Lyophilized composition

Abstract

The present invention relates to a solid composition obtained by lyophilizing an aqueous composition comprising rilpivirine or a pharma- ceutically acceptable salt thereof and, optionally, hyaluronidase. The present invention also relates to a reconstituted aqueous composition obtained by reconstituting the solid composition of the present invention, a process for making the solid composition of the present invention, and the use of the reconstituted aqueous composition in the treatment or prevention of HIV infection in a subject.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 333,557, filed April 22, 2022, and European Patent Application No. 22173920.4, filed May 17, 2022, the entireties of which are incorporated by reference herein.

[0002] FIELD OF THEINVENTION The present invention relates to a solid composition obtained by lyophilizing an aqueous composition comprising rilpivirine or a pharma- ceutically acceptable salt thereof and, optionally, hyaluronidase. The present invention also relates to a reconstituted aqueous composition obtained by reconstituting the solid composition of the present invention, a process for making the solid composition of the present invention, and the use of the reconstituted aqueous composition in the treatment or prevention of HIV infection in a subject. [Background technology]

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

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

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

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

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

[0008] WO 2007 / 147882 discloses an intramuscular or subcutaneous injection of a therapeutically effective amount of rilpivirine in the form of a microparticle or nanoparticle having a surface modifier adsorbed to the surface, and a pharma- ceutically acceptable aqueous carrier in which the rilpivirine active ingredient is suspended.

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

[0010] When rilpivirine is to be administered after extended storage, particularly at room temperature, e.g., 20-25°C, it is desirable to provide a composition comprising rilpivirine particles that can be stored for extended periods (e.g., weeks, months, or years), particularly at room temperature, e.g., 20-25°C, without substantially affecting the particle size distribution of the rilpivirine, such that bioavailability, efficacy, and sustained release characteristics are maintained over the storage period.

[0011] When rilpivirine is administered by subcutaneous or intramuscular injection, it may be desirable to formulate it or administer it with hyaluronidase to increase the dispersion and absorption of rilpivirine. Hyaluronidase may also be used to achieve other effects, for example, administration of hyaluronidase may reduce the swelling formed by administration of a high volume of aqueous composition at the injection site. However, storing hyaluronidase in a pharmaceutical composition, such as a composition containing rilpivirine, for weeks, months, or years is a great challenge. When stored for long periods at room temperature, hyaluronidase can rapidly denature and degrade. Therefore, it is also desirable to provide a composition containing rilpivirine and hyaluronidase, in which the hyaluronidase is stable for weeks, months, or years, especially during storage at room temperature, for example 20-25°C.

[0012] International Application / US2021 / 072453 (WO 2022 / 109555) relates to the treatment or prevention of HIV infection using rilpivirine or a pharma- ceutically acceptable salt thereof in the form of microparticles or nanoparticles in suspension in combination with hyaluronidase. Summary of the Invention

[0013] In a first aspect, the present invention relates to a solid composition obtained by lyophilization (synonymous with "freeze-drying") of an aqueous composition comprising rilpivirine or a pharma- ceutically acceptable salt thereof and hyaluronidase.

[0014] In a second aspect, the present invention relates to a reconstituted aqueous composition obtainable by reconstituting the solid composition according to the first aspect.

[0015] In a third aspect, there is provided a method of treating or preventing HIV infection in a subject, the method comprising administering to the subject a reconstituted aqueous composition according to the second aspect.

[0016] In a fourth aspect, there is provided a reconstituted aqueous composition according to the second aspect for use in the treatment or prevention of HIV infection in a subject.

[0017] In a fifth aspect, there is provided the use of a reconstituted aqueous composition according to the second aspect for the manufacture of a medicament for treating or preventing HIV infection in a subject.

[0018] In a sixth aspect, there is provided a solid composition according to the first aspect for use in the treatment or prevention of HIV infection in a subject.

[0019] In a seventh aspect, there is provided the use of a solid composition according to the first aspect for the manufacture of a medicament for treating or preventing HIV infection in a subject.

[0020] In an eighth aspect, there is provided a kit comprising (i) a solid composition according to the first aspect, and (ii) a diluent.

[0021] In a ninth aspect, there is provided a kit comprising (i) a solid composition according to the first aspect, (ii) a composition comprising one or more other antiretroviral agents, and optionally (iii) a diluent. In a tenth aspect, there is provided a kit comprising (i) a solid composition according to the first aspect, (ii) a composition comprising one or more other antiretroviral agents, and (iii) a diluent. [Brief description of the drawings]

[0022] The present invention will now be described, by way of example only, with reference to the accompanying drawings. [Figure 1] Hyaluronidase melting temperature test under different storage conditions. [Figure 1A-1] Hyaluronidase melting temperature test under different storage conditions. [Figure 1A-2] Hyaluronidase melting temperature test under different storage conditions. [Figure 1B-1] Hyaluronidase melting temperature test under different storage conditions. [Figure 1B-2] Hyaluronidase melting temperature test under different storage conditions. [Figure 1C] Hyaluronidase melting temperature test under different storage conditions - pH. [Diagram 2] Hyaluronidase melting temperature test. [Diagram 3] Hyaluronidase melting temperature test under different storage conditions. [Figure 3A] Hyaluronidase melting temperature test under different storage conditions - pH. [Figure 4] Hyaluronidase melting temperature test and CMC sodium concentration. [Diagram 5] Particle size of rilpivirine under different storage conditions. [Figure 6-1] Rilpivirine particle size and hyaluronidase stability study under different storage conditions. [Figure 6-2]Rilpivirine particle size and hyaluronidase stability study under different storage conditions. [Figure 6-3] Rilpivirine particle size and hyaluronidase stability study under different storage conditions. [Figure 6-4] Rilpivirine particle size and hyaluronidase stability study under different storage conditions. [Figure 6-5] Rilpivirine particle size and hyaluronidase stability study under different storage conditions. [Figure 7] Viscosity test. [Figure 8] Note entry test.

[0023] These figures are further explained in the Examples section.

[0024] Disclosure of the Invention This application is described in several sections for ease of reading. However, this does not mean that each section should be read separately. On the contrary, unless otherwise specified, each section should be read with cross-reference to other sections, i.e., by interpreting the entire application as a whole. Unless explicitly stated, no artificial separation of embodiments is intended. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Compositions of the Invention In a first aspect, the present invention relates to a solid composition obtained by lyophilizing an aqueous composition comprising rilpivirine or a pharma- ceutically acceptable salt thereof and hyaluronidase.

[0026] In a second aspect, the present invention relates to a reconstituted aqueous composition obtainable by reconstituting the solid composition according to the first aspect.

[0027] Freeze-drying is a process in which an aqueous composition is first frozen. During the first freezing step, water forms solid ice crystals and the composition condenses resulting in the separation of two phases. The pressure is then reduced during the primary drying stage, causing the ice to sublime. The temperature may be increased in the primary drying stage to increase the rate of sublimation. In the secondary drying stage, the temperature of the composition is slowly increased to facilitate the removal of residual water and provide a solid composition. The solid composition obtained by freeze-drying can be referred to by several terms, including "freeze-dried powder", "freeze-dried cake", "cake", "freeze-dried cake", "freeze-dried powder" and "freeze-dried product". In one embodiment, the solid composition obtained by freeze-drying is a freeze-dried cake, or a cake or a freeze-dried cake.

[0028] Rilpivirine (4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, TMC278, has the following structural formula:

[0029] [ka]

[0030] "Rilpivirine" means rilpivirine having the structural formula above, ie, the free base form.

[0031] In a preferred embodiment, the aqueous composition or reconstituted aqueous composition comprises rilpivirine, ie, rilpivirine in its free base form.

[0032] A pharmaceutically acceptable salt of rilpivirine means that the counter ion is pharmaceutically acceptable. A pharmaceutically acceptable salt is meant to include the therapeutically active non-toxic acid addition salt forms that rilpivirine can form. These salt forms can be conveniently obtained by treating rilpivirine with a suitable acid, such as an inorganic acid (e.g., hydrohalic acid (e.g., hydrochloric acid, hydrobromic acid, etc.)), sulfuric acid, nitric acid, phosphoric acid, etc.), or an organic acid, such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, etc.

[0033] In one embodiment, the rilpivirine or a pharma- ceutically acceptable salt thereof is in the form of particles suspended in the aqueous composition or in the reconstituted aqueous composition, e.g., in the form of microparticles or nanoparticles suspended in the aqueous composition or in the reconstituted aqueous composition.

[0034] Two embodiments having preferred particle sizes are contemplated herein.

[0035] In a first preferred particle size embodiment, the particles have a D of about 2 μm or less. v In this embodiment, the particles have a D of about 100 nm to about 2 μm. v In this embodiment, the particles may have a D of about 200 nm to about 2 μm, for example 200 nm to about 2 μm. v In this embodiment, the particles may have a D of 300 nm to about 2 μm. v In this embodiment, the particles may have a D of about 400 nm to about 2 μm, for example 400 nm to about 2 μm. v In this embodiment, the particles may have a D of about 500 nm to about 2 μm, for example 500 nm to about 2 μm. vPreferably, in this embodiment, the particles have a Dv90 of about 500 nm to about 1,600 nm, e.g., 500 nm to about 1,600 nm, or about 500 nm to about 1,000 nm, e.g., 500 nm to about 1,000 nm, e.g., about 800 nm. More preferably, in this embodiment, the particles have a Dv90 of about 500 nm to about 700 nm, even more preferably about 500 nm to about 650 nm, and most preferably about 525 nm to about 644 nm. v It has 90.

[0036] The term “D v "D 90" as used herein refers to the diameter below which 90% by volume of the particle population is found. v "D 50" as used herein refers to the diameter below which 50% by volume of the particle population is found. v "10" as used herein refers to the diameter below which 10% by volume of the particle population is found.

[0037] In a first preferred particle size embodiment, the particles may have a Dv50 of less than or about 1,000 nm. In this embodiment, the particles have a Dv50 of about 10 nm to about 1000 nm. v 50. In this embodiment, the particles may have a D of about 50 nm to about 700 nm. v 50. In this embodiment, the particles may have a D of about 100 nm to about 600 nm. v 50. In this embodiment, the particles may have a D of about 150 nm to about 500 nm. v 50. Preferably, in this embodiment, the particles have a D of about 200 nm to about 500 nm. v Has 50.

[0038] In a first preferred particle size embodiment, the particles have a D of about 500 nm or less. v In this embodiment, the particles may have a D of about 10 nm to about 500 nm. v In this embodiment, the particles may have a D of about 25 nm to about 400 nm. v In this embodiment, the particles may have a D of about 50 nm to about 300 nm.v In this embodiment, the particles may have a D of about 50 nm to about 200 nm. v 10. Preferably, in this embodiment, the particles have a D of about 75 nm to about 200 nm. v Has 10.

[0039] Preferably, in this embodiment, the particles have a D of about 500 nm to about 1,600 nm. v 90, D of about 200 nm to about 500 nm v 50, and D of about 75 nm to about 200 nm v Has 10.

[0040] Alternatively, the particles have a D of about 500 nm to about 1,000 nm. v 90, D of about 200 nm to about 500 nm v 50, and D of about 75 nm to about 200 nm v Has 10.

[0041] Alternatively, the particles have a D of about 500 nm to about 700 nm. v 90, D of about 200 nm to about 500 nm v 50, and D of about 75 nm to about 200 nm v Has 10.

[0042] In a second preferred particle size embodiment, the particles 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 In this embodiment, the particles may have a D of about 3 μm to about 8 μm. v In this embodiment, the particles may have a D of about 3 μm to about 7 μm. v 90. Preferably, in this embodiment, the particles have a D of about 4 μm to about 6 μm. v Preferably, in this embodiment, the particles have a D of about 5 μm to about 6 μm, for example about 5 μm or about 6 μm. v It has 90.

[0043] In a second preferred particle size embodiment, the particles have a D of about 3 μm or less. vIn this embodiment, the particles have a D of less than about 2.5 μm. v In this embodiment, the particles may have a D of about 1 μm to about 2.5 μm. v 50. In this embodiment, the particles may have a D of about 1.2 μm to about 2.2 μm. v 50. Preferably, in this embodiment, the particles have a D of about 1.5 μm to about 2.2 μm. v More preferably, in this embodiment, the particles have a D of about 1.5 μm to about 2 μm. v Has 50.

[0044] In a second preferred particle size embodiment, the particles have a D of about 1000 nm or less. v In this embodiment, the particles may have a D of about 10 nm to about 1000 nm. v In this embodiment, the particles may have a D of about 100 nm to about 700 nm. v In this embodiment, the particles may have a D of about 200 nm to about 600 nm. v 10. Preferably, in this embodiment, the particles have a D of about 300 nm to about 500 nm. v Has 10.

[0045] Preferably, in this embodiment, the particles have a D of about 4 μm to about 6 μm. v 90, D of about 1.5 μm to about 2 μm v 50, and D of about 300 nm to about 500 nm v Has 10.

[0046] Preferably, in this embodiment, the particles have a D of about 5 μm to about 6 μm. v 90, D of about 1.5 μm to about 2.2 μm v 50, and D of about 300 nm to about 500 nm v Has 10.

[0047] 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.

[0048] Laser diffraction relies on the principle that particles scatter light at angles that vary with particle size, and a collection of particles produces a pattern of scattered light defined by intensity and angle that can be correlated to particle size distribution. Many laser diffraction instruments are commercially available for fast and reliable measurement of particle size distribution. For example, particle size distribution can be measured by a conventional Malvern Mastersizer™ 3000 particle size analyzer manufactured by Malvern Instruments. The Malvern Mastersizer™ 3000 particle size analyzer works by projecting a helium-neon gas laser beam through a transparent cell that contains particles of interest suspended in an aqueous solution. The light that strikes the particles is scattered at angles that are inversely proportional to the particle size, a photodetector array measures the light intensity at several predefined angles, and the measured intensities at different angles are processed by a computer using standard theoretical principles to determine the particle size distribution. Laser diffraction values ​​can be obtained using a wet dispersion of particles in distilled water.

[0049] D v 10. D v 50, and D v Other methods commonly used in the art for measuring 90 include disk centrifugation, scanning electron microscopy (SEM), sedimentation field flow fractionation, and photon correlation spectroscopy.

[0050] In one embodiment, the aqueous composition or reconstituted aqueous composition contains about 100 to about 500 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition or reconstituted aqueous composition contains about 150 to about 450 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition or reconstituted aqueous composition contains about 200 to about 400 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof. In a preferred embodiment, the aqueous composition or reconstituted aqueous composition contains about 250 to about 350 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof, for example about 300 mg / mL, in particular 300 mg / mL of rilpivirine.

[0051] In one embodiment, the amount of rilpivirine or a pharma- ceutically acceptable salt thereof in the solid composition or reconstituted aqueous composition is about 900 mg to about 28,800 mg (e.g., about 900 mg to about 14,400 mg, or about 900 mg to about 7,200 mg, or about 900 mg to about 4,500 mg, or about 900 mg to about 3,600 mg), preferably about 1,200 mg to about 14,400 mg, preferably about 1,350 mg to about 13,200 mg, and more preferably about 1,500 mg to about 2,500 mg. or about 1500 mg to about 12000 mg (e.g., about 3000 mg to about 12000 mg), preferably about 1800 mg to about 10800 mg (e.g., about 2700 mg to about 10800 mg, or about 1800 mg to about 3600 mg), most preferably about 1800 mg to about 7200 mg, or about 1800 mg to about 4500 mg, or about 2700 mg to about 4500 mg, or about 3600 mg to about 4500 mg. The "mg" shown corresponds to mg of rilpivirine (i.e., rilpivirine in its free base form). Thus, for example, 1 mg of rilpivirine (i.e., rilpivirine in its free base form) corresponds to 1.1 mg of rilpivirine hydrochloride.

