Freeze-dried composition

Abstract

The present invention relates to a solid composition obtainable by freeze-drying an aqueous composition comprising rilpivirine or a pharmaceutically acceptable salt thereof and optionally a hyaluronidase. The invention also relates to a reconstituted aqueous composition obtainable by reconstituting a solid composition of the invention, a process for preparing a solid composition of the invention and the use of the reconstituted aqueous composition in the treatment or prevention of HIV infection in a subject.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 333,557 filed on April 22, 2022 and European Patent Application No. EP22173920.4 filed on May 17, 2022, the entire contents of which are expressly incorporated herein by reference. Technical Field

[0003] The present invention relates to a solid composition obtainable by freeze-drying an aqueous composition, the aqueous composition comprising rilpivirine or a pharmaceutically acceptable salt thereof and optionally a hyaluronidase. The present invention also relates to a reconstituted aqueous composition obtainable by reconstitution of the solid composition of the present invention, a method for preparing the solid composition of the present invention, and the use of the reconstituted aqueous composition in treating or preventing HIV infection in a subject. Background Art

[0004] Human immunodeficiency virus (HIV) infection is considered the etiology of acquired immunodeficiency syndrome (AIDS), and its treatment remains a major medical challenge. HIV is able to evade immune pressure, adapt to a variety of cell types and growth conditions, and develop resistance to anti-HIV drugs. The latter include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), HIV-protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and HIV fusion inhibitors.

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

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

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

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

[0009] WO2007 / 147882 discloses intramuscular or subcutaneous injection of a therapeutically effective amount of rilpivirine in the form of microparticles or nanoparticles having a surface modifier adsorbed to the surface thereof; and a pharmaceutically acceptable aqueous carrier; wherein the active ingredient of rilpivirine is suspended.

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

[0011] It is desirable to provide a composition comprising rilpivirine particles that can be stored for a long period of time (e.g., weeks, months, or years), particularly at room temperature (e.g., at 20°C-25°C) without substantially affecting the particle size distribution of rilpivirine, such that when rilpivirine is administered after storage for a long period of time, particularly at room temperature (e.g., at 20°C-25°C), the bioavailability, efficacy, and extended release properties are maintained during the storage period.

[0012] When rilpivirine is administered by subcutaneous or intramuscular injection, it may also be desirable to prepare or administer it with hyaluronidase to increase the dispersion and absorption of rilpivirine. Hyaluronidase can also be used to achieve other effects, for example, the administration of hyaluronidase can reduce the mass formed by administering a high volume of the pharmaceutical composition at the injection site. However, the storage of hyaluronidase in a pharmaceutical composition (e.g., a composition comprising rilpivirine) for weeks, months, or years presents a major challenge. When stored at room temperature for an extended period of time, hyaluronidase can be rapidly unfolded and degraded. Therefore, it is also desirable to provide a composition comprising rilpivirine and hyaluronidase, wherein the hyaluronidase is particularly stable during storage for weeks, months, or years at room temperature (e.g., at 20°C-25°C).

[0013] PCT / US2021 / 072453 (WO2022 / 109555) discloses the use of rilpivirine or a pharmaceutically acceptable salt thereof in the form of microparticles or nanoparticles in suspension in combination with hyaluronidase to treat or prevent HIV infection. Summary of the invention

[0014] In a first aspect, the present invention relates to a solid composition obtainable by freeze-drying (synonymous with "lyophilization") an aqueous composition comprising rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase.

[0015] In a second aspect, the present invention relates to a reconstituted aqueous composition obtainable by reconstitution of the solid composition according to the first aspect.

[0016] In a third aspect, there is provided a method for treating or preventing HIV infection in a subject, the method comprising administering to the subject the reconstituted aqueous composition according to the second aspect.

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

[0018] In a fifth aspect, there is provided use of the reconstituted aqueous composition according to the second aspect in the preparation of a medicament for treating or preventing HIV infection in a subject.

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

[0020] In a seventh aspect, there is provided use of the solid composition of the first aspect in the preparation of a medicament for treating or preventing HIV infection in a subject.

[0021] In an eighth aspect, a kit is provided, the kit comprising (i) the solid composition according to the first aspect, and (ii) a diluent.

[0022] In a ninth aspect, a kit is provided, 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, a kit is provided, 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

[0023] The present invention will now be described, by way of example only, with reference to the accompanying drawings.

[0024] Figure 1 :Study on the melting temperature of hyaluronidase under different storage conditions

[0025] Figure 1A :Study on the melting temperature of hyaluronidase under different storage conditions

[0026] Figure 1B :Study on the melting temperature of hyaluronidase under different storage conditions

[0027] Figure 1C :Study on the melting temperature of hyaluronidase under different storage conditions (pH)

[0028] Figure 2 :Study on the melting temperature of hyaluronidase

[0029] Figure 3 :Study on the melting temperature of hyaluronidase under different storage conditions

[0030] Figure 3A :Study on the melting temperature of hyaluronidase under different storage conditions (pH)

[0031] Figure 4 :Study on the melting temperature of hyaluronidase and CMC sodium concentration

[0032] Figure 5 : Particle size of rilpivirine under different storage conditions

[0033] Figure 6 : Study on the particle size and hyaluronidase stability of rilpivirine under different storage conditions

[0034] Figure 7 :Viscosity study

[0035] Figure 8 :Injection force study

[0036] These figures are further explained in the "Examples" section.

[0037] Disclosure of the Invention

[0038] This application has been drafted in sections to improve readability. However, this does not mean that each section should be read separately. Instead, unless otherwise indicated, each section should be read by cross-reference to other sections (i.e., the entire application as a whole). Unless explicitly stated, there is no intention to artificially separate the embodiments. DETAILED DESCRIPTION

[0039] Compositions of the present invention

[0040] In a first aspect, the present invention relates to a solid composition obtainable by freeze-drying an aqueous composition comprising rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase.

[0041] In a second aspect, the present invention relates to a reconstituted aqueous composition obtainable by reconstitution of the solid composition according to the first aspect.

[0042] Freeze drying is a process in which an aqueous composition is initially frozen. During the initial freezing step, water forms solid ice crystals and the composition is concentrated, resulting in the separation of two phases. Pressure is then reduced during the primary drying stage, and ice is sublimated. The temperature can be raised in the primary drying stage to increase the sublimation rate. In the secondary drying stage, the temperature of the composition is slowly raised to promote the removal of residual water and a solid composition is provided. The solid composition that can be obtained by freeze drying can be referred to by a plurality of 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 that can be obtained by freeze drying is a freeze-dried cake, or cake or freeze-dried cake.

[0043] Rilpivirine (4-[[4-[[4-[(1E)-2-cyanovinyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile; TMC278) has the following structural formula:

[0044]

[0045] The term "rilpivirine" refers to rilpivirine having the structural formula shown above (ie, the free base form).

[0046] In a preferred embodiment, the aqueous composition or reconstituted aqueous composition comprises rilpivirine, ie, rilpivirine in the free base form.

[0047] Pharmaceutically acceptable salts of rilpivirine refer to those salts in which the counterion is pharmaceutically acceptable. Pharmaceutically acceptable salts are intended to include therapeutically active non-toxic acid addition salt forms that rilpivirine can form. These salt forms can be conveniently obtained by treating rilpivirine with a suitable acid such as the following: such as an inorganic acid, for example a hydrohalic acid, for example hydrochloric acid, hydrobromic acid, etc.; sulfuric acid; nitric acid; phosphoric acid, etc.; or an organic acid, for example acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1,2,3-propane-tricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, etc.

[0048] In one embodiment, rilpivirine or a pharmaceutically acceptable salt thereof is in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition, such as microparticles or nanoparticles suspended in the aqueous composition or a reconstituted aqueous composition.

[0049] Two embodiments are contemplated herein with preferred particle sizes.

[0050] In a first preferred particle size embodiment, the rilpivirine particles have a D of less than or about 2 μm. v 90. In this embodiment, the particles may have a D of about 100 nm to about 2 μm. v 90. In this embodiment, the particles may have a D of about 200 nm to about 2 μm (e.g., 200 nm to about 2 μm). v 90. In this embodiment, the particles may have a D of 300 nm to about 2 μm. v 90. In this embodiment, the particles may have a D of about 400 nm to about 2 μm (e.g., 400 nm to about 2 μm). v 90. In this embodiment, the particles may have a D of about 500 nm to about 2 μm (e.g., 500 nm to about 2 μm). v 90. Preferably in this embodiment, the particles have a D of about 500 nm to about 1,600 nm (e.g., 500 nm to about 1,600 nm). v 90, or a D of about 500 nm to about 1,000 nm (e.g., 500 nm to about 1,000 nm, such as about 800 nm) v More preferably in this embodiment, the particles have a D 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 90.

[0051] As used herein, the term " v 90" refers to the diameter below which 90% of the particle population by volume is found. As used herein, the term "D v 50" refers to the diameter below which 50% of the particle population by volume is found. As used herein, the term "D v 10" refers to the diameter below which 10% by volume of the particle population is found.

[0052] In a first preferred particle size embodiment, the particles may have a D of less than or about 1,000 nm. v 50. In this embodiment, the particles may have a D of about 10 nm to about 1,000 nm. vIn this embodiment, the particles may have a D of about 50 nm to about 700 nm. v 50. In this embodiment, the particles may have a D of about 100 nm to about 600 nm. v In this embodiment, the particles may have a D of about 150 nm to about 500 nm. v 50. Preferably in this embodiment, the particles have a D of about 200 nm to about 500 nm. v 50.

[0053] In a first preferred particle size embodiment, the particles may have a D of less than or about 500 nm. v 10. In this embodiment, the particles may have a D of about 10 nm to about 500 nm. v 10. In this embodiment, the particles may have a D of about 25 nm to about 400 nm. v 10. In this embodiment, the particles may have a D of about 50 nm to about 300 nm. v 10. In this embodiment, the particles may have a D of about 50 nm to about 200 nm. v 10. Preferably in this embodiment, the particles have a D of about 75 nm to about 200 nm. v 10.

[0054] Preferably in this embodiment, the particles have a D of about 500 nm to about 1,600 nm. v 90, D from about 200nm to about 500nm v 50 and D from about 75nm to about 200nm v 10.

[0055] Alternatively, the particles have a D of about 500 nm to about 1,000 nm. v 90, D from about 200nm to about 500nm v 50 and D from about 75nm to about 200nm v 10.

[0056] Alternatively, the particles have a D of about 500 nm to about 700 nm. v 90, D from about 200nm to about 500nm v 50 and D from about 75nm to about 200nm v 10.

[0057] In a second preferred particle size embodiment, the particles may have a D of about 1 μm to about 10 μm. v In this embodiment, the particles may have a D of about 2 μm to about 9 μm. v90. In this embodiment, the particles may have a D of about 3 μm to about 8 μm. v 90. In this embodiment, the particles may have a D of about 3 μm to about 7 μm. v 90. Preferably in this embodiment, the particles have a D of about 4 μm to about 6 μm. v 90. Most preferably in this embodiment, the particles have a D of about 5 μm to about 6 μm (e.g., about 5 μm or about 6 μm). v 90.

[0058] In a second preferred particle size embodiment, the particles have a D of less than or about 3 μm. v 50. In this embodiment, the particles may have a D less than about 2.5 μm. v 50. In this embodiment, the particles may have a D of about 1 μm to about 2.5 μm. 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 50. Further preferably in this embodiment, the particles have a D of about 1.5 μm to about 2 μm. v 50.

[0059] In a second preferred particle size embodiment, the particles may have a D of less than or about 1000 nm. v 10. In this embodiment, the particles may have a D of about 10 nm to about 1000 nm. v 10. In this embodiment, the particles may have a D of about 100 nm to about 700 nm. v 10. In this embodiment, the particles may have a D of about 200 nm to about 600 nm. v 10. Preferably in this embodiment, the particles have a D of about 300 nm to about 500 nm. v 10.

[0060] Preferably in this embodiment, the particles have a D of about 4 μm to about 6 μm. v 90, D from about 1.5 μm to about 2 μm v 50 and D from about 300nm to about 500nm v 10.

[0061] Preferably in this embodiment, the particles have a D of about 5 μm to about 6 μm. v 90, D from about 1.5 μm to about 2.2 μm v 50 and D from about 300nm to about 500nm v10.

[0062] 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.

[0063] Laser diffraction relies on the principle that particles will scatter light at different angles depending on the size of the particle, and that a collection of particles will produce a pattern of scattered light defined by intensity and angle, which can be related to the particle size distribution. Many laser diffraction instruments are commercially available for quickly and reliably determining particle size distribution. For example, particle size distribution can be determined by the conventional Malvern Mastersizer from Malvern Instruments. TM The MalvernMastersizer 3000 particle size analyzer measures TM The 3000 particle size analyzer operates by projecting a helium-neon gas laser beam into a transparent cell containing target particles suspended in an aqueous solution. The light that strikes the particles is scattered through angles inversely proportional to the particle size, and an array of photodetectors measures the intensity of the light at several predetermined angles, and the measured intensities at different angles are processed by a computer using standard theoretical principles to determine the particle size distribution. Laser diffraction values ​​can be obtained using wet dispersions of the particles in distilled water.

[0064] The commonly used measurement D in this field v 10. D v 50 and D v 90 Other methods include disk centrifugation, scanning electron microscopy (SEM), sedimentation field flow fractionation, and photon correlation spectroscopy.

[0065] In one embodiment, the aqueous composition or the reconstructed aqueous composition comprises about 100 mg / mL to about 500 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition or the reconstructed aqueous composition comprises about 150 mg / mL to about 450 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition or the reconstructed aqueous composition comprises about 200 mg / mL to about 400 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the aqueous composition or the reconstructed aqueous composition comprises about 250 mg / mL to about 350 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof, for example about 300 mg / mL (particularly 300 mg / mL) of rilpivirine.

[0066] In one embodiment, the amount of rilpivirine or a pharmaceutically acceptable salt thereof in the aqueous composition or the reconstituted aqueous composition is from about 900 mg to about 28800 mg (e.g., from about 900 mg to about 14400 mg, or from about 900 mg to about 7200 mg, or from about 900 mg to about 4500 mg, or from about 900 mg to about 3600 mg), preferably from about 1200 mg to about 14400 mg, preferably from about 1350 mg to about 13200 mg, preferably The dosage range of the present invention is preferably 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 free base form). Thus, by way of example, 1 mg of rilpivirine (i.e., rilpivirine in free base form) corresponds to 1.1 mg of rilpivirine hydrochloride.

[0067] Solid composition or the aqueous composition of reconstruction comprise hyaluronidase.Hyaluronidase is an enzyme that degrades the hyaluronic acid (HA) in the skin and reduces the hyaluronic acid viscosity in the extracellular matrix.Because of this characteristic, it can be used to increase the dispersion and absorption of the active pharmaceutical ingredient injected and / or enable subcutaneous administration of a larger volume.The enzymatic activity of hyaluronidase (including rHuPH20) can be defined by the unit (U / mL) of every mL or by the total enzyme activity (U) in a specific preparation.

[0068] As used herein, the term "hyaluronidase" refers to any enzyme that degrades hyaluronic acid and reduces the viscosity of hyaluronic acid in the extracellular matrix.

[0069] In one embodiment, the hyaluronidase is a recombinant hyaluronidase. In a preferred embodiment, the hyaluronidase is a recombinant human hyaluronidase, such as rHuPH20. In one embodiment, rHuPH20 is defined by an amino acid sequence that can be obtained according to CAS registration number 757971-58-7. Further information about rHuPH20 is provided in International Patent Publication No. WO2004 / 078140. In one embodiment, the amino acid sequence of rHuPH20 comprises SEQ ID NO: 1. In some embodiments, the hyaluronidase is a variant of rHuPH20, which has an amino acid sequence of rHuPH20 comprising SEQ ID NO: 2 (i.e., residues 36-482 of wild-type human hyaluronidase). In some embodiments, the hyaluronidase is a variant of rHuPH20, which has an amino acid sequence comprising SEQ ID NO: 3. In some embodiments, the hyaluronidase is a variant of rHuPH20, which has an amino acid sequence comprising SEQ ID NO: 4. In some embodiments, the hyaluronidase is a variant of rHuPH20 having an amino acid sequence comprising SEQ ID NO:5.

[0070]

[0071]

[0072] In one embodiment, the concentration of hyaluronidase in the aqueous composition or reconstituted aqueous composition is from about 10 U / mL to about 10,000 U / mL, or from about 100 U / mL to about 10,000 U / mL, or from about 500 U / mL to about 10,000 U / mL, or from about 500 U / mL to about 5,000 U / mL, or from about 500 U / mL to about 2500 U / mL, or from about 1000 U / mL to about 2500 U / mL, or from about 1500 U / mL to about 2500 U / mL. Preferably, the concentration of hyaluronidase in the aqueous composition or reconstituted aqueous composition is from about 1800 U / mL to about 2200 U / mL (e.g., about 2000 U / mL).

