in this aspect (Aspect 1d) can be used to prepare the aqueous composition in the first aspect.

[0041] In a related aspect (Aspect 1e), the present invention relates to a kit comprising the components of the kit of Aspect 1b, the components of the kit of Aspect 1c or the aqueous composition of Aspect 1d, wherein the kit further comprises a composition comprising one or more other active agents, in particular one or more other antiretroviral agents, in particular one or more other antiretroviral agents of another class, such as, for example, an antiretroviral agent of the INSTI class, such as, for example, cabotegravir.

[0042] In a second aspect, the present invention relates to 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 in a method for stabilizing an aqueous composition, wherein the method comprises the step of preparing an aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; (ii) hyaluronidase; and (iii) 0.001 mg / mL-100 mg / mL of (a) and / or (b).

[0043] In a related aspect (Aspect 2a), the present invention relates to 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 in a method for stabilizing an aqueous composition, wherein the method comprises the steps of preparing an aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; and

[0044] (ii) 0.001 mg / mL to 100 mg / mL of (a) and / or (b).

[0045] In a related aspect (Aspect 2b), the present invention relates to 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 in a method for stabilizing an aqueous composition, wherein the method comprises the step of preparing an aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; (ii) hyaluronidase; and (iii) 0.001 mg / mL-100 mg / mL of (a) and / or (b).

[0046] In a related aspect (Aspect 2c), the present invention relates to the use of at least one sugar or sugar alcohol in a method for stabilizing an aqueous composition, wherein the method comprises the step of preparing an aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; (ii) hyaluronidase; and (iii) 0.1 mg / mL-100 mg / mL of at least one sugar or sugar alcohol, optionally wherein the pH of the aqueous composition is from about 5 to about 7, or from about 6 to 6.5, for example about 6.

[0047] In a third aspect, the present invention relates to a method for stabilizing an aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; and (ii) hyaluronidase;

[0048] The method comprises combining component (i) and component (ii) with component (iii) 0.001 mg / mL-100 mg / mL of at least one excipient, wherein the at least one excipient is selected from the group consisting 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.

[0049] In a related aspect (Aspect 3a), the invention relates to a method of stabilizing an aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof;

[0050] The method comprises combining component (i) with component (ii) 0.001 mg / mL-100 mg / mL of at least one excipient, wherein the at least one excipient is selected from the group consisting 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.

[0051] In a related aspect (Aspect 3b), the invention relates to a method of stabilizing an aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; and (ii) hyaluronidase;

[0052] The method comprises combining component (i) and component (ii); and component (iii) 0.001 mg / mL-100 mg / mL of at least one excipient, wherein the at least one excipient is selected from the group consisting 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.

[0053] In a third aspect (Aspect 3c), the present invention relates to a method for stabilizing an aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; and (ii) hyaluronidase; the method comprising combining component (i) and component (ii) with component (iii) 0.1 mg / mL-100 mg / mL of at least one sugar or sugar alcohol.

[0054] In a fourth aspect, a method for treating or preventing HIV infection in a subject is provided, the method comprising administering to the subject an aqueous composition of the present invention.

[0055] In a related aspect (Aspect 4a), there is provided a method for treating or preventing HIV infection in a subject, the method comprising administering to the subject a product of the kit of the invention, optionally after combining two or more products of the kit.

[0056] In a fifth aspect, an aqueous composition of the invention is provided for use in treating or preventing HIV infection in a subject. In a related aspect, a kit of the invention is provided for use in treating or preventing HIV infection in a subject.

[0057] In a sixth aspect, there is provided a use of the aqueous composition of the invention in the preparation 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 preparing a medicament for treating or preventing HIV infection in a subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] The present invention will now be described, by way of example only, with reference to the accompanying drawings.

[0059] Figure 1 : Appearance, resuspensibility and injectability studies under different storage conditions

[0060] Figure 2 :Study on the melting temperature of hyaluronidase under different storage conditions

[0061] Figure 2A :Study on the melting temperature of hyaluronidase under different storage conditions

[0062] Figure 2B :Study on the melting temperature of hyaluronidase under different storage conditions

[0063] Figure 2C : Study on the melting temperature of hyaluronidase under different storage conditions (remeasured pH)

[0064] Figure 3 :Study on the melting temperature of hyaluronidase

[0065] Figure 4 :Study on the melting temperature of hyaluronidase under different storage conditions

[0066] Figure 4A : Study on the melting temperature of hyaluronidase under different storage conditions (remeasured pH)

[0067] Figure 5 :Study on the melting temperature of hyaluronidase and CMC sodium concentration

[0068] These figures are further explained in the "Examples" section.

[0069] Disclosure of the Invention

[0070] This application has been drafted in sections to improve readability. However, this does not mean that each section should be read separately. Instead, unless otherwise indicated, each section should be read by cross-reference to other sections (i.e., the entire application as a whole). Unless explicitly stated, there is no intention to artificially separate the embodiments. For example, unless explicitly stated otherwise, the embodiments relate to all aspects. DETAILED DESCRIPTION

[0071] Compositions of the present invention

[0072] Rilpivirine (4-[[4-[[4-[(1E)-2-cyanovinyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile; TMC278) has the following structural formula:

[0073]

[0074] The term "rilpivirine" refers to rilpivirine having the structural formula shown above (ie, the free base form).

[0075] In a preferred embodiment, the aqueous composition comprises rilpivirine.

[0076] Pharmaceutically acceptable salts of rilpivirine refer to those salts in which the counterion is pharmaceutically acceptable. Pharmaceutically acceptable salts are intended to include 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 the following: such as an inorganic acid, for example a hydrohalic acid, for example hydrochloric acid, hydrobromic acid, etc.; sulfuric acid; nitric acid; phosphoric acid, etc.; or an organic acid, for example acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1,2,3-propane-tricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, etc.

[0077] In one embodiment, rilpivirine or a pharmaceutically acceptable salt thereof is in the form of particles suspended in the aqueous composition, such as microparticles or nanoparticles suspended in the aqueous composition.

[0078] Two embodiments are contemplated herein with preferred particle sizes.

[0079] In a first preferred particle size embodiment, the rilpivirine particles have a D of less than or about 2 μm. v 90. In this embodiment, the particles may have a D of about 100 nm to about 2 μm. v 90. In this embodiment, the particles may have a D of about 200 nm to about 2 μm. v 90. In this embodiment, the particles may have a D of 200 nm to about 2 μm. v 90. In this embodiment, the particles may have a D of about 300 nm to about 2 μm. v 90. In this embodiment, the particles may have a D of 300 nm to about 2 μm. v 90. In this embodiment, the particles may have a D of about 400 nm to about 2 μm (e.g., 400 nm to about 2 μm). v90. In this embodiment, the particles may have a D of about 500 nm to about 2 μm (e.g., 500 nm to about 2 μm). v 90. Preferably in this embodiment, the particles have a D of about 500 nm to about 1,600 nm. v 90, or about 500 nm to about 1,000 nm (e.g., 500 nm to about 1,600 nm or 500 nm to about 1,000 nm) v 90. 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 90.

[0080] As used herein, the term "D v 90" refers to the diameter below which 90% of the particle population by volume is found. As used herein, the term "D v 50" refers to the diameter below which 50% of the particle population by volume is found. As used herein, the term "D v 10" refers to the diameter below which 10% by volume of the particle population is found.

[0081] In a first preferred particle size embodiment, the particles may have a D of less than or about 1,000 nm. v 50. In this embodiment, the particles may have a D of about 10 nm to about 1,000 nm. v 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 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 50.

[0082] In a first preferred particle size embodiment, the particles may have a D of less than or about 500 nm. v 10. In this embodiment, the particles may have a D of about 10 nm to about 500 nm. v 10. In this embodiment, the particles may have a D of about 25 nm to about 400 nm. v 10. In this embodiment, the particles may have a D of about 50 nm to about 300 nm. v 10. In this embodiment, the particles may have a D of about 50 nm to about 200 nm.v 10. Preferably in this embodiment, the particles have a D of about 75 nm to about 200 nm. v 10.

[0083] Preferably in this embodiment, the rilpivirine particles have a D of about 500 nm to about 1,600 nm. v 90, D from about 200nm to about 500nm v 50 and D from about 75nm to about 200nm v 10.

[0084] Alternatively, the rilpivirine particles have a D of about 500 nm to about 1,000 nm. v 90, D from about 200nm to about 500nm v 50 and D from about 75nm to about 200nm v 10.

[0085] Alternatively, the rilpivirine particles have a D of about 450 nm to about 700 nm. v 90, D from about 200nm to about 500nm v 50 and D from about 75nm to about 200nm v 10.

[0086] In a second preferred particle size embodiment, the rilpivirine particles may have a D of about 1 μm to about 10 μm. v In this embodiment, the particles may have a D of about 2 μm to about 9 μm. v 90. In this embodiment, the particles may have a D of about 3 μm to about 8 μm. v 90. 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. v 90. Most preferably in this embodiment, the particles have a D of about 5 μm to about 6 μm (e.g., about 5 μm or about 6 μm). v 90. The particles may have a D of about 5 μm v 90. The particles may have a D of about 6 μm v 90.

[0087] In a second preferred particle size embodiment, the rilpivirine particles have a D of less than or about 3 μm. v 50. In this embodiment, the particles may have a D less than about 2.5 μm. v 50. In this embodiment, the particles may have a D of about 1 μm to about 2.5 μm. v50. 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 50. Further preferably in this embodiment, the particles have a D of about 1.5 μm to about 2 μm. v 50.

[0088] In a second preferred particle size embodiment, the rilpivirine particles may have a D of less than or about 1000 nm. v 10. In this embodiment, the particles may have a D of about 10 nm to about 1000 nm. v 10. In this embodiment, the particles may have a D of about 100 nm to about 700 nm. v 10. 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 10.

[0089] Preferably in this embodiment, the particles have a D of about 4 μm to about 6 μm. v 90, D from about 1.5 μm to about 2 μm v 50 and D from about 300nm to about 500nm v 10.

[0090] Preferably in this embodiment, the particles have a D of about 5 μm to about 6 μm. v 90, D from about 1.5 μm to about 2.2 μm v 50 and D from about 300nm to about 500nm v 10.

[0091] 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.

[0092] Laser diffraction relies on the principle that particles will scatter light at different angles depending on the size of the particle, and that a collection of particles will produce a pattern of scattered light defined by intensity and angle, which can be related to the particle size distribution. Many laser diffraction instruments are commercially available for quickly and reliably determining particle size distribution. For example, particle size distribution can be determined by the conventional Malvern Mastersizer from Malvern Instruments. TMThe MalvernMastersizer 3000 particle size analyzer measures TM The 3000 particle size analyzer operates by projecting a helium-neon gas laser beam into a transparent cell containing target particles suspended in an aqueous solution. The light that strikes the particles is scattered through angles inversely proportional to the particle size, and an array of photodetectors measures the intensity of the light at several predetermined angles, and the measured intensities at different angles are processed by a computer using standard theoretical principles to determine the particle size distribution. Laser diffraction values ​​can be obtained using wet dispersions of the particles in distilled water.

[0093] The commonly used measurement D in this field v 10. D v 50 and D v 90 Other methods include disk centrifugation, scanning electron microscopy (SEM), sedimentation field flow fractionation, and photon correlation spectroscopy.

[0094] In one embodiment, the aqueous composition comprises about 100 mg / mL to about 500 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 150 mg / mL to about 450 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 200 mg / mL to about 400 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the aqueous composition comprises about 250 mg / mL to about 350 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof, for example about 300 mg / mL (particularly 300 mg / mL) of rilpivirine.

[0095] In one embodiment, the amount of rilpivirine or a pharmaceutically acceptable salt thereof in the aqueous composition is from about 900 mg to about 28800 mg (e.g., from about 900 mg to about 14400 mg, or from about 900 mg to about 7200 mg, or from about 900 mg to about 4500 mg, or from about 900 mg to about 3600 mg), preferably from about 1200 mg to about 14400 mg, preferably from about 1350 mg to about 13200 mg, preferably from about 1500 mg to about 12000 mg (e.g., from about 3000 mg to about 12000 mg), preferably from about 1800 mg to about 10800 mg (e.g., from about 2700 mg to about 10800 mg, or from about 1800 mg to about 3600 mg), most preferably from about 1800 mg to about 7200 mg, or from about 2700 mg to about 4500 mg. The "mg" indicated corresponds to mg of rilpivirine (i.e., rilpivirine in free base form). Thus, by way of example, 1 mg of rilpivirine (ie rilpivirine in free base form) corresponds to 1.1 mg of rilpivirine hydrochloride.

[0096] In one embodiment, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to excipient (a) in the aqueous composition is about 200:1 (w / w) to about 400:1 (w / w), or the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to excipient (b) in the aqueous composition is about 2:1 (w / w) to about 30:1 (w / w).

[0097] In one embodiment, the ratio of rilpivirine or a pharmaceutically 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 pharmaceutically acceptable salt thereof to excipient (b) in the aqueous composition is from about 3:1 (w / w) to about 20:1 (w / w).

[0098] In one embodiment, the ratio of rilpivirine or a pharmaceutically 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 pharmaceutically acceptable salt thereof to excipient (b) in the aqueous composition is from about 10:1 (w / w) to about 4000:1 (w / w).

[0099] In one embodiment, the ratio of rilpivirine or a pharmaceutically 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 pharmaceutically acceptable salt thereof to excipient (b) in the aqueous composition is from about 10:1 (w / w) to about 500:1 (w / w).

[0100] In a preferred embodiment, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to excipient (a) in the aqueous composition is about 50:1 (w / w) to about 400:1 (w / w), or the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to excipient (b) in the aqueous composition is about 10:1 (w / w) to about 20:1 (w / w).

[0101] In some aspects of the present invention (e.g., first aspect to sixth aspect), aqueous composition comprises hyaluronidase (in aspect 1a, aspect 2a, aspect 3a, hyaluronidase is optional). Hyaluronidase is an enzyme that degrades the hyaluronic acid (HA) in the skin and reduces the viscosity of the hyaluronic acid in the extracellular matrix. Because of this characteristic, it can be used to increase the dispersion and absorption of the active pharmaceutical ingredient injected and / or enable subcutaneous administration of a larger volume. The enzymatic activity of hyaluronidase (including rHuPH20) can be defined by the unit (U / mL) of every mL or by the total enzyme activity (U) in a specific preparation.

[0102] As used herein, the term "hyaluronidase" refers to any enzyme that degrades hyaluronic acid and reduces the viscosity of hyaluronic acid in the extracellular matrix.

[0103] 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 an amino acid sequence that can be obtained according to CAS registration number 757971-58-7. Further information about rHuPH20 is provided in International Patent Publication No. WO2004 / 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, which has an amino acid sequence of rHuPH20 comprising SEQ ID NO: 2 (i.e., residues 36-482 of wild-type human hyaluronidase). In some embodiments, the hyaluronidase is a variant of rHuPH20, which has an amino acid sequence comprising SEQ ID NO: 3. In some embodiments, the hyaluronidase is a variant of rHuPH20, which has 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.

[0104]

[0105] In one embodiment, the concentration of hyaluronidase in the aqueous composition is from about 10 U / mL to about 10,000 U / mL, or from about 100 U / mL to about 10,000 U / mL, or from about 500 U / mL to about 10,000 U / mL, or from about 500 U / mL to about 5,000 U / mL, or from about 500 U / mL to about 2500 U / mL, or from about 1000 U / mL to about 2500 U / mL, or from about 1500 U / mL to about 2500 U / mL. Preferably, the concentration of hyaluronidase in the aqueous composition is from about 1800 U / mL to about 2200 U / mL (e.g., about 2000 U / mL).

[0106] In one embodiment, the concentration of hyaluronidase in the aqueous composition is from about 4.5 μg / mL to about 90 μg / mL, or from about 4.5 μg / mL to about 45 μg / mL, or from about 4.5 μg / mL to about 22.5 μg / mL, or from about 9 μg / mL to about 22.5 μg / mL, or from about 13.5 μg / mL to about 22.5 μg / mL. Preferably, the concentration of hyaluronidase in the aqueous composition is from about 16.2 μg / mL to about 19.8 μg / mL (e.g., about 18 μg / mL).

[0107] In one embodiment, the aqueous composition further comprises carboxymethylcellulose (CMC) or a derivative thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the cellulose or a derivative thereof in the aqueous composition is carboxymethylcellulose (CMC) or a derivative thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition further comprises CMC or a pharmaceutically acceptable salt thereof, preferably wherein the CMC is uncrosslinked. In one embodiment, the cellulose or a derivative thereof in the aqueous composition is CMC or a pharmaceutically acceptable salt thereof, preferably wherein the CMC is uncrosslinked. In one embodiment, CMC or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of CMC. Pharmaceutically acceptable salts of CMC mean those salts in which the counterion is pharmaceutically acceptable. Pharmaceutically acceptable salts are intended to include therapeutically active non-toxic acid addition salt forms that CMC is able to form. Preferred pharmaceutically acceptable salts of CMC include sodium CMC and potassium CMC. In particularly preferred embodiments, CMC or a pharmaceutically acceptable salt thereof is sodium CMC, particularly non-crosslinked sodium CMC. In another embodiment, CMC or a pharmaceutically acceptable salt thereof is CMC. Examples of CMC that may be used in the present invention are sodium carboxymethylcellulose (40 mPa.s (parenteral grade), available from Ashland) and Blanose CMC 7LF PH or Blanose 7LP EP (available from Ashland).