[0052] The solid composition or reconstituted aqueous composition contains hyaluronidase. Hyaluronidase is an enzyme that breaks down hyaluronic acid (HA) and reduces the viscosity of hyaluronan in the extracellular matrix. This property can be used to enhance the dispersion and absorption of injected active pharmaceutical ingredients or to allow for subcutaneous administration of large amounts. The enzymatic activity of hyaluronidase, including rHuPH20, can be defined by units per mL (U / mL) or total enzyme activity (U) in a particular formulation.

[0053] As used herein, the term "hyaluronidase" refers to any enzyme that degrades hyaluronic acid and reduces the viscosity of hyaluronan in the extracellular matrix.

[0054] In one embodiment, the hyaluronidase is a recombinant hyaluronidase. In a particularly preferred embodiment, the hyaluronidase is a recombinant human hyaluronidase, such as rHuPH20. In one embodiment, rHuPH20 is defined by the amino acid sequence available under CAS Registry Number 757971-58-7. Further information regarding rHuPH20 is described in WO 2004 / 078140. In one embodiment, the amino acid sequence of rHuPH20 comprises SEQ ID NO:1. In some embodiments, the hyaluronidase is a variant of rHuPH20 having an amino acid sequence of SEQ ID NO:2, i.e., rHuPH20 comprising residues 36-482 of wild-type human hyaluronidase. In some embodiments, the hyaluronidase is a variant of rHuPH20 having an amino acid sequence comprising SEQ ID NO:3. In some embodiments, the hyaluronidase is a variant of rHuPH20 having an amino acid sequence comprising SEQ ID NO:4. In some embodiments, the hyaluronidase is a variant of rHuPH20 having an amino acid sequence comprising SEQ ID NO:5.

[0055] [Table 1]

[0056] In one embodiment, the concentration of hyaluronidase in the aqueous composition or reconstituted aqueous composition is about 10 to about 10,000 U / mL, or about 100 to about 10,000 U / mL, or about 500 to about 10,000 U / mL, or about 500 to about 5000 U / mL, or about 500 to about 2500 U / mL, or about 1000 to about 2500 U / mL, or about 1500 to about 2500 U / mL. Preferably, the concentration of hyaluronidase in the aqueous composition or reconstituted aqueous composition is about 1800 to about 2200 U / mL (e.g., about 2000 U / mL).

[0057] In one embodiment, the concentration of hyaluronidase in the aqueous composition or reconstituted aqueous composition is about 0.1 to about 90 μg / mL, or about 0.9 to about 90 μg / mL, or about 4.5 to about 90 μg / mL, or about 4.5 to about 45 μg / mL, or about 4.5 to about 22.5 μg / mL, or about 9 to about 22.5 μg / mL, or about 13.5 to about 22.5 μg / mL. Preferably, the concentration of hyaluronidase in the aqueous composition or reconstituted aqueous composition is about 16.2 to about 19.8 μg / mL (e.g., about 18 μg / mL).

[0058] In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition further comprises carboxymethylcellulose (CMC) or a pharma- ceutically acceptable salt thereof, preferably, the CMC is not cross-linked. In one embodiment, the CMC or a pharma- ceutically acceptable salt thereof is a pharma- ceutically acceptable salt of CMC. By a pharma- ceutically acceptable salt of CMC is meant a salt in which the counterion is pharma- ceutically acceptable. A pharma- ceutically acceptable salt is intended to include the therapeutically active non-toxic base addition salt forms that CMC can form. Preferred pharma- ceutically acceptable salts of CMC include sodium CMC and potassium CMC. In a particularly preferred embodiment, the CMC or a pharma- ceutically acceptable salt thereof is sodium CMC, particularly non-cross-linked sodium CMC. In another embodiment, the CMC or a pharma- ceutically acceptable salt thereof is CMC. Examples of CMC that may be used in the present invention are carmellose sodium, 40 MPa.s (parenteral grade), available from Ashland, and Blanose CMC 7LF PH or Blanose 7LP EP, also available from Ashland.

[0059] CMC or a pharma- ceutically acceptable salt thereof can have any degree of substitution (DS). DS is the average number of carboxymethyl groups per cellulose unit. In a preferred embodiment, the DS is neutralized to a pH of about 0.4 to about 1.5. In one embodiment, CMC or a pharma- ceutically acceptable salt thereof has a DS of about 0.5 to about 1, for example, about 0.65 to about 0.95, for example, about 0.7.

[0060] In one embodiment, CMC or a pharma- ceutically acceptable salt thereof has a viscosity of about 10 MPa.s to about 100 MPa.s in a 1% (w / v) aqueous solution at room temperature. In one embodiment, CMC or a pharma- ceutically acceptable salt thereof has a viscosity of about 20 MPa.s to about 60 MPa.s in a 1% (w / v) aqueous solution at room temperature. In one embodiment, CMC or a pharma- ceutically acceptable salt thereof has a viscosity of about 30 mPa.s to about 50 MPa.s in a 1% (w / v) aqueous solution at room temperature, for example, about 40 MPa.s in a 1% (w / v) aqueous solution at room temperature.

[0061] In one embodiment, CMC or a pharma- ceutically acceptable salt thereof has a viscosity of about 10 MPa.s to about 100 MPa.s in a 2% (w / v) aqueous solution at room temperature. In one embodiment, CMC or a pharma- ceutically acceptable salt thereof has a viscosity of about 20 MPa.s to about 60 MPa.s in a 2% (w / v) aqueous solution at room temperature. In a preferred embodiment, CMC or a pharma- ceutically acceptable salt thereof has a viscosity of about 30 MPa.s to about 50 MPa.s in a 2% (w / v) aqueous solution at room temperature, for example, about 40 MPa.s in a 2% (w / v) aqueous solution at room temperature.

[0062] In one embodiment, the molecular weight of CMC or a pharma- ceutically acceptable salt thereof is about 50 kDa to about 2000 kDa. In one embodiment, the molecular weight of CMC or a pharma- ceutically acceptable salt thereof is about 50 kDa to about 1,000 kDa. In one embodiment, the molecular weight of CMC or a pharma- ceutically acceptable salt thereof is about 70 kDa to about 900 kDa. In a preferred embodiment, the molecular weight of CMC or a pharma- ceutically acceptable salt thereof is about 90 kDa to about 750 kDa. In a most preferred embodiment, the molecular weight of CMC or a pharma- ceutically acceptable salt thereof is about 70 kDa to about 110 kDa, for example, about 90 kDa.

[0063] The present inventors have surprisingly found that the addition of CMC or a pharma- ceutical acceptable salt thereof to the aqueous composition of the present invention containing hyaluronidase reduces the melting temperature (T m ) was found to increase (Example 2a), indicating improved storage stability.

[0064] The inventors have also found that the addition of CMC or a pharma- ceutically acceptable salt thereof to the aqueous compositions of the invention containing hyaluronidase results in reduced loss of hyaluronidase activity, reduced aggregation of hyaluronidase, and / or reduced oxidation of hyaluronidase in the reconstituted aqueous compositions of the invention, such as after storage of the lyophilized product under stress test conditions (Examples 6 and 8), indicating improved storage stability.

[0065] In one embodiment, the aqueous composition or reconstituted aqueous composition comprises about 1 mg / mL to about 100 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition or reconstituted aqueous composition comprises about 1 mg / mL to about 75 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition or reconstituted aqueous composition comprises about 1 mg / mL to about 50 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition or reconstituted aqueous composition comprises about 1 mg / mL to about 25 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition or reconstituted aqueous composition comprises about 5 mg / mL to about 25 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In one embodiment, the aqueous composition or reconstituted aqueous composition comprises about 5 mg / mL to about 15 mg / mL of CMC or a pharma- ceutically acceptable salt thereof. In a preferred embodiment, the aqueous composition or reconstituted aqueous composition comprises about 5 mg / mL to about 10 mg / mL of CMC or a pharma- ceutically acceptable salt thereof.In a more preferred embodiment, the aqueous composition or reconstituted aqueous composition comprises about 1 mg / mL to about 5 mg / mL, for example about 3 mg / mL of CMC or a pharma- ceutically acceptable salt thereof.

[0066] In a preferred embodiment, the CMC or its pharma- ceutically acceptable salt is sodium CMC, and the aqueous composition or reconstituted aqueous composition comprises sodium CMC in any one of the amounts specified in the immediately preceding paragraph. In a preferred embodiment, the CMC or its pharma-ceutically acceptable salt is sodium CMC, and the aqueous composition or reconstituted aqueous composition has any of the degrees of substitution, viscosities, and molecular weights specified herein.

[0067] In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition comprises about 0.002 mg to about 5 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition comprises about 0.01 mg to about 5 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition comprises about 0.05 mg to about 2.5 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition comprises about 0.1 mg to about 2 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. In a preferred embodiment, the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition comprises about 0.1 mg to about 1 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. In a more preferred embodiment, the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition comprises about 0.1 mg to about 0.25 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase, for example, about 0.15 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. In another more preferred embodiment, the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition comprises about 0.05 mg to about 0.25 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase, for example, about 0.15 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase.

[0068] In a preferred embodiment, the CMC or a pharma- ceutically acceptable salt thereof is CMC sodium, and the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition comprises any one of the ratios of CMC sodium to hyaluronidase specified in the immediately preceding paragraph.

[0069] In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition further comprises a cryoprotectant. In one embodiment, the cryoprotectant is a sugar, sugar alcohol or amino acid or a pharma- ceutically acceptable salt thereof, preferably the sugar is not a monosaccharide. A pharma- ceutically acceptable salt of a sugar, sugar alcohol or amino acid means one in which the counterion is pharma- ceutically acceptable. A pharma- ceutically acceptable salt is meant to include the therapeutically active non-toxic acid and base addition salt forms that a particular sugar, sugar alcohol, or amino acid can form. Suitable sugars and sugar alcohols include mannitol, lactose, sucrose, trehalose, sorbitol, dextrose, fructose, maltose, xylitol, and raffinose. Preferably, the sugar or sugar alcohol is selected from mannitol and sucrose. More preferably, the sugar or sugar alcohol is sucrose. Suitable amino acids or pharma- ceutically acceptable salts thereof include arginine, glycine, and histidine or a pharma- ceutically acceptable salt thereof. In one embodiment, the amino acid or a pharma- ceutically acceptable salt thereof is selected from arginine and glycine or a pharma- ceutically acceptable salt thereof. In a preferred embodiment, the amino acid or a pharma- ceutically acceptable salt thereof is arginine (e.g., arginine HCl). In one embodiment, the aqueous composition or the reconstituted aqueous composition further comprises two cryoprotectants. In one embodiment, the aqueous composition or the reconstituted aqueous composition further comprises two cryoprotectants, one cryoprotectant being a sugar or sugar alcohol and the other cryoprotectant being an amino acid or a pharma- ceutically acceptable salt thereof.

[0070] The inventors have surprisingly found that when rilpivirine or a pharma- ceutically acceptable salt thereof is in the form of particles suspended in the aqueous composition, the particle size distribution in the reconstituted aqueous composition according to the invention is similar to the particle size distribution in the aqueous composition before lyophilization (see, e.g., Example 4).

[0071] In one embodiment, the aqueous composition or reconstituted aqueous composition comprises from about 1 mg / mL to about 200 mg / mL of cryoprotectant. In one embodiment, the aqueous composition or reconstituted aqueous composition comprises from about 1 mg / mL to about 175 mg / mL of cryoprotectant. In one embodiment, the aqueous composition or reconstituted aqueous composition comprises from about 1 mg / mL to about 150 mg / mL of cryoprotectant.

[0072] In one embodiment, the aqueous composition or reconstituted aqueous composition comprises from about 20 mg / mL to about 150 mg / mL of cryoprotectant.

[0073] In one embodiment, the aqueous composition or reconstituted aqueous composition comprises a cryoprotectant that is a sugar or sugar alcohol in an amount of about 25 mg / mL to about 150 mg / mL. In one embodiment, the aqueous composition or reconstituted aqueous composition comprises a cryoprotectant that is a sugar or sugar alcohol in an amount of about 25 mg / mL to about 125 mg / mL. In a preferred embodiment, the aqueous composition or reconstituted aqueous composition comprises a cryoprotectant that is a sugar or sugar alcohol in an amount of about 50 mg / mL to about 100 mg / mL. In another preferred embodiment, the aqueous composition or reconstituted aqueous composition comprises a cryoprotectant that is a sugar or sugar alcohol in an amount of about 75 mg / mL to about 125 mg / mL, for example about 100 mg / mL. In one embodiment, the cryoprotectant is sucrose.

[0074] In one embodiment, the aqueous composition or reconstituted aqueous composition comprises a cryoprotectant that is an amino acid or a pharma- ceutically acceptable salt thereof in an amount of about 1 mg / mL to about 100 mg / mL. In a preferred embodiment, the aqueous composition or reconstituted aqueous composition comprises a cryoprotectant that is an amino acid or a pharma- ceutically acceptable salt thereof in an amount of about 25 mg / mL to about 75 mg / mL, for example about 50 mg / mL. In a more preferred embodiment, the aqueous composition or reconstituted aqueous composition comprises a cryoprotectant that is an amino acid or a pharma- ceutically acceptable salt thereof in an amount of about 25 mg / mL to about 35 mg / mL, for example about 30 mg / mL. In one embodiment, the cryoprotectant is arginine, preferably arginine HCl.

[0075] In one embodiment, the aqueous composition or reconstituted aqueous composition comprises two cryoprotectants, the total amount of the two cryoprotectants is about 25 mg / mL to about 150 mg / mL, preferably the two cryoprotectants are a sugar or sugar alcohol and an amino acid. In a preferred embodiment, the aqueous composition or reconstituted aqueous composition comprises two cryoprotectants, the total amount of the two cryoprotectants is about 50 mg / mL to about 125 mg / mL, preferably the two cryoprotectants are a sugar or sugar alcohol and an amino acid, for example the two cryoprotectants are a sugar or sugar alcohol and an amino acid or a pharma- ceutically acceptable salt thereof.

[0076] In a preferred embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition further comprises sucrose and CMC or a pharma- ceutically acceptable salt thereof. In a more preferred embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition further comprises sucrose and sodium CMC.

[0077] In a preferred embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition further comprises arginine or a pharma- ceutically acceptable salt thereof and CMC or a pharma- ceutically acceptable salt thereof. In a more preferred embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition further comprises arginine hydrochloride and CMC sodium.

[0078] In a preferred embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition further comprises arginine or a pharma- ceutically acceptable salt thereof, in a more preferred embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition further comprises arginine hydrochloride.

[0079] In one embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is from about 1:10 (w / w) to about 10:1 (w / w).

[0080] In one embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is from about 1:1 (w / w) to about 20:1 (w / w). In one embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is from about 1:1 (w / w) to about 10:1 (w / w). In one embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is from about 2 ...7:1 (w / w). In a preferred embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or in the reconstituted aqueous composition is from about 3:1 (w / w) to about 6:1 (w / w).

[0081] In a preferred embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is from about 1:1 (w / w) to about 15:1 (w / w). In a particularly preferred embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is from about 1:1 (w / w) to about 5:1 (w / w), for example about 3:1 (w / w). In another particularly preferred embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is from about 8:1 (w / w) to about 12:1 (w / w), for example about 10:1 (w / w).

[0082] In one embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is from about 1:1 (w / w) to about 1:10 (w / w). In one embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is from about 1:2 (w / w) to about 1:10 (w / w). In one embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is from about 1:2 (w / w) to about 1:7 (w / w). In a preferred embodiment, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is from about 1:3 (w / w) to about 1:6 (w / w).

[0083] In one embodiment, the ratio of CMC or a pharma- ceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is about 1:1 (w / w) to about 1:150 (w / w). In one embodiment, the ratio of CMC or a pharma- ceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is about 1:1 (w / w) to about 1:100 (w / w). In one embodiment, the ratio of CMC or a pharma- ceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is about 1:1 (w / w) to about 1:50 (w / w). In one embodiment, the ratio of CMC or a pharma- ceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is about 1:1 (w / w) to about 1:40 (w / w). In a preferred embodiment, the ratio of CMC or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition is about 1:8 (w / w) to about 1:40 (w / w). In one embodiment, the ratio of CMC or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition is about 1:8 (w / w) to about 1:35 (w / w), for example, about 1:10 (w / w) to about 1:33 (w / w).