[0073] In one embodiment, the concentration of hyaluronidase in the aqueous composition or reconstituted aqueous composition is from about 0.1 μg / mL to about 90 μg / mL, or from about 0.9 μg / mL to about 90 μg / mL, or from about 4.5 μg / mL to about 90 μg / mL, or from about 4.5 μg / mL to about 45 μg / mL, or from about 4.5 μg / mL to about 22.5 μg / mL, or from about 9 μg / mL to about 22.5 μg / mL, or from about 13.5 μg / mL to about 22.5 μg / mL. Preferably, the concentration of hyaluronidase in the aqueous composition or reconstituted aqueous composition is from about 16.2 μg / mL to about 19.8 μg / mL (e.g., about 18 μg / mL).

[0074] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition further comprises carboxymethylcellulose (CMC) or a pharmaceutically acceptable salt thereof, preferably wherein the CMC is not cross-linked. In one embodiment, CMC or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of CMC. Pharmaceutically acceptable salts of CMC mean those salts in which the counterion is pharmaceutically acceptable. Pharmaceutically acceptable salts are intended to include therapeutically active non-toxic acid addition salt forms that CMC is able to form. Preferred pharmaceutically acceptable salts of CMC include sodium CMC and potassium CMC. In a particularly preferred embodiment, CMC or a pharmaceutically acceptable salt thereof is sodium CMC, particularly non-cross-linked sodium CMC. In another embodiment, CMC or a pharmaceutically acceptable salt thereof is CMC. Examples of CMC that can be used in the present invention are sodium carboxymethylcellulose (40 mPa.s (parenteral grade), available from Ashland) and Blanose CMC 7LF PH or Blanose 7LP EP (available from Ashland).

[0075] CMC or its pharmaceutically acceptable salt can have any degree of substitution (DS). DS is the average number of carboxymethyl groups per cellulose unit. In a preferred embodiment, DS is from about 0.4 to about 1.5. In one embodiment, CMC or its pharmaceutically acceptable salt has a DS of from about 0.5 to about 1 (e.g., from about 0.65 to about 0.95, such as about 0.7).

[0076] In one embodiment, CMC or a pharmaceutically acceptable salt thereof has a viscosity of about 10 mPa.s to about 100 mPa.s in a 1% (w / v) aqueous solution at room temperature. In one embodiment, CMC or a pharmaceutically acceptable salt thereof has a viscosity of about 20 mPa.s to about 60 mPa.s in a 1% (w / v) aqueous solution at room temperature. In one embodiment, CMC or a pharmaceutically 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, a viscosity of about 40 mPa.s in a 1% (w / v) aqueous solution at room temperature.

[0077] In one embodiment, CMC or a pharmaceutically acceptable salt thereof has a viscosity of about 10 mPa.s to about 100 mPa.s in a 2% (w / v) aqueous solution at room temperature. In one embodiment, CMC or a pharmaceutically acceptable salt thereof has a viscosity of about 20 mPa.s to about 60 mPa.s in a 2% (w / v) aqueous solution at room temperature. In a preferred embodiment, CMC or a pharmaceutically acceptable salt thereof has a viscosity of about 30 mPa.s to about 50 mPa.s in a 2% (w / v) aqueous solution at room temperature, for example, a viscosity of about 40 mPa.s in a 2% (w / v) aqueous solution at room temperature.

[0078] In one embodiment, the molecular weight of CMC or a pharmaceutically acceptable salt thereof is from about 50 kDa to about 2,000 kDa. In one embodiment, the molecular weight of CMC or a pharmaceutically acceptable salt thereof is from about 50 kDa to about 1,000 kDa. In one embodiment, the molecular weight of CMC or a pharmaceutically acceptable salt thereof is from about 70 kDa to about 900 kDa. In a preferred embodiment, the molecular weight of CMC or a pharmaceutically acceptable salt thereof is from about 90 kDa to about 750 kDa, and in a most preferred embodiment, the molecular weight of CMC or a pharmaceutically acceptable salt thereof is from about 70 kDa to about 110 kDa, for example, about 90 kDa.

[0079] The present inventors have surprisingly found that adding CMC or a pharmaceutically acceptable salt thereof to an aqueous composition of the present invention comprising a hyaluronidase increases the melting temperature (T m ) (Example 2a). This indicates improved storage stability.

[0080] The inventors have also found that the addition of CMC or a pharmaceutically acceptable salt thereof to an aqueous composition of the invention comprising a hyaluronidase results in reduced loss of hyaluronidase activity, reduced aggregation of hyaluronidase and / or reduced oxidation of hyaluronidase in a reconstituted aqueous composition of the invention after storage under stress test conditions such as a freeze-dried product (Example 6 and Example 8). This indicates improved storage stability.

[0081] In one embodiment, the aqueous composition or the reconstructed aqueous composition comprises about 1 mg / mL to about 100 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition or the reconstructed aqueous composition comprises about 1 mg / mL to about 75 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition or the reconstructed aqueous composition comprises about 1 mg / mL to about 50 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition or the reconstructed aqueous composition comprises about 1 mg / mL to about 25 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition or the reconstructed aqueous composition comprises about 5 mg / mL to about 25 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In one embodiment, the aqueous composition or the reconstructed aqueous composition comprises about 5 mg / mL to about 15 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the aqueous composition or the reconstructed aqueous composition comprises about 5 mg / mL to about 10 mg / mL of CMC or a pharmaceutically acceptable salt thereof. In a most preferred embodiment, the aqueous composition or reconstituted aqueous composition comprises about 1 mg / mL to about 5 mg / mL (eg, about 3 mg / mL) of CMC or a pharmaceutically acceptable salt thereof.

[0082] In a preferred embodiment, CMC or a pharmaceutically acceptable salt thereof is sodium CMC, and the aqueous composition or the reconstituted aqueous composition comprises sodium CMC in any of the amounts specified in the above paragraphs. In a preferred embodiment, CMC or a pharmaceutically acceptable salt thereof is sodium CMC, and the aqueous composition or the reconstituted aqueous composition has any degree of substitution, viscosity, and molecular weight specified herein.

[0083] In one embodiment, the aqueous composition (and therefore solid composition) or the aqueous composition of reconstruction comprises about 0.002mg to about 5mg CMC or its pharmaceutically acceptable salt / 100U hyaluronidase. In one embodiment, the aqueous composition (and therefore solid composition) or the aqueous composition of reconstruction comprises about 0.01mg to about 5mg CMC or its pharmaceutically acceptable salt / 100U hyaluronidase. In one embodiment, the aqueous composition (and therefore solid composition) or the aqueous composition of reconstruction comprises about 0.05mg to about 2.5mg CMC or its pharmaceutically acceptable salt / 100U hyaluronidase. In one embodiment, the aqueous composition (and, therefore, solid composition) or the aqueous composition of reconstruction comprises about 0.1mg to about 2mg CMC or its pharmaceutically acceptable salt / 100U hyaluronidase. In a preferred embodiment, the aqueous composition (and therefore solid composition) or the aqueous composition of reconstruction comprises about 0.1mg to about 1mg CMC or its pharmaceutically acceptable salt / 100U hyaluronidase. In a more preferred embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises from about 0.1 mg to about 0.25 mg CMC or a pharmaceutically acceptable salt thereof / 100 U hyaluronidase, for example, from about 0.15 mg CMC or a pharmaceutically acceptable salt thereof / 100 U hyaluronidase. In another more preferred embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises from about 0.05 mg to about 0.25 mg CMC or a pharmaceutically acceptable salt thereof / 100 U hyaluronidase, for example, from about 0.15 mg CMC or a pharmaceutically acceptable salt thereof / 100 U hyaluronidase.

[0084] In a preferred embodiment, the CMC or a pharmaceutically acceptable salt thereof is sodium CMC, and the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises any of the ratios of sodium CMC to hyaluronidase specified in the above paragraphs.

[0085] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstructed aqueous composition further comprises a cryoprotectant. In one embodiment, the cryoprotectant is a sugar, a sugar alcohol or an amino acid or a pharmaceutically acceptable salt thereof, preferably wherein the sugar is not a monosaccharide. The pharmaceutically acceptable salt of a sugar, a sugar alcohol or an amino acid means those salts in which the counterion is pharmaceutically acceptable. Pharmaceutically acceptable salts are intended to include therapeutically active non-toxic acid and base addition salt forms that can be formed with a given sugar, sugar alcohol or amino acid. Suitable sugars and sugar alcohols include mannitol, lactose, sucrose, trehalose, sorbitol, dextrose, fructose, maltose, xylitol and raffinose. Preferably, sugar or sugar alcohol is selected from mannitol and sucrose. More preferably, sugar or sugar alcohol is sucrose. Suitable amino acids or pharmaceutically acceptable salts thereof include arginine, glycine and histidine or their pharmaceutically acceptable salts. In one embodiment, amino acids or pharmaceutically acceptable salts thereof are selected from arginine and glycine or their pharmaceutically acceptable salts. In a preferred embodiment, the amino acid or a pharmaceutically 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 of which is a sugar or a sugar alcohol, and the other cryoprotectant is an amino acid or a pharmaceutically acceptable salt thereof.

[0086] The inventors surprisingly found that when rilpivirine or a pharmaceutically acceptable salt thereof is in the form of particles suspended in an 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 freeze-drying (see e.g. Example 4).

[0087] In one embodiment, the aqueous composition or the reconstituted aqueous composition comprises from about 1 mg / mL to about 200 mg / mL of a cryoprotectant. In one embodiment, the aqueous composition or the reconstituted aqueous composition comprises from about 1 mg / mL to about 175 mg / mL of a cryoprotectant. In one embodiment, the aqueous composition or the reconstituted aqueous composition comprises from about 1 mg / mL to about 150 mg / mL of a cryoprotectant.

[0088] In one embodiment, the aqueous composition or reconstituted aqueous composition comprises from about 20 mg / mL to about 150 mg / mL of cryoprotectant.

[0089] In one embodiment, the aqueous composition or the aqueous composition of reconstruction comprises a cryoprotectant of about 25mg / mL to about 150mg / mL, and the cryoprotectant is a sugar or sugar alcohol. In one embodiment, the aqueous composition or the aqueous composition of reconstruction comprises a cryoprotectant of about 25mg / mL to about 125mg / mL, and the cryoprotectant is a sugar or sugar alcohol. In a preferred embodiment, the aqueous composition or the aqueous composition of reconstruction comprises a cryoprotectant of about 50mg / mL to about 100mg / mL, and the cryoprotectant is a sugar or sugar alcohol. In another preferred embodiment, the aqueous composition or the aqueous composition of reconstruction comprises a cryoprotectant of about 75mg / mL to about 125mg / mL (e.g., about 100mg / mL), and the cryoprotectant is a sugar or sugar alcohol. In one embodiment, the cryoprotectant is sucrose.

[0090] In one embodiment, the aqueous composition or the aqueous composition of reconstruction comprises a cryoprotectant of an amount of about 1mg / mL to about 100mg / mL, and the cryoprotectant is an amino acid or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the aqueous composition or the aqueous composition of reconstruction comprises a cryoprotectant of an amount of about 25mg / mL to about 75mg / mL (e.g., about 50mg / mL), and the cryoprotectant is an amino acid or a pharmaceutically acceptable salt thereof. In a more preferred embodiment, the aqueous composition or the aqueous composition of reconstruction comprises a cryoprotectant of an amount of about 25mg / mL to about 35mg / mL (e.g., about 30mg / mL), and the cryoprotectant is an amino acid or a pharmaceutically acceptable salt thereof. In one embodiment, the cryoprotectant is arginine, preferably arginine HCl.

[0091] In one embodiment, the aqueous composition or the reconstituted aqueous composition comprises two cryoprotectants, wherein the total amount of the two cryoprotectants is about 25 mg / mL to about 150 mg / mL, preferably wherein the two cryoprotectants are a sugar or sugar alcohol and an amino acid. In a preferred embodiment, the aqueous composition or the reconstituted aqueous composition comprises two cryoprotectants, wherein the total amount of the two cryoprotectants is about 50 mg / mL to about 125 mg / mL, preferably wherein the two cryoprotectants are a sugar or sugar alcohol and an amino acid, for example wherein the two cryoprotectants are a sugar or sugar alcohol and an amino acid or a pharmaceutically acceptable salt thereof.

[0092] In a preferred embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition further comprises sucrose and CMC or a pharmaceutically acceptable salt thereof. In a more preferred embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition further comprises sucrose and sodium CMC.

[0093] In a preferred embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition further comprises arginine or a pharmaceutically acceptable salt thereof and CMC or a pharmaceutically acceptable salt thereof. In a more preferred embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition further comprises arginine hydrochloride and CMC sodium.

[0094] In a preferred embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition further comprises arginine or a pharmaceutically acceptable salt thereof. In a more preferred embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition further comprises arginine hydrochloride.

[0095] In one embodiment, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition is from about 1:10 (w / w) to about 10:1 (w / w).

[0096] In one embodiment, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus 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 pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus 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 pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition is from about 2:1 (w / w) to about 10:1 (w / w). In one embodiment, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition is from about 2:1 (w / w) to about 7:1 (w / w). In a preferred embodiment, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition is from about 3:1 (w / w) to about 6:1 (w / w).

[0097] In a preferred embodiment, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus 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 pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus 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 pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus 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).

[0098] In one embodiment, the ratio of rilpivirine or a pharmaceutically 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 1:10 (w / w). In one embodiment, the ratio of rilpivirine or a pharmaceutically 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 1:10 (w / w). In one embodiment, the ratio of rilpivirine or a pharmaceutically 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 1:7 (w / w). In a preferred embodiment, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition is about 1:3 (w / w) to about 1:6 (w / w).

[0099] In one embodiment, the ratio of CMC or its pharmaceutically acceptable salt to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstructed aqueous composition is about 1:1 (w / w) to about 1:150 (w / w). In one embodiment, the ratio of CMC or its pharmaceutically acceptable salt to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstructed aqueous composition is about 1:1 (w / w) to about 1:100 (w / w). In one embodiment, the ratio of CMC or its pharmaceutically acceptable salt to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstructed aqueous composition is about 1:1 (w / w) to about 1:50 (w / w). In one embodiment, the ratio of CMC or its pharmaceutically acceptable salt to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstructed aqueous composition is about 1:1 (w / w) to about 1:40 (w / w). In a preferred embodiment, the ratio of CMC or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition is about 1:8 (w / w) to about 1:40 (w / w). In one embodiment, the ratio of CMC or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus the solid composition) or the 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).

[0100] In one embodiment, the cryoprotectant is arginine, such as arginine HCl, and the ratio of CMC or a pharmaceutically 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, such as arginine HCl, and the ratio of CMC or a pharmaceutically 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, such as arginine HCl, and the ratio of CMC or a pharmaceutically 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, such as arginine HCl, and the ratio of CMC or its pharmaceutically acceptable salt 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, such as arginine HCl, and the ratio of CMC or its pharmaceutically acceptable salt 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, such as arginine HCl, and the ratio of CMC or its pharmaceutically acceptable salt 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), for example, about 1:10 (w / w).

[0101] In one embodiment, the cryoprotectant is sucrose, and the ratio of CMC or its pharmaceutically acceptable salt to the cryoprotectant in the aqueous composition (and thus 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 its pharmaceutically acceptable salt to the cryoprotectant in the aqueous composition (and thus 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 its pharmaceutically acceptable salt to the cryoprotectant in the aqueous composition (and thus 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 pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition is about 1:30 (w / w) to about 1:35 (w / w), for example about 1:33 (w / w).

[0102] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition further comprises one or more surface modifiers. When rilpivirine or a pharmaceutically acceptable salt thereof is in the form of particles as defined herein, the one or more surface modifiers are adsorbed onto the surface of the particles.