[0108] CMC or its pharmaceutically acceptable salt can have any degree of substitution (DS). DS is the average number of carboxymethyl groups per cellulose unit. In a preferred embodiment, DS is from about 0.4 to about 1.5. In one embodiment, CMC or its pharmaceutically acceptable salt has a DS of from about 0.5 to about 1 (e.g., from about 0.65 to about 0.95, such as about 0.7).

[0109] In one embodiment, CMC or a pharmaceutically 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 pharmaceutically 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 pharmaceutically 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, a viscosity of about 40 mPa.s in a 1% (w / v) aqueous solution at room temperature.

[0110] In one embodiment, CMC or a pharmaceutically 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 pharmaceutically 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 pharmaceutically 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, a viscosity of about 40 mPa.s in a 2% (w / v) aqueous solution at room temperature.

[0111] In one embodiment, the molecular weight of CMC or a pharmaceutically acceptable salt thereof is from about 50 kDa to about 2,000 kDa. In one embodiment, the molecular weight of CMC or a pharmaceutically acceptable salt thereof is from about 50 kDa to about 1,000 kDa. In one embodiment, the molecular weight of CMC or a pharmaceutically acceptable salt thereof is from about 70 kDa to about 900 kDa. In a preferred embodiment, the molecular weight of CMC or a pharmaceutically acceptable salt thereof is from about 90 kDa to about 750 kDa, and in a most preferred embodiment, the molecular weight of CMC or a pharmaceutically acceptable salt thereof is from about 90 kDa to about 110 kDa, for example, about 90 kDa.

[0112] The present inventors have surprisingly found that adding cellulose or a derivative thereof (e.g. CMC or a derivative thereof, or a pharmaceutically acceptable salt thereof) and / or an amino acid or a pharmaceutically acceptable salt thereof to an aqueous composition of the present invention comprising a hyaluronidase increases the melting temperature (T m ) (Example 6a). This indicates improved storage stability.

[0113] The inventors have surprisingly found that the addition of cellulose or a derivative thereof (e.g. CMC or a derivative thereof or a pharmaceutically acceptable salt thereof) to an aqueous composition of the invention comprising a hyaluronidase results in a reduction in the loss of hyaluronidase activity, a reduction in the aggregation of the hyaluronidase and / or a reduction in the oxidation of the hyaluronidase after storage under stress test conditions (Example 9). This indicates improved storage stability.

[0114] In one embodiment, as defined elsewhere herein, the aqueous composition of the present invention may be storage stable if stored at refrigerated temperature (e.g., about 2°C-8°C, e.g., 5°C) for one of the time periods defined herein. In one embodiment, as defined elsewhere herein, the aqueous composition of the present invention may be storage stable if stored at about room temperature (e.g., about 25°C) for one of the time periods defined herein. In one embodiment, as defined elsewhere herein, the aqueous composition of the present invention may be storage stable if stored at about 30°C for one of the time periods defined herein.

[0115] In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 100 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 75 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 50 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 25 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 10 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 7 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 5 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 0.5 mg / mL to about 5 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In a further preferred embodiment, the aqueous composition comprises about 0.5 mg / mL to about 3 mg / mL (e.g., about 3 mg / mL) of CMC or a pharmaceutically 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 pharmaceutically acceptable salt thereof. In a more preferred embodiment, the aqueous composition comprises about 1 mg / mL to about 1.5 mg / mL (e.g., about 1 mg / mL) of CMC or a pharmaceutically acceptable salt thereof.

[0116] In a preferred embodiment, CMC or a pharmaceutically acceptable salt thereof is sodium CMC, and the aqueous composition comprises sodium CMC in any of the amounts specified in the above paragraphs. In a preferred embodiment, CMC or a pharmaceutically acceptable salt thereof is sodium CMC, and the aqueous composition or reconstituted aqueous composition has any degree of substitution, viscosity, and molecular weight specified herein.

[0117] In one embodiment, the aqueous composition comprises from about 0.002 mg to about 5 mg CMC or a pharmaceutically acceptable salt thereof per 100 U of hyaluronidase.

[0118] In one embodiment, the aqueous composition comprises about 0.01 mg to about 2 mg CMC or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase. In one embodiment, the aqueous composition comprises about 0.02 mg to about 1 mg CMC or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase. In one embodiment, the aqueous composition comprises about 0.02 mg to about 0.5 mg CMC or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase. In one embodiment, the aqueous composition comprises about 0.02 mg to about 0.1 mg CMC or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase. In a preferred embodiment, the aqueous composition comprises about 0.03 mg to about 0.07 mg CMC or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase. In another preferred embodiment, the aqueous composition comprises about 0.01 mg to about 0.25 mg CMC or a pharmaceutically acceptable salt thereof / 100 U hyaluronidase, for example, about 0.05 mg to about 0.15 mg CMC or a pharmaceutically acceptable salt thereof / 100 U hyaluronidase, for example, 0.05 mg CMC or a pharmaceutically acceptable salt thereof / 100 U hyaluronidase, or for example, about 0.15 mg CMC or a pharmaceutically acceptable salt thereof / 100 U hyaluronidase.

[0119] In a preferred embodiment, the CMC or a pharmaceutically acceptable salt thereof is sodium CMC, and the aqueous composition comprises any of the ratios of sodium CMC to hyaluronidase specified in the above paragraphs.

[0120] In one embodiment, the aqueous composition comprises an amino acid or a pharmaceutically acceptable salt thereof from about 0.1 mg / mL to about 100 mg / mL. In one embodiment, the aqueous composition comprises an amino acid or a pharmaceutically acceptable salt thereof from about 1 mg / mL to about 100 mg / mL. In one embodiment, the aqueous composition comprises an amino acid or a pharmaceutically acceptable salt thereof from about 5 mg / mL to about 100 mg / mL. In one embodiment, the aqueous composition comprises an amino acid or a pharmaceutically acceptable salt thereof from about 5 mg / mL to about 80 mg / mL. In a preferred embodiment, the aqueous composition comprises an amino acid or a pharmaceutically acceptable salt thereof from about 5 mg / mL to about 60 mg / mL. In another preferred embodiment, the aqueous composition comprises an amino acid or a pharmaceutically acceptable salt thereof from about 15 mg / mL to about 30 mg / mL or from about 15 mg / mL to about 25 mg / mL (e.g., about 20 mg / mL).

[0121] In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 100 mg / mL of glycine or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 1 mg / mL to about 100 mg / mL of glycine or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 5 mg / mL to about 50 mg / mL of glycine or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition comprises about 5 mg / mL to about 20 mg / mL of glycine or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the aqueous composition comprises about 10 mg / mL to about 15 mg / mL of glycine or a pharmaceutically acceptable salt thereof.

[0122] In one embodiment, the aqueous composition comprises arginine or arginine hydrochloride from about 0.1mg / mL to about 100mg / mL. In one embodiment, the aqueous composition comprises arginine or arginine hydrochloride from about 1mg / mL to about 100mg / mL. In one embodiment, the aqueous composition comprises arginine or arginine hydrochloride from about 5mg / mL to about 70mg / mL. In one embodiment, the aqueous composition comprises arginine or arginine hydrochloride from about 5mg / mL to about 50mg / mL. In a preferred embodiment, the aqueous composition comprises arginine or arginine hydrochloride from about 15mg / mL to about 25mg / mL. In another preferred embodiment, the aqueous composition comprises arginine or arginine hydrochloride of about 20mg / mL.

[0123] 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.

[0124] In a preferred embodiment, the aqueous composition comprises arginine or arginine hydrochloride (as amino acid) and CMC or a pharmaceutically acceptable salt thereof. In a more preferred embodiment, the aqueous composition comprises arginine hydrochloride (as amino acid) and sodium CMC.

[0125] 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, sugar or sugar alcohol is selected from glucose and sucrose. More preferably, sugar or sugar alcohol is sucrose. In one embodiment, the aqueous composition further comprises sugar or sugar alcohol and amino acid or their pharmaceutically acceptable salt. Pharmaceutically acceptable salts of sugar, sugar alcohol or amino acid mean those salts in which the counter ion is pharmaceutically acceptable. Pharmaceutically acceptable salts are intended to include therapeutically active non-toxic acid and base addition salt forms that can be formed with a given sugar, sugar alcohol or amino acid. Suitable amino acids or their pharmaceutically acceptable salts include arginine, glycine and histidine or their pharmaceutically acceptable salts. In one embodiment, amino acids or their pharmaceutically acceptable salts are selected from arginine and glycine or their pharmaceutically acceptable salts. In a preferred embodiment, amino acids or their pharmaceutically acceptable salts are arginine (e.g., arginine hydrochloride). In one embodiment, the aqueous composition further comprises a sugar or a sugar alcohol and CMC or a pharmaceutically acceptable salt thereof.

[0126] In a preferred embodiment, the aqueous composition further comprises sucrose (as sugar or sugar alcohol) and CMC or their pharmaceutically acceptable salts. In a more preferred embodiment, the aqueous composition further comprises sucrose (as sugar or sugar alcohol) and CMC sodium.

[0127] In one embodiment, the aqueous composition does not comprise glucose, for example it does not comprise glucose monohydrate.

[0128] In one embodiment, the aqueous composition comprises a sugar or sugar alcohol of about 0.1 mg / mL to about 100 mg / mL. In one embodiment, the aqueous composition comprises a sugar or sugar alcohol of about 1 mg / mL to about 100 mg / mL. In one embodiment, the aqueous composition comprises a sugar or sugar alcohol of about 5 mg / mL to about 100 mg / mL. In a preferred embodiment, the aqueous composition comprises a sugar or sugar alcohol of about 10 mg / mL to about 100 mg / mL. In a more preferred embodiment, the aqueous composition comprises a sugar or sugar alcohol of about 45 mg / mL to about 55 mg / mL, for example, a sugar or sugar alcohol of about 50 mg / mL.

[0129] In one embodiment, the aqueous composition comprises glucose and / or glucose monohydrate, eg as sugar or sugar alcohol.

[0130] In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 100 mg / mL of glucose monohydrate. In one embodiment, the aqueous composition comprises about 1 mg / mL to about 100 mg / mL of glucose monohydrate. In one embodiment, the aqueous composition comprises about 5 mg / mL to about 50 mg / mL of glucose monohydrate. In a preferred embodiment, the aqueous composition comprises about 10 mg / mL to about 30 mg / mL of glucose monohydrate.

[0131] In one embodiment, the aqueous composition comprises sucrose from about 0.1 mg / mL to about 100 mg / mL. In one embodiment, the aqueous composition comprises sucrose from about 1 mg / mL to about 100 mg / mL. In one embodiment, the aqueous composition comprises sucrose from about 10 mg / mL to about 100 mg / mL. In a preferred embodiment, the aqueous composition comprises sucrose from about 40 mg / mL to about 70 mg / mL. In a more preferred embodiment, the aqueous composition comprises sucrose from about 45 mg / mL to about 55 mg / mL (e.g., about 50 mg / mL). In one embodiment, the ratio of cellulose or its derivatives or its pharmaceutically acceptable salts to sugar or sugar alcohol is about 1:2 (w / w) to about 1:1000 (w / w). In one embodiment, the ratio of cellulose or its derivatives or its pharmaceutically acceptable salts to sugar or sugar alcohol is about 1:2 (w / w) to about 1:500 (w / w). In one embodiment, the ratio of cellulose or its derivative or its pharmaceutically acceptable salt to sugar or sugar alcohol is about 1:2 (w / w) to about 1:200 (w / w). In one embodiment, the ratio of cellulose or its derivative or its pharmaceutically acceptable salt to sugar or sugar alcohol is about 1:2 (w / w) to about 1:100 (w / w). In one embodiment, the ratio of cellulose or its derivative or its pharmaceutically acceptable salt to 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 its derivative or its pharmaceutically acceptable salt to 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).

[0132] In one embodiment, the ratio of sodium CMC to sucrose is from about 1:2 (w / w) to about 1:1000 (w / w). In one embodiment, the ratio of sodium CMC to sucrose is from about 1:2 (w / w) to about 1:500 (w / w). In one embodiment, the ratio of sodium CMC to sucrose is from about 1:2 (w / w) to about 1:200 (w / w). In one embodiment, the ratio of sodium CMC to sucrose is from about 1:2 (w / w) to about 1:100 (w / w). In one embodiment, the ratio of sodium CMC to sucrose is from about 1:10 (w / w) to about 1:100 (w / w). In a preferred embodiment, the ratio of sodium CMC to sucrose is from about 1:15 (w / w) to about 1:60 (w / w), for example, 1:16 (w / w) or 1:50 (w / w).

[0133] In one embodiment, the aqueous composition further comprises one or more surface modifiers. When rilpivirine or a pharmaceutically acceptable salt thereof is in the form of particles as defined herein, the one or more surface modifiers are adsorbed onto the surface of the particles.

[0134] The surface modifier can be selected from known organic and inorganic pharmaceutical excipients, including various polymers, low molecular weight oligomers, natural products and surfactants. Specific surface modifiers that can be used in the present invention include nonionic and anionic surfactants. Representative examples of surface modifiers include gelatin, casein, lecithin, salts of negatively charged phospholipids or their acid forms (such as phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphoric acid and their salts, such as alkali metal salts, such as their sodium salts, such as sodium phosphatidylglycerol, such as Lipoid TM EPG products), gum arabic, stearic acid, benzalkonium chloride, polyoxyethylene alkyl ethers (e.g., polyethylene glycol ethers, such as cetomacrogol 1000), polyoxyethylene castor oil derivatives; polyoxyethylene stearate, colloidal silicon dioxide, sodium lauryl sulfate, bile salts (such as sodium taurocholate, sodium deoxytaurocholate, sodium deoxycholate); methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, polyvinyl alcohol (PVA), poloxamers (such as Pluronic TM F68, F108 and F127, which are block copolymers of ethylene oxide and propylene oxide); tyloxapol; vitamin E-TGPS (alpha-tocopheryl polyethylene glycol succinate, particularly alpha-tocopheryl polyethylene glycol 1000 succinate); poloxamines such as Tetronic TM908 (T908), which is a tetrafunctional block copolymer derived from the sequential addition of ethylene oxide and propylene oxide to ethylenediamine; dextran; lecithin; dioctyl ester of sodium sulfosuccinate, such as sold under the trade name Aerosol OT TM (AOT) products sold; Sodium Lauryl Sulfate (Duponol TM P); trade name Triton TM X-200 obtained alkyl aryl polyether sulfonate; polyoxyethylene sorbitan fatty acid ester (Tweens TM 20, 40, 60 and 80); sorbitan esters of fatty acids (Span TM 20, 40, 60 and 80 or Arlacel TM 20, 40, 60 and 80); polyethylene glycol (such as those sold under the trade name Carbowax TM 3550 and 934); sucrose stearate and sucrose distearate mixtures, such as those sold under the trade names Crodesta TM F110 or Crodesta TM SL-40 obtained product; hexyldecyltrimethylammonium chloride (CTAC); polyvinylpyrrolidone (PVP). If necessary, two or more surface modifiers can be used in combination.

[0135] In one embodiment, the surface modifier is selected from the group consisting of poloxamers, α-tocopheryl polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid esters, and salts or acid forms of negatively charged phospholipids. In one embodiment, the surface modifier is selected from the group consisting of Pluronic TM F108, vitamin E TGPS (α-tocopheryl polyethylene glycol succinate, especially α-tocopheryl polyethylene glycol 1000 succinate), polyoxyethylene sorbitan fatty acid esters such as Tween TM 80, and phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatic acid; and salts thereof, such as alkali metal salts, for example, sodium salts thereof, for example, sodium egg phosphatidylglycerol, such as those sold under the trade name Lipoid TM Products available from EPG.

[0136] In a preferred embodiment, the surface modifier is a poloxamer, particularly Pluronic TM F108. Pluronic TM F108 corresponds to poloxamer 338, which is a block copolymer of polyoxyethylene and polyoxypropylene, usually conforming to 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 commercial names for Poloxamer 338 are Hodag Nonionic TM 1108-F and Synperonic TM PE / F108. In one embodiment, the surface modifier comprises a combination of polyoxyethylene sorbitan fatty acid ester and phosphatidylglycerol salt (particularly sodium egg phosphatidylglycerol).

[0137] In one embodiment, the aqueous composition comprises about 0.1 mg / mL to about 100 mg / mL of poloxamer. In one embodiment, the aqueous composition comprises about 5 mg / mL to about 100 mg / mL of poloxamer. In one embodiment, the aqueous composition comprises about 5 mg / mL to about 70 mg / mL of poloxamer. In one embodiment, the aqueous composition comprises about 5 mg / mL to about 60 mg / mL of poloxamer.