[0084] In one embodiment, the cryoprotectant is arginine, e.g., arginine HCl, and the ratio of CMC or a pharma- ceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition is about 1:1 (w / w) to about 1:30 (w / w). In one embodiment, the cryoprotectant is arginine, e.g., arginine HCl, and the ratio of CMC or a pharma- ceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition is about 1:1 (w / w) to about 1:15 (w / w). In one embodiment, the cryoprotectant is arginine, e.g., arginine HCl, and the ratio of CMC or a pharma- ceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition is about 1:2 (w / w) to about 1:15 (w / w). In one embodiment, the cryoprotectant is arginine, e.g., arginine HCl, and the ratio of CMC or a pharma- ceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition is about 1:4 (w / w) to about 1:11 (w / w). In a preferred embodiment, the cryoprotectant is arginine, e.g., arginine HCl, and the ratio of CMC or a pharma- ceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition is about 1:9 (w / w) to about 1:11 (w / w). In another preferred embodiment, the cryoprotectant is arginine, e.g., arginine HCl, and the ratio of CMC or a pharma- ceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition is about 1:5 (w / w) to about 1:10 (w / w), e.g., about 1:10 (w / w).

[0085] In one embodiment, the cryoprotectant is sucrose, and the ratio of CMC or a pharma- ceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is about 1:20 (w / w) to about 1:100 (w / w). In one embodiment, the cryoprotectant is sucrose, and the ratio of CMC or a pharma- ceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is about 1:20 (w / w) to about 1:50 (w / w). In one embodiment, the cryoprotectant is sucrose, and the ratio of CMC or a pharma- ceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition is about 1:30 (w / w) to about 1:40 (w / w). In a preferred embodiment, the cryoprotectant is sucrose and the ratio of CMC or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition (and, consequently, the solid composition) or in the reconstituted aqueous composition is about 1:30 (w / w) to about 1:35 (w / w), for example about 1:33 (w / w).

[0086] In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition further comprises one or more surface modifiers. When the rilpivirine or a pharma- ceutically acceptable salt thereof is in the form of particles as defined herein, the one or more surface modifiers are adsorbed to the surface of the particles.

[0087] The surface modifier may be selected from known organic and inorganic pharmaceutical excipients, including various polymers, low molecular weight oligomers, natural products, and surfactants. Specific surface modifiers that may be used in the present invention may include non-ionic surfactants and anionic surfactants. Representative examples of surface modifiers include gelatin, casein, lecithin, salts or acid forms of negatively charged phospholipids (phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphoric acid, and salts thereof, such as alkali metal salts, e.g., their sodium salts, e.g., sodium egg phosphatidylglycerol, such as products available under the trade name Lipoid™ EPG), gum acacia, stearic acid, benzalkonium chloride, polyoxyethylene alkyl ethers, e.g., macrogol ethers, such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, colloidal silicon dioxide, dodecyl sulfate, bile salts, such as sodium taurocholate, sodium desoxytaurocholate, sodium desoxycholate, methylcellulose ... cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminosilicate, polyvinyl alcohol (PVA), poloxamers such as Pluronic® F68, F108 and F127, which are block copolymers of ethylene oxide and propylene oxide, tyloxapol, vitamin E-TGPS (α-tocopheryl polyethylene glycol, in particular α-tocopheryl polyethylene glycol 1000), poloxamines such as Tetronic® 908 (T908), which is a tetrafunctional block copolymer derived from the sequential addition of ethylene oxide and propylene oxide to ethylenediamine, dextran, lecithin, dioctyl esters of sodium sulfosuccinate, such as those sold under the trade name AerosolExamples of suitable surface modifiers include those sold under the tradenames Crodesta™ F110 or Crodesta™ SL-40, hexyldecyltrimethylammonium chloride (CTAC), polyvinylpyrrolidone (PVP), and the like. If desired, two or more surface modifiers may be used in combination.

[0088] In one embodiment, the surface modifier is selected from poloxamers, α-tocopheryl polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid esters, and salts of negatively charged phospholipids or their acid forms. In one embodiment, the surface modifier is selected from polyoxyethylene sorbitan fatty acid esters such as Pluronic™ F108, Vitamin E TGPS (α-tocopheryl polyethylene glycol succinate, particularly α-tocopheryl polyethylene glycol 1000 succinate), Tween™ 80, and phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphoric acid, and salts thereof such as alkali metal salts, for example, their sodium salts, for example, egg phosphatidylglycerol sodium, such as the product available under the trade name Lipoid™ EPG.

[0089] In a preferred embodiment, the surface modifier is a poloxamer, in particular Pluronic™ F108. Pluronic™ F108 corresponds to poloxamer 338 and has the formula HO-[CH2CH2O] x-[CH(CH3)CH2O] y -[CH2CH2O] z -H, where the average values ​​of x, y, and z are 128, 54, and 128, respectively. Other trade names for poloxamer 338 are Hodag Nonionic™ 1108-F and Synperonic™ PE / F 108. In one embodiment, the surface modifier comprises a combination of a polyoxyethylene sorbitan fatty acid ester and a phosphatidylglycerol salt, particularly sodium egg phosphatidylglycerol.

[0090] In one embodiment, the aqueous composition (and thus a solid composition) or the reconstituted aqueous composition comprises from about 0.1 mg / mL to about 100 mg / mL of poloxamer. In one embodiment, the aqueous composition (and thus a solid composition) or the reconstituted aqueous composition comprises from about 1 mg / mL to about 100 mg / mL of poloxamer. In one embodiment, the aqueous composition (and thus a solid composition) or the reconstituted aqueous composition comprises from about 5 mg / mL to about 100 mg / mL of poloxamer. In one embodiment, the aqueous composition (and thus a solid composition) or the reconstituted aqueous composition comprises from about 5 mg / mL to about 70 mg / mL of poloxamer. In one embodiment, the aqueous composition (and thus a solid composition) or the reconstituted aqueous composition comprises from about 5 mg / mL to about 60 mg / mL of poloxamer.

[0091] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises from about 5 mg / mL to about 25 mg / mL of poloxamer. In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises from about 5 mg / mL to about 20 mg / mL of poloxamer, for example about 20 mg / mL. In a preferred embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises from about 5 mg / mL to about 15 mg / mL of poloxamer, for example about 10 mg / mL.

[0092] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises from about 20 mg / mL to about 60 mg / mL of poloxamer. In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises from about 25 mg / mL to about 60 mg / mL of poloxamer. In a particularly preferred embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises from about 40 mg / mL to about 60 mg / mL of poloxamer, for example about 50 mg / mL.

[0093] In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition comprises a poloxamer and rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, and the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to the poloxamer is about 15:1 when the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition comprises a poloxamer and rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, and the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to the poloxamer is about 15:1 to about 3:1 when the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition comprises a poloxamer and rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, and the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 15:1 to about 4:1 when the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition comprises a poloxamer and rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, and the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 15:1 to about 6:1 when the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. In a preferred embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition comprises a poloxamer and rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, and the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 6:1, where the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less.

[0094] In one embodiment, the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or reconstituted aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is less than about 15:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1 μm to about 10 μm, about 2 μm to about 9 μm, about 3 μm to about 8 μm, or about 3 μm to about 7 μm. In one embodiment, the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or reconstituted aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is from about 15:1 to about 60:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of from about 1 μm to about 10 μm, from about 2 μm to about 9 μm, from about 3 μm to about 8 μm, or from about 3 μm to about 7 μm. In one embodiment, the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or reconstituted aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 20:1 (w / w) to about 60:1 (w / w), and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1 μm to about 10 μm, about 2 μm to about 9 μm, about 3 μm to about 8 μm, or about 3 μm to about 7 μm. In one embodiment, the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or reconstituted aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 30:1 (w / w) to about 60:1 (w / w), and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1 μm to about 10 μm, about 2 μm to about 9 μm, about 3 μm to about 8 μm, or about 3 μm to about 7 μm.In a preferred embodiment, the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or reconstituted aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 30:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1 μm to about 10 μm, about 2 μm to about 9 μm, about 3 μm to about 8 μm, or about 3 μm to about 7 μm, e.g., about 4 μm to about 6 μm.

[0095] In one embodiment, the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof and a poloxamer in the form of particles suspended in the aqueous composition or reconstituted aqueous composition, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 15:1 (w / w) or less, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof and a poloxamer in the form of particles suspended in the aqueous composition or reconstituted aqueous composition, the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 3:1 (w / w) to about 15:1 (w / w), and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or reconstituted aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 4:1 (w / w) to about 15:1 (w / w), and the rilpivirine or a pharma-ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition comprises rilpivirine or a pharma-ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or reconstituted aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma-ceutically acceptable salt thereof to poloxamer is about 6:1 to about 15:1, and the rilpivirine or a pharma-ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm. In a preferred embodiment, the aqueous composition (and, consequently, the solid composition) or reconstituted aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or reconstituted aqueous composition, and a poloxamer, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 6:1, and the rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 500 nm to about 1600 nm, e.g., about 500 nm to about 700 nm.

[0096] In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and the surface modifier is about 1:1 to about 40:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and the surface modifier is about 1:1 to about 35:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and the surface modifier is about 15:1 to about 35:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and the surface modifier is about 25:1 to about 35:1, for example, about 30:1. The surface modifier is preferably a poloxamer, for example, poloxamer 338.

[0097] In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and the surface modifier is about 5:1 to about 25:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and the surface modifier is about 10:1 to about 20:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and the surface modifier is about 13:1 to about 17:1, for example, about 15:1. The surface modifier is preferably a poloxamer, for example, poloxamer 338.

[0098] In one embodiment, the relative amounts (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and surface modifier are less than about 15: 1. In a preferred embodiment, the relative amounts (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and surface modifier (e.g., a poloxamer, such as Poloxamer 338) are less than about 12:1.

[0099] In one embodiment, the relative amount (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof to the surface modifier is from about 1:2 to about 20:1, in particular from about 1:1 to about 10:1, such as from about 4:1 to about 8:1, for example from about 4:1 to about 6:1, preferably about 6:1. The surface modifier is preferably a poloxamer, for example poloxamer 338.

[0100] In one embodiment, the aqueous composition or reconstituted aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof as defined herein in the form of particles suspended in the aqueous composition or reconstituted aqueous composition, and comprises one or more surface modifiers as defined herein, wherein the amount of rilpivirine or a pharma- ceutically acceptable salt thereof is at least about 50% by weight of the particles, at least about 80% by weight of the particles, at least about 85% by weight of the particles, at least about 90% by weight of the particles, at least about 95% by weight of the particles, or at least about 99% by weight of the particles, particularly in the range of 80%-90% by weight of the particles, or in the range of 85%-90% by weight of the particles.

[0101] Aqueous compositions or reconstituted aqueous compositions include water, for example sterile water for injection.

[0102] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition further comprises a buffer and / or a pH adjuster. Particular buffers are salts of weak acids. Buffers and pH adjusters that can be added can be selected from tartaric acid, maleic acid, glycine, sodium lactate / lactic acid, ascorbic acid, sodium citrate / citric acid, sodium acetate / acetic acid, sodium bicarbonate / carbonic acid, sodium succinate / succinic acid, sodium benzoate / benzoic acid, sodium phosphate, tris(hydroxymethyl)aminomethane, sodium bicarbonate / sodium carbonate, ammonium hydroxide, benzenesulfonic acid, sodium benzoate / acid, diethanolamine, glucono-delta-lactone, hydrochloric acid, hydrogen bromide, lysine, methanesulfonic acid, monoethanolamine, sodium hydroxide, tromethamine, gluconic acid, glyceric acid, glutaric acid, glutamic acid, ethylenediaminetetraacetic acid (EDTA), triethanolamine, and mixtures thereof. In one embodiment, the buffer is a sodium phosphate buffer, such as sodium dihydrogen phosphate monohydrate. In one embodiment, the pH adjuster is sodium hydroxide. In a preferred embodiment, the aqueous composition or reconstituted aqueous composition comprises a buffer and a pH adjuster, the buffer is sodium dihydrogen phosphate monohydrate and the pH adjuster is sodium hydroxide.

[0103] In one embodiment, the pH of the aqueous composition or reconstituted aqueous composition is about 5 to about 7. In one embodiment, the pH of the aqueous composition or reconstituted aqueous composition is about 6 to about 7. In one embodiment, the pH of the aqueous composition or reconstituted aqueous composition is about 6 to about 6.5. In a preferred embodiment, the pH of the aqueous composition or reconstituted aqueous composition is about 6. The pH of the aqueous composition or reconstituted aqueous composition may be adjusted, for example, by varying the type and / or amount of buffering agent and / or pH adjusting agent present in the aqueous composition.

[0104] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted 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 an embodiment, the chelating agent is citric acid, e.g., citric acid monohydrate.

[0105] In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition further comprises an antioxidant. In one embodiment, the antioxidant is methionine. In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition comprises about 1.0 mg / mL to about 2.0 mg / mL of an antioxidant (e.g., methionine), for example, about 1.5 mg / mL.

[0106] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition does not include a tonicity agent.

[0107] In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition does not contain glucose.

[0108] In one embodiment, the aqueous composition (and consequently the solid composition) or the reconstituted aqueous composition does not comprise mannitol.

[0109] In one embodiment, the aqueous composition (and, consequently, the solid composition) or the reconstituted aqueous composition does not contain polyvinylpyrrolidone (PVP).

[0110] The aqueous composition may usefully have an osmolality suitable for reducing pain during subcutaneous injection. For example, in one embodiment, the aqueous composition and the reconstituted aqueous composition have an osmolality of about 280 mOsm / kg to about 600 mOsm / kg. In one embodiment, the aqueous composition and the reconstituted aqueous composition have an osmolality of about 280 mOsm / kg to about 300 mOsm / kg. In a more preferred embodiment, the aqueous composition and the reconstituted aqueous composition have an osmolality of about 290 mOsm / kg.

[0111] In one embodiment, the aqueous composition or reconstituted aqueous composition of the present invention may be contained in a container with an inert gas, which may be, for example, nitrogen.

[0112] The following specific embodiments are also part of the invention.