[0103] The surface modifier can be selected from known organic and inorganic pharmaceutical excipients, including various polymers, low molecular weight oligomers, natural products and surfactants. Specific surface modifiers that can be used in the present invention include nonionic and anionic surfactants. Representative examples of surface modifiers include gelatin, casein, lecithin, salts of negatively charged phospholipids or their acid forms (such as phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphoric acid and their salts, such as alkali metal salts, such as their sodium salts, such as sodium phosphatidylglycerol, such as Lipoid TM EPG products), gum arabic, stearic acid, benzalkonium chloride, polyoxyethylene alkyl ethers (e.g., polyethylene glycol ethers, such as cetomacrogol 1000), polyoxyethylene castor oil derivatives; polyoxyethylene stearate, colloidal silicon dioxide, sodium lauryl sulfate, bile salts (such as sodium taurocholate, sodium deoxytaurocholate, sodium deoxycholate); methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, polyvinyl alcohol (PVA), poloxamers (such as Pluronic TMF68, F108 and F127, which are block copolymers of ethylene oxide and propylene oxide); tyloxapol; vitamin E-TGPS (alpha-tocopheryl polyethylene glycol succinate, particularly alpha-tocopheryl polyethylene glycol 1000 succinate); poloxamines such as Tetronic TM 908 (T908), which is a tetrafunctional block copolymer derived from the sequential addition of ethylene oxide and propylene oxide to ethylenediamine; dextran; lecithin; dioctyl ester of sodium sulfosuccinate, such as sold under the trade name Aerosol OT TM (AOT) products sold; Sodium Lauryl Sulfate (Duponol TM P); trade name Triton TM X-200 obtained alkyl aryl polyether sulfonate; polyoxyethylene sorbitan fatty acid ester (Tweens TM 20, 40, 60 and 80); sorbitan esters of fatty acids (Span TM 20, 40, 60 and 80 or Arlacel TM 20, 40, 60 and 80); polyethylene glycol (such as those sold under the trade name Carbowax TM 3550 and 934); sucrose stearate and sucrose distearate mixtures, such as those sold under the trade names Crodesta TM F110 or Crodesta TM SL-40 obtained product; hexyldecyltrimethylammonium chloride (CTAC); polyvinylpyrrolidone (PVP). If necessary, two or more surface modifiers can be used in combination.

[0104] In one embodiment, the surface modifier is selected from the group consisting of poloxamers, α-tocopheryl polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid esters, and salts or acid forms of negatively charged phospholipids. In one embodiment, the surface modifier is selected from the group consisting of Pluronic TM F108, vitamin E TGPS (α-tocopheryl polyethylene glycol succinate, especially α-tocopheryl polyethylene glycol 1000 succinate), polyoxyethylene sorbitan fatty acid esters such as Tween TM 80, and phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatic acid; and salts thereof, such as alkali metal salts, for example, sodium salts thereof, for example, sodium egg phosphatidylglycerol, such as those sold under the trade name Lipoid TM Products available from EPG.

[0105] In a preferred embodiment, the surface modifier is a poloxamer, particularly Pluronic TMF108. Pluronic TM F108 corresponds to poloxamer 338, which is a block copolymer of polyoxyethylene and polyoxypropylene, usually conforming to the formula HO-[CH2CH2O] x -[CH(CH3)CH2O] y -[CH2CH2O] z -H, where the average values ​​of x, y, and z are 128, 54, and 128, respectively. Other commercial names for Poloxamer 338 are Hodag Nonionic TM 1108-F and Synperonic TM PE / F108. In one embodiment, the surface modifier comprises a combination of polyoxyethylene sorbitan fatty acid esters and phosphatidylglycerol salts (particularly sodium egg phosphatidylglycerol).

[0106] In one embodiment, the aqueous composition (and therefore the solid composition) or the aqueous composition of reconstruction comprises about 0.1mg / mL to about 100mg / mL of poloxamer. In one embodiment, the aqueous composition (and therefore the solid composition) or the aqueous composition of reconstruction comprises about 1mg / mL to about 100mg / mL of poloxamer. In one embodiment, the aqueous composition (and therefore the solid composition) or the aqueous composition of reconstruction comprises about 5mg / mL to about 100mg / mL of poloxamer. In one embodiment, the aqueous composition (and therefore the solid composition) or the aqueous composition of reconstruction comprises about 5mg / mL to about 70mg / mL of poloxamer. In one embodiment, the aqueous composition (and therefore the solid composition) or the aqueous composition of reconstruction comprises about 5mg / mL to about 60mg / mL of poloxamer.

[0107] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstructed 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 reconstructed aqueous composition comprises from about 5 mg / mL to about 20 mg / mL (e.g., about 20 mg / mL) of poloxamer. In a preferred embodiment, the aqueous composition (and thus the solid composition) or the reconstructed aqueous composition comprises from about 5 mg / mL to about 15 mg / mL (e.g., about 10 mg / mL) of poloxamer.

[0108] 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 particularly preferred embodiments, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises from about 40 mg / mL to about 60 mg / mL (e.g., about 50 mg / mL) of poloxamer.

[0109] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises a poloxamer and rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, wherein when rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is less than about 15: 1 (w / w). In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises a poloxamer and rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, wherein when rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is from about 15: 1 (w / w) to about 3: 1 (w / w). In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises a poloxamer and rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, wherein when rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is from about 15: 1 (w / w) to about 4: 1 (w / w). In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises a poloxamer and rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, wherein when rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is from about 15: 1 (w / w) to about 6: 1 (w / w). In a preferred embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises a poloxamer and rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is about 6:1 (w / w) when the rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than about 1600 nm.

[0110] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being greater than about 15:1 (w / w), and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 1 μm to about 10 μm, about 2 μm to about 9 μm, about 3 μm to about 8 μm, or about 3 μm to about 7 μm. In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being from about 15:1 (w / w) to about 60:1 (w / w), and the rilpivirine or a pharmaceutically acceptable salt thereof having 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 thus the solid composition) or the reconstituted aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being from about 20:1 (w / w) to about 60:1 (w / w), and the rilpivirine or a pharmaceutically acceptable salt thereof having 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 thus the solid composition) or the reconstituted aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 30:1 (w / w) to about 60:1 (w / w), and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 1 μm to about 10 μm, about 2 μm to about 9 μm, about 3 μm to about 8 μm, or about 3 μm to about 7 μm. In a preferred embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 30:1 (w / w), and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 1 μm to about 10 μm, about 2 μm to about 9 μm, about 3 μm to about 8 μm, or about 3 μm to about 7 μm (e.g., about 4 μm to about 6 μm).

[0111] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being less than about 15: 1 (w / w), and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 3: 1 (w / w) to about 15: 1 (w / w), and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 4: 1 (w / w) to about 15: 1 (w / w), and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm. In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 6: 1 (w / w) to about 15: 1 (w / w), and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm. In a preferred embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof, and a poloxamer in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer being about 6:1 (w / w), and the rilpivirine or a pharmaceutically acceptable salt thereof having a Dv90 of about 500 nm to about 1600 nm (e.g., about 500 nm to about 700 nm).

[0112] In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is from about 1:1 to about 40:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is from about 1:1 to about 35:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is from about 15:1 to about 35:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is from about 25:1 to about 35:1, for example, about 30:1. The surface modifier is preferably a poloxamer, for example, poloxamer 338.

[0113] In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is about 5:1 to about 25:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is about 10:1 to about 20:1. In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is about 13:1 to about 17:1, for example about 15:1. The surface modifier is preferably a poloxamer, for example poloxamer 338.

[0114] In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier (e.g., poloxamer) is less than about 15: 1. In a preferred embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier (e.g., poloxamer such as poloxamer 338) is less than about 12: 1.

[0115] In one embodiment, the relative amount (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the surface modifier is about 1:2 to about 20:1, in particular about 1:1 to about 10:1, such as about 4:1 to about 8:1, for example about 4:1 to about 6:1, preferably about 6: 1. The surface modifier is preferably a poloxamer, for example poloxamer 338.

[0116] In one embodiment, the aqueous composition or the reconstituted aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof as defined herein, and one or more surface modifiers as defined herein, in the form of particles suspended in the aqueous composition or the reconstituted aqueous composition, wherein the amount of rilpivirine or a pharmaceutically acceptable salt thereof is at least about 50% by weight of the particles, at least about 80% by weight of the particles, at least about 85% by weight of the particles, at least about 90% by weight of the particles, at least about 95% by weight of the particles, or at least about 99% by weight of the particles, in particular a range between 80% and 90% by weight of the particles or a range between 85% and 90% by weight of the particles.

[0117] Aqueous compositions or reconstituted aqueous compositions comprise water, such as sterile water for injection.

[0118] In one embodiment, the aqueous composition (and therefore the solid composition) or the aqueous composition of reconstruction further comprises a buffer and / or a pH adjusting agent.Specific buffer is a weak acid salt.The buffer and pH adjusting agent that can be added can be selected from tartaric acid, maleic acid, glycine, sodium lactate / lactic acid, ascorbic acid, sodium citrate / citric acid, sodium acetate / acetic acid, sodium bicarbonate / carbonic acid, sodium succinate / succinic acid, sodium benzoate / benzoic acid, sodium phosphate, tris (hydroxymethyl) aminomethane, sodium bicarbonate / sodium carbonate, ammonium hydroxide, benzenesulfonic acid, sodium benzoate / acid, diethanolamine, glucono delta lactone, hydrochloric acid, hydrogen bromide, lysine, methanesulfonic acid, monoethanolamine, sodium hydroxide, tromethamine, gluconic acid, glyceric acid, glutaric acid, ethylenediaminetetraacetic acid (EDTA), triethanolamine, including their mixture.In one embodiment, buffer is a sodium phosphate buffer, such as sodium dihydrogen phosphate monohydrate.In one embodiment, pH adjusting agent is sodium hydroxide. In a preferred embodiment, the aqueous composition or reconstituted aqueous composition comprises a buffer and a pH adjuster, wherein the buffer is sodium dihydrogen phosphate monohydrate and the pH adjuster is sodium hydroxide.

[0119] In one embodiment, the pH of the aqueous composition or the reconstituted aqueous composition is from about 5 to about 7. In one embodiment, the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 7. In one embodiment, the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5. In a preferred embodiment, the pH of the aqueous composition or the reconstituted aqueous composition is about 6. The pH of the aqueous composition or the reconstituted aqueous composition can be adjusted by, for example, changing the type and / or amount of buffer and / or pH adjuster present in the aqueous composition.

[0120] 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 a preferred embodiment, the chelating agent is citric acid, such as citric acid monohydrate.

[0121] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstructed aqueous composition further comprises an antioxidant. In one embodiment, the antioxidant is methionine. In one embodiment, the aqueous composition (and thus the solid composition) or the reconstructed aqueous composition comprises about 1.0 mg / mL to about 2.0 mg / mL (e.g., about 1.5 mg / mL) of an antioxidant (e.g., methionine).

[0122] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition does not comprise an isotonicity agent.

[0123] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition does not comprise glucose.

[0124] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition does not comprise mannitol.

[0125] In one embodiment, the aqueous composition (and thus the solid composition) or the reconstituted aqueous composition does not comprise polyvinylpyrrolidone (PVP).

[0126] The aqueous composition and the reconstructed aqueous composition can effectively have a molar osmotic pressure concentration suitable for reducing pain during subcutaneous injection. For example, in one embodiment, the aqueous composition and the reconstructed aqueous composition have a molar osmotic pressure concentration of about 280mOsm / kg to about 600mOsm / kg. In one embodiment, the aqueous composition and the reconstructed aqueous composition have a molar osmotic pressure concentration of about 280mOsm / kg to about 300mOsm / kg. In a preferred embodiment, the aqueous composition and the reconstructed aqueous composition have a molar osmotic pressure concentration of about 290mOsm / kg.

[0127] In one embodiment, the aqueous composition of the present invention or the reconstituted aqueous composition can be contained in a container with an inert gas. The inert gas can be, for example, nitrogen.

[0128] The following specific embodiments are also part of the present invention.

[0129] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0130] Hyaluronidase;

[0131] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0132] CMC or a pharmaceutically acceptable salt thereof,

[0133] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 7,

[0134] Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of a surfactant (e.g., poloxamer), a buffer (e.g., sodium dihydrogen phosphate), a chelating agent (e.g., citric acid), and a pH adjuster (e.g., sodium hydroxide), further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0135] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0136] rHuPH20;

[0137] Rilpivirine; and

[0138] Sodium CMC,

[0139] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5,

[0140] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0141] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0142] rHuPH20;

[0143] Rilpivirine; and

[0144] Sodium CMC,

[0145] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5, and

[0146] wherein the aqueous composition comprises about 0.5 mg CMC sodium / 100 U rHuPH20 to about 2 mg CMC sodium / 100 U rHuPH20,

[0147] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0148] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0149] rHuPH20;

[0150] Rilpivirine; and

[0151] Sodium CMC,

[0152] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5, and

[0153] wherein the aqueous composition comprises about 0.05 mg CMC sodium / 100 U rHuPH20 to about 0.25 mg CMC sodium / 100 U rHuPH20,

[0154] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0155] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0156] Hyaluronidase;

[0157] Rilpivirine or a pharmaceutically acceptable salt thereof;

[0158] CMC or a pharmaceutically acceptable salt thereof; and

[0159] Cryoprotectants,

[0160] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 7,

[0161] Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of a surfactant (e.g., poloxamer), a buffer (e.g., sodium dihydrogen phosphate), a chelating agent (e.g., citric acid), and a pH adjuster (e.g., sodium hydroxide), further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0162] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0163] rHuPH20;

[0164] Rilpivirine;

[0165] Sodium CMC; and

[0166] Sugar or sugar alcohol,

[0167] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5,

[0168] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0169] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0170] rHuPH20;

[0171] Rilpivirine;

[0172] Sodium CMC; and

[0173] Mannitol and / or sucrose,

[0174] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5,

[0175] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0176] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0177] rHuPH20;

[0178] Rilpivirine;

[0179] Sodium CMC; and

[0180] sucrose,

[0181] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5,

[0182] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0183] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0184] rHuPH20;

[0185] Rilpivirine;

[0186] Sodium CMC; and

[0187] sucrose,

[0188] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5,

[0189] wherein the aqueous composition or the reconstituted aqueous composition comprises about 0.05 mg CMC sodium / 100 U rHuPH20 to about 0.25 mg CMC sodium / 100 U rHuPH20,

[0190] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0191] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0192] rHuPH20;

[0193] Rilpivirine;

[0194] Sodium CMC; and

[0195] Mannitol and / or sucrose,

[0196] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5,

[0197] wherein the aqueous composition or the reconstituted aqueous composition comprises about 0.5 mg CMC sodium / 100 U rHuPH20 to about 2 mg CMC sodium / 100 U rHuPH20,

[0198] wherein the ratio of sodium CMC to mannitol or sucrose is from about 1:4 (w / w) to about 1:11 (w / w), and

[0199] wherein the ratio of rilpivirine to mannitol or sucrose is about 2:1 (w / w) to about 7:1 (w / w),

[0200] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0201] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0202] rHuPH20;

[0203] Rilpivirine;

[0204] Sodium CMC; and

[0205] sucrose,

[0206] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5,

[0207] wherein the aqueous composition or the reconstituted aqueous composition comprises about 0.05 mg CMC sodium / 100 U rHuPH20 to about 0.25 mg CMC sodium / 100 U rHuPH20,

[0208] wherein the ratio of sodium CMC to sucrose is from about 1:30 (w / w) to about 1:35 (w / w), and

[0209] wherein the ratio of rilpivirine to sucrose is about 2:1 (w / w) to about 7:1 (w / w),

[0210] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0211] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0212] Hyaluronidase;

[0213] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0214] Cryoprotectants,

[0215] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 7,

[0216] Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of a surfactant (e.g., poloxamer), a buffer (e.g., sodium dihydrogen phosphate), a chelating agent (e.g., citric acid), and a pH adjuster (e.g., sodium hydroxide), further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0217] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0218] rHuPH20;

[0219] Rilpivirine; and

[0220] An amino acid or a pharmaceutically acceptable salt thereof,

[0221] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5,

[0222] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0223] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0224] rHuPH20;

[0225] Rilpivirine; and

[0226] Arginine HCl,

[0227] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5,

[0228] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0229] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0230] rHuPH20;

[0231] Rilpivirine;

[0232] CMC or a pharmaceutically acceptable salt thereof; and

[0233] Arginine HCl,

[0234] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5,

[0235] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0236] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0237] rHuPH20;

[0238] Rilpivirine;

[0239] Sodium CMC; and

[0240] Arginine HCl,

[0241] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5,

[0242] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0243] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0244] rHuPH20;

[0245] Rilpivirine; and

[0246] Arginine HCl,

[0247] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5, and

[0248] wherein the ratio of rilpivirine to arginine HCl is about 1:1 (w / w) to about 20:1 (w / w),

[0249] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0250] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0251] rHuPH20;

[0252] Rilpivirine; and

[0253] Arginine HCl,

[0254] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5, and

[0255] wherein the ratio of rilpivirine to arginine is about 2:1 (w / w) to about 7:1 (w / w),

[0256] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0257] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0258] rHuPH20;

[0259] Rilpivirine; and

[0260] Arginine HCl,

[0261] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5, and

[0262] wherein the ratio of rilpivirine to arginine HCl is about 2:1 (w / w) to about 7:1 (w / w),

[0263] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0264] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0265] rHuPH20;

[0266] Rilpivirine;

[0267] CMC or a pharmaceutically acceptable salt thereof; and

[0268] Arginine HCl,

[0269] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5, and

[0270] wherein the ratio of rilpivirine to arginine HCl is about 1:1 (w / w) to about 20:1 (w / w),

[0271] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0272] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0273] rHuPH20;

[0274] Rilpivirine;

[0275] CMC or a pharmaceutically acceptable salt thereof; and

[0276] Arginine HCl,

[0277] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5,

[0278] wherein the ratio of rilpivirine to arginine HCl is about 1:1 (w / w) to about 20:1 (w / w),

[0279] wherein the ratio of CMC or a pharmaceutically acceptable salt thereof to arginine HCl is about 1:5 (w / w) to about 1:10 (w / w).