[0138] In one embodiment, the aqueous composition comprises about 15 mg / mL to about 35 mg / mL (e.g., about 20 mg / mL to about 30 mg / mL) of poloxamer. In one embodiment, the aqueous composition comprises about 15 mg / mL to about 25 mg / mL (e.g., about 20 mg / mL) of poloxamer. In one embodiment, the aqueous composition comprises about 25 mg / mL to about 35 mg / mL (e.g., about 30 mg / mL) of poloxamer.

[0139] In one embodiment, the aqueous composition comprises about 20 mg / mL to about 60 mg / mL of poloxamer. In one embodiment, the aqueous composition comprises about 25 mg / mL to about 60 mg / mL of poloxamer. In a preferred embodiment, the aqueous composition comprises about 40 mg / mL to about 60 mg / mL (e.g., about 50 mg / mL) of poloxamer.

[0140] In one embodiment, the aqueous composition comprises a poloxamer and rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, wherein when rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than or about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is greater than or about 10: 1. In one embodiment, the aqueous composition comprises a poloxamer and rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, wherein when rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than or about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is from about 10: 1 to about 60: 1. In one embodiment, the aqueous composition comprises a poloxamer and rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, wherein when rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than or about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is from about 10:1 to about 30:1. In one embodiment, the aqueous composition comprises a poloxamer and rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, wherein when rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than or about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is from about 10:1 to about 20:1. In one embodiment, the aqueous composition comprises a poloxamer and rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, wherein when rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than or about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is from about 10:1 to about 15:1. In a preferred embodiment, the aqueous composition comprises a poloxamer and rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, wherein when rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than or about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is about 15:1. In a preferred embodiment, the aqueous composition comprises a poloxamer and rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, wherein when the rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than or about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is about 10: 1. The ratio is a weight / weight ratio.

[0141] In one embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being less than about 10: 1, and the rilpivirine or a pharmaceutically acceptable salt thereof having 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 pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being less than about 10: 1 to about 3: 1, and the rilpivirine or a pharmaceutically acceptable salt thereof having 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 pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being less than about 10:1 to about 4:1, and the rilpivirine or a pharmaceutically acceptable salt thereof having 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 pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being less than about 10:1 to about 6:1, and the rilpivirine or a pharmaceutically acceptable salt thereof having 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 a preferred embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 6:1, and the rilpivirine or a pharmaceutically acceptable salt thereof having 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, such as about 4 μm or about 5 μm or about 6 μm). The ratio is a weight / weight ratio.

[0142] In one embodiment, the aqueous composition comprises rilpivirine, or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine, or a pharmaceutically acceptable salt thereof, to the poloxamer being less than or about 10: 1, and the rilpivirine, or a pharmaceutically acceptable salt thereof, having a Dv90 of less than or about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine, or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine, or a pharmaceutically acceptable salt thereof, to the poloxamer being from about 10: 1 to about 3: 1, and the rilpivirine, or a pharmaceutically acceptable salt thereof, having a Dv90 of less than or about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine, or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine, or a pharmaceutically acceptable salt thereof, to the poloxamer being from about 10:1 to about 4:1, and the rilpivirine, or a pharmaceutically acceptable salt thereof, having a Dv90 of less than or about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine, or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine, or a pharmaceutically acceptable salt thereof, to the poloxamer being from about 10:1 to about 6:1, and the rilpivirine, or a pharmaceutically acceptable salt thereof, having a Dv90 of less than or about 1600 nm. In a preferred embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 6:1, and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of less than or about 1600 nm. The ratio is a weight / weight ratio.

[0143] In one embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being greater than or about 10: 1, and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 10: 1 to about 60: 1, and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 10: 1 to about 30: 1, and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 10: 1 to about 20: 1, and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 10:1 to about 15:1, and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm. In a preferred embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 15:1, and the rilpivirine or a pharmaceutically acceptable salt thereof having 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 pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 10: 1, and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm (e.g., about 500 nm to about 700 nm). The ratio is a weight / weight ratio.

[0144] In one embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being less than or about 10: 1, and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 10: 1 to about 3: 1, and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 10:1 to about 4:1, and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 10:1 to about 6:1, and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm. In a preferred embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 6:1, and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm (e.g., about 500 nm to about 700 nm). The ratio is a weight / weight ratio.

[0145] In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is from about 1:1 to about 40:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is from about 1:1 to about 30:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is from about 1:1 to about 20:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is from about 5:1 to about 15:1, for example about 10:1. The surface modifier is preferably a poloxamer, for example poloxamer 338.

[0146] In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is about 5:1 to about 25:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is about 10:1 to about 20:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to 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.

[0147] In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is about 1:2 to about 20:1, in particular about 1:1 to about 10:1, such as about 4:1 to about 8:1, for example about 4:1 to about 6:1, preferably about 6: 1. The surface modifier is preferably a poloxamer, for example poloxamer 338.

[0148] In one embodiment, the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof as defined herein, and one or more surface modifiers as defined herein, in the form of particles suspended in the aqueous composition, wherein the amount of rilpivirine or a pharmaceutically 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, in particular in a range between 80% and 90% by weight of the particles or in a range between 85% and 90% by weight of the particles.

[0149] Aqueous compositions include water, such as sterile water for injection.

[0150] In one embodiment, the aqueous composition additionally comprises a buffer and / or a pH adjusting agent. Specific buffer is a weak acid salt. The buffer and pH adjusting agent 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, ethylenediaminetetraacetic acid (EDTA), triethanolamine, including their mixture. In one embodiment, the buffer 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 buffer and a pH adjuster, wherein the buffer is sodium dihydrogen phosphate monohydrate and the pH adjuster is sodium hydroxide.

[0151] In one embodiment, the pH of the aqueous composition is from about 5 to about 7. In one embodiment, the pH of the aqueous composition is from about 6 to about 7. In one embodiment, the pH of the aqueous composition is from 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 by, for example, changing the type and / or amount of buffer and / or pH adjuster present in the aqueous composition.

[0152] 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, such as citric acid monohydrate.

[0153] 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).

[0154] In one embodiment, the aqueous composition is isotonic.

[0155] In one embodiment, the aqueous composition does not include an isotonicity agent.

[0156] In one embodiment, the aqueous composition does not comprise polyvinylpyrrolidone (PVP).

[0157] In one embodiment, the aqueous composition comprises substantially no glucose, such as less than about 10% w / w glucose, or less than about 5% w / w glucose, or preferably less than about 1% w / w glucose.

[0158] In one embodiment, the aqueous composition of the present invention can be contained in a container with an inert gas. The inert gas can be, for example, nitrogen.

[0159] In a specific embodiment of the first aspect, the present invention relates to an aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; (ii) hyaluronidase; and (iii) 0.001 mg / mL-100 mg / mL of cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof.

[0160] In a specific embodiment of the first aspect, the present invention is directed to an aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; (ii) hyaluronidase; and (iii) 0.001 mg / mL-100 mg / mL of cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof; and (iv) sugar.

[0161] In a specific embodiment of the first aspect, the present invention relates to an aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; (ii) hyaluronidase; and (iii) 0.001 mg / mL-100 mg / mL of:

[0162] (a) cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof; and

[0163] (b) an amino acid or a pharmaceutically acceptable salt thereof.

[0164] In certain embodiments, the aqueous composition comprises:

[0165] Hyaluronidase;

[0166] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0167] CMC or a pharmaceutically acceptable salt thereof,

[0168] wherein the pH of the aqueous composition is from about 6 to about 7,

[0169] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0170] In certain embodiments, the aqueous composition comprises:

[0171] Hyaluronidase;

[0172] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0173] Dextrose monohydrate; and

[0174] CMC or a pharmaceutically acceptable salt thereof,

[0175] wherein the pH of the aqueous composition is from about 6 to about 7,

[0176] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0177] In certain embodiments, the aqueous composition comprises:

[0178] Hyaluronidase;

[0179] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0180] An amino acid or a pharmaceutically acceptable salt thereof,

[0181] wherein the pH of the aqueous composition is from about 6 to about 7,

[0182] Optionally, the aqueous composition further comprises one or more components selected from the group consisting of a surfactant (e.g., poloxamer), a buffer (e.g., sodium dihydrogen phosphate), a chelating agent (e.g., citric acid), and a pH adjuster (e.g., sodium hydroxide), further optionally, the aqueous composition further comprises poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0183] In certain embodiments, the aqueous composition comprises:

[0184] Hyaluronidase;

[0185] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0186] Glycine,

[0187] wherein the pH of the aqueous composition is from about 6 to about 7,

[0188] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0189] In certain embodiments, the aqueous composition comprises:

[0190] Hyaluronidase;

[0191] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0192] Glycine or a pharmaceutically acceptable salt thereof,

[0193] wherein the pH of the aqueous composition is from about 6 to about 7,

[0194] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0195] In certain embodiments, the aqueous composition comprises:

[0196] Hyaluronidase;

[0197] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0198] Arginine,

[0199] wherein the pH of the aqueous composition is from about 6 to about 7,

[0200] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0201] In certain embodiments, the aqueous composition comprises:

[0202] Hyaluronidase;

[0203] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0204] Arginine hydrochloride,

[0205] wherein the pH of the aqueous composition is from about 6 to about 7,

[0206] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0207] In certain embodiments, the aqueous composition comprises:

[0208] Hyaluronidase;

[0209] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0210] Arginine or a pharmaceutically acceptable salt thereof,

[0211] wherein the pH of the aqueous composition is from about 6 to about 7,

[0212] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0213] In certain embodiments, the aqueous composition comprises:

[0214] Hyaluronidase;

[0215] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0216] Sucrose; and

[0217] CMC or a pharmaceutically acceptable salt thereof,

[0218] wherein the pH of the aqueous composition is from about 6 to about 7,

[0219] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0220] In certain embodiments, the aqueous composition comprises:

[0221] Hyaluronidase;

[0222] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0223] Sucrose; and

[0224] Sodium CMC,

[0225] wherein the pH of the aqueous composition is from about 6 to about 7,

[0226] Optionally wherein the aqueous composition further comprises one or more components selected from the group consisting of poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0227] In certain embodiments, the aqueous composition comprises:

[0228] Hyaluronidase;

[0229] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0230] Arginine or a pharmaceutically acceptable salt thereof; and

[0231] CMC or a pharmaceutically acceptable salt thereof,

[0232] wherein the pH of the aqueous composition is from about 6 to about 7,

[0233] Optionally wherein the aqueous composition further comprises one or more components selected from the group consisting of poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0234] In certain embodiments, the aqueous composition comprises:

[0235] Hyaluronidase;

[0236] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0237] Arginine or a pharmaceutically acceptable salt thereof; and

[0238] Sodium CMC,

[0239] wherein the pH of the aqueous composition is from about 6 to about 7,

[0240] Optionally wherein the aqueous composition further comprises one or more components selected from the group consisting of poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0241] In certain embodiments, the aqueous composition comprises:

[0242] Hyaluronidase;

[0243] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0244] Arginine hydrochloride; and

[0245] CMC or a pharmaceutically acceptable salt thereof,

[0246] wherein the pH of the aqueous composition is from about 6 to about 7,

[0247] Optionally wherein the aqueous composition further comprises one or more components selected from the group consisting of poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0248] In certain embodiments, the aqueous composition comprises:

[0249] Hyaluronidase;

[0250] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0251] Arginine hydrochloride; and

[0252] Sodium CMC,

[0253] wherein the pH of the aqueous composition is from about 6 to about 7,

[0254] Optionally wherein the aqueous composition further comprises one or more components selected from the group consisting of poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0255] In certain embodiments, the aqueous composition comprises:

[0256] rHuPH20;

[0257] Rilpivirine; and

[0258] Sodium CMC,

[0259] wherein the pH of the aqueous composition is from about 6 to about 6.5,

[0260] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0261] In certain embodiments, the aqueous composition comprises:

[0262] rHuPH20;

[0263] Rilpivirine; and

[0264] Sodium CMC,

[0265] wherein the pH of the aqueous composition is from about 6 to about 6.5, and

[0266] wherein the aqueous composition comprises about 0.002 mg CMC sodium / 100 U rHuPH20 to about 5 mg CMC sodium / 100 U rHuPH20,

[0267] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0268] In certain embodiments, the aqueous composition comprises:

[0269] rHuPH20;

[0270] Rilpivirine; and

[0271] Sodium CMC,

[0272] wherein the pH of the aqueous composition is from about 6 to about 6.5, and

[0273] wherein the aqueous composition comprises about 0.01 mg CMC sodium / 100 U rHuPH20 to about 0.25 mg CMC sodium / 100 U rHuPH20,

[0274] Optionally wherein the aqueous composition further comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0275] In certain embodiments, the aqueous composition comprises:

[0276] rHuPH20;

[0277] Rilpivirine;

[0278] Sodium CMC; and

[0279] Sugar or sugar alcohol,

[0280] wherein the pH of the aqueous composition is from about 6 to about 6.5,

[0281] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0282] In certain embodiments, the aqueous composition comprises:

[0283] rHuPH20;

[0284] Rilpivirine;

[0285] Sodium CMC; and

[0286] Glucose monohydrate and / or sucrose,

[0287] wherein the pH of the aqueous composition is from about 6 to about 6.5,

[0288] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0289] In certain embodiments, the aqueous composition comprises:

[0290] rHuPH20;

[0291] Rilpivirine;

[0292] Sodium CMC; and

[0293] sucrose,

[0294] wherein the pH of the aqueous composition is from about 6 to about 6.5,

[0295] Optionally wherein the aqueous composition further comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0296] In certain embodiments, the aqueous composition comprises:

[0297] rHuPH20;

[0298] Rilpivirine;

[0299] Sodium CMC; and

[0300] Arginine or a pharmaceutically acceptable salt thereof,

[0301] wherein the pH of the aqueous composition is from about 6 to about 6.5,

[0302] Optionally wherein the aqueous composition further comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0303] In certain embodiments, the aqueous composition comprises:

[0304] rHuPH20;

[0305] Rilpivirine;

[0306] Sodium CMC; and

[0307] Arginine hydrochloride,

[0308] wherein the pH of the aqueous composition is from about 6 to about 6.5,

[0309] Optionally wherein the aqueous composition further comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0310] In certain embodiments, the aqueous composition comprises:

[0311] rHuPH20;

[0312] Rilpivirine;

[0313] Sodium CMC; and

[0314] Glucose monohydrate and / or sucrose,

[0315] wherein the pH of the aqueous composition is from about 6 to about 6.5,

[0316] wherein the aqueous composition comprises about 0.0025 mg CMC sodium / 100 U rHuPH20 to about 5 mg CMC sodium / 100 U rHuPH20,

[0317] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0318] In certain embodiments, the aqueous composition comprises:

[0319] rHuPH20;

[0320] Rilpivirine;

[0321] Sodium CMC; and

[0322] Glucose monohydrate and / or sucrose,

[0323] wherein the pH of the aqueous composition is from about 6 to about 6.5,

[0324] wherein the aqueous composition comprises about 0.01 mg CMC sodium / 100 U rHuPH20 to about 0.25 mg CMC sodium / 100 U rHuPH20, such as 0.05 mg CMC sodium / 100 U rHuPH20 or 0.15 mg CMC sodium / 100 U rHuPH20,

[0325] Optionally wherein the aqueous composition further comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0326] In certain embodiments, the aqueous composition comprises:

[0327] rHuPH20;

[0328] Rilpivirine;

[0329] Sodium CMC; and

[0330] sucrose,

[0331] wherein the pH of the aqueous composition is from about 6 to about 6.5,

[0332] wherein the aqueous composition comprises about 0.01 mg CMC sodium / 100 U rHuPH20 to about 0.25 mg CMC sodium / 100 U rHuPH20, such as 0.05 mg CMC sodium / 100 U rHuPH20 or 0.15 mg CMC sodium / 100 U rHuPH20,

[0333] Optionally wherein the aqueous composition further comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0334] In certain embodiments, the aqueous composition comprises:

[0335] rHuPH20;

[0336] Rilpivirine;

[0337] Sodium CMC; and

[0338] Arginine or a pharmaceutically acceptable salt thereof,

[0339] wherein the pH of the aqueous composition is from about 6 to about 6.5,

[0340] wherein the aqueous composition comprises about 0.01 mg CMC sodium / 100 U rHuPH20 to about 0.25 mg CMC sodium / 100 U rHuPH20, such as 0.05 mg CMC sodium / 100 U rHuPH20 or 0.15 mg CMC sodium / 100 U rHuPH20,

[0341] Optionally wherein the aqueous composition further comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0342] In certain embodiments, the aqueous composition comprises:

[0343] rHuPH20;

[0344] Rilpivirine;

[0345] Sodium CMC; and

[0346] Arginine hydrochloride,

[0347] wherein the pH of the aqueous composition is from about 6 to about 6.5,

[0348] wherein the aqueous composition comprises about 0.01 mg CMC sodium / 100 U rHuPH20 to about 0.25 mg CMC sodium / 100 U rHuPH20, such as 0.05 mg CMC sodium / 100 U rHuPH20 or 0.15 mg CMC sodium / 100 U rHuPH20,

[0349] Optionally wherein the aqueous composition further comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0350] In certain embodiments, the aqueous composition comprises:

[0351] rHuPH20;

[0352] Rilpivirine; and

[0353] An amino acid or a pharmaceutically acceptable salt thereof,

[0354] wherein the pH of the aqueous composition is from about 6 to about 6.5,

[0355] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0356] In certain embodiments, the aqueous composition comprises:

[0357] rHuPH20;

[0358] Rilpivirine; and

[0359] Arginine HCl,

[0360] wherein the pH of the aqueous composition is from about 6 to about 6.5,

[0361] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0362] In certain embodiments, the aqueous composition comprises:

[0363] rHuPH20;

[0364] Rilpivirine; and

[0365] amino acid or a pharmaceutically acceptable salt thereof and a sugar or a sugar alcohol,

[0366] wherein the pH of the aqueous composition is from about 6 to about 6.5,

[0367] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0368] In certain embodiments, the aqueous composition comprises:

[0369] rHuPH20;

[0370] Rilpivirine; and

[0371] amino acid or a pharmaceutically acceptable salt thereof and a sugar or a sugar alcohol,

[0372] wherein the pH of the aqueous composition is from about 6 to about 6.5, and

[0373] wherein the ratio of rilpivirine to the sugar or sugar alcohol and the amino acid or a pharmaceutically acceptable salt thereof is from about 2:1 (w / w) to about 30:1 (w / w),

[0374] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0375] In certain embodiments, the aqueous composition comprises:

[0376] rHuPH20;

[0377] Rilpivirine; and

[0378] an amino acid or a pharmaceutically acceptable salt thereof and a sugar or a sugar alcohol, and

[0379] wherein the pH of the aqueous composition is from about 6 to about 6.5, and

[0380] wherein the ratio of rilpivirine to the sugar or sugar alcohol and the amino acid or a pharmaceutically acceptable salt thereof is from about 5:1 (w / w) to about 16:1 (w / w),

[0381] Optionally wherein the aqueous composition additionally comprises one or more components selected from the group consisting of poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition additionally comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0382] In certain embodiments, the aqueous composition comprises:

[0383] rHuPH20;

[0384] Rilpivirine in the form of particles suspended in an aqueous composition;

[0385] Sodium CMC;

[0386] Sucrose; and

[0387] Poloxamer 338,

[0388] Optionally wherein when rilpivirine has a Dv90 of less than or about 1600 nm, the ratio of rilpivirine to poloxamer 338 is greater than or about 10:1.