[0113] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof, and CMC or a pharma- ceutically acceptable salt thereof. The pH of the aqueous composition or reconstituted aqueous composition is about 6 to about 7. Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from a surfactant, such as a poloxamer, a buffer, such as sodium dihydrogen phosphate, a chelating agent, such as citric acid, and a pH adjuster, such as sodium hydroxide; and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0114] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, and Contains sodium CMC, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0115] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, and Contains sodium CMC, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. the aqueous composition comprises about 0.5 mg of CMC sodium per 100 U of rHuPH20 to about 2 mg of CMC sodium per 100 U of rHuPH20; Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0116] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, and Contains sodium CMC, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. the aqueous composition comprising from about 0.05 mg of CMC sodium per 100 U of rHuPH20 to about 0.25 mg of CMC sodium per 100 U of rHuPH20; Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0117] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Hyaluronidase and (i) rilpivirine or a pharma- ceutically acceptable salt thereof; CMC or a pharma- ceutically acceptable salt thereof; and Contains cryoprotectant, The pH of the aqueous composition or reconstituted aqueous composition is about 6 to about 7. Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from a surfactant, such as a poloxamer, a buffer, such as sodium dihydrogen phosphate, a chelating agent, such as citric acid, and a pH adjuster, such as sodium hydroxide; and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0118] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, Sodium CMC, and Contains sugar or sugar alcohol, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0119] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, Sodium CMC, and Contains mannitol and / or sucrose, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0120] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, Sodium CMC, and Contains sucrose, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0121] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, Sodium CMC, and Contains sucrose, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. the aqueous composition or reconstituted aqueous composition comprises from about 0.05 mg of CMC sodium per 100 U of rHuPH20 to about 0.25 mg of CMC sodium per 100 U of rHuPH20; Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0122] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, Sodium CMC, and Contains mannitol and / or sucrose, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. the aqueous composition or reconstituted aqueous composition comprises from about 0.5 mg of CMC sodium per 100 U of rHuPH20 to about 2 mg of CMC sodium per 100 U of rHuPH20; the ratio of sodium CMC to mannitol or sucrose is about 1:4 (w / w) to about 1:11 (w / w); the ratio of rilpivirine to mannitol or sucrose is about 2:1 (w / w) to about 7:1 (w / w); Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0123] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, Sodium CMC, and Contains sucrose, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. the aqueous composition or reconstituted aqueous composition comprises from about 0.05 mg of CMC sodium per 100 U of rHuPH20 to about 0.25 mg of CMC sodium per 100 U of rHuPH20; The ratio of sodium CMC to sucrose is about 1:30 (w / w) to about 1:35 (w / w). The ratio of sodium CMC to sucrose is from about 2:1 (w / w) to about 7:1 (w / w). Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0124] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof, and Contains cryoprotectant, The pH of the aqueous composition or reconstituted aqueous composition is about 6 to about 7. Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from a surfactant, such as a poloxamer, a buffer, such as sodium dihydrogen phosphate, a chelating agent, such as citric acid, and a pH adjuster, such as sodium hydroxide; and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0125] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, and Includes an amino acid or a pharma- ceutically acceptable salt thereof. The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0126] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, and Contains Arginine HCl, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0127] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, CMC or a pharma- ceutically acceptable salt thereof; and Contains Arginine HCl, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0128] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, Sodium CMC, and Contains Arginine HCl, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0129] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, and Contains Arginine HCl, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. The ratio of rilpivirine to arginine HCl is from about 1:1 (w / w) to about 20:1 (w / w). Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0130] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, and Contains Arginine HCl, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. The ratio of rilpivirine to arginine is about 2:1 (w / w) to about 7:1 (w / w). Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0131] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, and Contains Arginine HCl, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. The ratio of rilpivirine to arginine HCl is about 2:1 (w / w) to about 7:1 (w / w). Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0132] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, CMC or a pharma- ceutically acceptable salt thereof; and Contains Arginine HCl, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. The ratio of rilpivirine to arginine HCl is from about 1:1 (w / w) to about 20:1 (w / w). Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0133] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, CMC or a pharma- ceutically acceptable salt thereof; and Contains Arginine HCl, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. The ratio of rilpivirine to arginine HCl is from about 1:1 (w / w) to about 20:1 (w / w). The ratio of CMC or a pharma- ceutically acceptable salt thereof to arginine HCl is about 1:5 (w / w) to about 1:10 (w / w). Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0134] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, CMC or a pharma- ceutically acceptable salt thereof; and Contains Arginine HCl, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. the aqueous composition or reconstituted aqueous composition comprises from about 0.05 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of rHuPH20 to about 0.25 mg of CMC or a pharma- ceutically acceptable salt thereof per 100 U of rHuPH20; The ratio of rilpivirine to arginine HCl is from about 1:1 (w / w) to about 20:1 (w / w). The ratio of CMC or a pharma- ceutically acceptable salt thereof to arginine HCl is about 1:5 (w / w) to about 1:10 (w / w). Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0135] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, Sodium CMC, and Contains Arginine HCl, The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. The ratio of rilpivirine to arginine HCl is from about 1:1 (w / w) to about 20:1 (w / w). Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0136] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Hyaluronidase and Rilpivirine or a pharma- ceutically acceptable salt thereof, and Contains two cryoprotectants, The pH of the aqueous composition or reconstituted aqueous composition is about 6 to about 7. Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from a surfactant, such as a poloxamer, a buffer, such as sodium dihydrogen phosphate, a chelating agent, such as citric acid, and a pH adjuster, such as sodium hydroxide; and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0137] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, and Contains a sugar or sugar alcohol and an amino acid or a pharma- ceutically acceptable salt thereof; The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0138] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, and Contains a sugar or sugar alcohol and an amino acid or a pharma- ceutically acceptable salt thereof; The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. the ratio of rilpivirine to sugar or sugar alcohol and amino acid or pharma- ceutically acceptable salt thereof is about 2:1 (w / w) to about 7:1 (w / w); Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0139] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine, and Contains a sugar or sugar alcohol and an amino acid or a pharma- ceutically acceptable salt thereof; The pH of the aqueous composition or reconstituted aqueous composition is from about 6 to about 6.5. the ratio of rilpivirine to sugar or sugar alcohol and amino acid or a pharma- ceutically acceptable salt thereof is about 1:1 (w / w) to about 20:1 (w / w); Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more ingredients selected from poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide, and further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0140] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Sodium CMC, Sucrose, and Contains poloxamer 338, Optionally, when the Dv90 of rilpivirine is less than about 1600 nm, the ratio of rilpivirine to poloxamer 338 is about 3:1 (w / w) to about 15:1 (w / w), for example, about 6:1 (w / w).

[0141] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Sodium CMC, Sucrose, and Contains poloxamer 338, Optionally, when rilpivirine has a Dv90 of about 1 μm to about 10 μm, the ratio of rilpivirine to poloxamer 338 is about 3:1 (w / w) to about 15:1 (w / w), for example, about 6:1 (w / w).

[0142] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 1800U / mL to approximately 2200U / mL of rHuPH20, about 250 to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; About 1 mg / mL to about 5 mg / mL of CMC sodium; About 75 mg / mL to about 125 mg / mL of sucrose, and Contains about 5 mg / mL to about 60 mg / mL of poloxamer 338, Optionally, when the Dv90 of rilpivirine is less than about 1600 nm, the ratio of rilpivirine to poloxamer 338 is about 3:1 (w / w) to about 15:1 (w / w), for example, about 6:1 (w / w).

[0143] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 1800U / mL to approximately 2200U / mL of rHuPH20, about 250 to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; About 1 mg / mL to about 5 mg / mL of CMC sodium; About 75 mg / mL to about 125 mg / mL of sucrose, and Contains about 5 mg / mL to about 60 mg / mL of poloxamer 338, Optionally, when rilpivirine has a Dv90 of about 1 μm to about 10 μm, the ratio of rilpivirine to poloxamer 338 is about 3:1 (w / w) to about 15:1 (w / w), for example, about 6:1 (w / w).

[0144] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; About 100 mg / mL sucrose, and Contains approximately 50 mg / mL poloxamer 338.

[0145] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; About 100 mg / mL sucrose, and and about 50 mg / mL of poloxamer 338; The particles have a Dv90 of about 1 nm to about 10 μm.

[0146] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; About 100 mg / mL sucrose, and and about 50 mg / mL of poloxamer 338; The particles have a Dv90 of less than about 1600 nm.

[0147] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 1800U / mL to approximately 2200U / mL of rHuPH20, about 250 to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; About 1 mg / mL to about 5 mg / mL of CMC sodium; About 75 mg / mL to about 125 mg / mL of sucrose, and and about 5 mg / mL to about 15 mg / mL of poloxamer 338, The particles have a Dv90 of about 1 nm to about 10 μm.

[0148] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; About 100 mg / mL sucrose, and and about 10 mg / mL of poloxamer 338; The particles have a Dv90 of about 1 nm to about 10 μm.

[0149] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; Approximately 100 mg / mL sucrose; Poloxamer 338 at approximately 10 mg / mL; Approximately 2 mg / mL NaH2PO4·H2O, Approximately 1 mg / mL citric acid·H2O, Sodium hydroxide (enough for pH 6), and Contains water (1mL) The particles have a Dv90 of about 1 nm to about 10 μm.

[0150] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; Approximately 100 mg / mL sucrose; Poloxamer 338 at approximately 50 mg / mL; Approximately 2 mg / mL NaH2PO4·H2O, Approximately 1 mg / mL citric acid·H2O, Sodium hydroxide (enough for pH 6), and Contains water (approximate amount: 1 mL).

[0151] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Sodium CMC, Arginine HCl, and Poloxamer 338, Optionally, when the Dv90 of rilpivirine is less than about 1600 nm, the ratio of rilpivirine to poloxamer 338 is about 3:1 (w / w) to about 15:1 (w / w), for example, about 6:1 (w / w).

[0152] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is rHuPH20 and Rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Sodium CMC, Arginine HCl, and Poloxamer 338, Optionally, when rilpivirine has a Dv90 of about 1 μm to about 10 μm, the ratio of rilpivirine to poloxamer 338 is about 3:1 (w / w) to about 15:1 (w / w), for example, about 6:1 (w / w).

[0153] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 1800U / mL to approximately 2200U / mL of rHuPH20, about 250 to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; About 1 mg / mL to about 5 mg / mL of CMC sodium; about 25 mg / mL to about 35 mg / mL arginine HCl; and and about 5 mg / mL to about 60 mg / mL of poloxamer 338, Optionally, when the Dv90 of rilpivirine is less than about 1600 nm, the ratio of rilpivirine to poloxamer 338 is about 3:1 (w / w) to about 15:1 (w / w), for example, about 6:1 (w / w).

[0154] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 1800U / mL to approximately 2200U / mL of rHuPH20, about 250 to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; About 1 mg / mL to about 5 mg / mL of CMC sodium; about 25 mg / mL to about 35 mg / mL arginine HCl; and and about 5 mg / mL to about 60 mg / mL of poloxamer 338, Optionally, when rilpivirine has a Dv90 of about 1 μm to about 10 μm, the ratio of rilpivirine to poloxamer 338 is about 3:1 (w / w) to about 15:1 (w / w), for example, about 6:1 (w / w).

[0155] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; Arginine HCl at about 30 mg / mL, and and approximately 50 mg / mL poloxamer 338.

[0156] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; Arginine HCl at about 30 mg / mL, and and about 50 mg / mL of poloxamer 338; The particles have a Dv90 of about 1 nm to about 10 μm.

[0157] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; Arginine HCl at about 30 mg / mL, and and about 50 mg / mL of poloxamer 338; The particles have a Dv90 of less than about 1600 nm.

[0158] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 1800U / mL to approximately 2200U / mL of rHuPH20, about 250 to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; About 1 mg / mL to about 5 mg / mL of CMC sodium; About 25 mg / mL to about 35 mg / mL of arginine HCl; and about 5 mg / mL to about 15 mg / mL of poloxamer 338, The particles have a Dv90 of about 1 nm to about 10 μm.

[0159] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; Arginine HCl at about 30 mg / mL, and and about 10 mg / mL of poloxamer 338; The particles have a Dv90 of about 1 nm to about 10 μm.

[0160] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; Arginine HCl at about 30 mg / mL; Poloxamer 338 at approximately 10 mg / mL; Approximately 2 mg / mL NaH2PO4·H2O, Approximately 1 mg / mL citric acid·H2O, Sodium hydroxide (enough for pH 6), and Contains water (1mL) The particles have a Dv90 of about 1 nm to about 10 μm.

[0161] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; Arginine HCl at about 30 mg / mL; Poloxamer 338 at approximately 50 mg / mL; Approximately 2 mg / mL NaH2PO4·H2O, Approximately 1 mg / mL citric acid·H2O, Sodium hydroxide (enough to achieve a pH of 6), and Contains water (approximate amount: 1 mL).

[0162] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 1800U / mL to approximately 2200U / mL of rHuPH20, about 250 to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; About 1 mg / mL to about 5 mg / mL of CMC sodium; about 25 mg / mL to about 35 mg / mL arginine HCl; and and about 20 mg / mL to about 75 mg / mL of poloxamer 338; Optionally, when the Dv90 of rilpivirine is less than about 1600 nm, the ratio of rilpivirine to poloxamer 338 is about 3:1 (w / w) to about 15:1 (w / w), for example, about 6:1 (w / w).

[0163] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 1800U / mL to approximately 2200U / mL of rHuPH20, about 250 to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; About 1 mg / mL to about 5 mg / mL of CMC sodium; about 25 mg / mL to about 35 mg / mL arginine HCl; and and about 20 mg / mL to about 75 mg / mL of poloxamer 338; Optionally, when rilpivirine has a Dv90 of about 1 μm to about 10 μm, the ratio of rilpivirine to poloxamer 338 is about 3:1 (w / w) to about 15:1 (w / w), for example, about 6:1 (w / w).

[0164] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; Arginine HCl at about 30 mg / mL, and Contains approximately 50 mg / mL poloxamer 338.

[0165] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; Arginine HCl at about 30 mg / mL, and and about 50 mg / mL of poloxamer 338; The particles have a Dv90 of about 1 nm to about 10 μm.

[0166] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; Arginine HCl at about 30 mg / mL, and and about 50 mg / mL of poloxamer 338; The particles have a Dv90 of less than about 1600 nm.

[0167] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 1800U / mL to approximately 2200U / mL of rHuPH20, about 250 to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; About 1 mg / mL to about 5 mg / mL of CMC sodium; About 75 mg / mL to about 125 mg / mL of sucrose, and and about 20 mg / mL to about 75 mg / mL of poloxamer 338; Optionally, when the Dv90 of rilpivirine is less than about 1600 nm, the ratio of rilpivirine to poloxamer 338 is about 3:1 (w / w) to about 15:1 (w / w), for example, about 6:1 (w / w).

[0168] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; About 100 mg / mL sucrose, and and approximately 50 mg / mL poloxamer 338.

[0169] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; About 100 mg / mL sucrose, and and about 50 mg / mL of poloxamer 338; The particles have a Dv90 of less than about 1600 nm.

[0170] In certain embodiments, the aqueous composition or the reconstituted aqueous composition is Approximately 2,000 U / mL of rHuPH20, about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition; Approximately 3 mg / mL of CMC sodium; About 100 mg / mL sucrose, and and about 50 mg / mL of poloxamer 338; The particles have a Dv90 of about 1 nm to about 10 μm.

[0171] The present invention also relates to lyophilized forms corresponding to the specific embodiments described above.

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

[0173] Unless otherwise specified, in any of the above specific embodiments, the particles may have a Dv90 of about 1 μm to about 10 μm (e.g., about 5 μm to about 6 μm). Alternatively, unless otherwise specified, in any of the above specific embodiments, the particles may have a Dv90 of about 500 nm to about 1600 nm (e.g., about 500 nm to about 700 nm).

[0174] The present invention also relates to a solid composition comprising rilpivirine or a pharma- ceutically acceptable salt thereof and hyaluronidase. The solid composition may optionally have the features (e.g., excipients, amounts and pH) and combinations of features described herein for the aqueous and solid compositions of the first aspect of the invention. Thus, purely by way of example, the present invention also relates to a solid composition comprising rilpivirine or a pharma- ceutically acceptable salt thereof, hyaluronidase and a cryoprotectant as defined in relation to the first aspect of the invention.

[0175] The present invention also relates to a solid composition obtained by freeze-drying an aqueous composition comprising rilpivirine or a pharma- ceutically acceptable salt thereof, optionally with the aqueous composition having the characteristics (e.g., excipients, amounts and pH) and combinations of characteristics described herein for the aqueous and solid compositions of the first aspect of the invention. The present invention also relates to a solid composition comprising rilpivirine or a pharma- ceutically acceptable salt thereof: the solid composition may optionally have the characteristics (e.g., excipients, amounts and pH) and combinations of characteristics described herein for the aqueous and solid compositions of the first aspect of the invention. In one embodiment, the solid composition does not comprise hyaluronidase. The present invention also relates to a solid composition having the characteristics of any of the specific embodiments described above, omitting only hyaluronidase. The present invention also relates to an aqueous composition or a reconstituted aqueous composition according to any of the specific embodiments described above, omitting only hyaluronidase.

[0176] Reconstitution of solid compositions The solid compositions of the invention can be reconstituted to provide a reconstituted aqueous composition. Thus, a second aspect of the invention relates to a reconstituted aqueous composition obtained by reconstituting a solid composition as defined herein.