[0280] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0281] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0282] rHuPH20;

[0283] Rilpivirine;

[0284] CMC or a pharmaceutically acceptable salt thereof; and

[0285] Arginine HCl,

[0286] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5,

[0287] wherein the aqueous composition or the reconstituted aqueous composition comprises about 0.05 mg CMC or a pharmaceutically acceptable salt thereof / 100 U rHuPH20 to about 0.25 mg CMC or a pharmaceutically acceptable salt thereof / 100 U rHuPH20,

[0288] wherein the ratio of rilpivirine to arginine HCl is about 1:1 (w / w) to about 20:1 (w / w),

[0289] wherein the ratio of CMC or a pharmaceutically acceptable salt thereof to arginine HCl is about 1:5 (w / w) to about 1:10 (w / w).

[0290] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0291] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0292] rHuPH20;

[0293] Rilpivirine;

[0294] Sodium CMC; and

[0295] Arginine HCl,

[0296] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5, and

[0297] wherein the ratio of rilpivirine to arginine HCl is about 1:1 (w / w) to about 20:1 (w / w),

[0298] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0299] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0300] Hyaluronidase;

[0301] Rilpivirine or a pharmaceutically acceptable salt thereof; and

[0302] Two cryoprotectants,

[0303] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 7,

[0304] Optionally, the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of a surfactant (e.g., poloxamer), a buffer (e.g., sodium dihydrogen phosphate), a chelating agent (e.g., citric acid), and a pH adjuster (e.g., sodium hydroxide), further optionally, the aqueous composition or the reconstituted aqueous composition further comprises poloxamer, sodium dihydrogen phosphate, citric acid, and sodium hydroxide.

[0305] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0306] rHuPH20;

[0307] Rilpivirine; and

[0308] Sugar or sugar alcohol and amino acid or pharmaceutically acceptable salts thereof,

[0309] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5,

[0310] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0311] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0312] rHuPH20;

[0313] Rilpivirine; and

[0314] Sugar or sugar alcohol and amino acid or pharmaceutically acceptable salts thereof,

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

[0316] wherein the ratio of rilpivirine to the sugar or sugar alcohol and the amino acid or a pharmaceutically acceptable salt thereof is from about 2:1 (w / w) to about 7:1 (w / w),

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

[0318] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0319] rHuPH20;

[0320] Rilpivirine; and

[0321] Sugar or sugar alcohol and amino acid or pharmaceutically acceptable salts thereof,

[0322] wherein the pH of the aqueous composition or the reconstituted aqueous composition is from about 6 to about 6.5, and

[0323] wherein the ratio of rilpivirine to the sugar or sugar alcohol and the amino acid or a pharmaceutically acceptable salt thereof is from about 1:1 (w / w) to about 20:1 (w / w),

[0324] Optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises one or more components selected from the group consisting of: poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide, further optionally wherein the aqueous composition or the reconstituted aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0325] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0326] rHuPH20;

[0327] Rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0328] Sodium CMC;

[0329] Sucrose; and

[0330] Poloxamer 338,

[0331] Optionally wherein when rilpivirine has a Dv90 of less than about 1600 nm, the ratio of rilpivirine to poloxamer 338 is from about 3:1 (w / w) to or about 15:1 (w / w), such as about 6:1 (w / w).

[0332] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0333] rHuPH20;

[0334] Rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0335] Sodium CMC;

[0336] Sucrose; and

[0337] Poloxamer 338,

[0338] Optionally wherein 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), such as about 6:1 (w / w).

[0339] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0340] about 1800 U / mL to about 2200 U / mL of rHuPH20;

[0341] about 250 mg / mL to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0342] about 1 mg / mL to about 5 mg / mL of sodium CMC;

[0343] about 75 mg / mL to about 125 mg / mL of sucrose; and

[0344] about 5 mg / mL to about 60 mg / mL of Poloxamer 338,

[0345] Optionally wherein when rilpivirine has a Dv90 of less than about 1600 nm, the ratio of rilpivirine to poloxamer 338 is from about 3:1 (w / w) to or about 15:1 (w / w), such as about 6:1 (w / w).

[0346] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0347] about 1800 U / mL to about 2200 U / mL of rHuPH20;

[0348] about 250 mg / mL to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0349] about 1 mg / mL to about 5 mg / mL of sodium CMC;

[0350] about 75 mg / mL to about 125 mg / mL of sucrose; and

[0351] about 5 mg / mL to about 60 mg / mL of Poloxamer 338,

[0352] Optionally wherein 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), such as about 6:1 (w / w).

[0353] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0354] About 2000 U / mL of rHuPH20;

[0355] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0356] About 3 mg / mL of CMC sodium;

[0357] about 100 mg / mL sucrose; and

[0358] About 50 mg / mL of Poloxamer 338.

[0359] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0360] About 2000 U / mL of rHuPH20;

[0361] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0362] About 3 mg / mL of CMC sodium;

[0363] about 100 mg / mL sucrose; and

[0364] about 50 mg / mL of poloxamer 338;

[0365] Wherein the particles have a Dv90 of about 1 μm to about 10 μm.

[0366] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0367] About 2000 U / mL of rHuPH20;

[0368] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0369] About 3 mg / mL of CMC sodium;

[0370] about 100 mg / mL sucrose; and

[0371] about 50 mg / mL of poloxamer 338;

[0372] Wherein the particles have a Dv90 of less than about 1600 nm.

[0373] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0374] about 1800 U / mL to about 2200 U / mL of rHuPH20;

[0375] about 250 mg / mL to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0376] about 1 mg / mL to about 5 mg / mL of sodium CMC;

[0377] about 75 mg / mL to about 125 mg / mL of sucrose; and

[0378] about 5 mg / mL to about 15 mg / mL of Poloxamer 338,

[0379] Wherein the particles have a Dv90 of about 1 μm to about 10 μm.

[0380] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0381] About 2000 U / mL of rHuPH20;

[0382] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0383] About 3 mg / mL of CMC sodium;

[0384] about 100 mg / mL sucrose; and

[0385] About 10 mg / mL of Poloxamer 338,

[0386] Wherein the particles have a Dv90 of about 1 μm to about 10 μm.

[0387] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0388] About 2000 U / mL of rHuPH20;

[0389] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0390] About 3 mg / mL of CMC sodium;

[0391] About 100 mg / mL of sucrose;

[0392] About 10 mg / mL of Poloxamer 338,

[0393] About 2mg / mL of NaH2PO4.H2O,

[0394] About 1mg / mL of citric acid.H2O,

[0395] Sodium hydroxide (qs to pH 6), and

[0396] Water (add to 1 mL),

[0397] Wherein the particles have a Dv90 of about 1 μm to about 10 μm.

[0398] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0399] About 2000 U / mL of rHuPH20;

[0400] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0401] About 3 mg / mL of CMC sodium;

[0402] About 100 mg / mL of sucrose;

[0403] About 50 mg / mL of Poloxamer 338,

[0404] About 2mg / mL of NaH2PO4.H2O,

[0405] About 1mg / mL of citric acid.H2O,

[0406] Sodium hydroxide (qs to pH 6), and

[0407] Water (add to 1 mL as needed).

[0408] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0409] rHuPH20;

[0410] Rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0411] Sodium CMC;

[0412] Arginine HCl; and

[0413] Poloxamer 338,

[0414] Optionally wherein when rilpivirine has a Dv90 of less than about 1600 nm, the ratio of rilpivirine to poloxamer 338 is from about 3:1 (w / w) to or about 15:1 (w / w), such as about 6:1 (w / w).

[0415] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0416] rHuPH20;

[0417] Rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0418] Sodium CMC;

[0419] Arginine HCl; and

[0420] Poloxamer 338,

[0421] Optionally wherein 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), such as about 6:1 (w / w).

[0422] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0423] about 1800 U / mL to about 2200 U / mL of rHuPH20;

[0424] about 250 mg / mL to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0425] about 1 mg / mL to about 5 mg / mL of sodium CMC;

[0426] about 25 mg / mL to about 35 mg / mL of arginine HCl; and

[0427] about 5 mg / mL to about 60 mg / mL of Poloxamer 338,

[0428] Optionally wherein when rilpivirine has a Dv90 of less than about 1600 nm, the ratio of rilpivirine to poloxamer 338 is from about 3:1 (w / w) to or about 15:1 (w / w), such as about 6:1 (w / w).

[0429] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0430] about 1800 U / mL to about 2200 U / mL of rHuPH20;

[0431] about 250 mg / mL to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0432] about 1 mg / mL to about 5 mg / mL of sodium CMC;

[0433] about 25 mg / mL to about 35 mg / mL of arginine HCl; and

[0434] about 5 mg / mL to about 60 mg / mL of Poloxamer 338,

[0435] Optionally wherein 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), such as about 6:1 (w / w).

[0436] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0437] About 2000 U / mL of rHuPH20;

[0438] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0439] About 3 mg / mL of CMC sodium;

[0440] about 30 mg / mL of arginine HCl; and

[0441] About 50 mg / mL of Poloxamer 338.

[0442] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0443] About 2000 U / mL of rHuPH20;

[0444] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0445] About 3 mg / mL of CMC sodium;

[0446] about 30 mg / mL of arginine HCl; and

[0447] about 50 mg / mL of poloxamer 338;

[0448] Wherein the particles have a Dv90 of about 1 μm to about 10 μm.

[0449] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0450] About 2000 U / mL of rHuPH20;

[0451] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0452] About 3 mg / mL of CMC sodium;

[0453] about 30 mg / mL of arginine HCl; and

[0454] about 50 mg / mL of poloxamer 338;

[0455] Wherein the particles have a Dv90 of less than about 1600 nm.

[0456] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0457] about 1800 U / mL to about 2200 U / mL of rHuPH20;

[0458] about 250 mg / mL to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0459] about 1 mg / mL to about 5 mg / mL of sodium CMC;

[0460] about 25 mg / mL to about 35 mg / mL of arginine HCl; and

[0461] about 5 mg / mL to about 15 mg / mL of Poloxamer 338,

[0462] Wherein the particles have a Dv90 of about 1 μm to about 10 μm.

[0463] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0464] About 2000 U / mL of rHuPH20;

[0465] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0466] About 3 mg / mL of CMC sodium;

[0467] about 30 mg / mL of arginine HCl; and

[0468] About 10 mg / mL of Poloxamer 338,

[0469] Wherein the particles have a Dv90 of about 1 μm to about 10 μm.

[0470] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0471] About 2000 U / mL of rHuPH20;

[0472] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0473] About 3 mg / mL of CMC sodium;

[0474] About 30 mg / mL of arginine HCl;

[0475] About 10 mg / mL of Poloxamer 338,

[0476] About 2mg / mL of NaH2PO4.H2O,

[0477] About 1mg / mL of citric acid.H2O,

[0478] Sodium hydroxide (qs to pH 6), and

[0479] Water (add to 1 mL),

[0480] Wherein the particles have a Dv90 of about 1 μm to about 10 μm.

[0481] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0482] About 2000 U / mL of rHuPH20;

[0483] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0484] About 3 mg / mL of CMC sodium;

[0485] About 30 mg / mL of arginine HCl;

[0486] About 50 mg / mL of Poloxamer 338,

[0487] About 2mg / mL of NaH2PO4.H2O,

[0488] About 1mg / mL of citric acid.H2O,

[0489] Sodium hydroxide (qs to pH 6), and

[0490] Water (add to 1 mL as needed).

[0491] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0492] about 1800 U / mL to about 2200 U / mL of rHuPH20;

[0493] about 250 mg / mL to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0494] about 1 mg / mL to about 5 mg / mL of sodium CMC;

[0495] about 25 mg / mL to about 35 mg / mL of arginine HCl; and

[0496] about 20 mg / mL to about 75 mg / mL of Poloxamer 338,

[0497] Optionally wherein when rilpivirine has a Dv90 of less than about 1600 nm, the ratio of rilpivirine to poloxamer 338 is from about 3:1 (w / w) to or about 15:1 (w / w), such as about 6:1 (w / w).

[0498] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0499] about 1800 U / mL to about 2200 U / mL of rHuPH20;

[0500] about 250 mg / mL to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0501] about 1 mg / mL to about 5 mg / mL of sodium CMC;

[0502] about 25 mg / mL to about 35 mg / mL of arginine HCl; and

[0503] about 20 mg / mL to about 75 mg / mL of Poloxamer 338,

[0504] Optionally wherein 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), such as about 6:1 (w / w).

[0505] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0506] About 2000 U / mL of rHuPH20;

[0507] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0508] About 3 mg / mL of CMC sodium;

[0509] about 30 mg / mL of arginine HCl; and

[0510] About 50 mg / mL of Poloxamer 338.

[0511] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0512] About 2000 U / mL of rHuPH20;

[0513] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0514] About 3 mg / mL of CMC sodium;

[0515] about 30 mg / mL of arginine HCl; and

[0516] about 50 mg / mL of poloxamer 338;

[0517] Wherein the particles have a Dv90 of about 1 μm to about 10 μm.

[0518] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0519] About 2000 U / mL of rHuPH20;

[0520] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0521] About 3 mg / mL of CMC sodium;

[0522] about 30 mg / mL of arginine HCl; and

[0523] about 50 mg / mL of poloxamer 338;

[0524] Wherein the particles have a Dv90 of less than about 1600 nm.

[0525] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0526] about 1800 U / mL to about 2200 U / mL of rHuPH20;

[0527] about 250 mg / mL to about 350 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0528] about 1 mg / mL to about 5 mg / mL of sodium CMC;

[0529] about 75 mg / mL to about 125 mg / mL of sucrose; and

[0530] about 20 mg / mL to about 75 mg / mL of Poloxamer 338,

[0531] Optionally wherein when rilpivirine has a Dv90 of less than about 1600 nm, the ratio of rilpivirine to poloxamer 338 is from about 3:1 (w / w) to or about 15:1 (w / w), such as about 6:1 (w / w).

[0532] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0533] About 2000 U / mL of rHuPH20;

[0534] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0535] About 3 mg / mL of CMC sodium;

[0536] about 100 mg / mL sucrose; and

[0537] About 50 mg / mL of Poloxamer 338.

[0538] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0539] About 2000 U / mL of rHuPH20;

[0540] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0541] About 3 mg / mL of CMC sodium;

[0542] about 100 mg / mL sucrose; and

[0543] about 50 mg / mL of poloxamer 338;

[0544] Wherein the particles have a Dv90 of less than about 1600 nm.

[0545] In a particular embodiment, the aqueous composition or reconstituted aqueous composition comprises:

[0546] About 2000 U / mL of rHuPH20;

[0547] about 300 mg / mL of rilpivirine in the form of particles suspended in an aqueous composition or a reconstituted aqueous composition;

[0548] About 3 mg / mL of CMC sodium;

[0549] about 100 mg / mL sucrose; and

[0550] about 50 mg / mL of poloxamer 338;

[0551] Wherein the particles have a Dv90 of about 1 μm to about 10 μm.

[0552] The invention also relates to freeze-dried forms corresponding to the specific embodiments described above.

[0553] In any of the above specific embodiments, the aqueous composition or reconstituted aqueous composition may further comprise an antioxidant (eg, methionine), optionally in an amount of about 1.0 mg / mL to about 2.0 mg / mL (eg, 1.5 mg / mL).

[0554] Unless otherwise stated, in any of the above specific embodiments, the particles can have a Dv90 of about 1 μm to about 10 μm (e.g., about 5 μm to about 6 μm). Alternatively, unless otherwise stated, in any of the above specific embodiments, the particles can have a Dv90 of about 500 nm to about 1600 nm (e.g., about 500 nm to about 700 nm).

[0555] The present invention also relates to a solid composition comprising rilpivirine or a pharmaceutically acceptable salt thereof and a hyaluronidase. The solid composition may optionally have the features (e.g., excipients, amounts, and pH) and combinations of features as described herein for the aqueous composition and solid composition of the first aspect of the present invention. Therefore, by way of example only, the present invention also relates to a solid composition comprising rilpivirine or a pharmaceutically acceptable salt thereof, a hyaluronidase, and a cryoprotectant as defined with respect to the first aspect of the present invention.