[0389] In certain embodiments, the aqueous composition comprises:

[0390] about 1800 U / mL to about 2200 U / mL of rHuPH20;

[0391] about 250 mg / mL to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition;

[0392] about 0.5 mg / mL to about 5 mg / mL of sodium CMC;

[0393] about 45 mg / mL to about 55 mg / mL of sucrose; and

[0394] about 10 mg / mL to about 60 mg / mL of Poloxamer 338,

[0395] Optionally wherein rilpivirine has a Dv90 of about 3 μm to about 7 μm (eg, about 6 μm) when the aqueous composition comprises about 40 mg / mL to about 60 mg / mL (eg, about 50 mg / mL) of poloxamer 338. In another specific embodiment, the Dv90 is about 5 μm.

[0396] In certain embodiments, the aqueous composition comprises:

[0397] about 1800 U / mL to about 2200 U / mL of rHuPH20;

[0398] about 250 mg / mL to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition;

[0399] about 0.5 mg / mL to about 5 mg / mL of sodium CMC;

[0400] about 45 mg / mL to about 55 mg / mL of sucrose; and

[0401] about 10 mg / mL to about 60 mg / mL of Poloxamer 338,

[0402] Optionally wherein the aqueous composition comprises about 40 mg / mL to about 60 mg / mL (eg, about 50 mg / mL) of poloxamer 338, and the rilpivirine has a Dv90 of about 500 nm to 1600 nm.

[0403] In certain embodiments, the aqueous composition comprises:

[0404] about 1800 U / mL to about 2200 U / mL of rHuPH20;

[0405] about 250 mg / mL to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition;

[0406] about 0.5 mg / mL to about 5 mg / mL of sodium CMC;

[0407] about 45 mg / mL to about 55 mg / mL of sucrose; and

[0408] about 10 mg / mL to about 60 mg / mL of Poloxamer 338,

[0409] Optionally wherein when the aqueous composition comprises about 20 mg / mL to about 30 mg / mL of poloxamer 338, rilpivirine has a Dv90 of about 500 nm to 1600 nm.

[0410] In certain embodiments, the aqueous composition comprises:

[0411] About 2000 U / mL of rHuPH20;

[0412] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition;

[0413] about 1 mg / mL to about 3 mg / mL of sodium CMC;

[0414] about 50 mg / mL of sucrose; and

[0415] About 50 mg / mL of Poloxamer 338,

[0416] Wherein the rilpivirine has a Dv90 of about 4 μm to about 6 μm (eg, about 6 μm). In another specific embodiment, the Dv90 is about 5 μm.

[0417] In certain embodiments, the aqueous composition comprises:

[0418] About 2000 U / mL of rHuPH20;

[0419] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition;

[0420] about 1 mg / mL to about 3 mg / mL of sodium CMC;

[0421] about 50 mg / mL sucrose; and

[0422] About 50 mg / mL of Poloxamer 338,

[0423] Wherein the rilpivirine has a Dv90 of about 500 nm to about 1600 μm.

[0424] In certain embodiments, the aqueous composition comprises:

[0425] About 2000U / mL of rHuPH20;

[0426] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition;

[0427] about 1 mg / mL to about 3 mg / mL of sodium CMC;

[0428] about 50 mg / mL sucrose; and

[0429] about 20 mg / mL to about 30 mg / mL of Poloxamer 338,

[0430] Wherein the rilpivirine has a Dv90 of about 500 nm to about 1600 μm.

[0431] In certain embodiments, the aqueous composition comprises:

[0432] rHuPH20;

[0433] Rilpivirine in the form of particles suspended in an aqueous composition;

[0434] Sodium CMC;

[0435] Arginine HCl; and

[0436] Poloxamer 338,

[0437] Optionally wherein when rilpivirine has a Dv90 of less than or about 1600 nm, the weight / weight ratio of rilpivirine to poloxamer 338 is greater than or about 10:1.

[0438] In certain embodiments, the aqueous composition comprises:

[0439] about 1800 U / mL to about 2200 U / mL of rHuPH20;

[0440] about 250 mg / mL to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition;

[0441] about 0.5 mg / mL to about 5 mg / mL of sodium CMC;

[0442] about 15 mg / mL to about 25 mg / mL of arginine HCl; and

[0443] about 10 mg / mL to about 60 mg / mL of Poloxamer 338,

[0444] Optionally wherein when rilpivirine has a Dv90 of less than or about 1600 nm, the weight / weight ratio of rilpivirine to poloxamer 338 is greater than or about 10:1.

[0445] In certain embodiments, the aqueous composition comprises:

[0446] about 1800 U / mL to about 2200 U / mL of rHuPH20;

[0447] about 250 mg / mL to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition;

[0448] about 0.5 mg / mL to about 5 mg / mL of sodium CMC;

[0449] about 15 mg / mL to about 25 mg / mL of arginine HCl; and

[0450] about 10 mg / mL to about 60 mg / mL of Poloxamer 338,

[0451] Optionally wherein when rilpivirine has a Dv90 of less than or about 1600 nm, the weight / weight ratio of rilpivirine to poloxamer 338 is equal to or less than about 10:1.

[0452] In certain embodiments, the aqueous composition comprises:

[0453] About 2000U / mL of rHuPH20;

[0454] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition;

[0455] about 1 mg / mL to about 3 mg / mL of sodium CMC;

[0456] about 20 mg / mL of arginine HCl; and

[0457] About 50 mg / mL of Poloxamer 338,

[0458] Wherein the rilpivirine has a Dv90 of about 4 μm to about 6 μm (eg, about 6 μm). In another specific embodiment, the Dv90 is about 5 μm.

[0459] In certain embodiments, the aqueous composition comprises:

[0460] About 2000 U / mL of rHuPH20;

[0461] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition;

[0462] about 1 mg / mL to about 3 mg / mL of sodium CMC;

[0463] about 20 mg / mL of arginine HCl; and

[0464] About 50 mg / mL of Poloxamer 338,

[0465] Among them, rilpivirine has a Dv90 of about 500nm to 1600μm.

[0466] In certain embodiments, the aqueous composition comprises:

[0467] About 2000 U / mL of rHuPH20;

[0468] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition;

[0469] about 1 mg / mL to about 3 mg / mL of sodium CMC;

[0470] about 20 mg / mL of arginine HCl; and

[0471] about 20 mg / mL to about 30 mg / mL of Poloxamer 338,

[0472] Among them, rilpivirine has a Dv90 of about 500nm to 1600nm.

[0473] In certain embodiments, the aqueous composition comprises:

[0474] About 2000 U / mL of rHuPH20;

[0475] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition;

[0476] about 1 mg / mL to about 3 mg / mL of sodium CMC;

[0477] about 20 mg / mL of arginine HCl; and

[0478] About 50 mg / mL of Poloxamer 338,

[0479] About 2mg / mL of NaH2PO4.H2O,

[0480] About 1mg / mL of citric acid.H2O,

[0481] Sodium hydroxide (qs to pH 6), and

[0482] Water (add to 1 mL),

[0483] Wherein the rilpivirine has a Dv90 of about 4 μm to about 6 μm (eg, about 6 μm). In another specific embodiment, the Dv90 is about 5 μm.

[0484] In certain embodiments, the aqueous composition comprises:

[0485] About 2000 U / mL of rHuPH20;

[0486] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition;

[0487] about 1 mg / mL to about 3 mg / mL of sodium CMC;

[0488] about 20 mg / mL of arginine HCl; and

[0489] About 50 mg / mL of Poloxamer 338,

[0490] About 2mg / mL of NaH2PO4.H2O,

[0491] About 1mg / mL of citric acid.H2O,

[0492] Sodium hydroxide (qs to pH 6), and

[0493] Water (add to 1 mL),

[0494] Among them, rilpivirine has a Dv90 of about 500nm to 1600μm.

[0495] In certain embodiments, the aqueous composition comprises:

[0496] About 2000 U / mL of rHuPH20;

[0497] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition;

[0498] about 1 mg / mL to about 3 mg / mL of sodium CMC;

[0499] about 20 mg / mL of arginine HCl; and

[0500] about 20 mg / mL to about 30 mg / mL of Poloxamer 338,

[0501] About 2mg / mL of NaH2PO4.H2O,

[0502] About 1mg / mL of citric acid.H2O,

[0503] Sodium hydroxide (qs to pH 6), and

[0504] Water (add to 1 mL),

[0505] Among them, rilpivirine has a Dv90 of about 500nm to 1600nm.

[0506] In any of these specific embodiments, the aqueous composition can further comprise an antioxidant (eg, methionine), optionally in an amount of about 1.0 mg / mL to about 2.0 mg / mL (eg, 1.5 mg / mL).

[0507] In a preferred embodiment, an aqueous composition is provided having a pH of about 5 to about 7 (preferably about 6) and comprising:

[0508] (i) rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition;

[0509] (ii) hyaluronidase;

[0510] (iii) 0.1 mg / mL to 100 mg / mL of glucose or glucose monohydrate (e.g., dextrose);

[0511] (iv) an inert gas (e.g. nitrogen) blanket; and

[0512] (v) Antioxidant (eg, methionine), eg, from about 1 mg / mL to about 2 mg / mL, eg, 1.5 mg / mL.

[0513] In one aspect, an aqueous composition is provided having a pH of about 6 to about 6.5 (preferably 6) and comprising:

[0514] (i) rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition; and

[0515] (ii) Hyaluronidase.

[0516] In one aspect, an aqueous composition is provided having a pH of about 6 to about 6.5 (preferably 6) and comprising:

[0517] (i) rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition;

[0518] (ii) hyaluronidase; and

[0519] (iii) an antioxidant (eg, methionine), eg, about 1 mg / mL to about 2 mg / mL, eg, 1.5 mg / mL.

[0520] In one aspect, an aqueous composition is provided having a pH of about 6 to about 6.5 (preferably 6) and comprising:

[0521] (i) rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition;

[0522] (ii) hyaluronidase;

[0523] (iii) an antioxidant (e.g., methionine), e.g., about 1 mg / mL to about 2 mg / mL, e.g., 1.5 mg / mL; and

[0524] (iv) 0.1 mg / mL to 100 mg / mL of glucose or glucose monohydrate (eg, dextrose).

[0525] In a preferred embodiment, the composition of the present invention reduces the change in the particle size distribution of the rilpivirine microparticles or nanoparticles over time. This reduction may be relative to a composition in which excipients (a) and / or (b) are not added to the composition.

[0526] In a preferred embodiment, the composition of the invention reduces the change in the particle size distribution of the rilpivirine microparticles or nanoparticles over time. This reduction may be relative to a composition in which excipient (a) is not added to the composition.

[0527] In a preferred embodiment, the composition of the invention reduces the change in the particle size distribution of the rilpivirine microparticles or nanoparticles over time. This reduction may be relative to a composition in which no excipient (b) is added to the composition.

[0528] In a preferred embodiment, the composition of the present invention reduces the change in the particle size distribution of the rilpivirine microparticles or nanoparticles over time. This reduction may be relative to a composition in which excipients (a) and (b) are not added to the composition.

[0529] In the use of the present invention (use in a method for stabilizing an aqueous composition), stabilization may be a reduction in the change in the particle size distribution of the rilpivirine microparticles or nanoparticles over time. This reduction may be relative to a composition in which excipients (a) and / or (b) are not added to the composition.

[0530] In the use of the present invention (use in a method for stabilizing an aqueous composition), stabilization may be a reduction in the change in the particle size distribution of the rilpivirine microparticles or nanoparticles over time. This reduction may be relative to a composition in which excipient (a) is not added to the composition.

[0531] In the use of the present invention (use in a method for stabilizing an aqueous composition), stabilization may be a reduction in the change in the particle size distribution of the rilpivirine microparticles or nanoparticles over time. This reduction may be relative to a composition in which no excipient (b) is added to the composition.

[0532] In the use of the present invention (use in a method for stabilizing an aqueous composition), stabilization may be a reduction in the change in the particle size distribution of the rilpivirine microparticles or nanoparticles over time. This reduction may be relative to a composition in which excipients (a) and (b) are not added to the composition.

[0533] For example, after storing the aqueous composition at about 5°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months, the Dv10, Dv50, and Dv90 values ​​of the particles can remain within about 20% of the original values.

[0534] As another example, after storing the aqueous composition at about 5° C. for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months, the Dv10, Dv50, and Dv90 values ​​of the particles can remain within about 10% of the original values.

[0535] For example, after storing the aqueous composition at about 5°C for about 1 week, about 2 weeks, about 4 weeks, about 8 weeks, about 16 weeks, or about 32 weeks, the Dv10, Dv50, and Dv90 values ​​of the particles can remain within about 20% of the original values.

[0536] As another example, after storing the aqueous composition at about 5°C for about 1 week, about 2 weeks, about 4 weeks, about 8 weeks, about 16 weeks, or about 32 weeks, the Dv10, Dv50, and Dv90 values ​​of the particles can remain within about 10% of the original values.

[0537] For example, after storing the aqueous composition at about 25°C for about 1 week, about 2 weeks, about 4 weeks, about 8 weeks, about 16 weeks, or about 32 weeks, the Dv10, Dv50, and Dv90 values ​​of the particles can remain within about 20% of the original values.

[0538] As another example, after storing the aqueous composition at about 25°C for about 1 week, about 2 weeks, about 4 weeks, about 8 weeks, about 16 weeks, or about 32 weeks, the Dv10, Dv50, and Dv90 values ​​of the particles can remain within about 10% of the original values.

[0539] For example, after storing the aqueous composition at about 25°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months, the Dv10, Dv50, and Dv90 values ​​of the particles can remain within about 20% of the original values.

[0540] As another example, after storing the aqueous composition at about 25° C. for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months, the Dv10, Dv50, and Dv90 values ​​of the particles can remain within about 30% of the original values.

[0541] In a preferred embodiment, the compositions of the invention retain hyaluronidase activity over a period of time (e.g., about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months). This retention may be relative to a composition in which excipients (a) and / or (b) are not added to the composition.

[0542] In a preferred embodiment, the compositions of the present invention retain hyaluronidase activity over a period of time (e.g., about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months). This retention may be relative to a composition in which excipient (a) is not added to the composition.

[0543] In a preferred embodiment, the compositions of the invention retain hyaluronidase activity over a period of time (e.g., about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months). This retention may be relative to a composition in which excipient (b) is not added to the composition.

[0544] In a preferred embodiment, the compositions of the invention retain hyaluronidase activity over a period of time (e.g., about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months). This retention may be relative to a composition in which excipients (a) and (b) are not added to the composition.

[0545] In the use of the present invention (use in a method for stabilizing an aqueous composition), stabilization may be the maintenance of hyaluronidase activity over time. This maintenance may be relative to a composition in which excipients (a) and / or (b) are not added to the composition.