[0177] For the avoidance of doubt, the reconstituted aqueous composition contains the same components in the same amounts as the aqueous composition in the first aspect of the invention, which is then freeze-dried to provide the solid composition of the first aspect of the invention. Thus, all of the embodiments described in the first aspect of the invention with respect to the aqueous composition apply equally to the reconstituted aqueous composition of the second aspect of the invention. The volume of the reconstituted aqueous composition is not necessarily the same as the volume of the aqueous composition in the first aspect of the invention, so the concentrations of the components in these compositions may differ from each other. For example, the aqueous composition in the first aspect of the invention may have a concentration of a component of 300 mg / mL, but when reconstituted in twice the volume after freeze-drying, the concentration of that component in the reconstituted aqueous composition is 150 mg / mL.

[0178] In one embodiment, reconstitution comprises adding an aqueous dispersion medium to a solid composition as defined herein, the aqueous dispersion medium being preferably water.

[0179] In one embodiment, the dispersion medium includes one or more other active pharmaceutical agents, particularly one or more other antiretroviral agents, particularly one or more other antiretroviral agents of another class, e.g., an antiretroviral agent of the INSTI class, such as cabotegravir.

[0180] In another embodiment, the aqueous dispersion medium is an aqueous solution of CMC or a pharma- ceutically acceptable salt thereof. In another embodiment, the aqueous dispersion medium is an aqueous solution of CMC sodium.

[0181] Freeze drying The aqueous compositions described herein can be converted to solid compositions of the invention by lyophilizing the aqueous compositions using standard procedures known in the art. An exemplary procedure is provided below.

[0182] Vials are filled with the aqueous composition. Freeze drying is performed in a laboratory scale freeze dryer (LyoStar3, SP Scientific, USA). Freezing is performed at -40°C (shelf inlet temperature) for 60 minutes, including equilibration steps at +5°C and then -5°C for 15 minutes each. An annealing step is performed at -20°C (shelf inlet temperature) for 90 minutes. The shelf temperature ramp rate from the freezing set point to the primary drying shelf temperature set is 1°C / min throughout the process. The shelf inlet temperature set point during primary drying is about -20°C, and during secondary drying is about 25°C. The hold times (soak periods) for these steps are 600 minutes and 60 minutes, respectively, to allow for adjustment of the moisture content in the sample. The chamber pressure during primary and secondary drying is about 100 mTorr for the primary drying step and about 300 mTorr for the secondary drying step. The product temperature during freeze drying is measured using a wired thermocouple. Each thermocouple wire is placed at the bottom center of a vial to obtain both a representative temperature monitoring of the product and accurate end point detection of the ice sublimation phase.

[0183] Use of the composition of the present invention The reconstituted aqueous composition can be used to treat or prevent HIV infection in a subject.

[0184] Thus, in a third aspect, the present invention relates to a method for the treatment or prevention of HIV infection in a subject, comprising administering to the subject a reconstituted aqueous composition as defined herein. In a fourth aspect, the present invention relates to a reconstituted aqueous composition as defined herein for use in the treatment or prevention of HIV infection in a subject. In a fifth aspect, the present invention relates to the use of a reconstituted aqueous composition as defined herein for the manufacture of a medicament for the treatment or prevention of HIV infection in a subject. In a sixth aspect, a solid composition as defined herein for use in the treatment or prevention of HIV infection in a subject is provided. In a seventh aspect, the present invention relates to the use of a solid composition as defined herein for the manufacture of a medicament for the treatment or prevention of HIV infection in a subject.

[0185] In a preferred embodiment, the subject is a human.

[0186] In one embodiment, the reconstituted aqueous composition is administered such that the time interval between doses (i.e., the administration interval) is from about 3 months to about 2 years. In one embodiment, the time interval is from about 3 months to about 1.5 years. In one embodiment, the time interval is from about 3 months to about 1 year. In one embodiment, the time interval is from about 3 months to about 6 months. In one embodiment, the time interval is from about 6 months to about 1 year. In one embodiment, the time interval is about 1 year; in one embodiment, the time interval is about 3 months. In one embodiment, the time interval is about 6 months.

[0187] In one embodiment, the reconstituted aqueous composition is administered intermittently to a subject such that the time interval between administrations (i.e., the administration interval) is about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, or about 1 year to about 2 years.

[0188] In one embodiment, the reconstituted aqueous composition is administered by subcutaneous or intramuscular injection. In one embodiment, the reconstituted aqueous composition is administered by intramuscular injection. In a preferred embodiment, the reconstituted aqueous composition is administered by subcutaneous injection.

[0189] In another embodiment, the reconstituted aqueous composition is administered by a manual injection process.

[0190] Rilpivirine or a pharma- ceutically acceptable salt thereof is present in the reconstituted 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.

[0191] In one embodiment, each dose contains up to about 150 mL of the reconstituted aqueous composition described herein. In another embodiment, each dose contains about 3 mL to about 150 mL of the reconstituted aqueous composition. In another embodiment, each dose contains about 3 mL to about 100 mL of the reconstituted aqueous composition. In another embodiment, each dose contains about 3 mL to about 25 mL of the reconstituted aqueous composition. In another embodiment, each dose contains about 3 mL to about 15 mL of the reconstituted aqueous composition. In another embodiment, each dose contains about 5 mL to about 25 mL of the reconstituted aqueous composition. In another embodiment, each dose contains about 6 mL to about 20 mL of the reconstituted aqueous composition. In another embodiment, each dose contains about 6 mL to about 18 mL of the reconstituted aqueous composition. In another embodiment, each dose contains about 6 mL to about 15 mL of the reconstituted aqueous composition. In another embodiment, each dose contains about 6 mL to about 12 mL of the reconstituted aqueous composition. In another embodiment, each dose contains about 9 mL to about 18 mL of the reconstituted aqueous composition. In another embodiment, each dose comprises about 9 mL to about 15 mL of the reconstituted aqueous composition. In another embodiment, each dose comprises about 9 mL to about 12 mL of the reconstituted aqueous composition. In another embodiment, each dose comprises about 3 mL of the reconstituted aqueous composition. In another embodiment, each dose comprises about 4 mL of the reconstituted aqueous composition. In another embodiment, each dose comprises about 5 mL of the reconstituted aqueous composition. In another embodiment, each dose comprises about 6 mL of the reconstituted aqueous composition. In another embodiment, each dose comprises about 7 mL of the reconstituted aqueous composition. In another embodiment, each dose comprises about 8 mL of the reconstituted aqueous composition. In another embodiment, each dose comprises about 9 mL of the reconstituted aqueous composition. In another embodiment, each dose comprises about 12 mL of the reconstituted aqueous composition. In another embodiment, each dose comprises about 15 mL of the reconstituted aqueous composition. In another embodiment, each dose comprises about 18 mL of the reconstituted aqueous composition. In a preferred embodiment, each dose comprises about 3 mL, about 7 mL, or about 15 mL of the reconstituted aqueous composition.

[0192] In one embodiment, for the treatment of HIV infection, the dose of rilpivirine administered can be calculated based on about 300 mg to about 1200 mg / month, or about 450 mg to about 1200 mg / month, or about 450 mg to about 900 mg / month, or about 600 mg to about 900 mg / month, or about 450 mg to about 750 mg / month, or 450 mg / month, or 600 mg / month, or 750 mg / month, or 900 mg / month. Doses for other dosing regimens can be easily calculated by multiplying the monthly dose by the number of months between each administration. For example, for a dose of 450 mg / month and a time interval of 6 months between each administration, the dose of rilpivirine administered in each administration is 2700 mg. The "mg" indicated corresponds to mg of rilpivirine (i.e., rilpivirine in its free base form). Thus, by way of example, 1 mg of rilpivirine (ie, rilpivirine in its free base form) is equivalent to 1.1 mg of rilpivirine hydrochloride.

[0193] In one embodiment, for the treatment of HIV infection, the dose of rilpivirine administered at time intervals can be calculated based on about 300 mg to about 1200 mg / 4 weeks (28 days), or about 450 mg to about 1200 mg / 4 weeks (28 days), or about 450 mg to about 900 mg / 4 weeks (28 days), or about 600 mg to about 900 mg / 4 weeks (28 days), or about 450 mg to about 750 mg / 4 weeks (28 days) or 450 mg / 4 weeks (28 days), or 600 mg / 4 weeks (28 days), or 750 mg / 4 weeks (28 days) or 900 mg / 4 weeks (28 days). Doses for other dosing regimens can be easily calculated by multiplying the weekly or daily dose by the number of weeks between each administration. For example, in the case of a dose of 450 mg / 4 weeks (28 days), and when the time interval between each administration is 24 weeks, the dose of rilpivirine administered in each administration is 2700 mg. Alternatively, for example, in the case of a dose of 750 mg / 4 weeks (28 days), and when the time interval between each administration is 24 weeks, the dose of rilpivirine administered in each administration is 4500 mg. The "mg" shown corresponds to mg of rilpivirine (i.e., rilpivirine in its free base form). Thus, for example, 1 mg of rilpivirine (i.e., rilpivirine in its free base form) is equivalent to 1.1 mg of rilpivirine hydrochloride.

[0194] In one embodiment, the rilpivirine or pharma- ceutically acceptable salt thereof in the reconstituted aqueous composition is used in an amount such that the plasma concentration of rilpivirine in the subject is maintained at a level of greater than about 12 ng / ml, preferably in the range of about 12 ng / ml to about 100 ng / ml, more preferably about 12 ng / ml to about 50 ng / ml, for at least 3 months after administration, or at least 6 months after administration, or at least 9 months after administration, or at least 1 year after administration, or at least 2 years after each administration. In a preferred embodiment, the rilpivirine or pharma-ceutically acceptable salt thereof in the reconstituted aqueous composition is used in an amount such that the plasma concentration of rilpivirine in the subject is maintained at a level of about 12 ng / ml to 100 ng / ml for at least 6 months.

[0195] In the case of prevention of HIV infection, each administration of rilpivirine or a pharma- ceutically acceptable salt thereof may contain the same dose as for therapeutic applications as described above.

[0196] In one embodiment, the reconstituted aqueous composition is used in combination with one or more other active pharmaceutical agents, particularly one or more other antiretroviral agents, particularly one or more other antiretroviral agents of another class, for example an antiretroviral agent of the INSTI class, such as cabotegravir.

[0197] In one embodiment, the one or more other antiretroviral agents, e.g., cabotegravir, are administered as an intramuscular or subcutaneous injection, particularly as an injectable micro- or nanosuspension, at a time interval of about 3 months to about 2 years. In one embodiment, the one or more other antiretroviral agents, e.g., cabotegravir, are administered at the same intermittent time intervals as the reconstituted aqueous composition described herein, e.g., the reconstituted aqueous composition and the other antiretroviral agents are administered intermittently at a time interval of about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 10 months, about 11 months, about 1 year, or about 1 year to about 2 years. In one embodiment, the reconstituted aqueous composition and the one or more other antiretroviral agents, e.g., cabotegravir, are administered simultaneously or sequentially by intramuscular or subcutaneous injection, particularly subcutaneous injection. In one embodiment, the reconstituted aqueous composition and the one or more other antiretroviral agents, e.g., cabotegravir, are administered simultaneously, particularly by subcutaneous injection. In one embodiment, the reconstituted aqueous composition and one or more other antiretroviral agents, such as cabotegravir, are administered sequentially, particularly by subcutaneous injection, hi one embodiment, the reconstituted aqueous composition is administered first, followed by the cabotegravir injection.

[0198] As used herein, the term "treatment of HIV infection" refers to the treatment of subjects infected with HIV. The term "treatment of HIV infection" also refers to the treatment of diseases associated with HIV infection (e.g., AIDS) or other symptoms associated with HIV infection (including thrombocytopenia, Kaposi's sarcoma, and infection of the central nervous system characterized by progressive demyelination resulting in dementia and symptoms (e.g., progressive dysarthria, ataxia, and disorientation)), as well as further symptoms with which HIV infection is also associated (e.g., peripheral neuropathy, progressive generalized lymphadenopathy GL, and AIDS-related syndrome (RC)).

[0199] As used herein, the term "prevention of HIV infection" refers to preventing or avoiding a subject (not infected with HIV) from becoming infected with HIV. The source of infection can be various HIV-containing materials, particularly HIV-containing body fluids, such as blood or semen, or another subject infected with HIV. Prevention of HIV infection refers to preventing the transmission of the virus from HIV-containing materials or HIV-infected individuals to uninfected individuals, or to preventing the virus from entering the body of an uninfected individual. Transmission of the HIV virus can be by any of the known causes of HIV transfer, such as by sexual transmission or by contact with the blood of an infected subject (e.g., medical staff providing care to an infected subject). Transfer of HIV can also occur by contact with HIV-infected blood, for example, when handling blood samples or using blood transfusions. It can also be by contact with infected cells, for example, when performing laboratory experiments with HIV-infected cells.

[0200] The term "treatment of HIV infection" refers to a treatment in which the HIV viral load (expressed as the number of copies of viral RNA in a specific volume of serum) is reduced. The more effective the treatment, the lower the viral load. Preferably, the viral load should be reduced to the lowest possible level, for example below about 200 copies / mL, in particular below about 100 copies / mL, more in particular below 50 copies / mL, and if possible below the detection limit of the virus. A reduction in viral load of one, two or even three orders of magnitude (for example, from about 10 to about 10 2 , or more, for example, about 10 3 A decrease in the CD4 count (of the order of magnitude of a decrease in the CD4 count) is an indication of the effectiveness of the treatment. Another parameter for measuring the effectiveness of HIV treatment is the CD4 count, which ranges from 500 to 1500 cells per μL in healthy adults. A decrease in the CD4 count is an indication of HIV infection, and when it falls below about 200 cells / μL, AIDS may develop. An increase in the CD4 count (e.g., about 50, 100, 200, or more cells per μL) is also an indication of the effectiveness of anti-HIV treatment. In particular, the CD4 count should increase to a level of more than about 200 cells per μL, or to a level of more than about 350 cells per μL. The viral load or the CD4 count, or both, can be used to diagnose the extent of HIV infection. Another parameter for measuring the effectiveness of HIV treatment is the maintenance of an HIV-infected subject in a virologically suppressed state (HIV-1 RNA<50 copies / mL) when undergoing treatment according to the invention.

[0201] The term "treatment of HIV infection" and similar terms refer to that treatment that reduces viral load, increases CD4 count, or both, or keeps HIV-infected subjects in a virologically suppressed state, as described above. The term "prevention of HIV infection" and similar terms refer to a situation in which there is a reduction in the relative number of newly infected subjects in a population that is in contact with a source of HIV infection (e.g., a material containing HIV) or an HIV-infected subject. Effective prevention can be measured, for example, by measuring in a mixed population of HIV-infected and uninfected individuals, when there is a reduction in the relative number of newly infected individuals when comparing uninfected individuals treated with the aqueous composition of the present invention with uninfected individuals that are not treated. This reduction can be measured by statistical analysis of the number of infected and uninfected individuals in a given population over time.

[0202] kit In an eighth aspect, there is provided a kit comprising (i) a solid composition of the invention as described herein, and (ii) a diluent, particularly a diluent for reconstituting solid composition (i).

[0203] In a ninth aspect, there is provided a kit comprising (i) a solid composition of the invention as described herein; (ii) 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 an antiretroviral agent of the INSTI class, such as cabotegravir, and optionally (iii) a diluent, in particular a diluent for reconstituting the solid composition (i).

[0204] general definition The term "comprising" encompasses "including" as well as "consisting," e.g., a composition "comprising" X may consist only of X, or may include something additional, e.g., X+Y. As used herein, the term "comprising" also encompasses "consisting essentially of," e.g., a composition "comprising" X may consist of X plus any other components that do not substantially affect the essential characteristics of the composition.

[0205] The term "about" in reference to a numerical value Y is optional and means, for example, Y±10%.

[0206] When a time interval is expressed as a specified number of months, the time interval extends from a given numbered day in a given month to the same numbered day in the month that falls the specified number of months later. If the same numbered day does not exist in the month that falls the specified number of months later, the time interval extends the same number of days into the next month, if the same numbered day does exist in the month that falls the specified number of months later.