[0556] The present invention also relates to a solid composition that can be obtained by freeze-drying an aqueous composition, the aqueous composition comprising rilpivirine or a pharmaceutically acceptable salt thereof, optionally wherein the aqueous composition has the characteristics (e.g., excipients, amounts, and pH) and combinations of characteristics as described herein for the aqueous composition and solid composition of the first aspect of the invention. The present invention also relates to a solid composition comprising rilpivirine or a pharmaceutically acceptable salt thereof: the solid composition may optionally have the characteristics (e.g., excipients, amounts, and pH) and combinations of characteristics as described herein for the aqueous composition and solid composition of the first aspect of the invention. In one embodiment, the solid composition does not contain hyaluronidase. The present invention relates to a solid composition having the characteristics of any of the foregoing specific embodiments, only omitting hyaluronidase. The present invention also relates to an aqueous composition or a reconstructed aqueous composition according to any of the foregoing specific embodiments, only omitting hyaluronidase.

[0557] Reconstitution of solid compositions

[0558] The solid composition of the invention may be reconstituted to provide a reconstituted aqueous composition.Accordingly, a second aspect of the invention relates to a reconstituted aqueous composition obtainable by reconstitution of a solid composition as defined herein.

[0559] For the avoidance of doubt, the reconstituted aqueous composition comprises the same components in the same amounts as the aqueous composition of the first aspect of the invention, which is subsequently freeze-dried to provide the solid composition of the first aspect of the invention. Therefore, all embodiments described in the first aspect of the invention regarding the aqueous composition are equally applicable to the reconstituted aqueous composition of the second aspect of the invention. The volume of the reconstituted aqueous composition does not have to be the same as the volume of the aqueous composition of 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 of the first aspect of the invention may have a component concentration of 300 mg / mL, but if it is reconstituted with twice the volume after freeze-drying, the concentration of the component in the reconstituted aqueous composition will be 150 mg / mL.

[0560] In one embodiment, reconstitution comprises adding an aqueous dispersion medium, preferably water, to the solid composition as defined herein.

[0561] In one embodiment, the dispersion medium comprises one or more additional active agents, particularly one or more additional antiretroviral agents, particularly one or more additional antiretroviral agents of another class (eg, an antiretroviral agent of the INSTI class, such as cabotegravir).

[0562] In another embodiment, the aqueous dispersion medium is an aqueous solution of CMC or a pharmaceutically acceptable salt thereof. In another embodiment, the aqueous dispersion medium is an aqueous solution of sodium CMC.

[0563] Freeze drying

[0564] The aqueous compositions described herein can be converted into solid compositions of the present invention by freeze drying the aqueous compositions using standard procedures known in the art. An exemplary procedure is provided below:

[0565] Fill the vial with an aqueous composition. Freeze drying is performed on a laboratory-scale freeze dryer (LyoStar3, SP Scientific, USA). Freeze drying is performed at -40 ° C (shelf inlet temperature) for 60 minutes, including a balance step at +5 ° C, then -5 ° C for 15 minutes each. An annealing step of 90 minutes is implemented at -20 ° C (shelf inlet temperature). Throughout the process, the shelf temperature rise and fall rate from the freezing set point to the primary drying shelf temperature setting is 1 ° C / min. The shelf inlet temperature set point during the primary drying is about -20 ° C, and the secondary drying is about 25 ° C. The holding time (immersion period) of these steps is 600 minutes or 60 minutes to allow the adjustment of the water content in the sample. The chamber pressure during the primary drying 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 was positioned at the bottom center of the vial to obtain representative temperatures monitored in the product and accurate endpoint detection of the ice sublimation stage.

[0566] Use of the composition of the present invention

[0567] The reconstituted aqueous composition can be used to treat or prevent HIV infection in a subject.

[0568] Thus, in a third aspect, the present invention relates to a method for treating or preventing HIV infection in a subject, the method comprising administering to the subject a reconstructed aqueous composition as defined herein. In a fourth aspect, the present invention relates to a reconstructed aqueous composition as defined herein, for treating or preventing HIV infection in a subject. In a fifth aspect, the present invention relates to the use of a reconstructed aqueous composition as defined herein in the preparation of a medicament for treating or preventing HIV infection in a subject. In a sixth aspect, there is provided a solid composition as defined herein, the solid composition being used to treat or prevent HIV infection in a subject. In a seventh aspect, there is provided the use of a solid composition as defined herein in the preparation of a medicament for treating or preventing HIV infection in a subject.

[0569] In a preferred embodiment, the subject is a human.

[0570] In one embodiment, the reconstructed aqueous composition is intermittently applied to the subject so that the time interval between administrations (i.e., dosing interval) is about three months to about two years. In one embodiment, the time interval is about three months to about eighteen months. In one embodiment, the time interval is about three months to about one year. In one embodiment, the time interval is about three months to about six months. In one embodiment, the time interval is about six months to about one year. In one embodiment, the time interval is about one year. In one embodiment, the time interval is about three months. In one embodiment, the time interval is about six months.

[0571] In one embodiment, the reconstituted aqueous composition is intermittently administered to the subject such that the time interval between administrations (i.e., the dosing interval) is about three months, or about four months, or about five months, or about six months, or about seven months, or about eight months, or about nine months, or about ten months, or about eleven months, or about one year, or about one year to about two years.

[0572] In one embodiment, the reconstituted aqueous composition is administered by subcutaneous injection 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.

[0573] In another embodiment, the reconstituted aqueous composition is administered by manual injection.

[0574] Rilpivirine or a pharmaceutically 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.

[0575] In one embodiment, each administration comprises up to about 150mL of a reconstructed aqueous composition as described herein. In another embodiment, each administration comprises about 3mL to about 150mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 3mL to about 100mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 3mL to about 25mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 3mL to about 15mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 5mL to about 25mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 6mL to about 20mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 6mL to about 18mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 6mL to about 15mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 6mL to about 12mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 9mL to about 18mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 9mL to about 15mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 9mL to about 12mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 3mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 4mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 5mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 6mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 7mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 8mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 9mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 12mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 15mL of a reconstructed aqueous composition. In another embodiment, each administration comprises about 18mL of a reconstructed aqueous composition. In a preferred embodiment, each administration comprises about 3mL, about 7mL or about 15mL of a reconstructed aqueous composition.

[0576] In one embodiment, for the treatment of HIV infection, the dose of rilpivirine to be administered can be calculated based on about 300 mg to about 1200 mg / month, or about 450 mg to about 1200 mg / month, or about 450 mg to about 900 mg / month, or about 600 mg to about 900 mg / month, or about 450 mg to about 750 mg / month, or about 450 mg / month, or about 600 mg / month, or about 750 mg / month, or about 900 mg / month. Doses for other dosing regimens can be easily calculated by multiplying the monthly dose by the number of months between each administration. For example, in the case of a dose of 450 mg / month, and in the case of a time interval of 6 months between each administration, the dose of rilpivirine to be administered in each administration is 2700 mg. The "mg" shown corresponds to mg of rilpivirine (i.e., rilpivirine in free base form). Thus, by way of example, 1 mg of rilpivirine (ie rilpivirine in free base form) corresponds to 1.1 mg of rilpivirine hydrochloride.

[0577] In one embodiment, for the treatment of HIV infection, the dose of rilpivirine to be administered can be calculated based on about 300 mg to about 1200 mg / 4 weeks (28 days), or about 450 mg to about 1200 mg / 4 weeks (28 days), or about 450 mg to about 900 mg / 4 weeks (28 days), or about 600 mg to about 900 mg / 4 weeks (28 days), or about 450 mg to about 750 mg / 4 weeks (28 days), or about 450 mg / 4 weeks (28 days), or about 600 mg / 4 weeks (28 days), or about 750 mg / 4 weeks (28 days), or about 900 mg / 4 weeks (28 days). The dosage of other dosing regimens can be easily calculated by multiplying the weekly or daily dose by the number of weeks between each administration. For example, in the case of a dose of 450 mg / 4 weeks (28 days), and in the case of a time interval of 24 weeks between each administration, the dose of rilpivirine to be administered in each administration is 2700 mg. Or, for example, in the case of a dose of 750 mg / 4 weeks (28 days), and in the case of a time interval of 24 weeks between each administration, the dose of rilpivirine to be administered in each administration is 4500 mg. The "mg" shown corresponds to mg of rilpivirine (i.e., rilpivirine in free base form). Thus, by way of example, 1 mg of rilpivirine (i.e., rilpivirine in free base form) corresponds to 1.1 mg of rilpivirine hydrochloride.

[0578] In one embodiment, the rilpivirine or a pharmaceutically 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 above about 12 ng / ml, preferably in the range of about 12 ng / ml to about 100 ng / ml, more preferably about 12 ng / ml to about 50 ng / ml, for at least 3 months after administration, or at least 6 months after administration, or at least 9 months after administration, or at least 1 year after administration, or at least 2 years after each administration. In a preferred embodiment, the rilpivirine or a pharmaceutically acceptable salt thereof in the reconstituted aqueous composition is used in an amount such that the plasma concentration of rilpivirine in the subject is maintained at a level of 12 ng / ml to 100 ng / ml for at least 6 months.

[0579] In the case of prevention of HIV infection, each administration of rilpivirine or a pharmaceutically acceptable salt thereof may comprise the same dose as described above for therapeutic use.

[0580] In one embodiment, the reconstituted aqueous composition is used in combination with one or more other active agents, in particular one or more other antiretroviral agents, in particular one or more other antiretroviral agents of another class, such as, for example, an antiretroviral agent of the INSTI class, such as, for example, cabotegravir.

[0581] In one embodiment, the one or more other antiretroviral agents (e.g., cabotegravir) are administered as intramuscular or subcutaneous injections, particularly as injectable microsuspensions or nanosuspensions, at intervals of about three months to about two years. In one embodiment, the one or more other antiretroviral agents (e.g., cabotegravir) are administered at the same intermittent intervals as the reconstructed aqueous composition (e.g., reconstructed aqueous composition) as described herein, and the other antiretroviral agents are intermittently administered at intervals of about three months, or about four months, or about five months, or about six months, or about seven months, or about eight months, or about ten months, or about eleven months, or about one year, or about one year to about 2 years. In one embodiment, the reconstructed aqueous composition and 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 reconstructed aqueous composition and 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 (e.g., cabotegravir) are administered sequentially, particularly by subcutaneous injection. In one embodiment, the reconstituted aqueous composition is administered first, followed by cabotegravir injection.

[0582] As used herein, the term "treatment of HIV infection" relates to treating a subject infected with HIV. The term "treatment of HIV infection" also relates to treating diseases associated with HIV infection (e.g., AIDS) or other conditions associated with HIV infection (including thrombocytopenia, Kaposi's sarcoma, and central nervous system infections characterized by progressive demyelination, leading to dementia and symptoms such as progressive dysarthria, ataxia, and disorientation), as well as other conditions to which HIV infection is also associated, such as peripheral neuropathy, progressive generalized lymphadenopathy (PGL), and AIDS-related complex (ARC).

[0583] As used herein, the term "prevention of HIV infection" relates to preventing or avoiding a subject (who will not be infected with HIV) from being infected with HIV. The source of infection can be various, containing HIV, particularly containing HIV body fluids, such as blood or semen, or other subjects infected with HIV. Preventing HIV infection relates to preventing the virus from being transmitted to uninfected people from HIV-containing substances or HIV-infected individuals, or relates to preventing the virus from entering the body of an uninfected person. The spread of the HIV virus can be carried out by any known HIV transmission cause (such as by sexual transmission or by contact with the blood of an infected subject (e.g., medical staff providing care for an infected subject)). HIV transmission can also occur by contact with HIV infected blood (e.g., when handling a blood sample or a blood transfusion). It can also be carried out by contact with infected cells (e.g., when HIV infected cells are subjected to laboratory experiments).

[0584] The term "treatment of HIV infection" refers to a treatment that reduces the viral load of HIV (expressed as the number of copies of viral RNA in a specific volume of serum). The more effective the treatment, the lower the viral load. Preferably, the viral load should be reduced to a level as low as possible, for example, below 200 copies / mL, particularly below about 100 copies / mL, more particularly below 50 copies / mL, and if possible, below the detection limit of the virus. A reduction in viral load by one, two or even three orders of magnitude (e.g., a reduction of about 10 to about 10 2 or more, such as about 10 3) is an indication of the effectiveness of treatment. Another parameter measuring the effectiveness of HIV treatment is CD4 count, which ranges from 500 to 1500 cells / μL in normal adults. Reduced CD4 counts are indications of HIV infection, and once less than about 200 cells / μL, AIDS may occur. The increase in CD4 counts, such as an increase of about 50, 100, 200 or more cells per μL, is also an indication of the effectiveness of anti-HIV treatment. In particular, CD4 counts should be increased to a level higher than about 200 cells / μL or higher than about 350 cells / μL. Viral load or CD4 counts or both can be used to diagnose the extent of HIV infection. Another parameter measuring the effectiveness of HIV treatment is when treated according to the present invention, HIV-infected subjects are kept virologically suppressed (HIV-1RNA<50 copies / mL).

[0585] The term "treatment of HIV infection" and similar terms refer to the treatment of reducing viral load, increasing CD4 counts, or both, or maintaining virological suppression in HIV-infected subjects as described above. The term "prevention of HIV infection" and similar terms refer to the situation in which the relative number of newly infected subjects in a population contacted with a HIV infection source (such as a substance containing HIV) or a HIV-infected subject is reduced. For example, when an uninfected individual treated with a pharmaceutical composition of the present invention is compared with an untreated uninfected individual, effective prevention can be measured, for example, by measuring whether the relative number of newly infected individuals is reduced in a mixed population of HIV-infected and uninfected individuals. This reduction can be measured by statistically analyzing the number of infected and uninfected individuals in a given population over time.

[0586] Reagent test kit

[0587] In an eighth aspect, a kit is provided, the kit comprising: (i) a solid composition of the invention as described herein, and (ii) a diluent, in particular a diluent for reconstituting the solid composition (i).

[0588] In a ninth aspect, a kit is provided, comprising: (i) a solid composition of the invention as described herein, (ii) a composition comprising one or more further active agents, in particular one or more further antiretroviral agents, in particular one or more further antiretroviral agents of another class, such as, for example, an antiretroviral agent of the INSTI class, such as, for example, cabotegravir, and optionally (iii) a diluent, in particular a diluent for reconstituting the solid composition (i).

[0589] General Definition

[0590] The term "comprising" encompasses "including" as well as "consisting of", e.g., a composition "comprising" X may consist of only X or may include something else, e.g., X + Y. As used herein, the term "comprising" also encompasses "consisting essentially of", e.g., a composition "comprising" X may consist of X and any other components that do not materially affect the basic characteristics of the composition.

[0591] The term "about" in connection with a value Y is optional and means, for example, Y ± 10%.

[0592] When an interval is expressed as a specified number of months, it runs from a given numbered day in a given month to the same numbered day in the month after the specified number of months. In the event that the same numbered day does not exist in the month after the specified number of months, the interval runs into the next month for the same number of days as it would otherwise run if the same numbered day would exist in the month after the specified number of months.

[0593] When a time interval is expressed as a number of years, it runs from a given date in a given year to the same date in the year that is the specified number of years later. In the event that the same date does not exist in the year that is the specified number of years later, the time interval runs for the same number of days as it would otherwise have run if the same numbered date would have existed in the month that is the specified number of months later. In other words, if the time interval begins on February 29 in a given year, but ends in a year that does not have a February 29, the time period ends on March 1 in that year instead.

[0594] The term "about" in connection with this definition means that the time interval may end on a date that is ±10% of the time interval.

[0595] 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.

[0596] All references cited herein are incorporated by reference in their entirety.

[0597] The present invention will now be described with reference to the following examples. For the avoidance of doubt, these examples do not limit the scope of the present invention. Modifications may be made while remaining within the scope and spirit of the present invention.

[0598] Example

[0599] Example 1 - Melting temperature study under different storage conditions

[0600] This example compares the T of rHuPH20 in various compositions, each with different excipient combinations and / or pH, under different storage conditions. m .

[0601] Higher T m Indicating higher thermal stability. T of about 25°C to about 30°C higher than expected long-term storage conditions m Designed to provide optimal thermodynamic stability of hyaluronidase.

[0602] Compositions 1 to 21 were prepared by adding the components shown in Table 1 below to Composition A below:

[0603] Glucose monohydrate (19.25 mg / mL)

[0604] rHuPH20 (2000U / mL)

[0605] Sodium dihydrogen phosphate monohydrate (2 mg / mL)

[0606] Citric acid monohydrate (1 mg / mL)

[0607] Poloxamer 338 (50 mg / mL)

[0608] Sodium hydroxide (varied to provide target pH)

[0609] Water for injection (add to 1 mL)

[0610] The pH of the composition was adjusted to 5.0, 6.0, 6.5 or 7.0 by varying the amount of sodium hydroxide as needed.