[0546] In the use of the present invention (use in a method for stabilizing an aqueous composition), stabilization may be the maintenance of hyaluronidase activity over time. This maintenance may be relative to a composition in which excipient (a) is not added to the composition.

[0547] In the use of the present invention (use in a method of stabilizing an aqueous composition), stabilization may be the maintenance of hyaluronidase activity over time. This maintenance may be relative to a composition in which excipient (b) is not added to the composition.

[0548] In the use of the present invention (use in a method for stabilizing an aqueous composition), stabilization may be the maintenance of hyaluronidase activity over time. This maintenance may be relative to a composition in which excipients (a) and (b) are not added to the composition.

[0549] For example, the composition can retain hyaluronidase activity for a period of time, such as about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months. This can be the case when stored at about 5°C or about 25°C.

[0550] As another example, the hyaluronidase activity can retain at least 50% of the original activity after storing the aqueous composition at about 5°C or about 25°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months.

[0551] As another example, the hyaluronidase activity can retain at least 50% of the original activity after storing the aqueous composition at about 5°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months.

[0552] As another example, the hyaluronidase activity can retain at least 25% of the original activity after storing the aqueous composition at about 5°C or about 25°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months.

[0553] In a preferred embodiment, the compositions of the invention maintain hyaluronidase concentrations (e.g., as determined by size exclusion chromatography) over a period of time (e.g., about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months).

[0554] This maintenance may be relative to a composition wherein excipients (a) and / or (b) are not added to the composition.

[0555] This maintenance may be relative to a composition wherein no excipient (a) is added to the composition.

[0556] This maintenance may be relative to a composition wherein no excipient (b) is added to the composition.

[0557] This maintenance may be relative to a composition wherein excipients (a) and (b) are not added to the composition.

[0558] In the use of the invention (use in a method of stabilizing an aqueous composition), stabilization may be maintaining the hyaluronidase concentration over time (e.g., as determined by size exclusion chromatography). This maintenance may be relative to a composition in which excipients (a) and / or (b) are not added to the composition.

[0559] In the use of the invention (use in a method of stabilizing an aqueous composition), stabilization may be maintaining the hyaluronidase concentration over time (e.g., as determined by size exclusion chromatography). This maintenance may be relative to a composition in which excipient (a) is not added to the composition.

[0560] In the use of the invention (use in a method of stabilizing an aqueous composition), stabilization may be maintaining the hyaluronidase concentration over time (e.g., as determined by size exclusion chromatography). This maintenance may be relative to a composition in which excipient (b) is not added to the composition.

[0561] In the use of the invention (use in a method of stabilizing an aqueous composition), stabilization may be maintaining the hyaluronidase concentration over time (e.g., as determined by size exclusion chromatography). This maintenance may be relative to a composition in which excipients (a) and (b) are not added to the composition.

[0562] For example, the composition can maintain a hyaluronidase concentration (e.g., as determined by size exclusion chromatography) over a period of time (e.g., 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). This can be the case when stored at about 5°C or about 25°C.

[0563] As another example, at least 25% of the original concentration of the hyaluronidase can be maintained after storing 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.

[0564] As another example, after the aqueous composition is stored 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 the hyaluronidase concentration can be maintained.

[0565] As another example, after the aqueous composition is stored 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 the hyaluronidase concentration can be maintained.

[0566] In a preferred embodiment, the compositions of the invention maintain hyaluronidase purity over a period of time (e.g., 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).

[0567] This maintenance may be relative to a composition wherein excipients (a) and / or (b) are not added to the composition.

[0568] This maintenance may be relative to a composition wherein no excipient (a) is added to the composition.

[0569] This maintenance may be relative to a composition wherein no excipient (b) is added to the composition.

[0570] This maintenance may be relative to a composition wherein excipients (a) and b) are not added to the composition.

[0571] In the use of the present invention (use in a method of stabilizing an aqueous composition), stabilization may be the maintenance of hyaluronidase purity over time. This maintenance may be relative to a composition in which excipients (a) and / or (b) are not added to the composition.

[0572] In the use of the invention (use in a method of stabilizing an aqueous composition), stabilization may be the maintenance of hyaluronidase purity over time. This maintenance may be relative to a composition in which excipient (a) is not added to the composition.

[0573] In the use of the invention (use in a method of stabilizing an aqueous composition), stabilization may be the maintenance of hyaluronidase purity over time. This maintenance may be relative to a composition in which no excipient (b) is added to the composition.

[0574] In the use of the present invention (use in a method of stabilizing an aqueous composition), stabilization may be the maintenance of hyaluronidase purity over time. This maintenance may be relative to a composition in which excipients (a) and (b) are not added to the composition.

[0575] For example, the composition can maintain the purity of the hyaluronidase (i.e., reduce the presence of degradation products) over a period of time (e.g., 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). This can be the case when stored at about 5°C or about 25°C.

[0576] As another example, after storing 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.

[0577] As another example, after storing the aqueous composition at about 5°C or about 25°C (e.g., about 5°C) for about 6 months, about 12 months, about 18 months, or about 24 months, less than 25% of the original hyaluronidase is degraded into degradants.

[0578] As another example, after storing the aqueous composition at about 5°C or about 25°C (eg, about 5°C) for about 6 months, about 12 months, about 18 months, or about 24 months, less than 20% of the original hyaluronidase is degraded into degradants.

[0579] As another example, after storing the aqueous composition at about 5°C or about 25°C (eg, about 5°C) for about 6 months, about 12 months, about 18 months, or about 24 months, less than 5% of the original hyaluronidase is degraded into degradants.

[0580] In one embodiment, the measured degradants are oxidized species of hyaluronidase. In a specific embodiment, the measured degradants are oxidized species of hyaluronidase with reduced enzymatic activity.

[0581] Use of the composition of the present invention

[0582] The aqueous composition can be used to treat or prevent HIV infection in a subject.

[0583] Thus, in one aspect, the present invention relates to a method for treating or preventing 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 treating or preventing HIV infection in a subject. In a sixth aspect, the present invention relates to the use of an aqueous composition as defined herein in the preparation of a medicament for treating or preventing HIV infection in a subject.

[0584] In a preferred embodiment, the subject is a human.

[0585] In one embodiment, the aqueous composition is intermittently applied to the subject so that the time interval between administrations (i.e., dosing interval) is about three months to about two years. In one embodiment, the time interval is about three months to about eighteen months. In one embodiment, the time interval is about three months to about one year. In one embodiment, the time interval is about three months to about six months. In one embodiment, the time interval is about six months to about one year. In one embodiment, the time interval is about one year. In one embodiment, the time interval is about three months. In one embodiment, the time interval is about four months. In one embodiment, the time interval is about five months. In one embodiment, the time interval is about six months. In one embodiment, the time interval is about seven months. In one embodiment, the time interval is about eight months. In one embodiment, the time interval is about nine months. In one embodiment, the time interval is about 10 months. In one embodiment, the time interval is about 11 months.

[0586] In one embodiment, the aqueous composition is administered by subcutaneous injection 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.

[0587] In another embodiment, the aqueous composition is administered by manual injection.

[0588] The aqueous composition can effectively have a molar osmotic pressure concentration suitable for reducing pain during subcutaneous injection. For example, in one embodiment, the aqueous composition has a molar osmotic pressure concentration of about 280mOsm / kg to about 600mOsm / kg. In another embodiment, the aqueous composition has a molar osmotic pressure concentration of about 280mOsm / kg to about 300mOsm / kg. In a more preferred embodiment, the aqueous composition has a molar osmotic pressure concentration of about 290mOsm / kg.

[0589] Rilpivirine or a pharmaceutically 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.

[0590] In one embodiment, each application comprises up to about 150mL of an aqueous composition as described herein. In another embodiment, each application comprises an aqueous composition of about 3mL to about 150mL. In another embodiment, each application comprises an aqueous composition of about 3mL to about 100mL. In another embodiment, each application comprises an aqueous composition of about 3mL to about 15mL. In another embodiment, each application comprises an aqueous composition of about 5mL to about 25mL. In another embodiment, each application comprises an aqueous composition of about 6mL to about 20mL. In another embodiment, each application comprises an aqueous composition of about 6mL to about 18mL. In another embodiment, each application comprises an aqueous composition of about 6mL to about 15mL. In another embodiment, each application comprises an aqueous composition of about 6mL to about 12mL. In another embodiment, each application comprises an aqueous composition of about 9mL to about 18mL. In another embodiment, each application comprises an aqueous composition of about 9mL to about 15mL. In another embodiment, each application comprises an aqueous composition of about 9mL to about 12mL. In another embodiment, each application comprises an aqueous composition of about 3mL. In another embodiment, each application comprises about 4 mL of an aqueous composition. In another embodiment, each application comprises about 5 mL of an aqueous composition. In another embodiment, each application comprises about 6 mL of an aqueous composition. In another embodiment, each application comprises about 7 mL of an aqueous composition. In another embodiment, each application comprises about 8 mL of an aqueous composition. In another embodiment, each application comprises about 9 mL of an aqueous composition. In another embodiment, each application comprises about 10 mL of an aqueous composition. In another embodiment, each application comprises about 11 mL of an aqueous composition. In another embodiment, each application comprises about 12 mL of an aqueous composition. In another embodiment, each application comprises about 13 mL of an aqueous composition. In another embodiment, each application comprises about 14 mL of an aqueous composition. In another embodiment, each application comprises about 15 mL of an aqueous composition. In another embodiment, each application comprises about 18 mL of an aqueous composition. In a preferred embodiment, each application comprises about 3 mL, about 7 mL, or about 15 mL of an aqueous composition.

[0591] In one embodiment, for the treatment of HIV infection, the dose of rilpivirine to be 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 about 450 mg / month, or about 600 mg / month, or about 750 mg / month, or about 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, in the case of a dose of 450 mg / month, and in the case of a time interval of 6 months between each administration, the dose of rilpivirine to be administered in each administration is 2700 mg. The "mg" shown corresponds to mg of rilpivirine (i.e., rilpivirine in free base form). Thus, by way of example, 1 mg of rilpivirine (ie rilpivirine in free base form) corresponds to 1.1 mg of rilpivirine hydrochloride.

[0592] In one embodiment, for the treatment of HIV infection, the dose of rilpivirine to be administered 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 about 450 mg / 4 weeks (28 days), or about 600 mg / 4 weeks (28 days), or about 750 mg / 4 weeks (28 days), or about 900 mg / 4 weeks (28 days). The dosage of 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 in the case of a time interval of 24 weeks between each administration, the dose of rilpivirine to be administered in each administration is 2700 mg. Or, for example, in the case of a dose of 750 mg / 4 weeks (28 days), and in the case of a time interval of 24 weeks between each administration, the dose of rilpivirine to be administered in each administration is 4500 mg. The "mg" shown corresponds to mg of rilpivirine (i.e., rilpivirine in free base form). Thus, by way of example, 1 mg of rilpivirine (i.e., rilpivirine in free base form) corresponds to 1.1 mg of rilpivirine hydrochloride.

[0593] In one embodiment, the rilpivirine or a pharmaceutically 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 above 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, the rilpivirine or a pharmaceutically 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 12 ng / ml to 100 ng / ml for at least 6 months.

[0594] In the case of prevention of HIV infection, each administration of rilpivirine or a pharmaceutically acceptable salt thereof may comprise the same dose as described above for therapeutic use.

[0595] In one embodiment, the aqueous composition is used in combination with one or more other active agents, in particular one or more other antiretroviral agents, in particular one or more other antiretroviral agents of another class, such as, for example, antiretroviral agents of the INSTI class, such as, for example, cabotegravir. In a specific 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.

[0596] In one embodiment, the one or more other antiretroviral agents (e.g., cabotegravir) are administered as intramuscular or subcutaneous injections, in particular as injectable microsuspensions or nanosuspensions, at intervals of about three months to about two years. In one embodiment, the one or more other antiretroviral agents (e.g., cabotegravir) are administered at the same intermittent intervals as the aqueous composition (e.g., aqueous composition) as described herein, and the other antiretroviral agents are intermittently administered at intervals of about three months, or about four months, or about five months, or about six months, or about seven months, or about eight months, or about ten months, or about eleven months, or about one year, or about one year to about 2 years. 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 (in particular subcutaneous injection). In one embodiment, the aqueous composition and the one or more other antiretroviral agents (e.g., cabotegravir) are administered simultaneously, in particular by subcutaneous injection. In one embodiment, the aqueous composition and the one or more other antiretroviral agents (e.g., cabotegravir) are administered sequentially, in particular by subcutaneous injection. In one embodiment, the aqueous composition is administered first, followed by the cabotegravir injection.

[0597] As used herein, the term "treatment of HIV infection" relates to treating a subject infected with HIV. The term "treatment of HIV infection" also relates to treating diseases associated with HIV infection (e.g., AIDS) or other conditions associated with HIV infection (including thrombocytopenia, Kaposi's sarcoma, and central nervous system infections characterized by progressive demyelination, leading to dementia and symptoms such as progressive dysarthria, ataxia, and disorientation), as well as other conditions to which HIV infection is also associated, such as peripheral neuropathy, progressive generalized lymphadenopathy (PGL), and AIDS-related complex (ARC).

[0598] As used herein, the term "prevention of HIV infection" relates to preventing or avoiding a subject (who will not be infected with HIV) from being infected with HIV. The source of infection can be various, containing HIV, particularly containing HIV body fluids, such as blood or semen, or other subjects infected with HIV. Preventing HIV infection relates to preventing the virus from being transmitted to uninfected people from HIV-containing substances or HIV-infected individuals, or relates to preventing the virus from entering the body of an uninfected person. The spread of the HIV virus can be carried out by any known HIV transmission cause (such as by sexual transmission or by contact with the blood of an infected subject (e.g., medical staff providing care for an infected subject)). HIV transmission can also occur by contact with HIV infected blood (e.g., when handling a blood sample or a blood transfusion). It can also be carried out by contact with infected cells (e.g., when HIV infected cells are subjected to laboratory experiments).

[0599] The term "treatment of HIV infection" refers to a treatment that reduces the viral load of HIV (expressed as the number of copies of viral RNA in a specific volume of serum). The more effective the treatment, the lower the viral load. Preferably, the viral load should be reduced to a level as low as possible, for example, below 200 copies / mL, particularly below about 100 copies / mL, more particularly below 50 copies / mL, and if possible, below the detection limit of the virus. A reduction in viral load by one, two or even three orders of magnitude (e.g., a reduction of about 10 to about 10 2 or more, such as about 10 3) is an indication of the effectiveness of treatment. Another parameter measuring the effectiveness of HIV treatment is CD4 count, which ranges from 500 to 1500 cells / μL in normal adults. Reduced CD4 counts are indications of HIV infection, and once less than about 200 cells / μL, AIDS may occur. The increase in CD4 counts, such as an increase of about 50, 100, 200 or more cells per μL, is also an indication of the effectiveness of anti-HIV treatment. In particular, CD4 counts should be increased to a level higher than about 200 cells / μL or higher than about 350 cells / μL. Viral load or CD4 counts or both can be used to diagnose the extent of HIV infection. Another parameter measuring the effectiveness of HIV treatment is when treated according to the present invention, HIV-infected subjects are kept virologically suppressed (HIV-1RNA<50 copies / mL).

[0600] The term "treatment of HIV infection" and similar terms refer to the treatment of reducing viral load as described above, or increasing CD4 counts, or both, or maintaining virological suppression in HIV-infected subjects. The term "prevention of HIV infection" and similar terms refer to the situation in which the relative number of newly infected subjects in a population contacted with a HIV infection source (such as a substance containing HIV) or HIV-infected subjects is reduced. For example, when an uninfected individual treated with a pharmaceutical composition of the present invention is compared with an untreated uninfected individual, effective prevention can be measured, for example, by measuring whether the relative number of newly infected individuals is reduced in a mixed population of HIV-infected and uninfected individuals. This reduction can be measured by statistically analyzing the number of infected and uninfected individuals in a given population over time.

[0601] General Definition

[0602] The term "comprising" encompasses "including" as well as "consisting of", e.g., a composition "comprising" X may consist of only X or may include something else, 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 and any other components that do not materially affect the basic characteristics of the composition.

[0603] The term "about" in connection with a value Y is optional and means, for example, Y ± 10%.

[0604] When an interval is expressed as a specified number of months, it runs from a given numbered day in a given month to the same numbered day in the month after the specified number of months. In the event that the same numbered day does not exist in the month after the specified number of months, the interval runs into the next month for the same number of days as it would otherwise run if the same numbered day would exist in the month after the specified number of months.

[0605] When a time interval is expressed as a number of years, it runs from a given date in a given year to the same date in the year that is the specified number of years later. In the event that the same date does not exist in the year that is the specified number of years later, the time interval runs for the same number of days as it would otherwise have run if the same numbered date would have existed in the month that is the specified number of months later. In other words, if the time interval begins on February 29 in a given year, but ends in a year that does not have a February 29, the time period ends on March 1 in that year instead.