[0207] When a time interval is expressed as a number of years, the time interval lasts from a given date in a given year to the same date in the year that falls the specified number of years later. If the same date does not exist in the year that falls the specified number of years later, the time interval lasts for the same number of days, if there is an identically numbered day in the month that falls the specified number of months later. In other words, if the time interval begins on February 29th of a given year but ends in a year that does not have February 29th, the period ends on March 1st of that year.

[0208] The term "about" in connection with such a definition means that the time interval may end on a date that is ±10% of the time interval.

[0209] 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.

[0210] All publications cited herein are incorporated by reference in their entirety.

[0211] The present invention will now be described with reference to the following examples. For the avoidance of doubt, these examples are not intended to limit the scope of the present invention. Modifications may be made within the scope and spirit of the present invention. EXAMPLES

[0212] Example 1 - Melting temperature test under different storage conditions This example shows the T of rHuPH20 in various compositions, each having a different combination of excipients and / or pH, under different storage conditions. m Compare.

[0213] Higher T m To provide optimal thermodynamic stability of hyaluronidase, the T is set to about 25 to about 30° C. higher than the intended long-term storage conditions. m The goal is to

[0214] Compositions 1-21 were prepared by adding the ingredients shown in Table 1 below to the following compositions. Glucose monohydrate (19.25 mg), rHuPH20 (2000U / mL) Sodium dihydrogen phosphate monohydrate (2mg / ml) Citric acid monohydrate (1 mg), Poloxamer 338 (50 mg), · Sodium hydroxide (varied to provide target pH). ·Water for injection (appropriate amount 1mL)

[0215] By varying the amount of sodium hydroxide, the pH of the composition was adjusted to 5.0, 6.0, 6.5, or 7.0 as needed.

[0216] [Table 2]

[0217] In this embodiment, T m Values ​​were measured using a nano-differential scanning fluorimetry (nDSF) assay, which uses intrinsic tryptophan and tyrosine fluorescence to monitor protein unfolding. The nDSF assay was performed as follows.

[0218] All nDSF assays were performed using a Prometheus NT.Plex instrument controlled by PR.ThermControl-CFR software. A temperature range of 20-95°C with a temperature gradient of 1°C / min was used when measuring samples. In all cases, 95% excitation power was used. The instrument determined the fluorescence ratio at 350 nm (tryptophan) and 330 nm (tyrosine) of the protein during a heating ramp to 95°C. The unfolding onset temperature (T on ) and the inflection point of this unfolding transition (T m ) was calculated from the unfolding curve.

[0219] To enable high-throughput sample testing, the nanoDSF instrument was operated in conjunction with a robotic autosampler. The autosampler performs the loading and transfer of capillary tips from 384-well plates for nanoDSF measurements. Preparation of the 384-well plates was automated using a Tecan Fluent 760 liquid handling system in conjunction with a custom-made sample holder for the 2R vials typically provided for sample testing.

[0220] Compositions 1-21 were prepared as described above and then stored in a refrigerator at 5° C. for 2 days to 2 weeks. Then, after storage at 25° C. for 1 week, after storage at 25° C. for 2 weeks, and after storage under extreme storage conditions, i.e., storage at 40° C. for 1 week, after storage at 40° C. for 2 weeks, T m was measured immediately. m Immediately prior to measuring the values, the pH of the aqueous composition was remeasured.

[0221] The results are shown in Figures 1, 1A, 1B, and 1C.

[0222] Example 2a - Melting Temperature Test This example shows the T of rHuPH20 in various compositions, each having a different combination of excipients and / or pH. m Compare.

[0223] Composition B was prepared containing the following excipients: Sodium dihydrogen phosphate monohydrate (2mg / ml) Citric acid monohydrate (1 mg), rHuPH20 (2000U / mL) · Sodium hydroxide (varied to provide target pH). ·Water for injection (appropriate amount 1mL)

[0224] Compositions 22 to 44 were prepared by adding the components shown in Table 2 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.

[0225] [Table 3]

[0226] Compositions 22-44 were prepared as above and then stored in a refrigerator at 5°C for 2 days to 2 weeks. m was immediately measured for each composition using the method described in Example 1.

[0227] The results are shown in Table 2 and FIG.

[0228] Example 2b - Enzyme stability test under different storage conditions This example compares the fluorescence emission spectra of rHuPH20 compositions after storage under different conditions. Fluorescence emission spectroscopy uses light that is absorbed by an enzyme (rHuPH20) and a ground state fluorophore is excited to a higher energy state, thereby resulting in light emission. For an enzyme such as rHuPH20, tryptophan fluorescence can be used to measure changes in tertiary enzyme structure during or after storage under different conditions, thus quantifying the thermal stability of rHuPH20. The maximum emission wavelengths for folded and unfolded rHuPH20 are 330 nm and 350 nm, respectively.

[0229] Spectra of the compositions were collected immediately after storage at 5° C. and after 1 and 2 weeks of storage at 40° C. The peak maxima and minima as well as the intensity ratio 350 / 330 nm were calculated for each time point and plotted as a function of storage time. The slope of the curves was used to perform semi-quantitative thermal stability assessment and comparison between compositions.

[0230] Preparation of the Composition 200 μl of each composition was manually dispensed into a UV-STAR®, COC, 96-well flat-bottom microplate.

[0231] Fluorescence emission spectra of the samples were measured before and after stress via a Tecan plate reader (Infinite 200). The following method parameters were used:

[0232] temperature: Parameter (on), Temperature = 25.0℃

[0233] Wait for temperature: Parameter Min=24.5℃; Max=25.5℃

[0234] Fluorescence Intensity Scanning: Scanning selection (light emission scanning) Mode (top) Excitation wavelength: origin = 280 nm; Bandwidth: 230...315: 5 nm; 316...850: 9 nm Emission wavelength: start = 310nm; end = 420nm; scale = 1nm; bandwidth: 280...850: 20nm; 111 measured values Integration: Delay time = 0μs; Integration time = 20μs Read: Flash count = 25; Settling time = 0 ms Gain (Manual = 95) ·Label:name=Label1

[0235] The results are shown in Table 3 below.

[0236] [Table 4]

[0237] Example 3 - Melting temperature test under different storage conditions This example compares the melting temperatures of rHuPH20 in various compositions under different storage conditions.

[0238] Composition C was prepared containing the following excipients: rHuPH20 (2000U / mL) Sodium dihydrogen phosphate monohydrate (2mg / ml) Citric acid monohydrate (1 mg) Poloxamer 338 (50 mg) Sodium hydroxide (enough to achieve a pH of 6.0) ·Water for injection (appropriate amount 1mL)

[0239] Next, compositions 45 to 57 were prepared by adding the components shown in Table 4, and the pH was adjusted to 6.0 by varying the amount of sodium hydroxide in the composition.

[0240] [Table 5]

[0241] Compositions 45-57 were prepared as above and then stored in a refrigerator at 5° C. for 2 days to 2 weeks. mValues ​​were measured immediately (ie, "t=0") and after storage at 40° C. for 1 week using the methods described in Example 1.

[0242] T m Immediately prior to measuring the value, the pH of the composition was remeasured.

[0243] The results are shown in Table 4 and Figures 3 and 3A, where rHuPH20 was degraded when the Tm value at 40°C for t = 1 week was not shown (i.e., when Tm and its SD are "-").

[0244] Example 4 - CMC sodium concentration In this example, the T m Check the dependency of.

[0245] Composition D was prepared containing the following excipients: rHuPH20 (2000U / mL) Sodium dihydrogen phosphate monohydrate (2mg / ml) Citric acid monohydrate (1 mg), Poloxamer 338 (50 mg), · Sodium hydroxide (adequate amount for pH 6.0). Mannitol (50mg / mL) or sucrose (100mg / mL) ·Water for injection (appropriate amount 1mL)

[0246] Next, compositions 58 to 63 were prepared by adding sodium CMC shown in Table 5 below to composition D, and the amount of sodium hydroxide in the composition was changed to adjust the pH to 6.0.

[0247] [Table 6]

[0248] Compositions 58-63 were prepared as above and then stored in a refrigerator at 5° C. for 2 days to 2 weeks. m The values ​​were measured.

[0249] The results are shown in Figure 4.

[0250] Example 5 - Rilpivirine particle size under different storage conditions This example investigates the effect that lyophilization of an aqueous composition containing rilpivirine particles in suspension has on the particle size of rilpivirine in the corresponding reconstituted aqueous composition. The lyophilized compositions were reconstituted immediately, i.e., at time t=0, after one month of storage, and after six months of storage under various conditions.

[0251] An aqueous composition of rilpivirine nanoparticles (Dv10 about 96.5 nm, Dv50 about 224 nm, Dv90 about 509 nm) was prepared containing the following excipients: Rilpivirine (300 mg / mL) rHuPH20 (2000U / mL) Sodium dihydrogen phosphate monohydrate (2mg / ml) Citric acid monohydrate (1 mg), Poloxamer 338 (50 mg), Sodium hydroxide (enough to achieve a pH of 6) ·Water for injection (appropriate amount 1mL)

[0252] The additional ingredients shown in Table 6 were added and the pH was adjusted to 6.0 with sodium hydroxide.

[0253] [Table 7]

[0254] The compositions were lyophilized and reconstituted with water to provide 9 mL of reconstituted aqueous composition at time t=0, lyophilized and reconstituted with water to provide 9 mL of reconstituted aqueous composition after 1 month storage under 25° C. / 60% RH and 40° C. / 75% RH conditions, and lyophilized and reconstituted with water to provide 9 mL of reconstituted aqueous composition after 6 months storage under 25° C. / 60% RH conditions. In both cases, rilpivirine particle size was measured according to the following method.

[0255] Volumetric particle size distribution of the rilpivirine suspension was determined by wet dispersion laser diffraction using a Malvern Mastersizer3000 laser diffraction (Malvern Instruments) and a HydroMV wet dispersion module.

[0256] The results are shown in Figure 5.

[0257] At time t=0, ie, after lyophilization and immediate reconstitution, particle size was conserved in all compositions.

[0258] Example 6 - Lyophilization and enzyme stability testing under different storage conditions This example investigates the effect that lyophilization of aqueous compositions containing rHuPH20 and rilpivirine has on enzyme stability in the corresponding reconstituted aqueous compositions. The lyophilized compositions were reconstituted immediately, i.e., at time t=0, after 1 month of storage, and after 6 months of storage under various conditions.

[0259] Aqueous compositions 64 to 70 were prepared as described in Example 5. These compositions were lyophilized, reconstituted with water, and stored under conditions of 25°C / 60% RH for 1 month and 6 months, after which 9 mL of reconstituted aqueous composition was obtained.

[0260] Enzyme stability was assessed by one or more of the following: (i) activity (bioassay); (ii) quantification / aggregation (size exclusion chromatography / SEC); (iii) purity (reversed phase liquid chromatography / RP-LC).

[0261] SEC: A size-exclusion chromatography separation technique that uses a column to distribute molecules in a flowing solution according to their broad size range. Monomers, aggregates and fragments elute from the column at different times, so that their relative proportions in a sample can be quantified using a standard UV detector.

[0262] The results are shown in Table 8.

[0263] [Table 8] * Ox1 and Ox2 are oxidized forms of rHuPH20. Ox1 retains higher enzymatic activity than Ox2. Ox1 and Ox2 are less active than rHuPH20.

[0264] The appearance of all compositions was acceptable. All lyophilized compositions had relatively low water content (<1% as measured by Karl Fischer). IR analysis confirmed that the samples were homogeneous. Identical IR spectra were obtained for samples from the top, middle, and bottom of vials of lyophilized compositions 64-70.

[0265] Example 7 - Freeze-drying and collapse temperature testing under different storage conditions This example shows that a lyophilized aqueous composition containing rHuPH20 and rilpivirine has a collapse temperature (T c ) to investigate the effect it has on

[0266] Aqueous compositions 64-70 were prepared as described in Example 5 above. The compositions were then freeze-dried. The collapse temperatures were measured.

[0267] The results are shown in Table 9.

[0268] [Table 9] "-" means not tested.

[0269] Example 8 - Lyophilization, enzyme stability, and rilpivirine particle size studies under different storage conditions. This example investigates the effect that lyophilized aqueous compositions containing rHuPH20 and rilpivirine have on collapse temperature, enzyme stability, viscosity, and injection force in the corresponding reconstituted aqueous compositions. The lyophilized compositions were stored under various conditions for 2 weeks, 1 month, and 3 months, and then reconstituted immediately, i.e., at time t=0.

[0270] Aqueous compositions of either (i) rilpivirine nanoparticles (having a Dv10 of about 75-200 nm, a Dv50 of about 200-500 nm, and a Dv90 of about 500-1600 nm, i.e., "nano") or (ii) rilpivirine microparticles (having a Dv10 of about 0.2-0.6 μm, a Dv50 of about 1.0-2.5 μm, and a Dv90 of about 4.0-6.5 μm, i.e., "micro") were prepared. Rilpivirine (300 mg / mL) rHuPH20 (2000U / mL) Sodium phosphate monohydrate (2mg / ml) Citric acid monohydrate (1 mg) Poloxamer 338 (see Table 10) Sodium hydroxide (enough to achieve a pH of 6.0) ·Water for injection (appropriate amount 1mL)

[0271] The additional ingredients shown in Table 10 were added and the pH was adjusted to 6.0 with sodium hydroxide.

[0272] [Table 10] T c A "-" in a column means that the test was not performed.

[0273] The compositions were lyophilized and the collapse temperatures were measured, and the results are shown in Table 10.

[0274] All lyophilized compositions had relatively low water content (<1% as measured by Karl Fischer). The appearance of all compositions was acceptable.

[0275] The composition was then reconstituted with water to yield 9 mL of reconstituted aqueous composition after storage under the following conditions: 2 weeks: 50℃ / 75%RH 1 month: 30℃ / 75%RH and 40℃ / 75%RH 3 months: 30℃ / 75%RH and 40℃ / 75%RH

[0276] Enzyme stability was assessed by one or more of the following: (i) activity (bioassay); (ii) quantification / aggregation (size exclusion chromatography / SEC) and (iii) purity (reversed phase liquid chromatography / RP-LC).

[0277] Rilpivirine particle size was measured as follows: Volumetric particle size distribution of rilpivirine suspensions was determined by wet dispersion laser diffraction using a Malvern Mastersizer3000 laser diffraction (Malvern Instruments) and a HydroMV wet dispersion module.

[0278] The viscosity of the compositions was measured using a HAAKE Mars 60 rheometer. 1.5 mL of the aqueous reconstituted composition was removed from the vial using a 2 mL syringe with an 18 G needle. The sample was dropped onto the plate (no air bubbles were present). Shear rate sweeps were performed from 0.1 to 1000 s-1 using a cone 60 / 1° and plate.

[0279] Injection forces were measured using a 20 mL Luer lock syringe with a 23G x 3 / 4 inch winged infusion set.

[0280] The results are shown in Figures 6, 7 and 8 (nb. Ox1 and Ox2 are oxidized forms of rHuPH20. Ox1 retains higher enzymatic activity than Ox2. Ox1 and Ox2 are less active than rHuPH20).

[0281] Example 9 - Enzyme stability test under different storage conditions This example compares the fluorescence emission spectra of rHuPH20 compositions after storage under different conditions.

[0282] Aqueous compositions 45-57 were prepared as described in Example 3 above. Spectra of the compositions were collected immediately after storage at 5° C. and after storage at 50° C. for 1 day. The peak maxima and minima as well as the intensity ratio 350 / 330 nm were calculated for each time point and plotted as a function of storage time. The slope of the curves was used to perform semi-quantitative thermal stability assessment and comparison between compositions.

[0283] Preparation of the Composition 200 μl of each composition was manually dispensed into a UV-STAR®, COC, 96-well flat-bottom microplate.