[0611] Composition pH Additional component 1 Additional component 2 1 5.0 - - 2 5.0 Mannitol (50 mg / mL) - 3 5.0 Sucrose (50 mg / mL) - 4 5.0 Histidine (25 mg / mL) - 5 5.0 Glycine (25 mg / mL) - 6 5.0 Glycine (10 mg / mL) Sucrose (50 mg / mL) 7 5.0 Glycine (10 mg / mL) Mannitol (25 mg / mL) 8 6.0 - - 9 6.0 Mannitol (50 mg / mL) - 10 6.0 Sucrose (50 mg / mL) - 11 6.0 Histidine (25 mg / mL) - 12 6.0 Glycine (25 mg / mL) - 13 6.0 Glycine (10 mg / mL) Sucrose (50 mg / mL) 14 6.0 Glycine (10 mg / mL) Mannitol (25 mg / mL) 15 6.5 Glycine (10 mg / mL) Sucrose (50 mg / mL) 16 7.0 Histidine (25 mg / mL) - 17 7.0 Glycine (10 mg / mL) Sucrose (50 mg / mL) 18 7.0 Glycine (10 mg / mL) Mannitol (25 mg / mL) 19 7.0 Glycine (15 mg / mL) - 20 7.0 Glycine (10 mg / mL) - 21 7.0 Glycine (5 mg / mL) -

[0612] Table 1 :T m Research

[0613] Nano differential scanning fluorimetry (nDSF) was used to measure the T m nDSF uses intrinsic tryptophan and tyrosine fluorescence to monitor protein unfolding. The nDSF assay was performed as follows.

[0614] All nDSF assays were run using a Prometheus NT.Plex instrument controlled by PR.ThermControl-CFR software. When measuring samples, a temperature range of 20°C-95°C with a temperature gradient of 1°C / min was used. An excitation power of 95% was used in all cases. The instrument determined the fluorescence ratio of the protein at 350nm (tryptophan) and 330nm (tyrosine) during heating to 95°C. The unfolding onset temperature (T) of the current unfolding transition was then calculated from the unfolding curve. 起始 ) and the inflection point (T m ).

[0615] To enable high-throughput sample testing, the nanoDSF instrument is operated in combination with a robotic autosampler. The autosampler performs the loading and transfer of the capillary chips from the 384-well plate for nanoDSF measurements. The 384-well plate is automatically prepared using a Tecan Fluent760 liquid handling system in combination with a custom sample holder that typically provides 2R vials for sample testing.

[0616] Compositions 1 to 21 were prepared as described above and then stored in a refrigerator at 5°C for 2 days to 2 weeks. T was then measured immediately, after 1 week at 25°C and 2 weeks at 25°C, and under extreme storage conditions (i.e., 1 week at 40°C and 2 weeks at 40°C). m When measuring T m Remeasure the pH of the aqueous composition immediately before taking the value.

[0617] The results are shown in Figure 1 , Figure 1A , Figure 1B and Figure 1C middle.

[0618] Example 2a - Melting Temperature Studies

[0619] This example compares the T of rHuPH20 in various compositions, each with different excipient combinations and / or pH. m .

[0620] Composition B was prepared containing the following excipients:

[0621] Sodium dihydrogen phosphate monohydrate (2 mg / mL)

[0622] Citric acid monohydrate (1 mg / mL)

[0623] rHuPH20 (2000U / mL)

[0624] Sodium hydroxide (varied to provide target pH)

[0625] Water for injection (add to 1 mL)

[0626] Compositions 22 to 44 were prepared by adding the components shown in Table 2 below to Composition B, and the pH was adjusted to 6.0, 6.5, or 7.0 by varying the amount of sodium hydroxide in the composition.

[0627]

[0628]

[0629] Table 2 :T m Research

[0630] Compositions 22 to 44 were prepared as described above and then stored in a refrigerator at 5°C for 2 days to 2 weeks. The T of rHuPH20 of each composition was then immediately measured using the method described in Example 1. m .

[0631] The results are shown in Table 2 and Figure 2 middle.

[0632] Example 2b - Enzyme stability studies under different storage conditions

[0633] This example compares the fluorescence emission spectra of rHuPH20 compositions after storage under different conditions. Fluorescence emission spectroscopy uses a beam absorbed by the enzyme (rHuPH20), and the fluorophore in the ground state is excited to a higher energy state, thereby causing emission. For enzymes such as rHuPH20, the fluorescence of tryptophan can be used to measure the changes in the tertiary enzyme structure during or after storage under different conditions, and therefore quantify the thermal stability of rHuPH20. The maximum emission wavelengths of folded and unfolded rHuPH20 are 330nm and 350nm respectively.

[0634] Spectra of the compositions were collected immediately after storage at 5°C and after one and two weeks of storage at 40°C. In addition to the peak maxima and minima, the intensity ratio 350nm / 330nm was calculated at each time point and plotted as a function of storage time. The slope of this curve was used to perform semi-quantitative thermal stability assessments and comparisons between compositions.

[0635] Composition preparation

[0636] 200 μl of each composition was manually dispensed into the UV- COC, 96-well flat-bottom microtiter plates.

[0637] Fluorescence emission spectra of the samples were measured before and after stress by a Tecan plate reader (Infinite 200). The following method parameters were used:

[0638] temperature:

[0639] Parameters (starting), temperature = 25.0°C

[0640] Waiting temperature:

[0641] ·Parameter minimum value = 24.5℃; maximum value = 25.5℃

[0642] Fluorescence intensity scan:

[0643] Scan selection (transmit scan)

[0644] Mode (top)

[0645] Excitation wavelength: from = 280nm; bandwidth: 230…315: 5nm; 316…850: 9nm

[0646] Emission wavelength: from = 310nm; to = 420nm; step length = 1nm; bandwidth: 280…

[0647] 850: 20nm; 111 measurements

[0648] Integration: lag time = 0 μs; integration time = 20 μs

[0649] Reading: Number of flashes = 25; Settling time = 0ms

[0650] Gain (manual = 95)

[0651] ·Tag: Name = Tag1

[0652] The results are shown in Table 3 below.

[0653]

[0654]

[0655] Table 3 : The slope of the ratio between 350nm / 330nm versus time

[0656] Example 3 - Melting temperature study under different storage conditions

[0657] This example compares the melting temperatures of rHuPH20 in various compositions under different storage conditions.

[0658] Composition C was prepared containing the following excipients:

[0659] rHuPH20 (2000U / mL)

[0660] Sodium dihydrogen phosphate monohydrate (2 mg / mL)

[0661] Citric acid monohydrate (1 mg / mL)

[0662] Poloxamer 338 (50 mg / mL)

[0663] Sodium hydroxide (to pH 6.0)

[0664] Water for injection (add to 1 mL)

[0665] Compositions 45 to 57 were then prepared by adding the components as shown in Table 4 to Composition C, and the pH was adjusted to 6.0 by varying the amount of sodium hydroxide in the composition.

[0666]

[0667]

[0668] Table 4 : T under different storage conditions m

[0669] Compositions 45 to 57 were prepared as described above and then stored in a refrigerator at 5°C for 2 days to 2 weeks. T was measured immediately (ie, "t=0") and after storage at 40°C for 1 week using the method described in Example 1. m value.

[0670] When measuring T m Remeasure the pH of the composition immediately before the value.

[0671] The results are shown in Table 4 and Figure 3 and Figure 3A The T at t = 1 week at 40°C is not shown. m value (i.e., "-" for Tm and its SD), rHuPH20 has decomposed.

[0672] Example 4 - CMC Sodium Concentration

[0673] This example tests T m Dependence on CMC sodium concentration.

[0674] Composition D was prepared containing the following excipients:

[0675] rHuPH20 (2000U / mL)

[0676] Sodium dihydrogen phosphate monohydrate (2 mg / mL)

[0677] Citric acid monohydrate (1 mg / mL)

[0678] Poloxamer 338 (50 mg / mL)

[0679] Sodium hydroxide (to pH 6.0)

[0680] Mannitol (50 mg / mL) or sucrose (100 mg / mL)

[0681] Water for injection (add to 1 mL)

[0682] Compositions 58 to 63 were then prepared by adding sodium CMC as shown in Table 5 below to Composition D, and the pH was adjusted to 6.0 by varying the amount of sodium hydroxide in the composition.

[0683] Composition CMC concentration / mg / mL Sugar / Sugar Alcohols 58 5 Mannitol (50 mg / mL) 59 5 Sucrose (100 mg / mL) 60 10 Mannitol (50 mg / mL) 61 10 Sucrose (100 mg / mL) 62 15 Mannitol (50 mg / mL) 63 15 Sucrose (100 mg / mL)

[0684] Table 5 : CMC sodium concentration

[0685] Compositions 58 to 63 were prepared as described above and then stored in a refrigerator at 5°C for 2 days to 2 weeks. T was then measured using the method described in Example 1. m value.

[0686] The results are shown in Figure 4 middle.

[0687] Example 5 - Rilpivirine Particle Size under Different Storage Conditions

[0688] This example explores the effect of freeze drying an aqueous composition comprising rilpivirine particles in suspension on the particle size of rilpivirine in the corresponding reconstituted aqueous composition. The freeze dried composition was reconstituted immediately (i.e. at time t=0) and after 1 month storage under various conditions and after 6 months storage.

[0689] An aqueous composition of rilpivirine nanoparticles (having a Dv10 of about 96.5 nm, a Dv50 of about 224 nm, and a Dv90 of about 509 nm) and the following excipients was prepared:

[0690] Rilpivirine (300 mg / mL)

[0691] rHuPH20 (2000U / mL)

[0692] Sodium phosphate monohydrate (2 mg / mL)

[0693] Citric acid monohydrate (1 mg / mL)

[0694] Poloxamer 338 (50 mg / mL)

[0695] Sodium hydroxide (qs to pH 6)

[0696] Water for injection (add to 1 mL)

[0697] Additional components as shown in Table 6 were added and the pH was adjusted to 6.0 using sodium hydroxide.

[0698]

[0699]

[0700] Table 6 : Additional components

[0701] At time t=0, the composition was freeze-dried and reconstituted with water to provide 9 mL of the reconstituted aqueous composition, after storage for 1 month at 25°C / 60% RH and 40°C / 75% RH, the composition was freeze-dried and reconstituted with water to provide 9 mL of the reconstituted aqueous composition, and after storage for 6 months at 25°C / 60% RH, the composition was freeze-dried and reconstituted with water to provide 9 mL of the reconstituted aqueous composition. The particle size of rilpivirine was measured in both cases according to the following method.

[0702] The volume-based particle size distribution of the rilpivirine suspension was determined by means of wet dispersion laser diffraction using a Malvern Mastersizer 3000 laser diffractometer (Malvern Instruments) and a Hydro MV wet dispersion module.

[0703] The results are shown in Figure 5 middle.

[0704] At time t=0, particle size was maintained in all compositions after freeze drying and immediate reconstitution.

[0705] Example 6 - Freeze-drying and enzyme stability studies under different storage conditions

[0706] This example explores the effect of freeze-drying an aqueous composition comprising rHuPH20 and rilpivirine on the enzyme stability in the corresponding reconstituted aqueous composition. The freeze-dried composition was reconstituted immediately (ie, at time t=0), after 1 month of storage under various conditions, and after 6 months of storage.

[0707] Aqueous compositions 64 to 70 were prepared as described above in Example 5. After storage for 1 month and 6 months at 25°C / 60%RH, these compositions were freeze-dried and reconstituted with water to provide 9 mL of the reconstituted aqueous composition.

[0708] Enzyme stability was assessed by one or more of the following: (i) activity (bioassay); (ii) quantitation / aggregation (size exclusion chromatography / SEC); and (iii) purity (reverse phase liquid chromatography / RP-LC).

[0709] SEC is a size exclusion chromatography separation method whereby a column is used to distribute the molecules in a solution flowing through it according to their broad size range. Monomers, aggregates and fragments elute from the column at different times and therefore their relative proportions in the sample can be quantified using a standard UV detector.

[0710] The results are shown in Table 8.

[0711]

[0712] *Ox1 and Ox2 are oxidized forms of rHuPH20. Ox1 retains more enzyme activity than Ox2. Ox1 and Ox2 have lower activity than rHuPH20.

[0713] Table 8 :Enzyme stability

[0714] The appearance of all compositions was acceptable. The freeze-dried compositions all had relatively low water content (<1%, as determined by Karl Fisher). IR analysis confirmed that the samples were uniform. The same IR spectra were obtained from samples of the top, middle and bottom of the vials of freeze-dried compositions 64 to 70.

[0715] Example 7 - Freeze Drying and Collapse Temperature Study under Different Storage Conditions

[0716] This example explores the effect of freeze drying an aqueous composition comprising rHuPH20 and rilpivirine on the collapse temperature (T c )’s impact.

[0717] Aqueous compositions 64 to 70 were prepared as described above in Example 5. The compositions were then freeze dried. The collapse temperature was determined.

[0718] The results are shown in Table 9.

[0719]

[0720] "-" means not tested.

[0721] Table 9 : Collapse temperature (T c )

[0722] Example 8 - Freeze-drying, enzyme stability and rilpivirine particle size studies under different storage conditions

[0723] This example explores the effect of freeze drying an aqueous composition comprising rHuPH20 and rilpivirine on collapse temperature, enzyme stability, viscosity and injection force in the corresponding reconstituted aqueous composition. The freeze dried composition was reconstituted immediately (i.e., at time t=0), after 2 weeks, 1 month and 3 months of storage under various conditions.

[0724] An aqueous composition of (i) rilpivirine nanoparticles (having a Dv10 of about 75 nm-200 nm, a Dv50 of about 200 nm-500 nm, and a Dv90 of about 500 nm-1600 nm, i.e., "nano") or (ii) rilpivirine microparticles (having a Dv10 of about 0.2 μm-0.6 μm, a Dv50 of about 1.0 μm-2.5 μm, and a Dv90 of about 4.0 μm-6.5 μm, i.e., "micro") with the following excipients is prepared:

[0725] Rilpivirine (300 mg / mL)

[0726] rHuPH20 (2000U / mL)

[0727] Sodium phosphate monohydrate (2 mg / mL)

[0728] Citric acid monohydrate (1 mg / mL)

[0729] Poloxamer 338 (see Table 10)

[0730] Sodium hydroxide (to pH 6.0)

[0731] Water for injection (add to 1 mL)

[0732] Additional components as shown in Table 10 were added and the pH was adjusted to 6.0 using sodium hydroxide.

[0733]

[0734] T c "-" in the column means not tested Table 10 : Composition and T c

[0735] The compositions were freeze dried and the collapse temperature was determined. The results are shown in Table 10.

[0736] The freeze-dried compositions all had relatively low water content (<1% as determined by Karl Fisher). The appearance of all compositions was acceptable.

[0737] The composition was then reconstituted with water to provide 9 mL of the reconstituted aqueous composition after storage under the following conditions:

[0738] 2 weeks: 50℃ / 75%RH

[0739] 1 month: 30℃ / 75%RH and 40℃ / 75%RH

[0740] 3 months: 30℃ / 75%RH and 40℃ / 75%RH

[0741] Enzyme stability was assessed by one or more of the following: (i) activity (bioassay); (ii) quantitation / aggregation (size exclusion chromatography / SEC) and (iii) purity (reverse phase liquid chromatography / RP-LC).

[0742] Rilpivirine particle size was measured as follows: The volume-based particle size distribution of the rilpivirine suspension was determined by means of wet dispersion laser diffraction using a Malvern Mastersizer 3000 laser diffractometer (Malvern Instruments) and a Hydro MV wet dispersion module.

[0743] The viscosity of the composition was measured using a HAAKE Mars 60 rheometer. 1.5 mL of the reconstructed aqueous composition was taken out from a vial using a 2 mL syringe equipped with an 18G needle. The sample was added dropwise to the plate (without bubbles). A shear rate scan from 0.1 sec-1 to 1000 sec-1 was performed using a 60 / 1° cone and plate.

[0744] Use a 23G× 3 / 4 inch 20mL Luer Lock syringe with winged infusion set to measure injection force.

[0745] The results are shown in Figure 6 , Figure 7 and Figure 8 (Note: Ox1 and Ox2 are oxidized forms of rHuPH20. Ox1 retains more enzyme activity than Ox2. The activities of Ox1 and Ox2 are lower than rHuPH20).

[0746] Example 9 - Enzyme stability study under different storage conditions

[0747] This example compares the fluorescence emission spectra of rHuPH20 compositions after storage under different conditions.

[0748] Aqueous compositions 45 to 57 were prepared as described above in Example 3. Spectra of the compositions were collected immediately after storage at 5°C and after one day of storage at 50°C. In addition to the peak maxima and minima, the intensity ratio 350nm / 330nm was calculated at each time point and plotted as a function of storage time. The slope of this curve was used for semi-quantitative thermal stability assessment and comparison between compositions.