[0606] The term "about" in connection with this definition means that the time interval may end on a date that is ±10% of the time interval.

[0607] 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.

[0608] All references cited herein are incorporated by reference in their entirety.

[0609] The present invention will now be described with reference to the following examples. For the avoidance of doubt, these examples do not limit the scope of the present invention. Modifications may be made while remaining within the scope and spirit of the present invention.

[0610] Example

[0611] Example 1 - Appearance study under stress test conditions

[0612] This example compares the appearance of various compositions, each having a different combination of excipients, after storage under different conditions.

[0613] An aqueous composition of rilpivirine nanoparticles and the following excipients was prepared:

[0614] Rilpivirine (300 mg / mL)

[0615] rHuPH20 (2000U / mL)

[0616] Sodium dihydrogen phosphate monohydrate (2 mg / mL)

[0617] Citric acid monohydrate (1 mg / mL)

[0618] Poloxamer 338 (50 mg / mL)

[0619] 5N sodium hydroxide aqueous solution (add to pH 6.0)

[0620] Water for injection (add to 1 mL)

[0621] Compositions A to E were prepared by adding or adjusting the components described above, as summarized in Table 1 below. In compositions A to E, the pH was adjusted to 6.0 using 5N sodium hydroxide solution.

[0622]

[0623] Table 1: Compositions A to E

[0624] Composition A and Composition B were prepared using rilpivirine nanoparticles (Dv10 = 95 nm, Dv50 = 220 nm, and Dv90 = 494 nm).

[0625] Compositions C to E were prepared using rilpivirine nanoparticles (having Dv10 = 102 nm, Dv50 = 234 nm, and Dv90 = 512 nm).

[0626] The results are shown in Figure 1 Medium. Tested for syringeability using a 25G x 3 / 4” needle.

[0627] Example 2 - Particle Size

[0628] This example studies the effect of various compositions, each with a different combination of excipients, on the particle size of Rilpivirine in suspension after storage at 5°C for 1 month, 3 months and 6 months.

[0629] Compositions A to E of rilpivirine nanoparticles were prepared as described in Example 1 (with Dv10, Dv50 and Dv90 as described in Example 1).

[0630] The composition was stored at 5° C. for 1 month. The particle size of Rilpivirine was measured according to the following method.

[0631] Particle size distribution measurement

[0632] The volume-based particle size distribution of the rilpivirine suspension was determined by means of wet dispersion laser diffraction using a Malvern Mastersizer 3000 laser diffractometer (Malvern Instruments) and a Hydro MV wet dispersion module.

[0633] The results are shown in Table 2 and Table 2A.

[0634]

[0635] Table 2: Particle size

[0636]

[0637] Table 2A: Particle Size

[0638] Example 3 - Purity Determination

[0639] This example compares rilpivirine assay data for various compositions, each having a different combination of excipients, after storage under different conditions.

[0640] Compositions A to E of rilpivirine nanoparticles were prepared as described in Example 1.

[0641] The composition was then stored in a refrigerator at 5° C. for 2 days to 2 weeks. Rilpivirine assay measurements of the composition were performed immediately and after 1 month storage at 5° C., 25° C. and 40° C. The amount of Rilpivirine was determined according to the following method.

[0642] Rilpivirine Assay Measurement

[0643] The determination 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 (hereinafter referred to as Impurity 1) in the composition.

[0644] The results are shown in Table 3.

[0645]

[0646] Table 3: Measurement data

[0647] Example 4 - pH

[0648] This example compares the pH of various rilpivirine compositions, each with a different combination of excipients, after storage under different conditions.

[0649] Compositions A to E of rilpivirine nanoparticles were prepared as described in Example 1.

[0650] The composition was stored at 5° C., 25° C. and 40° C. for 1 month. The pH was determined according to the following method.

[0651] pH Measurement

[0652] The pH of the composition was measured using a benchtop pH meter. The pH meter was calibrated in advance with two points calibrated to 4.0 and 7.0, and corrected for temperature. The pH was measured by immersing the probe in the aqueous composition.

[0653] The results are shown in Table 4.

[0654] Composition <![CDATA[t0]]> <![CDATA[t 1个月 (5℃)]]> <![CDATA[t 1个月 (25℃)]]> <![CDATA[t 1个月 (40℃)]]> A 6.1 6.1 (Initial: 4.712, remeasured: 4.441) 5.8 B 6.4 6.1 6.0 6.1 C 6.1 6.1 6.1 6.1 D 6.0 6.1 6.0 6.0 E 6.1 6.1 6.2 6.1

[0655] Table 4: pH data

[0656] The pH value of Composition A measured after storage at 25°C for 1 month was abnormal.

[0657] Example 5 - Melting temperature study under different storage conditions

[0658] This example compares the T of rHuPH20 in various compositions, each with different excipient combinations and / or pH, under different storage conditions. m . Higher T m Indicating higher thermal stability. T of about 25°C to about 30°C higher than expected long-term storage conditions m Designed to provide optimal thermodynamic stability of hyaluronidase.

[0659] Compositions 1 to 21 were prepared by adding the components shown in Table 5 below to the following composition (Composition F):

[0660] Glucose monohydrate (19.25 mg / mL)

[0661] rHuPH20 (2000U / mL)

[0662] Sodium dihydrogen phosphate monohydrate (2 mg / mL)

[0663] Citric acid monohydrate (1 mg / mL)

[0664] Poloxamer 338 (50 mg / mL)

[0665] Sodium hydroxide (varied to provide target pH)

[0666] Water for injection (add to 1 mL)

[0667] The pH of the composition was adjusted to 5.0, 6.0, 6.5 or 7.0 by varying the amount of sodium hydroxide as needed.

[0668] Composition pH Additional component 1 Additional component 2 1 5.0 - - 2 5.0 Mannitol (50 mg / mL) - 3 5.0 Sucrose (50 mg / mL) - 4 5.0 Histidine (25 mg / mL) - 5 5.0 Glycine (25 mg / mL) - 6 5.0 Glycine (10 mg / mL) Sucrose (50 mg / mL) 7 5.0 Glycine (10 mg / mL) Mannitol (25 mg / mL) 8 6.0 - - 9 6.0 Mannitol (50 mg / mL) - 10 6.0 Sucrose (50 mg / mL) - 11 6.0 Histidine (25 mg / mL) - 12 6.0 Glycine (25 mg / mL) - 13 6.0 Glycine (10 mg / mL) Sucrose (50 mg / mL) 14 6.0 Glycine (10 mg / mL) Mannitol (25 mg / mL) 15 6.5 Glycine (10 mg / mL) Sucrose (50 mg / mL) 16 7.0 Histidine (25 mg / mL) - 17 7.0 Glycine (10 mg / mL) Sucrose (50 mg / mL) 18 7.0 Glycine (10 mg / mL) Mannitol (25 mg / mL) 19 7.0 Glycine (15 mg / mL) - 20 7.0 Glycine (10 mg / mL) - 21 7.0 Glycine (5 mg / mL) -

[0669] Table 5: T m Research

[0670] Nano differential scanning fluorimetry (nDSF) was used to measure the T m nDSF uses intrinsic tryptophan and tyrosine fluorescence to monitor protein unfolding. The nDSF assay was performed as follows.

[0671] All nDSF assays were run using a Prometheus NT.Plex instrument controlled by PR.ThermControl-CFR software. When measuring samples, a temperature range of 20°C-95°C with a temperature gradient of 1°C / min was used. An excitation power of 95% was used in all cases. The instrument determined the fluorescence ratio of the protein at 350nm (tryptophan) and 330nm (tyrosine) during heating to 95°C. The unfolding onset temperature (T) of the current unfolding transition was then calculated from the unfolding curve. 起始 ) and the inflection point (T m ).

[0672] To enable high-throughput sample testing, the nanoDSF instrument is operated in combination with a robotic autosampler. The autosampler performs the loading and transfer of the capillary chips from the 384-well plate for nanoDSF measurements. The 384-well plate is automatically prepared using a Tecan Fluent760 liquid handling system in combination with a custom sample holder that typically provides 2R vials for sample testing.

[0673] Compositions 1 to 21 were prepared as described above and then stored in a refrigerator at 5°C for 2 days to 2 weeks. T was then measured immediately, after 1 week at 25°C and 1 week at 40°C, and under extreme storage conditions (i.e., 2 weeks at 25°C and 2 weeks at 40°C). m When measuring T m Remeasure the pH of the aqueous composition immediately before taking the value.

[0674] The results are shown in Figure 2 , Figure 2A , Figure 2B and Figure 2C middle.

[0675] Example 6a - Melting Temperature Studies

[0676] This example compares the T of rHuPH20 in various compositions, each with different excipient combinations and / or pH. m .

[0677] A composition (Composition G) was prepared containing the following excipients:

[0678] Sodium dihydrogen phosphate monohydrate (2 mg / mL)

[0679] Citric acid monohydrate (1 mg / mL)

[0680] rHuPH20 (2000U / mL)

[0681] Sodium hydroxide (varied to provide desired pH)

[0682] Water for injection (add to 1 mL)

[0683] 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.

[0684]

[0685]

[0686] Table 6: T m Research

[0687] Compositions 22 to 44 were prepared as described above and then stored in a refrigerator at 5°C for 2 days to 2 weeks. The T of rHuPH20 for each composition was then immediately measured using the method described in Example 5. m .

[0688] The results are shown in Table 6 and Figure 3 middle.

[0689] Example 6b - Melting temperature study under different storage conditions

[0690] This example compares the fluorescence emission spectra of rHuPH20 compositions after storage under different conditions. Fluorescence emission spectroscopy uses a beam absorbed by the enzyme (rHuPH20), and the fluorophore in the ground state is excited to a higher energy state, thereby causing emission. For enzymes such as rHuPH20, the fluorescence of tryptophan can be used to measure the changes in the tertiary enzyme structure during or after storage under different conditions, and therefore quantify the thermal stability of rHuPH20. The maximum emission wavelengths of folded and unfolded rHuPH20 are 330nm and 350nm respectively.

[0691] Spectra of the compositions were collected immediately after storage at 5°C and after one and two weeks of storage at 40°C. In addition to the peak maxima and minima, the intensity ratio 350nm / 330nm was calculated and plotted as a function of time. The slope of this curve was used to make semi-quantitative thermal stability assessments and comparisons between compositions.

[0692] Composition preparation

[0693] 200 μl of each composition was manually dispensed into COC, 96-well flat-bottom microtiter plates.

[0694] Fluorescence emission spectra of samples were measured before and after stress by a Tecan plate reader (Infinite 200). The following method parameters were used:

[0695] temperature:

[0696] Parameters (starting), temperature = 25.0°C

[0697] Waiting temperature:

[0698] ·Parameter minimum value = 24.5℃; maximum value = 25.5℃

[0699] Fluorescence intensity scan:

[0700] Scan selection (transmit scan)

[0701] Mode (top)

[0702] Excitation wavelength: from = 280nm; bandwidth: 230…315: 5nm; 316…850: 9nm

[0703] Emission wavelength: from = 310nm; to = 420nm; step length = 1nm; bandwidth: 280…850: 20nm; 111 measurements

[0704] Integration: lag time = 0 μs; integration time = 20 μs

[0705] Reading: Flash count = 25; Settling time = 0ms

[0706] Gain (manual = 95)

[0707] ·Tag: Name = Tag1

[0708] The data are shown in Table 7 below.

[0709] Composition Additional components pH Slope 350nm / 330nm 22 - 6.5 23 - 7 24 Glycine (10 mg / mL) 6 0.004300 25 Glycine (10 mg / mL) 6.5 0.005389 26 Glycine (10 mg / mL) 7 0.006196 27 Glycine (25 mg / mL) 6 0.001013 28 Glycine (25 mg / mL) 6.5 0.004787 29 Glycine (25 mg / mL) 7 0.002456 30 Histidine (10 mg / mL) 6 0.004556 31 Histidine (10 mg / mL) 6.5 0.005702 32 Histidine (10 mg / mL) 7 0.004277 33 Arginine (10 mg / mL) 6 0.002788 34 Arginine (10 mg / mL) 6.5 0.001392 35 Arginine (10 mg / mL) 7 0.002748 36 Mannitol (50 mg / mL) 6 0.004070 37 Mannitol (50 mg / mL) 6.5 0.005511 38 Mannitol (50 mg / mL) 7 0.005598 39 Sucrose (50 mg / mL) 6 0.001455 40 Sucrose (50 mg / mL) 6.5 0.002963 41 Sucrose (50 mg / mL) 7 0.006229 42 CMC sodium (25mg / mL) 6 -0.00035 43 CMC sodium (25mg / mL) 6.5 0.001466 44 CMC sodium (25mg / mL) 7 0.003267

[0710] Table 7: Slope of the ratio between 350nm / 330nm versus time

[0711] Example 7 - Melting Temperature Study under Different Storage Conditions

[0712] This example compares the melting temperatures of rHuPH20 in various compositions under different storage conditions.

[0713] Composition F was prepared as described in Example 5. Compositions 45 to 57 were then prepared by omitting glucose monohydrate (19.25 mg / mL) and adding the components as shown in Table 8 to Composition F, and the pH was adjusted to 6.0 by varying the amount of sodium hydroxide in the composition.

[0714]

[0715] Table 8: T under different storage conditions m

[0716] Compositions 45 to 57 were prepared as described above and then stored in a refrigerator at 5°C for 2 days to 2 weeks. T was measured immediately (ie, "t=0") and after storage at 40°C for 1 week using the method described in Example 5. m value.

[0717] When measuring T m Remeasure the pH of the aqueous composition immediately before taking the value.

[0718] The results are shown in Table 8 and Figure 4 and Figure 4A The T at t = 1 week at 40°C is not shown. m value (i.e., "-" for Tm and its SD), rHuPH20 has decomposed.

[0719] Example 8 - CMC Sodium Concentration

[0720] This example tests T m Dependence on CMC sodium concentration.

[0721] Composition H was prepared containing the following excipients:

[0722] rHuPH20 (2000U / mL)

[0723] Sodium dihydrogen phosphate monohydrate (2 mg / mL)

[0724] Citric acid monohydrate (1 mg / mL)

[0725] Poloxamer 338 (50 mg / mL)

[0726] Sodium hydroxide (to pH 6.0)

[0727] Mannitol (50 mg / mL) or sucrose (100 mg / mL)

[0728] Water for injection (add to 1 mL)

[0729] Compositions 58 to 63 were then prepared by adding sodium CMC as shown in Table 9 below to the above composition H, and the pH was adjusted to 6.0 by varying the amount of sodium hydroxide in the composition.

[0730] Composition CMC concentration / mg / mL Sugar / Sugar Alcohols 58 5 Mannitol (50 mg / mL) 59 5 Sucrose (100 mg / mL) 60 10 Mannitol (50 mg / mL) 61 10 Sucrose (100 mg / mL) 62 15 Mannitol (50 mg / mL) 63 15 Sucrose (100 mg / mL)

[0731] Table 9: CMC sodium concentration

[0732] Compositions 58 to 63 were prepared as described above and then stored in a refrigerator at 5°C for 2 days to 2 weeks. T was then measured using the method described in Example 5. m value.

[0733] The results are shown in Figure 5 middle.

[0734] Example 9 - Enzyme Stability

[0735] This example compares the stability of rHuPH20 in various compositions under stress test conditions.

[0736] Compositions A to E comprising rilpivirine nanoparticles were prepared as described in Example 1.

[0737] The compositions were stored at 5°C or 25°C / 60% RH for 6 months. Enzyme stability was evaluated by one or more of the following: (i) activity (bioassay); (ii) quantitation / aggregation (size exclusion chromatography / SEC) and (iii) purity (reverse phase liquid chromatography / RP-LC).

[0738] SEC is a size exclusion chromatography separation method whereby a column is used to distribute the molecules in a solution flowing through it according to their broad size range. Monomers, aggregates and fragments elute from the column at different times and therefore their relative proportions in the sample can be quantified using a standard UV detector.

[0739] The results are shown in Table 10.

[0740]

[0741] *Ox2 is the oxidized form of rHuPH20. Ox2 is less active than rHuPH20.

[0742] Table 10: 6 Month Stability Data Comparing Bioassay, SEC and RP(Ox2) Results Example 10 - 6 Month Stability Data Comparing Bioassay, SEC and RP(Ox2) Results Study on enzyme stability under storage conditions

[0743] This example compares the fluorescence emission spectra of rHuPH20 compositions after storage under different conditions.

[0744] Aqueous compositions 45 to 57 were prepared as described above in Example 7. Spectra of the compositions were collected immediately after storage at 5°C and after one day of storage at 50°C. In addition to the peak maxima and minima, the intensity ratio 350nm / 330nm was calculated at each time point and plotted as a function of storage time. The slope of this curve was used to perform semi-quantitative thermal stability assessments and comparisons between compositions.

[0745] Composition preparation

[0746] 200 μl of each composition was manually dispensed into COC, 96-well flat-bottom microtiter plates.