[0284] Fluorescence emission spectra of the samples were measured before and after stress via a Tecan plate reader (Infinite 200). The following method parameters were used:

[0285] temperature: Parameter (on), Temperature = 25.0℃

[0286] Wait for temperature: Parameter Min=24.5℃; Max=25.5℃

[0287] Fluorescence Intensity Scanning: Scanning selection (light emission scanning) Mode (top) Excitation wavelength: origin = 280 nm; Bandwidth: 230...315: 5 nm; 316...850: 9 nm Emission wavelength: start = 310nm; end = 420nm; scale = 1nm; bandwidth: 280...850: 20nm; 111 measured values Integration: Delay time = 0μs; Integration time = 20μs Read: Flash count = 25; Settling time = 0 ms Gain (Manual = 95) ·Label:name=Label1

[0288] The results are shown in Table 11 below.

[0289] [Table 11]

[0290] Example 10 - Melting temperature test under different storage conditions This example compares the melting temperatures of rHuPH20 in various compositions under different storage conditions.

[0291] Aqueous compositions of rilpivirine nanoparticles (having a Dv10 of 75-200 nm, a Dv50 of 200-500 nm, and a Dv90 of 500-1600 nm) were prepared containing the following excipients: rHuPH20 (2000U / mL) Sodium dihydrogen phosphate monohydrate (2mg / ml) Citric acid monohydrate (1 mg), Poloxamer 338 (50 mg), Sodium hydroxide (enough to achieve a pH of 6) ·Water for injection (appropriate amount 1mL)

[0292] Next, compositions 86 to 171 were prepared by adding the components shown in Table 12, and the pH was adjusted to 6.0 by varying the amount of sodium hydroxide in the composition.

[0293] [Table 12-1]

[0294] [Table 12-2]

[0295] [Table 12-3] N / A * = Note that for high CMC sodium concentrations (>17 mg / mL), the capillary tip of the nanoDSF instrument could not be loaded, likely due to high solution viscosity. N / A ** = Note that in these conditions the enzyme either denatured due to the applied temperature stress or could not be loaded until the capillaries became highly viscous.

[0296] Compositions 86-171 were prepared as above and then stored in a refrigerator at 5° C. for 2 days to 2 weeks. mValues ​​were measured immediately (ie, "t=0") and after storage at 40° C. for 1 week using the methods described in Example 1.

[0297] The results are shown in Table 12.

[0298] The following numbered clauses are also set forth herein: 1. A solid composition obtainable by lyophilizing an aqueous composition comprising rilpivirine or a pharma- ceutically acceptable salt thereof. 2. The solid composition described in clause 1, wherein the aqueous composition further comprises hyaluronidase. 3. The solid composition of clause 2, wherein the hyaluronidase is recombinant human hyaluronidase. 4. The solid composition of clause 3, wherein the recombinant human hyaluronidase is rHuPH20. 5. The solid composition of any one of clauses 2 to 4, wherein the aqueous composition comprises from about 1500 U / mL to about 2500 U / mL of hyaluronidase. 6. The solid composition of clause 5, wherein the aqueous composition comprises from about 1800 U / mL to about 2200 U / mL of hyaluronidase. 7. The solid composition of clause 6, wherein the aqueous composition comprises about 2000 U / mL of hyaluronidase. 8. A solid composition according to any one of clauses 1 to 7, wherein the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition. 9. The solid composition according to clause 8, wherein the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of microparticles or nanoparticles suspended in the aqueous composition. 10. The solid composition according to clause 8 or 9, wherein the particles have a Dv90 of from about 100 nm to about 10 μm. 11. The solid composition of clause 10, wherein the particles have a Dv90 of about 500 nm to about 6 nm, and optionally the particles have a Dv90 of about 500 nm to about 1,600 nm. 12. The solid composition according to clause 10, wherein the particles have a Dv90 of about 500 nm to about 700 nm. 13. A solid composition according to any one of clauses 8 to 12, wherein the particles have a Dv10 of from about 75 nm to about 200 nm. 14. A solid composition according to any one of clauses 8 to 13, wherein the particles have a Dv50 of from about 200 nm to about 500 nm. 15. A solid composition according to any one of clauses 8 to 10, wherein the particles have a Dv90 of from about 4 μm to about 6 μm. 16. The solid composition according to clause 15, wherein the particles have a Dv90 of about 5 μm to about 6 μm. 17. The solid composition of any one of clauses 8-10 or 15 or 16, wherein the particles have a Dv10 of about 300 nm to about 500 nm and / or the particles have a Dv50 of about 1.5 μm to about 2 μm. 18. The solid composition according to any one of clauses 1 to 17, wherein the aqueous composition comprises from about 200 mg / mL to about 400 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof. 19. The solid composition according to clause 18, wherein the aqueous composition comprises from about 250 mg / mL to about 350 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof. 20. The solid composition according to clause 19, wherein the aqueous composition comprises about 300 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof. 21. The solid composition according to any one of clauses 1 to 20, wherein the aqueous composition comprises rilpivirine, i.e. rilpivirine in free base form. 22. The solid composition of any one of clauses 1 to 21, wherein the aqueous composition further comprises carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 23. The solid composition according to clause 22, wherein the carboxymethylcellulose or a pharma- ceutically acceptable salt thereof is sodium carboxymethylcellulose. 24. A solid composition according to clause 22 or 23, wherein the carboxymethylcellulose or a pharma- ceutically acceptable salt thereof is not cross-linked. 25. The solid composition according to any one of clauses 22 to 24, wherein the carboxymethyl cellulose or a pharma- ceutically acceptable salt thereof has a degree of substitution (carboxymethyl to cellulose) of about 0.5 to about 1. 26. The solid composition according to any one of clauses 22 to 25, wherein the carboxymethylcellulose or the pharma- ceutically acceptable salt thereof has a molecular weight of about 90 kDa to about 750 kDa, and / or the carboxymethylcellulose or the pharma- ceutically acceptable salt thereof has a viscosity of about 30 MPa.s to about 50 MPa.s. 27. The solid composition according to clause 22 or 26, wherein the aqueous composition comprises from about 1 mg / mL to about 100 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 28. The solid composition according to clause 27, wherein the aqueous composition comprises from about 1 mg / mL to about 50 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 29. The solid composition according to clause 27, wherein the aqueous composition comprises from about 1 mg / mL to about 5 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 30. The solid composition according to clause 29, wherein the aqueous composition comprises about 3 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 31. The solid composition according to clause 27, wherein the aqueous composition comprises from about 10 mg / mL to about 25 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 32. The solid composition of clause 22 or 31, wherein the aqueous composition comprises from about 0.05 mg of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase to about 2.5 mg of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. 33. The solid composition of clause 32, wherein the aqueous composition comprises from about 0.5 mg of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase to about 2 mg of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. 34. The solid composition of clause 32, wherein the aqueous composition comprises from about 0.05 mg of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase to about 0.25 mg of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. 35. The solid composition of clause 34, wherein the aqueous composition comprises about 0.15 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. 36. A solid composition according to any one of clauses 1 to 35, wherein the aqueous composition further comprises a cryoprotectant. 37. A solid composition according to clause 36, wherein the cryoprotectant is a sugar, sugar alcohol or amino acid or a pharma- ceutically acceptable salt thereof. 38. A solid composition according to clause 37, wherein the cryoprotectant is a sugar or sugar alcohol. 39. A solid composition according to clause 38, wherein the sugar or sugar alcohol is selected from mannitol and sucrose. 40. A solid composition according to clause 38, wherein the sugar or sugar alcohol is sucrose. 41. A solid composition according to clause 37, wherein the cryoprotectant is an amino acid or a pharma- ceutically acceptable salt thereof. 42. The solid composition according to clause 41, wherein the amino acid or a pharma- ceutically acceptable salt thereof is selected from arginine, glycine, and histidine, and optionally, the amino acid or a pharma- ceutically acceptable salt thereof is selected from arginine and glycine. 43. A solid composition according to clause 42, wherein the amino acid or a pharma- ceutically acceptable salt thereof is arginine, such as arginine HCl. 44. A solid composition according to any one of clauses 36 to 43, wherein the cryoprotectant is at least 95% crystalline. 45. The solid composition of any one of clauses 36-45, wherein the aqueous composition comprises from about 1 mg / mL to about 200 mg / mL of cryoprotectant. 46. ​​The solid composition according to clause 44, wherein the aqueous composition comprises from about 1 to about 150 mg / mL of cryoprotectant. 47. A solid composition according to any one of clauses 37 to 39, wherein the aqueous composition comprises from about 25 mg / mL to about 125 mg / mL of sugar or sugar alcohol. 48. The solid composition according to clause 47, wherein the aqueous composition comprises from about 75 to about 125 mg / mL of sugar or sugar alcohol. 49. The solid composition according to clause 48, wherein the aqueous composition comprises about 100 mg / mL of sugar or sugar alcohol. 50. The solid composition according to clause 47, wherein the aqueous composition comprises from about 50 to about 100 mg / mL of sugar or sugar alcohol. 51. The solid composition according to any one of clauses 37 and 41 to 43, wherein the aqueous composition comprises from about 1 mg / mL to about 75 mg / mL of an amino acid or a pharma- ceutically acceptable salt thereof. 52. The solid composition according to clause 51, wherein the aqueous composition comprises from about 1 mg / mL to about 50 mg / mL of the amino acid or a pharma- ceutically acceptable salt thereof. 53. The solid composition according to clause 52, wherein the aqueous composition comprises from about 25 mg / mL to about 35 mg / mL of an amino acid or a pharma- ceutically acceptable salt thereof. 54. The solid composition according to clause 53, wherein the aqueous composition comprises about 30 mg / mL of an amino acid or a pharma- ceutically acceptable salt thereof. 55. A solid composition according to any one of clauses 36 to 54, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition is from about 1:1 (w / w) to about 20:1 (w / w). 56. The solid composition according to clause 55, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition is from about 2:1 (w / w) to about 10:1 (w / w). 57. The solid composition according to clause 56, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition is from about 3:1 (w / w) to about 10:1 (w / w). 58. The solid composition according to clause 56, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition is from about 2:1 (w / w) to about 7:1 (w / w). 59. The solid composition according to clause 58, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition is from about 3:1 (w / w) to about 6:1 (w / w). 60. A solid composition according to any one of clauses 36 to 59, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:1 (w / w) to about 1:100 (w / w), optionally from about 1:1 (w / w) to about 1:50 (w / w). 61. The solid composition according to clause 60, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:8 (w / w) to about 1:40 (w / w). 62. A solid composition according to any one of clauses 36 to 59, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:2 (w / w) to about 1:15 (w / w). 63. The solid composition according to clause 62, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:4 (w / w) to about 1:11 (w / w). 64. The solid composition according to clause 63, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:5 (w / w) to about 1:10 (w / w). 65. A solid composition according to any one of clauses 36 to 59, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:9 (w / w) to about 1:11 (w / w). 66. A solid composition according to any one of clauses 36 to 59, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:30 (w / w) to about 1:35 (w / w). 67. A solid composition according to any one of clauses 1 to 66, wherein the aqueous composition further comprises a poloxamer, for example poloxamer 338. 68. A solid composition according to clause 67 when dependent on clause 8, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is from about 3:1 (w / w) to about 15:1 (w / w), when rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. 69. The solid composition according to clause 68, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is from about 6:1 (w / w) to about 15:1 (w / w), when rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. 70. The solid composition according to clause 69, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 6:1, when rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. 71. The solid composition according to clause 67, wherein the relative amounts (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and poloxamer are less than about 12:1 (w / w). 72. The solid composition of any one of clauses 1-71, wherein the aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide. 73. The solid composition according to clause 72, wherein the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide. 74. The solid composition of any one of clauses 67 to 73, wherein the aqueous composition comprises from about 5 mg / mL to about 15 mg / mL of poloxamer. 75. The solid composition of any one of clauses 67 to 73, wherein the aqueous composition comprises from about 40 mg / mL to about 60 mg / mL of poloxamer. 76. A solid composition according to any one of clauses 1 to 75, wherein the aqueous composition further comprises an antioxidant, optionally the antioxidant being methionine. 77. The solid composition according to clause 76, wherein the aqueous composition comprises from about 1.0 mg / mL to about 2.0 mg / mL, for example about 1.5 mg / mL, of the antioxidant. 78. A solid composition according to any one of clauses 1 to 77, wherein the aqueous composition does not contain glucose. 79. A solid composition described in any one of clauses 1 to 78, wherein the aqueous composition has a pH of about 5 to about 7. 80. The solid composition of claim 79, wherein the aqueous composition has a pH in the range of about 6 to about 7. 81. The solid composition according to claim 80, wherein the aqueous composition has a pH in the range of about 6 to about 6.5. 82. The solid composition according to clause 81, wherein the aqueous composition has a pH of about 6. 83. A reconstituted aqueous composition obtained by reconstituting a solid composition as defined in any one of clauses 1 to 82. 84. The reconstituted aqueous composition of clause 83, wherein reconstitution comprises adding an aqueous dispersion medium to the solid composition. 85. The reconstituted aqueous composition according to clause 84, wherein the aqueous dispersion medium is water. 86. A method for the treatment or prevention of HIV infection in a subject, in particular for the treatment of HIV infection in a subject, comprising administering to the subject a reconstituted aqueous composition as defined in any one of clauses 83 to 85. 87. A reconstituted aqueous composition as defined in any one of clauses 83 to 85 for use in the treatment or prevention of HIV infection in a subject, in particular for the treatment of HIV infection in a subject. 88. Use of a reconstituted aqueous composition as defined in any one of clauses 83 to 85 for the manufacture of a medicinal product for treating or preventing HIV infection in a subject, in particular for treating HIV infection in a subject. 89. The method, reconstituted aqueous composition for use or use according to clause 86, 87 or 88, wherein the reconstituted aqueous composition is administered to the subject by intramuscular or subcutaneous injection. 90. The method, reconstituted aqueous composition for use or use according to clause 89, wherein the reconstituted aqueous composition is administered to the subject by intramuscular injection. 91. The method, reconstituted aqueous composition for use or use according to clause 89, wherein the reconstituted aqueous composition is administered to the subject by subcutaneous injection. 92. The method, reconstituted aqueous composition for use or use according to any one of clauses 86 to 91, wherein the reconstituted aqueous composition is administered to the subject intermittently at time intervals of from about 3 months to about 2 years. 93. The method, reconstituted aqueous composition for use or use according to clause 92, wherein the time interval is from about 3 months to about 1 year. 94. The method, the reconstituted aqueous composition for use, or the use according to clause 93, wherein the time interval is from about 3 months to about 6 months. 95. The method, the reconstituted aqueous composition for use, or the use according to clause 93, wherein the time interval is from about 6 months to about 1 year. 96. The method, reconstituted aqueous composition for use or use according to clause 94 or 95, wherein the time interval is about 6 months. 97. The method, the reconstituted aqueous composition for use, or the use according to any one of clauses 86 to 96, wherein the HIV infection is HIV type 1 (HIV-1) infection. 98. The method, the reconstituted aqueous composition for use, or the use according to any one of clauses 86 to 97, wherein the subject is a human. 99. A solid composition according to any one of clauses 1 to 82 for use in the treatment or prevention of HIV infection in a subject, in particular for the treatment of HIV infection in a subject. 100. Use of a solid composition according to any one of clauses 1 to 82 for the manufacture of a medicinal product for treating or preventing an HIV infection in a subject, in particular for treating an HIV infection in a subject. 101. A solid composition obtained by lyophilizing an aqueous composition comprising rilpivirine or a pharma- ceutically acceptable salt thereof. 102. A solid composition according to clause 101, wherein the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition. 103. A solid composition according to clause 102, wherein the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of microparticles or nanoparticles suspended in the aqueous composition. 104. The solid composition according to clause 102 or 103, wherein the particles have a Dv90 of from about 100 nm to about 10 μm. 105. The solid composition of clause 104, wherein the particles have a Dv90 of about 500 nm to about 6 nm, and optionally the particles have a Dv90 of about 500 nm to about 1,600 nm. 106. The solid composition according to clause 105, wherein the particles have a Dv90 of about 500 nm to about 700 nm. 107. A solid composition according to any one of clauses 102 to 106, wherein the particles have a Dv10 of from about 75 nm to about 200 nm. 108. A solid composition according to any one of clauses 102 to 107, wherein the particles have a Dv50 of from about 200 nm to about 500 nm. 109. A solid composition according to clauses 102 to 104, wherein the particles have a Dv90 of from about 4 nm to about 6 μm. 110. The solid composition according to clause 109, wherein the particles have a Dv90 of about 5 μm to about 6 μm. 111. The solid composition of any one of clauses 102-104 or 109, wherein the particles have a Dv10 of about 300 nm to about 500 nm, and / or the particles have a Dv50 of about 1.5 μm to about 2 μm. 112. The solid composition according to any one of clauses 101-111, wherein the aqueous composition comprises from about 200 mg / mL to about 400 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof. 113. The solid composition according to clause 112, wherein the aqueous composition comprises from about 250 mg / mL to about 350 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof. 114. The solid composition according to clause 113, wherein the aqueous composition comprises about 300 mg / mL of rilpivirine or a pharma- ceutically acceptable salt thereof. 115. A solid composition according to any one of clauses 101 to 114, wherein the aqueous composition comprises rilpivirine, i.e. rilpivirine in free base form. 116. The solid composition according to any one of clauses 101 to 115, wherein the aqueous composition further comprises carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 117. The solid composition according to clause 116, wherein the carboxymethylcellulose or a pharma- ceutically acceptable salt thereof is sodium carboxymethylcellulose. 118. The solid composition according to clause 116 or 117, wherein the carboxymethylcellulose or a pharma- ceutically acceptable salt thereof is not cross-linked. 119. The solid composition according to any one of clauses 116 to 118, wherein the carboxymethylcellulose or a pharma- ceutically acceptable salt thereof has a degree of saturation of the carboxymethyl group relative to the cellulose of about 0.5 to 1. 120. A solid composition according to any one of clauses 116 to 119, wherein the carboxymethylcellulose or the pharma- ceutically acceptable salt thereof has a molecular weight of about 90 kDa to about 750 kDa, and / or the carboxymethylcellulose or the pharma- ceutically acceptable salt thereof has a viscosity of about 30 MPa.s to about 50 MPa.s. 121. The solid composition according to clause 116 or 120, wherein the aqueous composition comprises from about 1 mg / mL to about 100 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 122. The solid composition according to clause 121, wherein the aqueous composition comprises from about 1 mg / mL to about 50 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 123. The solid composition according to clause 122, wherein the aqueous composition comprises from about 1 mg / mL to about 5 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 124. The solid composition according to clause 123, wherein the aqueous composition comprises about 3 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 125. The solid composition according to clause 122, wherein the aqueous composition comprises from about 10 mg / mL to about 25 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 126. A solid composition according to any one of clauses 101 to 125, wherein the aqueous composition further comprises a cryoprotectant. 127. A solid composition according to clause 126, wherein the cryoprotectant is a sugar, sugar alcohol or amino acid or a pharma- ceutically acceptable salt thereof. 128. A solid composition according to clause 127, wherein the cryoprotectant is a sugar or sugar alcohol. 129. A solid composition according to clause 128, wherein the sugar or sugar alcohol is selected from mannitol and sucrose. 130. A solid composition according to clause 129, wherein the sugar or sugar alcohol is sucrose. 131. A solid composition according to clause 127, wherein the cryoprotectant is an amino acid or a pharma- ceutically acceptable salt thereof. 132. The solid composition according to clause 131, wherein the amino acid or a pharma- ceutically acceptable salt thereof is selected from arginine, glycine, and histidine or a pharma- ceutically acceptable salt thereof, and optionally, the amino acid or a pharma- ceutically acceptable salt thereof is selected from arginine and glycine or a pharma- ceutically acceptable salt thereof. 133. The solid composition according to clause 132, wherein the amino acid or a pharma- ceutically acceptable salt thereof is arginine or a pharma- ceutically acceptable salt thereof, such as arginine HCl. 134. The solid composition according to any one of clauses 126 to 133, wherein the aqueous composition comprises from about 1 mg / mL to about 200 mg / mL of cryoprotectant. 135. The solid composition according to clause 134, wherein the aqueous composition comprises about 1 to about 150 mg / mL of cryoprotectant. 136. The solid composition according to clause 135, wherein the aqueous composition comprises about 30 to about 100 mg / mL of cryoprotectant. 137. A solid composition according to any one of clauses 127 to 130, wherein the aqueous composition comprises from about 25 mg / mL to about 125 mg / mL of sugar or sugar alcohol. 138. The solid composition according to clause 137, wherein the aqueous composition comprises about 75 to about 125 mg / mL of sugar or sugar alcohol. 139. The solid composition according to clause 138, wherein the aqueous composition comprises about 50 to about 100 mg / mL of sugar or sugar alcohol. 140. The solid composition according to clause 139, wherein the aqueous composition comprises about 100 mg / mL of sugar or sugar alcohol. 141. The solid composition according to any one of clauses 127 and 131-133, wherein the aqueous composition comprises from about 1 mg / mL to about 75 mg / mL of an amino acid or a pharma- ceutically acceptable salt thereof. 142. The solid composition according to clause 141, wherein the aqueous composition comprises from about 1 mg / mL to about 50 mg / mL of an amino acid or a pharma- ceutically acceptable salt thereof. 143. The solid composition according to clause 142, wherein the aqueous composition comprises from about 25 mg / mL to about 35 mg / mL of the amino acid or a pharma- ceutically acceptable salt thereof, optionally wherein the aqueous composition comprises about 30 mg / mL of the amino acid or a pharma- ceutically acceptable salt thereof. 144. A solid composition according to any one of clauses 126 to 143, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition is from about 1:1 (w / w) to about 20:1 (w / w). 145. A solid composition according to clause 144, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition is from about 2:1 (w / w) to about 10:1 (w / w), or the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition is from about 3:1 (w / w) to about 10:1 (w / w). 146. The solid composition according to clause 144, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition is from about 2:1 (w / w) to about 7:1 (w / w). 147. The solid composition according to clause 146, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition is from about 3:1 (w / w) to about 6:1 (w / w). 148. A solid composition according to any one of clauses 126 to 147, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:1 (w / w) to about 1:100 (w / w), optionally from about 1:1 (w / w) to about 1:50 (w / w). 149. The solid composition according to clause 148, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:8 (w / w) to about 1:40 (w / w). 150. A solid composition according to any one of clauses to 148, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:2 (w / w) to about 1:15 (w / w). 151. The solid composition according to clause 150, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:4 (w / w) to about 1:11 (w / w). 152. The solid composition according to clause 151, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:5 (w / w) to about 1:10 (w / w). 153. The solid composition according to clause 151, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:9 (w / w) to about 1:11 (w / w). 154. The solid composition according to clause 149, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:30 (w / w) to about 1:35 (w / w). 155. A solid composition according to any one of clauses 101 to 154, wherein the aqueous composition further comprises a poloxamer, for example poloxamer 338. 156. A solid composition according to clause 155 when dependent on clause 102, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is from about 3:1 (w / w) to about 15:1 (w / w), when rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. 157. The solid composition according to clause 156, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is from about 6:1 (w / w) to about 15:1 (w / w), when rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. 158. The solid composition according to clause 157, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to poloxamer is about 6:1, when rilpivirine or a pharma- ceutically acceptable salt thereof has a Dv90 of about 1600 nm or less. 159. A solid composition according to any one of clauses 155 to 158, wherein the relative amounts (w / w) of rilpivirine or a pharma- ceutically acceptable salt thereof and poloxamer are less than about 12:1 (w / w). 160. A solid composition according to any one of clauses 101 to 159, wherein the aqueous composition further comprises a poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide. 161. The solid composition of any one of clauses -160, wherein the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide. 162. The solid composition according to any one of clauses 160-161, wherein the aqueous composition comprises from about 5 mg / mL to about 15 mg / mL of poloxamer. 163. The solid composition according to any one of clauses 160-161, wherein the aqueous composition comprises from about 40 mg / mL to about 60 mg / mL of poloxamer. 164. A solid composition according to any one of clauses 101 to 163, wherein the aqueous composition further comprises an antioxidant, optionally the antioxidant being methionine. 165. The solid composition according to clause 164, wherein the aqueous composition comprises from about 1.0 mg / mL to about 2.0 mg / mL, for example about 1.5 mg / mL, of the antioxidant. 166. A solid composition according to any one of clauses 101 to 165, wherein the aqueous composition does not contain glucose. 167. A solid composition according to any one of clauses 101 to 166, wherein the aqueous composition has a pH of about 5 to about 7. 168. The solid composition according to paragraph 167, wherein the aqueous composition has a pH in the range of about 6 to about 7. 169. The solid composition according to paragraph 168, wherein the aqueous composition has a pH in the range of about 6 to about 6.5. 170. The solid composition according to clause 169, wherein the aqueous composition has a pH of about 6. 171. A solid composition according to any one of clauses 101 to 170, wherein the aqueous composition does not contain hyaluronidase. 172. A reconstituted aqueous composition obtained by reconstituting a solid composition as defined in any one of clauses 101 to 171. 173. The reconstituted aqueous composition of clause 172, wherein reconstitution comprises adding an aqueous dispersion medium to the solid composition. 174. The reconstituted aqueous composition according to clause 173, wherein the aqueous dispersion medium is water. 175. A method for the treatment or prevention of HIV infection in a subject, in particular for the treatment of HIV infection in a subject, comprising administering to the subject a reconstituted aqueous composition as defined in any one of clauses 172 to 174. 176. A reconstituted aqueous composition as defined in any one of clauses 172 to 174 for use in the treatment or prevention of HIV infection in a subject, in particular for the treatment of HIV infection in a subject. 177. Use of a reconstituted aqueous composition as defined in any one of clauses 172 to 174 for the manufacture of a medicinal product for treating or preventing HIV infection in a subject, in particular for treating HIV infection in a subject. 178. The method, the reconstituted aqueous composition for use or the use according to any one of clauses 175 to 177, wherein the reconstituted aqueous composition is administered to the subject by intramuscular or subcutaneous injection. 179. The method, reconstituted aqueous composition for use or use according to clause 178, wherein the reconstituted aqueous composition is administered to the subject by intramuscular injection. 180. The method, reconstituted aqueous composition for use or use according to clause 178, wherein the reconstituted aqueous composition is administered to the subject by subcutaneous injection. 181. The method, reconstituted aqueous composition for use or use according to any one of clauses 175 to 180, wherein the reconstituted aqueous composition is administered to the subject intermittently at time intervals of from about 3 months to about 2 years. 182. The method, reconstituted aqueous composition for use or use according to clause 181, wherein the time interval is from about 3 months to about 1 year. 183. The method, the reconstituted aqueous composition for use, or the use according to clause 182, wherein the time interval is from about 3 months to about 6 months. 184. The method, the reconstituted aqueous composition for use, or the use according to clause 182, wherein the time interval is from about 6 months to about 1 year. 185. The method, the reconstituted aqueous composition for use or the use according to clause 183 or 184, wherein the time interval is about 6 months. 186. The method, the reconstituted aqueous composition for use, or the use according to any one of clauses 175 to 185, wherein the HIV infection is HIV type 1 (HIV-1) infection. 187. The method, the reconstituted aqueous composition for use, or the use according to any one of clauses 175 to 186, wherein the subject is a human. 188. A solid composition according to any one of clauses 101 to 171 for use in the treatment or prevention of HIV infection in a subject, in particular for the treatment of HIV infection in a subject. 189. Use of a solid composition according to any one of clauses 101 to 171 for the manufacture of a medicinal product for treating or preventing an HIV infection in a subject, in particular for treating an HIV infection in a subject.