[0749] Composition preparation

[0750] 200 μl of each composition was manually dispensed into the UV- COC, 96-well flat-bottom microtiter plates.

[0751] Fluorescence emission spectra of the samples were measured before and after stress by a Tecan plate reader (Infinite 200). The following method parameters were used:

[0752] temperature:

[0753] Parameters (starting), temperature = 25.0°C

[0754] Waiting temperature:

[0755] ·Parameter minimum value = 24.5℃; maximum value = 25.5℃

[0756] Fluorescence intensity scan:

[0757] Scan selection (transmit scan)

[0758] Mode (top)

[0759] Excitation wavelength: from = 280nm; bandwidth: 230…315: 5nm; 316…850: 9nm

[0760] Emission wavelength: from = 310nm; to = 420nm; step length = 1nm; bandwidth: 280…850:

[0761] 20nm; 111 measurements

[0762] Integration: lag time = 0 μs; integration time = 20 μs

[0763] Reading: Number of flashes = 25; Settling time = 0ms

[0764] Gain (manual = 95)

[0765] ·Tag: Name = Tag1

[0766] The data are shown in Table 11 below.

[0767]

[0768] Table 11 : The slope of the ratio between 350nm / 330nm versus time

[0769] Example 10 - Melting Temperature Study under Different Storage Conditions

[0770] This example compares the melting temperatures of rHuPH20 in various compositions under different storage conditions.

[0771] An aqueous composition of rilpivirine nanoparticles (having a Dv10 of 75nm-200nm, a Dv50 of 200nm-500nm, and a Dv90 of 500nm-1600nm) and the following excipients was prepared:

[0772] rHuPH20 (2000U / mL)

[0773] Sodium dihydrogen phosphate monohydrate (2 mg / mL)

[0774] Citric acid monohydrate (1 mg / mL)

[0775] Poloxamer 338 (50 mg / mL)

[0776] Sodium hydroxide (qs to pH 6)

[0777] Water for injection (add to 1 mL)

[0778] Compositions 86 to 171 were then prepared by adding the components as shown in Table 12, and the pH was adjusted to 6.0 by varying the amount of sodium hydroxide in the composition.

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785] N / A* = Note that for high CMC sodium concentrations (>17 mg / mL), the capillary chip of the nanoDSF instrument could not be loaded, presumably due to high solution viscosity.

[0786] N / A** = Note that for these conditions either the enzyme was denatured due to the applied temperature stress or the capillary could not be loaded due to high viscosity.

[0787] Table 12 : T under different storage conditions m

[0788] Compositions 86 to 171 were prepared as described above and then stored in a refrigerator at 5°C for 2 days to 2 weeks. T was measured immediately (ie, "t=0") and after storage at 40°C for 1 week using the method described in Example 1. m value.

[0789] The results are shown in Table 12.

[0790] This article also describes the following numbered clauses.

[0791] 1. A solid composition, which can be obtained by freeze-drying an aqueous composition, wherein the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof.

[0792] 2. The solid composition according to clause 1, wherein the aqueous composition further comprises a hyaluronidase.

[0793] 3. The solid composition according to clause 2, wherein the hyaluronidase is recombinant human hyaluronidase.

[0794] 4. A solid composition according to clause 3, wherein the recombinant human hyaluronidase is rHuPH20.

[0795] 5. A solid composition according to any one of clauses 2 to 4, wherein the aqueous composition comprises about 1,500 U / mL to about 2,500 U / mL of the hyaluronidase.

[0796] 6. The solid composition according to clause 5, wherein the aqueous composition comprises about 1,800 U / mL to about 2,200 U / mL of the hyaluronidase.

[0797] 7. The solid composition according to clause 6, wherein the aqueous composition comprises about 2,000 U / mL of the hyaluronidase.

[0798] 8. A solid composition according to any one of the preceding clauses, wherein the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition.

[0799] 9. The solid composition according to clause 8, wherein the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof in the form of microparticles or nanoparticles suspended in the aqueous composition.

[0800] 10. A solid composition according to clause 8 or 9, wherein the particles have a Dv90 of about 100 nm to about 10 μm.

[0801] 11. The solid composition of clause 10, wherein the particles have a Dv90 of about 500 nm to about 6 μm, optionally wherein the particles have a Dv90 of about 500 nm to about 1,600 nm.

[0802] 12. A solid composition according to clause 10, wherein the particles have a Dv90 of about 500 nm to about 700 nm.

[0803] 13. A solid composition according to any one of clauses 8 to 12, wherein the particles have a Dv10 of about 75 nm to about 200 nm.

[0804] 14. A solid composition according to any one of clauses 8 to 13, wherein the particles have a Dv50 of about 200 nm to about 500 nm.

[0805] 15. A solid composition according to any one of clauses 8 to 10, wherein the particles have a Dv90 of about 4 μm to about 6 μm.

[0806] 16. A solid composition according to clause 15, wherein the particles have a Dv90 of about 5 μm to about 6 μm.

[0807] 17. A solid composition according to any one of clauses 8 to 10 or 15 or 16, wherein the particles have a Dv10 of about 300 nm to about 500 nm, and / or wherein the particles have a Dv50 of about 1.5 μm to about 2 μm.

[0808] 18. A solid composition according to any of the preceding clauses, wherein the aqueous composition comprises from about 200 mg / mL to about 400 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof.

[0809] 19. The solid composition according to clause 18, wherein the aqueous composition comprises about 250 mg / mL to about 350 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof.

[0810] 20. The solid composition according to clause 19, wherein the aqueous composition comprises about 300 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof.

[0811] 21. A solid composition according to any one of the preceding clauses, wherein the aqueous composition comprises rilpivirine, ie rilpivirine in free base form.

[0812] 22. A solid composition according to any of the preceding clauses, wherein the aqueous composition further comprises carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

[0813] 23. The solid composition according to clause 22, wherein the carboxymethylcellulose or a pharmaceutically acceptable salt thereof is sodium carboxymethylcellulose.

[0814] 24. A solid composition according to clause 22 or 23, wherein the carboxymethylcellulose or a pharmaceutically acceptable salt thereof is not cross-linked.

[0815] 25. A solid composition according to any one of clauses 22 to 24, wherein the carboxymethyl cellulose or a pharmaceutically acceptable salt thereof has a degree of substitution (carboxymethyl to cellulose) of about 0.5 to about 1.

[0816] 26. A solid composition according to any one of clauses 22 to 25, wherein the carboxymethyl cellulose or a pharmaceutically acceptable salt thereof has a molecular weight of about 90 kDa to about 750 kDa, and / or wherein the carboxymethyl cellulose or a pharmaceutically acceptable salt thereof has a viscosity of about 30 mPa.s to about 50 mPa.s.

[0817] 27. A 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 pharmaceutically acceptable salt thereof.

[0818] 28. A 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 pharmaceutically acceptable salt thereof.

[0819] 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 pharmaceutically acceptable salt thereof.

[0820] 30. The solid composition according to clause 29, wherein the aqueous composition comprises about 3 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

[0821] 31. The solid composition of clause 27, wherein the aqueous composition comprises from about 10 mg / mL to about 25 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

[0822] 32. A solid composition according to clause 22 or 31, wherein the aqueous composition comprises from about 0.05 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase to about 2.5 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase.

[0823] 33. A solid composition according to clause 32, wherein the aqueous composition comprises from about 0.5 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase to about 2 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase.

[0824] 34. A solid composition according to clause 32, wherein the aqueous composition comprises from about 0.05 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase to about 0.25 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase.

[0825] 35. A solid composition according to clause 34, wherein the aqueous composition comprises about 0.15 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U of hyaluronidase.

[0826] 36. A solid composition according to any of the preceding clauses, wherein the aqueous composition comprises a cryoprotectant.

[0827] 37. A solid composition according to clause 36, wherein the cryoprotectant is a sugar, a sugar alcohol or an amino acid or a pharmaceutically acceptable salt thereof.

[0828] 38. A solid composition according to clause 37, wherein the cryoprotectant is a sugar or a sugar alcohol.

[0829] 39. A solid composition according to clause 38, wherein the sugar or sugar alcohol is selected from mannitol and sucrose.

[0830] 40. A solid composition according to Clause 38, wherein the sugar or sugar alcohol is sucrose.

[0831] 41. The solid composition according to clause 37, wherein the cryoprotectant is an amino acid or a pharmaceutically acceptable salt thereof.

[0832] 42. A solid composition according to clause 41, wherein the amino acid or a pharmaceutically acceptable salt thereof is selected from arginine, glycine and histidine, optionally wherein the amino acid or a pharmaceutically acceptable salt thereof is selected from arginine and glycine.

[0833] 43. A solid composition according to clause 42, wherein the amino acid or a pharmaceutically acceptable salt thereof is arginine, such as arginine HCl.

[0834] 44. A solid composition according to any one of clauses 36 to 43, wherein the cryoprotectant is at least 95% crystalline.

[0835] 45. A solid composition according to any one of clauses 36 to 45, wherein the aqueous composition comprises from about 1 mg / mL to about 200 mg / mL of the cryoprotectant.

[0836] 46. ​​A solid composition according to clause 44, wherein the aqueous composition comprises from about 1 mg / mL to about 150 mg / mL of the cryoprotectant.

[0837] 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 the sugar or sugar alcohol.

[0838] 48. A solid composition according to clause 47, wherein the aqueous composition comprises from about 75 mg / mL to about 125 mg / mL of the sugar or sugar alcohol.

[0839] 49. A solid composition according to clause 48, wherein the aqueous composition comprises about 100 mg / mL of the sugar or sugar alcohol.

[0840] 50. A solid composition according to clause 47, wherein the aqueous composition comprises from about 50 mg / mL to about 100 mg / mL of the sugar or sugar alcohol.

[0841] 51. A 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 pharmaceutically acceptable salt thereof.

[0842] 52. A 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 pharmaceutically acceptable salt thereof.

[0843] 53. A solid composition according to clause 52, wherein the aqueous composition comprises from about 25 mg / mL to about 35 mg / mL of the amino acid or a pharmaceutically acceptable salt thereof.

[0844] 54. A solid composition according to clause 53, wherein the aqueous composition comprises about 30 mg / mL of the amino acid or a pharmaceutically acceptable salt thereof.

[0845] 55. A solid composition according to any one of clauses 36 to 54, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition is from about 1:1 (w / w) to about 20:1 (w / w).

[0846] 56. A solid composition according to clause 55, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition is from about 2:1 (w / w) to about 10:1 (w / w).

[0847] 57. A solid composition according to clause 56, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition is from about 3:1 (w / w) to about 10:1 (w / w).

[0848] 58. A solid composition according to clause 56, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition is from about 2:1 (w / w) to about 7:1 (w / w).

[0849] 59. A solid composition according to clause 58, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition is from about 3:1 (w / w) to about 6:1 (w / w).

[0850] 60. A solid composition according to any one of clauses 36 to 59, wherein the ratio of carboxymethyl cellulose or a pharmaceutically acceptable salt thereof to the 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).

[0851] 61. A solid composition according to clause 60, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to the cryoprotectant is from about 1:8 (w / w) to about 1:40 (w / w).

[0852] 62. A solid composition according to any one of clauses 36 to 59, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to the cryoprotectant is from about 1:2 (w / w) to about 1:15 (w / w).

[0853] 63. A solid composition according to clause 62, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to the cryoprotectant is from about 1:4 (w / w) to about 1:11 (w / w).

[0854] 64. A solid composition according to clause 63, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to the cryoprotectant is from about 1:5 (w / w) to about 1:10 (w / w).

[0855] 65. A solid composition according to any one of clauses 36 to 59, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to the cryoprotectant is from about 1:9 (w / w) to about 1:11 (w / w).

[0856] 66. A solid composition according to any one of clauses 36 to 59, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to the cryoprotectant is from about 1:30 (w / w) to about 1:35 (w / w).

[0857] 67. A solid composition according to any of the preceding clauses, wherein the aqueous composition further comprises a poloxamer, such as poloxamer 338.

[0858] 68. A solid composition according to clause 67 when dependent on clause 8, wherein when the rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to poloxamer is from about 3:1 (w / w) to about 15:1 (w / w).

[0859] 69. A solid composition according to clause 68, wherein when the rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is from about 6:1 (w / w) to about 15:1 (w / w).

[0860] 70. The solid composition of clause 69, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to poloxamer is about 6:1 (w / w) when the rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than about 1600 nm.

[0861] 71. A solid composition according to clause 67, wherein the relative amounts (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer are less than about 12:1 (w / w).

[0862] 72. A solid composition according to any of the preceding clauses, wherein the aqueous composition further comprises poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0863] 73. A solid composition according to clause 72, wherein the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate and sodium hydroxide.

[0864] 74. A solid composition according to any one of clauses 67 to 73, wherein the aqueous composition comprises from about 5 mg / mL to about 15 mg / mL of the poloxamer.

[0865] 75. A solid composition according to any one of clauses 67 to 73, wherein the aqueous composition comprises from about 40 mg / mL to about 60 mg / mL of the poloxamer.

[0866] 76. A solid composition according to any of the preceding clauses, wherein the aqueous composition further comprises an antioxidant, optionally wherein the antioxidant is methionine.

[0867] 77. A solid composition according to clause 76, wherein the aqueous composition comprises about 1.0 mg / mL to about 2.0 mg / mL (e.g., about 1.5 mg / mL) of the antioxidant.

[0868] 78. A solid composition according to any of the preceding clauses, wherein the aqueous composition does not contain glucose.

[0869] 79. A solid composition according to any of the preceding clauses, wherein the aqueous composition has a pH of about 5 to about 7.

[0870] 80. A solid composition according to clause 79, wherein the aqueous composition has a pH of about 6 to about 7.

[0871] 81. A solid composition according to clause 80, wherein the aqueous composition has a pH of about 6 to about 6.5.

[0872] 82. A solid composition according to clause 81, wherein the aqueous composition has a pH of about 6.

[0873] 83. A reconstituted aqueous composition obtainable by reconstitution of a solid composition as defined in any one of clauses 1 to 82.

[0874] 84. The reconstituted aqueous composition of clause 83, wherein the reconstitution comprises adding an aqueous dispersion medium to the solid composition.

[0875] 85. A reconstituted aqueous composition according to clause 84, wherein the aqueous dispersion medium is water.

[0876] 86. 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 any one of clauses 83 to 85, in particular for treating HIV infection in a subject.

[0877] 87. A reconstituted aqueous composition as defined in any one of clauses 83 to 85 for use in treating or preventing HIV infection in a subject, in particular for treating HIV infection in a subject.

[0878] 88. Use of a reconstituted aqueous composition as defined in any one of clauses 83 to 85 for the preparation of a medicament for treating or preventing HIV infection in a subject, particularly for treating HIV infection in a subject.

[0879] 89. The method, the reconstituted aqueous composition for the use or the use according to clause 86, 87 or 88, wherein the reconstituted aqueous composition is administered to the subject by intramuscular injection or subcutaneous injection.

[0880] 90. The method, the reconstituted aqueous composition for the use or the use according to clause 89, wherein the reconstituted aqueous composition is administered to the subject by intramuscular injection.

[0881] 91. The method, the reconstituted aqueous composition for the use or the use according to clause 89, wherein the reconstituted aqueous composition is administered to the subject by subcutaneous injection.

[0882] 92. The method, the reconstituted aqueous composition for the use, or the use according to any one of clauses 86 to 91, wherein the reconstituted aqueous composition is administered to the subject intermittently at intervals of about three months to about two years.

[0883] 93. The method, the reconstituted aqueous composition for the use or the use according to clause 92, wherein the time interval is from about three months to about one year.

[0884] 94. The method, the reconstituted aqueous composition for the use or the use according to clause 93, wherein the time interval is from about three months to about six months.

[0885] 95. The method, the reconstituted aqueous composition for the use or the use according to clause 93, wherein the time interval is from about six months to about one year.

[0886] 96. The method, the reconstituted aqueous composition for the use or the use according to clause 94 or 95, wherein the time interval is about six months.

[0887] 97. The method, the reconstituted aqueous composition for the use, or the use according to any one of clauses 86 to 96, wherein the HIV infection is an HIV type 1 (HIV-1) infection.

[0888] 98. The method, the reconstituted aqueous composition for the use, or the use according to any one of clauses 86 to 97, wherein the subject is a human.

[0889] 99. A solid composition according to any one of clauses 1 to 82 for use in treating or preventing HIV infection in a subject, in particular for treating HIV infection in a subject.

[0890] 100. Use of a solid composition according to any one of clauses 1 to 82 for the preparation of a medicament for treating or preventing HIV infection in a subject, particularly for treating HIV infection in a subject.