[0747] Fluorescence emission spectra of samples were measured before and after stress by a Tecan plate reader (Infinite 200). The following method parameters were used:

[0748] temperature:

[0749] Parameters (starting), temperature = 25.0°C

[0750] Waiting temperature:

[0751] ·Parameter minimum value = 24.5℃; maximum value = 25.5℃

[0752] Fluorescence intensity scan:

[0753] Scan selection (transmit scan)

[0754] Mode (top)

[0755] Excitation wavelength: from = 280nm; bandwidth: 230…315: 5nm; 316…850: 9nm

[0756] Emission wavelength: from = 310nm; to = 420nm; step length = 1nm; bandwidth: 280…850: 20nm; 111 measurements

[0757] Integration: lag time = 0 μs; integration time = 20 μs

[0758] Reading: Flash count = 25; Settling time = 0ms

[0759] Gain (manual = 95)

[0760] ·Tag: Name = Tag1

[0761] The data are shown in Table 11 below.

[0762]

[0763] Table 11: Slope of the ratio between 350nm / 330nm versus time

[0764] Example 11 - Melting temperature study under different storage conditions

[0765] This example compares the melting temperatures of rHuPH20 in various compositions under different storage conditions.

[0766] An aqueous composition of rilpivirine nanoparticles (having a Dv10 of 75nm-200nm, a Dv50 of 200nm-500nm, and a Dv90 of 500nm-1600nm) and the following excipients was prepared:

[0767] rHuPH20 (2000U / mL)

[0768] Sodium dihydrogen phosphate monohydrate (2 mg / mL)

[0769] Citric acid monohydrate (1 mg / mL)

[0770] Poloxamer 338 (50 mg / mL)

[0771] Sodium hydroxide (qs to pH 6)

[0772] Water for injection (add to 1 mL)

[0773] Compositions 64 to 149 were then prepared by adding the components as shown in Table 12, and the pH was adjusted to 6.0 by varying the amount of sodium hydroxide in the composition.

[0774]

[0775]

[0776]

[0777] Table 12: T under different storage conditions m

[0778] Compositions 64 to 149 were prepared as described above and then stored in a refrigerator at 5°C for 2 days to 2 weeks. T was measured immediately (ie, "t=0") and after storage at 40°C for 1 week using the method described in Example 5. m value.

[0779] The results are shown in Table 12.

[0780] This article also describes the following numbered clauses.

[0781] 1. An aqueous composition, comprising:

[0782] (i) rilpivirine or a pharmaceutically acceptable salt thereof;

[0783] (ii) hyaluronidase; and

[0784] (iii) 0.001 mg / mL to 100 mg / mL of at least one excipient, the at least one excipient being selected from the group consisting of:

[0785] (a) cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof; and / or

[0786] (b) an amino acid or a pharmaceutically acceptable salt thereof.

[0787] 2. The aqueous composition according to clause 1, wherein the rilpivirine is in the form of particles suspended in the aqueous composition.

[0788] 3. The aqueous composition according to clause 2, wherein the rilpivirine is in the form of microparticles or nanoparticles suspended in the aqueous composition.

[0789] 4. An aqueous composition according to clause 2 or 3, wherein the particles have a Dv90 of about 100 nm to about 10 μm.

[0790] 5. The aqueous composition of clause 4, wherein the particles have a Dv90 of about 300 nm to about 6 μm.

[0791] 6. The aqueous composition of clause 5, wherein the particles have a Dv90 of about 300 nm to about 1,600 nm.

[0792] 7. An aqueous composition according to clause 6, wherein the particles have a Dv90 of about 450 nm to about 700 nm.

[0793] 8. An aqueous composition according to clause 7, wherein the particles have a Dv90 of about 475 nm to about 650 nm (eg, about 525 nm to about 644 nm).

[0794] 9. An aqueous composition according to any one of clauses 2 to 8, wherein the particles have a Dv10 of about 75 nm to about 200 nm.

[0795] 10. An aqueous composition according to any one of clauses 2 to 9, wherein the particles have a Dv50 of about 200 nm to about 500 nm.

[0796] 11. The aqueous composition of any one of clauses 2 to 4, wherein the particles have a Dv90 of about 4 μm to about 6 μm.

[0797] 12. The aqueous composition of clause 11, wherein the particles have a Dv90 of about 5 μm to about 6 μm.

[0798] 13. An aqueous composition according to any one of clauses 2 to 5 or 11 or 12, wherein the particles have a Dv10 of about 300 nm to about 500 nm, and / or wherein the particles have a Dv50 of about 1.5 μm to about 2 μm.

[0799] 14. The aqueous composition of any of the preceding clauses, wherein the aqueous composition comprises from about 200 mg / mL to about 400 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof.

[0800] 15. An aqueous composition according to clause 14, wherein the aqueous composition comprises about 250 mg / mL to about 350 mg / mL (eg, 300 mg / mL) of rilpivirine or a pharmaceutically acceptable salt thereof.

[0801] 16. An aqueous composition according to any of the preceding clauses, wherein the aqueous composition comprises rilpivirine.

[0802] 17. An aqueous composition according to any of the preceding clauses, wherein the hyaluronidase is a recombinant human hyaluronidase.

[0803] 18. An aqueous composition according to any of the preceding clauses, wherein the hyaluronidase is rHuPH20.

[0804] 19. The aqueous composition of any of the preceding clauses, wherein the aqueous composition comprises about 1,500 U / mL to about 2,500 U / mL of the hyaluronidase.

[0805] 20. The aqueous composition of any of the preceding clauses, wherein the aqueous composition comprises about 1,750 U / mL to about 2,250 U / mL of the hyaluronidase.

[0806] 21. The aqueous composition of clause 20, wherein the aqueous composition comprises about 2,000 U / mL of the hyaluronidase.

[0807] 22. An aqueous composition according to any of the preceding clauses, wherein the at least one excipient comprises cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof.

[0808] 23. The aqueous composition according to clause 22, wherein the cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof is carboxymethyl cellulose or a pharmaceutically acceptable salt thereof.

[0809] 24. The aqueous composition according to clause 23, wherein the carboxymethylcellulose or a pharmaceutically acceptable salt thereof is sodium carboxymethylcellulose.

[0810] 25. An aqueous composition according to clause 23 or 24, wherein the aqueous composition comprises from about 0.1 mg / mL to about 50 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

[0811] 26. The aqueous composition of clause 25, wherein the aqueous composition comprises from about 0.1 mg / mL to about 10 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

[0812] 27. The aqueous composition of clause 26, wherein the aqueous composition comprises from about 1 mg / mL to about 5 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

[0813] 28. The aqueous composition of clause 27, wherein the aqueous composition comprises from about 1 mg / mL to about 3 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

[0814] 29. The aqueous composition of clause 26, wherein the aqueous composition comprises about 1 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

[0815] 30. The aqueous composition of clause 28, wherein the aqueous composition comprises about 3 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

[0816] 31. An aqueous composition according to any one of clauses 22 to 30, wherein the aqueous composition comprises from about 0.01 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase to about 0.25 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase.

[0817] 32. An aqueous composition according to clause 31, wherein the aqueous composition comprises from about 0.05 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase to about 0.15 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase.

[0818] 33. An aqueous composition according to clause 31, wherein the aqueous composition comprises from about 0.02 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase to about 0.1 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase.

[0819] 34. An aqueous composition according to clause 33, wherein the aqueous composition comprises from about 0.03 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase to about 0.07 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase.

[0820] 35. An aqueous composition according to any of the preceding clauses, wherein the at least one excipient comprises an amino acid or a pharmaceutically acceptable salt thereof.

[0821] 36. The aqueous composition of clause 33, wherein the aqueous composition comprises from about 5 mg / mL to about 60 mg / mL of an amino acid or a pharmaceutically acceptable salt thereof.

[0822] 37. An aqueous composition according to clause 36, wherein the aqueous composition comprises from about 15 mg / mL to about 25 mg / mL of an amino acid or a pharmaceutically acceptable salt thereof.

[0823] 38. The aqueous composition of any one of clauses 35 to 37, wherein the amino acid is selected from glycine and arginine, pharmaceutically acceptable salts thereof, and combinations thereof.

[0824] 39. An aqueous composition according to clause 38, wherein the amino acid is glycine.

[0825] 40. The aqueous composition of any one of clause 39, wherein the aqueous composition comprises about 5 mg / mL to about 20 mg / mL of glycine.

[0826] 41. The aqueous composition of clause 38, wherein the aqueous composition comprises about 10 mg / mL to about 15 mg / mL of glycine.

[0827] 42. An aqueous composition according to clause 41, wherein the aqueous composition comprises about 13 mg / mL of glycine.

[0828] 43. An aqueous composition according to any one of clauses 35 to 38, wherein the amino acid is arginine or arginine hydrochloride.

[0829] 44. An aqueous composition according to clause 43, wherein the aqueous composition comprises from about 5 mg / mL to about 50 mg / mL of arginine or arginine hydrochloride.

[0830] 45. An aqueous composition according to clause 44, wherein the aqueous composition comprises from about 15 mg / mL to about 25 mg / mL of arginine or arginine hydrochloride.

[0831] 46. ​​An aqueous composition according to clause 45, wherein the aqueous composition comprises about 21 mg / mL of arginine or arginine hydrochloride.

[0832] 47. An aqueous composition according to clause 43, wherein the amino acid is arginine hydrochloride.

[0833] 48. An aqueous composition according to clause 47, wherein the aqueous composition comprises from about 5 mg / mL to about 50 mg / mL of arginine hydrochloride.

[0834] 49. An aqueous composition according to clause 48, wherein the aqueous composition comprises from about 15 mg / mL to about 25 mg / mL of arginine hydrochloride.

[0835] 50. An aqueous composition according to clause 49, wherein the aqueous composition comprises about 20 mg / mL of arginine hydrochloride.

[0836] 51. An aqueous composition according to any one of the preceding claims, wherein the at least one excipient further comprises a sugar or a sugar alcohol.

[0837] 52. The aqueous composition of clause 51, wherein the aqueous composition comprises from about 10 mg / mL to about 100 mg / mL of a sugar or sugar alcohol.

[0838] 53. An aqueous composition according to clause 52, wherein the aqueous composition comprises from about 45 mg / mL to about 55 mg / mL of a sugar or sugar alcohol.

[0839] 54. An aqueous composition according to clause 53, wherein the aqueous composition comprises about 50 mg / mL of a sugar or sugar alcohol.

[0840] 55. An aqueous composition according to any one of clauses 51 to 54, wherein the sugar or sugar alcohol is selected from glucose and sucrose and combinations thereof.

[0841] 56. An aqueous composition according to clause 55, wherein the sugar or sugar alcohol is sucrose.

[0842] 57. An aqueous composition according to clause 56, wherein the aqueous composition comprises from about 10 mg / mL to about 100 mg / mL of sucrose.

[0843] 58. An aqueous composition according to clause 57, wherein the aqueous composition comprises about 40 mg / mL to about 70 mg / mL of sucrose.

[0844] 59. An aqueous composition according to clause 58, wherein the aqueous composition comprises about 57 mg / mL of sucrose.

[0845] 60. An aqueous composition according to clause 58, wherein the aqueous composition comprises about 50 mg / mL of sucrose.

[0846] 61. An aqueous composition according to clause 55, wherein the sugar or sugar alcohol is glucose.

[0847] 62. An aqueous composition according to clause 61, wherein the aqueous composition comprises about 1 mg / mL to about 100 mg / mL of glucose.

[0848] 63. An aqueous composition according to clause 62, wherein the aqueous composition comprises about 10 mg / mL to about 30 mg / mL of glucose.

[0849] 64. An aqueous composition according to clause 63, wherein the aqueous composition comprises about 17 mg / mL of glucose.

[0850] 65. An aqueous composition according to any one of clauses 1 to 54 and 56 to 60, wherein the aqueous composition comprises substantially no glucose, such as less than 10% w / w glucose, preferably less than 1% w / w glucose.

[0851] 66. An aqueous composition according to any one of clauses 1 to 65, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to excipient (a) in the aqueous composition is from about 50:1 (w / w) to about 400:1 (w / w), or wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to excipient (b) in the aqueous composition is from about 10:1 (w / w) to about 20:1 (w / w).

[0852] 67. An aqueous composition according to any one of clauses 1 to 65, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to excipient (a) in the aqueous composition is from about 200:1 (w / w) to about 400:1 (w / w), or wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to excipient (b) in the aqueous composition is from about 2:1 (w / w) to about 30:1 (w / w).

[0853] 68. An aqueous composition according to clause 67, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to excipient (a) in the aqueous composition is from about 250:1 (w / w) to about 350:1 (w / w), or wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to excipient (b) in the aqueous composition is from about 3:1 (w / w) to about 20:1 (w / w).

[0854] 69. An aqueous composition according to any one of clauses 1 to 65, wherein the ratio of rilpivirine or a pharmaceutically 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).

[0855] 70. An aqueous composition according to any one of clauses 1 to 65, wherein the ratio of rilpivirine or a pharmaceutically 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).

[0856] 71. An aqueous composition according to any one of clauses 52 to 65, when dependent on any one of clauses 22 to 34, wherein the ratio of cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof to sugar or sugar alcohol is from about 1:2 (w / w) to about 1:1000 (w / w).

[0857] 72. An aqueous composition according to any one of clauses 52 to 65, when dependent on any one of clauses 22 to 34, wherein the ratio of cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof to sugar or sugar alcohol is from about 1:2 (w / w) to about 1:200 (w / w).

[0858] 73. An aqueous composition according to clause 72, wherein the ratio of cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof to sugar or sugar alcohol is from about 1:2 (w / w) to about 1:100 (w / w).

[0859] 74. An aqueous composition according to clause 73, wherein the ratio of cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof to sugar or sugar alcohol is from about 1:10 (w / w) to about 1:100 (w / w).

[0860] 75. An aqueous composition according to clause 74, wherein the ratio of cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof to sugar or sugar alcohol is from about 1:15 (w / w) to about 1:60 (w / w).

[0861] 76. An aqueous composition according to any of the preceding clauses, wherein the aqueous composition further comprises a poloxamer, such as poloxamer 338.

[0862] 77. An aqueous composition according to clause 76, when dependent on clause 2, wherein when the rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than or about 1600 nm, the weight / weight ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is greater than or about 10:1, for example from about 10:1 to about 20:1.

[0863] 78. An aqueous composition according to clause 76, when dependent on clause 2, wherein when the rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than or about 1600 nm, the weight / weight ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is about 15:1.

[0864] 79. An aqueous composition according to clause 76, when dependent on clause 2, wherein when the rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than or about 1600 nm, the weight / weight ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is about 10:1.

[0865] 80. An aqueous composition according to clause 76, when dependent on clause 2, wherein when the rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than or about 1600 nm, the weight / weight ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is less than or about 10:1.

[0866] 81. An aqueous composition according to clause 76, when dependent on clause 2, wherein when the rilpivirine or a pharmaceutically 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, the weight / weight ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is less than about 10:1.

[0867] 82. An aqueous composition according to any one of clauses 1 to 81 wherein the aqueous composition further comprises one or more of the following: poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0868] 83. An aqueous composition according to any one of clauses 1 to 81 wherein the aqueous composition further comprises poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0869] 84. An aqueous composition according to any one of clauses 1 to 81 wherein the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0870] 85. An aqueous composition according to any one of clauses 76 to 84 wherein the aqueous composition comprises from about 15 mg / mL to about 35 mg / mL of poloxamer.

[0871] 86. An aqueous composition according to any one of clauses 76 to 84 wherein the aqueous composition comprises from about 20 mg / mL to about 30 mg / mL of poloxamer.

[0872] 87. An aqueous composition according to any one of clauses 76 to 84 wherein the aqueous composition comprises from about 40 mg / mL to about 60 mg / mL of poloxamer.

[0873] 88. An aqueous composition according to any of the preceding clauses, wherein the aqueous composition further comprises an antioxidant, optionally wherein the antioxidant is methionine.

[0874] 89. An aqueous composition according to clause 88, wherein the aqueous composition comprises about 1.0 mg / mL to about 2.0 mg / mL (e.g., about 1.5 mg / mL) of the antioxidant.

[0875] 90. A solid composition according to any of the preceding clauses, wherein the aqueous composition does not comprise glucose, for example it does not comprise glucose monohydrate.

[0876] 91. An aqueous composition according to any of the preceding clauses, wherein the aqueous composition has a pH of about 5 to about 7.

[0877] 92. An aqueous composition according to clause 91, wherein the aqueous composition has a pH of about 6 to about 7.

[0878] 93. An aqueous composition according to clause 92, wherein the aqueous composition has a pH of about 6 to about 6.5.

[0879] 94. An aqueous composition according to clause 93, wherein the aqueous composition has a pH of about 6.

[0880] 95. An aqueous composition according to any one of clauses 2 to 94, wherein the Dv10, Dv50 and Dv90 of the particles increase by no more than about 30% after storing the aqueous composition at about 5°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months or about 24 months.

[0881] 96. An aqueous composition according to clause 95, wherein the Dv10, Dv50 and Dv90 of the particles increase by no more than about 20% after storing the aqueous composition at about 5°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months or about 24 months.

[0882] 97. An aqueous composition according to clause 95, wherein the Dv10, Dv50 and Dv90 of the particles increase by no more than about 10% after storing the aqueous composition at about 5°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months or about 24 months.