[0299] The following numbered embodiments are also described herein: 1. A solid composition obtained by lyophilizing an aqueous composition comprising rilpivirine or a pharma- ceutically acceptable salt thereof and hyaluronidase. 2. The method of embodiment 1, wherein the hyaluronidase is rHuPH20. 3. A solid composition according to any one of embodiments 1-2, wherein the aqueous composition comprises rilpivirine or a pharma- ceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, optionally the particles being microparticles or nanoparticles suspended in the aqueous composition. 4. The solid composition of any one of embodiments 1 to 3, wherein the aqueous composition further comprises carboxymethylcellulose or a pharma- ceutically acceptable salt thereof. 5. The solid composition according to embodiment 4, wherein the carboxymethylcellulose or a pharma- ceutically acceptable salt thereof is sodium carboxymethylcellulose. 6. The solid composition according to embodiment 4 or 5, wherein the carboxymethylcellulose or a pharma- ceutically acceptable salt thereof is not crosslinked. 7. A solid composition according to any one of embodiments 4 to 6, wherein the aqueous composition comprises from about 0.5 mg / mL to about 2 mg / mL of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof per 100 U of hyaluronidase. 8. The solid composition according to any one of the preceding embodiments, wherein the aqueous composition further comprises a cryoprotectant. 9. The solid composition according to embodiment 8, wherein the cryoprotectant is a sugar, sugar alcohol or amino acid, or a pharma- ceutically acceptable salt thereof. 10. A solid composition according to embodiment 9, wherein the sugar or sugar alcohol is mannitol or sucrose, and the amino acid or a pharma- ceutically acceptable salt thereof is arginine or glycine. 11. A solid composition according to any one of embodiments 8 to 10, wherein the ratio of rilpivirine or a pharma- ceutically acceptable salt thereof to cryoprotectant in the aqueous composition is from about 2:1 (w / w) to about 7:1 (w / w). 12. A solid composition according to any one of embodiments 8 to 11, wherein the ratio of carboxymethylcellulose or a pharma- ceutically acceptable salt thereof to cryoprotectant is from about 1:4 (w / w) to about 1:11 (w / w). 13. The solid composition of any one of embodiments 1 to 12, wherein the aqueous composition has a pH of about 6 to about 6.5. 14. A reconstituted aqueous composition obtainable by reconstituting a solid composition as defined in any one of embodiments 1 to 13 with an aqueous dispersion medium. 15. A method for treating or preventing HIV infection in a subject, the method comprising administering to the subject a reconstituted aqueous composition as defined in embodiment 14.

Claims

1. A solid composition obtained by freeze-drying an aqueous composition containing rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase.

2. The solid composition according to claim 1, wherein the hyaluronidase is rHuPH20.

3. The solid composition according to claim 1, wherein the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, and optionally the particles are microparticles or nanoparticles suspended in the aqueous composition.

4. The solid composition according to claim 1, wherein the aqueous composition further comprises carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

5. The solid composition according to claim 4, wherein the carboxymethylcellulose or a pharmaceutically acceptable salt thereof is sodium carboxymethylcellulose.

6. The solid composition according to claim 4, wherein the carboxymethylcellulose or a pharmaceutically acceptable salt thereof is not crosslinked.

7. The solid composition according to claim 4, wherein the aqueous composition contains about 0.05 mg / mL to about 0.25 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U of hyaluronidase.

8. The solid composition according to claim 1, wherein the aqueous composition further comprises an antifreeze agent.

9. The solid composition according to claim 8, wherein the antifreeze agent is a sugar, a sugar alcohol, or an amino acid or a pharmaceutically acceptable salt thereof.

10. The solid composition according to claim 9, wherein the sugar or sugar alcohol is sucrose, and the amino acid or a pharmaceutically acceptable salt thereof is arginine, preferably arginine HCl.

11. The solid composition according to claim 8, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to an antifreeze agent in the aqueous composition is about 1:1 (w / w) to about 20:1 (w / w).

12. The solid composition according to claim 8, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to an antifreeze agent is about 1:8 (w / w) to about 1:40 (w / w).

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

5.

14. A reconstituted aqueous composition obtained by reconstituting a solid composition defined in any one of claims 1 to 13 with an aqueous dispersion medium.

15. A method for treating or preventing HIV infection in a subject, the method comprising administering a reconstituted aqueous composition as defined in claim 14 to the subject.

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