[0891] 101. A solid composition obtainable by freeze-drying an aqueous composition, wherein the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof.

[0892] 102. The solid composition of clause 101, wherein the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition.

[0893] 103. A solid composition according to clause 102, wherein the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof in the form of microparticles or nanoparticles suspended in the aqueous composition.

[0894] 104. A solid composition according to clause 102 or 103, wherein the particles have a Dv90 of about 100 nm to about 10 μm.

[0895] 105. The solid composition of clause 104, wherein the particles have a Dv90 of about 500 nm to about 6 μm, optionally wherein the particles have a Dv90 of about 500 nm to about 1,600 nm.

[0896] 106. A solid composition according to clause 105, wherein the particles have a Dv90 of about 500 nm to about 700 nm.

[0897] 107. A solid composition according to any one of clauses 102 to 106, wherein the particles have a Dv10 of about 75 nm to about 200 nm.

[0898] 108. A solid composition according to any one of clauses 102 to 107, wherein the particles have a Dv50 of about 200 nm to about 500 nm.

[0899] 109. A solid composition according to clauses 102 to 104, wherein the particles have a Dv90 of about 4 μm to about 6 μm.

[0900] 110. The solid composition of clause 109, wherein the particles have a Dv90 of about 5 μm to about 6 μm.

[0901] 111. A solid composition according to any one of clauses 102 to 104 or 109, wherein the particles have a Dv10 of about 300 nm to about 500 nm, and / or wherein the particles have a Dv50 of about 1.5 μm to about 2 μm.

[0902] 112. A solid composition according to any one of clauses 101 to 111, wherein the aqueous composition comprises from about 200 mg / mL to about 400 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof.

[0903] 113. A solid composition according to clause 112, wherein the aqueous composition comprises about 250 mg / mL to about 350 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof.

[0904] 114. A solid composition according to clause 113, wherein the aqueous composition comprises about 300 mg / mL of rilpivirine or a pharmaceutically acceptable salt thereof.

[0905] 115. A solid composition according to any one of clauses 101 to 114, wherein the aqueous composition comprises rilpivirine, ie rilpivirine in free base form.

[0906] 116. A solid composition according to any one of clauses 101 to 115, wherein the aqueous composition further comprises carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

[0907] 117. A solid composition according to clause 116, wherein the carboxymethylcellulose or a pharmaceutically acceptable salt thereof is sodium carboxymethylcellulose.

[0908] 118. A solid composition according to clause 116 or 117, wherein the carboxymethylcellulose or a pharmaceutically acceptable salt thereof is not cross-linked.

[0909] 119. A solid composition according to any one of clauses 116 to 118, wherein the carboxymethyl cellulose or a pharmaceutically acceptable salt thereof has a degree of saturation of carboxymethyl groups to cellulose of about 0.5 to 1.

[0910] 120. A solid composition according to any one of clauses 116 to 119, wherein the carboxymethyl cellulose or a pharmaceutically acceptable salt thereof has a molecular weight of about 90 kDa to about 750 kDa and / or wherein the carboxymethyl cellulose or a pharmaceutically acceptable salt thereof has a viscosity of about 30 mPa.s to about 50 mPa.s.

[0911] 121. A 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 pharmaceutically acceptable salt thereof.

[0912] 122. A 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 pharmaceutically acceptable salt thereof.

[0913] 123. A solid composition according to clause 122, wherein the aqueous composition comprises about 1 mg / mL to about 5 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

[0914] 124. A solid composition according to clause 123, wherein the aqueous composition comprises about 3 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

[0915] 125. A solid composition according to clause 122, wherein the aqueous composition comprises about 10 mg / mL to about 25 mg / mL of carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

[0916] 126. A solid composition according to any one of clauses 101 to 125, wherein the aqueous composition comprises a cryoprotectant.

[0917] 127. A solid composition according to clause 126, wherein the cryoprotectant is a sugar, a sugar alcohol or an amino acid or a pharmaceutically acceptable salt thereof.

[0918] 128. A solid composition according to clause 127, wherein the cryoprotectant is a sugar or a sugar alcohol.

[0919] 129. A solid composition according to clause 128, wherein the sugar or sugar alcohol is selected from mannitol and sucrose.

[0920] 130. A solid composition according to clause 129, wherein the sugar or sugar alcohol is sucrose.

[0921] 131. A solid composition according to clause 127, wherein the cryoprotectant is an amino acid or a pharmaceutically acceptable salt thereof.

[0922] 132. A solid composition according to clause 131, wherein the amino acid or a pharmaceutically acceptable salt thereof is selected from arginine, glycine and histidine or a pharmaceutically acceptable salt thereof, optionally wherein the amino acid or a pharmaceutically acceptable salt thereof is selected from arginine and glycine or a pharmaceutically acceptable salt thereof.

[0923] 133. A solid composition according to clause 132, wherein the amino acid or a pharmaceutically acceptable salt thereof is arginine or a pharmaceutically acceptable salt thereof, such as arginine HCl.

[0924] 134. A 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 the cryoprotectant.

[0925] 135. A solid composition according to clause 134, wherein the aqueous composition comprises about 1 mg / mL to about 150 mg / mL of the cryoprotectant.

[0926] 136. A solid composition according to clause 135, wherein the aqueous composition comprises about 30 mg / mL to about 100 mg / mL of the cryoprotectant.

[0927] 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 the sugar or sugar alcohol.

[0928] 138. A solid composition according to clause 137, wherein the aqueous composition comprises about 75 mg / mL to about 125 mg / mL of the sugar or sugar alcohol.

[0929] 139. A solid composition according to clause 138, wherein the aqueous composition comprises about 50 mg / mL to about 100 mg / mL of the sugar or sugar alcohol.

[0930] 140. A solid composition according to clause 139, wherein the aqueous composition comprises about 100 mg / mL of the sugar or sugar alcohol.

[0931] 141. A solid composition according to any one of clauses 127 and 131 to 133, wherein the aqueous composition comprises from about 1 mg / mL to about 75 mg / mL of an amino acid or a pharmaceutically acceptable salt thereof.

[0932] 142. A solid composition according to clause 141, wherein the aqueous composition comprises from about 1 mg / mL to about 50 mg / mL of the amino acid or a pharmaceutically acceptable salt thereof.

[0933] 143. A solid composition according to clause 142, wherein the aqueous composition comprises about 25 mg / mL to about 35 mg / mL of the amino acid or a pharmaceutically acceptable salt thereof, optionally wherein the aqueous composition comprises about 30 mg / mL of the amino acid or a pharmaceutically acceptable salt thereof.

[0934] 144. A solid composition according to any one of clauses 126 to 143, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition is from about 1:1 (w / w) to about 20:1 (w / w).

[0935] 145. A solid composition according to clause 144, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition is about 2:1 (w / w) to about 10:1 (w / w), optionally wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition is about 3:1 (w / w) to about 10:1 (w / w).

[0936] 146. A solid composition according to clause 144, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition is from about 2:1 (w / w) to about 7:1 (w / w).

[0937] 147. A solid composition according to clause 146, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition is from about 3:1 (w / w) to about 6:1 (w / w).

[0938] 148. A solid composition according to any one of clauses 126 to 147, wherein the ratio of carboxymethyl cellulose or a pharmaceutically acceptable salt thereof to the 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).

[0939] 149. A solid composition according to clause 148, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to the cryoprotectant is from about 1:8 (w / w) to about 1:40 (w / w).

[0940] 150. A solid composition according to any one of clauses -148, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to the cryoprotectant is from about 1:2 (w / w) to about 1:15 (w / w).

[0941] 151. A solid composition according to clause 150, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to the cryoprotectant is from about 1:4 (w / w) to about 1:11 (w / w).

[0942] 152. A solid composition according to clause 151, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to the cryoprotectant is from about 1:5 (w / w) to about 1:10 (w / w).

[0943] 153. A solid composition according to clause 151, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to the cryoprotectant is from about 1:9 (w / w) to about 1:11 (w / w).

[0944] 154. A solid composition according to clause 149, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to the cryoprotectant is from about 1:30 (w / w) to about 1:35 (w / w).

[0945] 155. A solid composition according to any one of clauses 101 to 154, wherein the aqueous composition further comprises a poloxamer, such as poloxamer 338.

[0946] 156. A solid composition according to clause 155 when dependent on clause 102, wherein when the rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to poloxamer is from about 3:1 (w / w) to about 15:1 (w / w).

[0947] 157. A solid composition according to clause 156, wherein when the rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than about 1600 nm, the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer is from about 6:1 (w / w) to about 15:1 (w / w).

[0948] 158. A solid composition according to clause 157, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to poloxamer is about 6:1 (w / w) when the rilpivirine or a pharmaceutically acceptable salt thereof has a Dv90 of less than about 1600 nm.

[0949] 159. A solid composition according to any one of clauses 155 to 158, wherein the relative amounts (w / w) of rilpivirine or a pharmaceutically acceptable salt thereof to the poloxamer are less than about 12:1 (w / w).

[0950] 160. A solid composition according to any one of clauses 101 to 159 wherein the aqueous composition further comprises poloxamer, sodium dihydrogen phosphate, citric acid and sodium hydroxide.

[0951] 161. A solid composition according to clause 160, wherein the aqueous composition further comprises poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, and sodium hydroxide.

[0952] 162. A solid composition according to any one of clauses 160 to 161 wherein the aqueous composition comprises from about 5 mg / mL to about 15 mg / mL of the poloxamer.

[0953] 163. A solid composition according to any one of clauses 160 to 161, wherein the aqueous composition comprises about 40 mg / mL to about 60 mg / mL of the poloxamer.

[0954] 164. A solid composition according to any one of clauses 101 to 163 wherein the aqueous composition further comprises an antioxidant, optionally wherein the antioxidant is methionine.

[0955] 165. A solid composition according to clause 164, wherein the aqueous composition comprises about 1.0 mg / mL to about 2.0 mg / mL (e.g., about 1.5 mg / mL) of the antioxidant.

[0956] 166. A solid composition according to any one of clauses 101 to 165, wherein the aqueous composition does not comprise glucose.

[0957] 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.

[0958] 168. A solid composition according to clause 167, wherein the aqueous composition has a pH of about 6 to about 7.

[0959] 169. A solid composition according to clause 168, wherein the aqueous composition has a pH of about 6 to about 6.5.

[0960] 170. A solid composition according to clause 169, wherein the aqueous composition has a pH of about 6.

[0961] 171. A solid composition according to any one of clauses 101 to 170, wherein the aqueous composition does not comprise a hyaluronidase.

[0962] 172. A reconstituted aqueous composition obtainable by reconstitution of a solid composition as defined in any one of clauses 101 to 171.

[0963] 173. A reconstituted aqueous composition according to clause 172, wherein the reconstitution comprises adding an aqueous dispersion medium to the solid composition.

[0964] 174. A reconstituted aqueous composition according to clause 173, wherein the aqueous dispersion medium is water.

[0965] 175. 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 any one of clauses 172 to 174, in particular for treating HIV infection in a subject.

[0966] 176. A reconstituted aqueous composition as defined in any one of clauses 172 to 174 for use in treating or preventing HIV infection in a subject, in particular for treating HIV infection in a subject.

[0967] 177. Use of a reconstituted aqueous composition as defined in any one of clauses 172 to 174 for the preparation of a medicament for treating or preventing HIV infection in a subject, particularly for treating HIV infection in a subject.

[0968] 178. The method, the reconstituted aqueous composition for the use or the use according to clauses 175 to 177, wherein the reconstituted aqueous composition is administered to the subject by intramuscular injection or subcutaneous injection.

[0969] 179. The method, the reconstituted aqueous composition for the use or the use according to clause 178, wherein the reconstituted aqueous composition is administered to the subject by intramuscular injection.

[0970] 180. The method, the reconstituted aqueous composition for the use or the use according to clause 178, wherein the reconstituted aqueous composition is administered to the subject by subcutaneous injection.

[0971] 181. The method, the reconstituted aqueous composition for the use, or the use according to any one of clauses 175 to 180, wherein the reconstituted aqueous composition is administered to the subject intermittently at intervals of about three months to about two years.

[0972] 182. The method, the reconstituted aqueous composition for the use or the use according to clause 181, wherein the time interval is from about three months to about one year.

[0973] 183. The method, the reconstituted aqueous composition for the use or the use according to clause 182, wherein the time interval is from about three months to about six months.

[0974] 184. The method, the reconstituted aqueous composition for the use or the use according to clause 182, wherein the time interval is from about six months to about one year.

[0975] 185. The method, the reconstituted aqueous composition for the use or the use according to clause 183 or 184, wherein the time interval is about six months.

[0976] 186. The method, the reconstituted aqueous composition for the use, or the use according to any one of clauses 175 to 185, wherein the HIV infection is an HIV type 1 (HIV-1) infection.

[0977] 187. The method, the reconstituted aqueous composition for the use, or the use according to any one of clauses 175 to 186, wherein the subject is a human.

[0978] 188. A solid composition according to any one of clauses 101 to 171 for use in treating or preventing HIV infection in a subject, in particular for treating HIV infection in a subject.

[0979] 189. Use of a solid composition according to any one of clauses 101 to 171 for the preparation of a medicament for treating or preventing HIV infection in a subject, particularly for treating HIV infection in a subject.

[0980] The following numbered embodiments are also described herein:

[0981] 1. A solid composition, which can be obtained by freeze-drying an aqueous composition, wherein the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase.

[0982] 2. A solid composition according to embodiment 1, wherein the hyaluronidase is rHuPH20.

[0983] 3. A solid composition according to any one of the preceding embodiments, wherein the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, optionally wherein the particles are microparticles or nanoparticles suspended in the aqueous composition.

[0984] 4. The solid composition according to any one of the preceding embodiments, wherein the aqueous composition further comprises carboxymethylcellulose or a pharmaceutically acceptable salt thereof.

[0985] 5. The solid composition according to embodiment 4, wherein the carboxymethylcellulose or a pharmaceutically acceptable salt thereof is sodium carboxymethylcellulose.

[0986] 6. The solid composition according to embodiment 4 or 5, wherein the carboxymethyl cellulose or a pharmaceutically acceptable salt thereof is not cross-linked.

[0987] 7. A solid composition according to any one of embodiments 4 to 6, wherein the aqueous composition comprises about 0.5 mg to about 2 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase.

[0988] 8. A solid composition according to any one of the preceding embodiments, wherein the aqueous composition comprises a cryoprotectant.

[0989] 9. The solid composition according to embodiment 8, wherein the cryoprotectant is a sugar, a sugar alcohol or an amino acid or a pharmaceutically acceptable salt thereof.

[0990] 10. The solid composition according to embodiment 9, wherein the sugar or sugar alcohol is mannitol or sucrose, and the amino acid or a pharmaceutically acceptable salt thereof is arginine or glycine.

[0991] 11. A solid composition according to any one of embodiments 8 to 10, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition is about 2:1 (w / w) to about 7:1 (w / w).

[0992] 12. The solid composition of any one of embodiments 8 to 11, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to the cryoprotectant is from about 1:4 (w / w) to about 1:11 (w / w).

[0993] 13. A solid composition according to any one of the preceding embodiments, wherein the aqueous composition has a pH of about 6 to about 6.5.

[0994] 14. A reconstituted aqueous composition obtainable by reconstituted a solid composition as defined in any one of embodiments 1 to 13 with an aqueous dispersion medium.

[0995] 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, which can be obtained by freeze-drying an aqueous composition, wherein the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof and hyaluronidase.

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

3. A solid composition according to any one of the preceding claims, wherein the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, optionally wherein the particles are microparticles or nanoparticles suspended in the aqueous composition.

4. A solid composition according to any one of the preceding claims, 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 or 5, wherein the carboxymethyl cellulose or a pharmaceutically acceptable salt thereof is not cross-linked.

7. The solid composition according to any one of claims 4 to 6, wherein the aqueous composition comprises about 0.05 mg to about 0.25 mg carboxymethylcellulose or a pharmaceutically acceptable salt thereof per 100 U hyaluronidase.

8. A solid composition according to any one of the preceding claims, wherein the aqueous composition further comprises a cryoprotectant.

9. The solid composition according to claim 8, wherein the cryoprotectant 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 any one of claims 8 to 10, wherein the ratio of rilpivirine or a pharmaceutically acceptable salt thereof to the cryoprotectant in the aqueous composition is from about 1:1 (w / w) to about 20:1 (w / w).

12. The solid composition according to any one of claims 8 to 11, wherein the ratio of carboxymethylcellulose or a pharmaceutically acceptable salt thereof to the cryoprotectant is from about 1:8 (w / w) to about 1:40 (w / w).

13. The solid composition of any one of the preceding claims, 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 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 to the subject a reconstituted aqueous composition as defined in claim 14.

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