[0883] 98. An aqueous composition according to clause 95, wherein the Dv10, Dv50 and Dv90 of the particles increase by no more than about 50% after storing the aqueous composition at about 25°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months or about 24 months.

[0884] 99. An aqueous composition according to clause 95, wherein the Dv10, Dv50 and Dv90 of the particles increase by no more than about 20% after storing the aqueous composition at about 25°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months or about 24 months.

[0885] 100. An aqueous composition according to any of the preceding clauses, wherein the hyaluronidase activity retains at least 25% of the original activity after storing the aqueous composition at about 5°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months or about 24 months.

[0886] 101. The aqueous composition of clause 100, wherein the hyaluronidase activity retains at least 25% of the original activity after storage of the aqueous composition at about 5°C for about 24 months.

[0887] 102. The aqueous composition of clause 100, wherein the hyaluronidase activity retains at least 25% of the original activity after storage of the aqueous composition at about 5°C for about 18 months.

[0888] 103. An aqueous composition according to any of the preceding clauses, wherein the hyaluronidase activity retains at least 50% of the original activity after storing the aqueous composition at about 5°C or about 25°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months or about 24 months.

[0889] 104. The aqueous composition of clause 103, wherein the hyaluronidase activity retains 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.

[0890] 105. The aqueous composition of clause 104, wherein the hyaluronidase activity retains at least 50% of the original activity after storage of the aqueous composition at about 5°C for about 24 months.

[0891] 106. The aqueous composition of clause 103, wherein the hyaluronidase activity retains at least 50% of the original activity after storage of the aqueous composition at about 5°C for about 18 months.

[0892] 107. An aqueous composition according to clause 103, wherein the hyaluronidase activity retains at least 75% of the original activity after storing the aqueous composition at about 5°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months or about 24 months.

[0893] 108. The aqueous composition of clause 103, wherein the hyaluronidase activity retains at least 75% of the original activity after storage of the aqueous composition at about 5°C for about 24 months.

[0895] 109. The aqueous composition of clause 103, wherein the hyaluronidase activity retains at least 75% of the original activity after storage of the aqueous composition at about 5°C for about 18 months.

[0896] 110. An aqueous composition according to any of the preceding clauses, wherein the hyaluronidase concentration retains at least 25% of the original concentration after storing the aqueous composition at about 5°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months or about 24 months, wherein the concentration is determined by size exclusion chromatography.

[0897] 111. An aqueous composition according to clause 110, wherein the hyaluronidase concentration retains at least 50% of the original concentration after storing the aqueous composition at about 5°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months or about 24 months, wherein the concentration is determined by size exclusion chromatography.

[0898] 112. An aqueous composition according to any of the preceding clauses, wherein after storing the aqueous composition at about 5°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months or about 24 months, less than 50% of the original hyaluronidase is degraded into degradation products.

[0899] 113. An aqueous composition according to clause 112, wherein after storing the aqueous composition at about 5°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months or about 24 months, less than 20% of the original hyaluronidase is degraded into degradants.

[0900] 114. Use of: in a method for stabilizing an aqueous composition:

[0901] (a) cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof; and / or

[0902] (b) an amino acid or a pharmaceutically acceptable salt thereof,

[0903] The method comprises the step of preparing an aqueous composition comprising:

[0904] (i) rilpivirine or a pharmaceutically acceptable salt thereof;

[0905] (ii) hyaluronidase; and

[0906] (iii) 0.001 mg / mL to 100 mg / mL of (a) and / or (b).

[0907] 115. The use according to clause 114, wherein the aqueous composition is as defined in any one of clauses 1 to 113.

[0908] 116. The use according to clause 114 or clause 115, wherein the stabilization is retention of hyaluronidase activity over time, such as about 6 months, about 12 months, about 18 months or about 24 months.

[0909] 117. The use according to clause 114 or clause 115, wherein the stabilization is maintenance of hyaluronidase concentration over time, for example about 6 months, about 12 months, about 18 months or about 24 months.

[0910] 118. The use according to clause 114 or clause 115, wherein the stabilization is a reduction in the presence of hyaluronidase degradants over time, for example about 6 months, about 12 months, about 18 months or about 24 months.

[0911] 119. The use according to one of clauses 114 to 118, wherein the stabilization is a reduction in the change in the particle size distribution of the rilpivirine microparticles or nanoparticles over time, for example about 6 months, about 12 months, about 18 months or about 24 months.

[0912] 120. A method of stabilizing an aqueous composition, the aqueous composition comprising:

[0913] (i) rilpivirine or a pharmaceutically acceptable salt thereof; and

[0914] (ii) hyaluronidase,

[0915] The method comprises combining component (i) and component (ii) with 0.001 mg / mL to 100 mg / mL of at least one excipient selected from the group consisting of:

[0916] (a) cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof; and / or (b) an amino acid or a pharmaceutically acceptable salt thereof.

[0917] 121. A method for treating or preventing HIV infection in a subject, the method comprising administering to the subject an aqueous composition as defined in any one of clauses 1 to 113, in particular for treating HIV infection in a subject.

[0918] 122. An aqueous composition as defined in any one of clauses 1 to 113 for use in treating or preventing HIV infection in a subject, in particular for treating HIV infection in a subject.

[0919] 123. Use of an aqueous composition as defined in any one of clauses 1 to 113 for the preparation of a medicament for treating or preventing HIV infection in a subject, particularly for treating HIV infection in a subject.

[0920] 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 injection or subcutaneous injection.

[0921] 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.

[0922] 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.

[0923] 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 intervals of about three months to about two years.

[0924] 128. The method, aqueous composition for use, or use according to clause 127, wherein the time interval is from about three months to about one year.

[0925] 129. The method, aqueous composition for use, or use according to clause 110, wherein the time interval is from about three months to about six months.

[0926] 130. The method, aqueous composition for use, or use according to clause 113, wherein the time interval is from about six months to about one year.

[0927] 131. The method, aqueous composition for use, or use according to clause 129 or 130, wherein the time interval is about six months.

[0928] 132. The method, aqueous composition for use, or the use according to any one of clauses 121 to 131, wherein the HIV infection is an HIV type 1 (HIV-1) infection.

[0929] 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. An aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; (ii) hyaluronidase; and (iii) 0.001 mg / mL to 100 mg / mL of at least one excipient, wherein the at least one excipient is selected from the group consisting 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.

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

3. The aqueous composition of claim 2, wherein the rilpivirine is in the form of microparticles or nanoparticles suspended in the aqueous composition.

4. The aqueous composition of any one of claims 1 to 3, wherein the hyaluronidase is rHuPH20.

5. An aqueous composition according to any one of the preceding claims, wherein the at least one excipient comprises cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof. 6 . The aqueous composition according to claim 5 , wherein the cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof is carboxymethyl cellulose or a pharmaceutically acceptable salt thereof.

7. The aqueous composition according to claim 6, wherein the carboxymethylcellulose or a pharmaceutically acceptable salt thereof is sodium carboxymethylcellulose.

8. The aqueous composition of any one of claims 5 to 7, wherein the aqueous composition comprises from about 0.1 mg / mL to about 50 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

9. The aqueous composition of claim 8, wherein the aqueous composition comprises about 1 mg / mL to about 5 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

10. The aqueous composition according to any one of claims 5 to 9, wherein the aqueous composition comprises from about 0.01 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase to about 0.25 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase.

11. The aqueous composition of claim 10, wherein the aqueous composition comprises from about 0.05 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase to about 0.15 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase.

12. The aqueous composition of claim 10, wherein the aqueous composition comprises from about 0.02 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase to about 0.1 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase.

13. The aqueous composition of claim 12, wherein the aqueous composition comprises from about 0.03 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase to about 0.07 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase.

14. The aqueous composition according to any one of claims 8 to 13, wherein the carboxymethylcellulose or a pharmaceutically acceptable salt thereof is sodium carboxymethylcellulose.

15. An aqueous composition according to any one of the preceding claims, wherein the at least one excipient comprises an amino acid or a pharmaceutically acceptable salt thereof.

16. The aqueous composition of claim 15, wherein the amino acid is selected from the group consisting of glycine, arginine, pharmaceutically acceptable salts thereof, and combinations thereof.

17. The aqueous composition of claim 16, wherein the amino acid is glycine.

18. The aqueous composition of any one of the preceding claims, wherein the aqueous composition comprises from about 5 mg / mL to about 60 mg / mL of an amino acid or a pharmaceutically acceptable salt thereof.

19. The aqueous composition of any one of claims 15 to 18, wherein the aqueous composition comprises about 5 mg / mL to about 20 mg / mL of glycine.

20. The aqueous composition of claim 19, wherein the aqueous composition comprises about 10 mg / mL to about 15 mg / mL of glycine.

21. The aqueous composition of claim 20, wherein the aqueous composition comprises about 13 mg / mL of glycine.

22. The aqueous composition of claim 16, wherein the amino acid is arginine or arginine hydrochloride.

23. The aqueous composition of any one of claims 16 and 22, wherein the aqueous composition comprises from about 5 mg / mL to about 50 mg / mL of arginine or arginine hydrochloride.

24. The aqueous composition of claim 23, wherein the aqueous composition comprises from about 15 mg / mL to about 25 mg / mL of arginine or arginine hydrochloride.

25. The aqueous composition of claim 24, wherein the aqueous composition comprises about 20 mg / mL of arginine or arginine hydrochloride.

26. The aqueous composition of claim 24, wherein the aqueous composition comprises about 21 mg / mL of arginine or arginine hydrochloride.

27. An aqueous composition according to any one of claims 22 to 26, wherein the amino acid is arginine hydrochloride.

28. An aqueous composition according to any one of the preceding claims, wherein the at least one excipient additionally comprises a sugar or a sugar alcohol.

29. The aqueous composition of claim 28, wherein the sugar or sugar alcohol is selected from glucose, such as glucose monohydrate, and sucrose, and combinations thereof.

30. The aqueous composition of claim 28, wherein the sugar or sugar alcohol is sucrose.

31. The aqueous composition of claim 30, wherein the aqueous composition comprises about 10 mg / mL to about 100 mg / mL of sucrose.

32. The aqueous composition of claim 31, wherein the aqueous composition comprises about 40 mg / mL to about 70 mg / mL of sucrose.

33. The aqueous composition of claim 32, wherein the aqueous composition comprises about 57 mg / mL of sucrose.

34. The aqueous composition of claim 32, wherein the aqueous composition comprises about 50 mg / mL of sucrose.

35. The aqueous composition according to any one of claims 28 to 34, wherein the ratio of cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof to sugar or sugar alcohol is from about 1:2 (w / w) to about 1:200 (w / w).

36. The aqueous composition of claim 35, wherein the ratio of cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof to sugar or sugar alcohol is from about 1:2 (w / w) to about 1:100 (w / w).

37. The aqueous composition of claim 36, wherein the ratio of cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof to sugar or sugar alcohol is from about 1:10 (w / w) to about 1:100 (w / w).

38. The aqueous composition of claim 37, wherein the ratio of cellulose or a derivative thereof or a pharmaceutically acceptable salt thereof to sugar or sugar alcohol is from about 1:15 (w / w) to about 1:60 (w / w).

39. An aqueous composition according to any one of the preceding claims, wherein the aqueous composition further comprises an antioxidant.

40. The aqueous composition of any preceding claim, wherein the aqueous composition has a pH of about 6.

41. The aqueous composition of any of the preceding claims, wherein the Dv10, Dv50, and Dv90 values ​​of the particles remain within about 20% of the original values ​​after storing the aqueous composition at about 5°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months.

42. The aqueous composition of claim 41, wherein the Dv10, Dv50, and Dv90 values ​​of the particles remain within about 10% of the original values ​​after storing the aqueous composition at about 5°C for about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months.

43. An aqueous composition according to any of the preceding claims, which retains hyaluronidase activity over a period of time, such as about 1 month, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months.

44. The aqueous composition of claim 43, wherein the storing is performed at about 5°C or about 25°C.

45. The aqueous composition of claim 43 or 44, wherein the hyaluronidase activity retains at least 50% of the original activity 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.

46. ​​An aqueous composition comprising: rilpivirine or a pharmaceutically acceptable salt thereof, sucrose and sodium carboxymethylcellulose.

47. The aqueous composition of claim 46, further comprising a poloxamer.

48. An aqueous composition comprising: rilpivirine or a pharmaceutically acceptable salt thereof, arginine hydrochloride and sodium carboxymethylcellulose.

49. The aqueous composition of claim 48, further comprising a poloxamer.

50. The aqueous composition of any of the preceding claims, comprising: rHuPH20; rilpivirine in the form of particles suspended in the aqueous composition; Sodium CMC; and sucrose.

51. The aqueous composition of any of the preceding claims, comprising: rHuPH20; rilpivirine in the form of particles suspended in the aqueous composition; Sodium CMC; Sucrose; and Poloxamer 338.

52. The aqueous composition of any of the preceding claims, comprising: rHuPH20; rilpivirine in the form of particles suspended in the aqueous composition; Sodium CMC; and Arginine HCl.

53. The aqueous composition of any of the preceding claims, comprising: rHuPH20; rilpivirine in the form of particles suspended in the aqueous composition; Sodium CMC; Arginine HCl; as well as Poloxamer 338.

54. An aqueous composition according to any one of claims 1 to 32 or 34 to 53, comprising: About 2000 U / mL of rHuPH20; about 300 mg / mL of rilpivirine in the form of particles suspended in the aqueous composition; about 1 mg / mL to about 3 mg / mL of sodium CMC; about 50 mg / mL of sucrose; and About 50 mg / mL of Poloxamer 338, wherein the rilpivirine is in the form of particles suspended in the aqueous composition and has a Dv90 of about 4 μm to about 6 μm.

55. An aqueous composition according to any one of claims 1 to 32 or 34 to 53, comprising: About 2000 U / mL of rHuPH20; about 300 mg / mL of rilpivirine in the form of particles suspended in the aqueous composition; about 1 mg / mL to about 3 mg / mL of sodium CMC; about 50 mg / mL of sucrose; and About 50 mg / mL of Poloxamer 338, 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.

56. An aqueous composition according to any one of claims 1 to 32 or 34 to 53, comprising: About 2000 U / mL of rHuPH20; about 300 mg / mL of rilpivirine in the form of particles suspended in the aqueous composition; about 1 mg / mL to about 3 mg / mL of sodium CMC; about 50 mg / mL of sucrose; and about 20 mg / mL to about 30 mg / mL of Poloxamer 338, 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.

57. An aqueous composition according to any one of claims 1 to 53, comprising: About 2000 U / mL of rHuPH20; about 300 mg / mL of rilpivirine in the form of particles suspended in the aqueous composition; about 1 mg / mL to about 3 mg / mL of sodium CMC; about 20 mg / mL of arginine HCl; and About 50 mg / mL of Poloxamer 338, wherein the rilpivirine is in the form of particles suspended in the aqueous composition and has a Dv90 of about 4 μm to about 6 μm, such as about 6 μm.

58. An aqueous composition according to any one of claims 1 to 53, comprising: About 2000 U / mL of rHuPH20; about 300 mg / mL of rilpivirine in the form of particles suspended in the aqueous composition; about 1 mg / mL to about 3 mg / mL of sodium CMC; about 20 mg / mL of arginine HCl; and About 50 mg / mL of Poloxamer 338, 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.

59. An aqueous composition according to any one of claims 1 to 53, comprising: About 2000 U / mL of rHuPH20; about 300 mg / mL of rilpivirine in the form of particles suspended in the aqueous composition; about 1 mg / mL to about 3 mg / mL of sodium CMC; about 20 mg / mL of arginine HCl; and about 20 mg / mL to about 30 mg / mL of Poloxamer 338, 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.

60. 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 in a method for stabilizing an aqueous composition, wherein the method comprises the step of preparing an aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; (ii) hyaluronidase; and (iii) 0.001 mg / mL to 100 mg / mL of (a) and / or (b).

61. Use according to claim 60, wherein the aqueous composition is as defined in any one of claims 1 to 59.

62. The use of claim 60 or claim 61, wherein the stabilization is maintenance of hyaluronidase activity over time.

63. The use of claim 60 or claim 61, wherein the stabilization is retention of at least 10% of the original hyaluronidase concentration over time as determined by size exclusion chromatography.

64. The use of claim 60 or claim 61, wherein the stabilization is less than 20% of the original hyaluronidase is degraded over time.

65. The use according to one of claims 60 to 63, wherein the stabilization is a reduction in the change in the particle size distribution of the rilpivirine microparticles or nanoparticles over time.

66. A method of stabilizing an aqueous composition, the aqueous composition comprising: (i) rilpivirine or a pharmaceutically acceptable salt thereof; (ii) hyaluronidase; The method comprises combining component (i) and component (ii) with component (iii) 0.001 mg / mL-100 mg / mL of at least one excipient, wherein the at least one excipient is selected from the group consisting 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.

67. A method for treating or preventing HIV infection in a subject, the method comprising administering to the subject an aqueous composition as defined in any one of claims 1 to 59.

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