Pharmaceutical formulations comprising tenofovir and emtricitabine

Abstract

The present invention provides a solid oral dosage form comprising tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, and emtricitabine, or a pharmaceutically acceptable salt thereof.

Description

[0001] This application is a divisional application of a patent application with an application date of June 29, 2016, application number 201680045136.1, and name “Pharmaceutical preparation containing tenofovir and emtricitabine”. Technical Field

[0002] Disclosed are pharmaceutical formulations suitable for treating viral infections such as HIV, in particular solid oral dosage forms comprising emtricitabine and tenofovir alafenamide. Also disclosed are pharmaceutical formulations suitable for treating viral infections such as HIV: and in particular solid oral dosage forms comprising rilpivirine, emtricitabine and tenofovir alafenamide. background

[0004] Human immunodeficiency virus type 1 (HIV-1) infection is a serious, life-threatening disease of major public health significance, with approximately 35 million people infected worldwide (United Nations Programme on HIV / AIDS (UNAIDS); Global Report: UNAIDS Report on the Global AIDS Epidemic, 2013). The standard of care for the treatment of HIV-1 infection uses combination antiretroviral therapy (ART) to suppress viral replication to below detection limits, increase CD4 cell counts and halt disease progression.

[0005] The success of potent and well-tolerated ART means that morbidity and mortality in HIV-infected populations are increasingly driven by non-AIDS-related comorbidities. Clinical attention is increasingly focused on optimizing tolerance, long-term safety, and compliance (Costagliola D. Demographics of HIV and aging. Curr. Opin. HIV AIDS, 2014, 9(4), 294). There is still a significant medical need for safe and effective new therapies that take into account the elderly patient population, non-HIV-related comorbidities, virological resistance, and simplified regimens. Summary of the invention

[0006] The present inventors have successfully prepared an oral dosage form comprising tenofovir alafenamide and emtricitabine. This oral dosage form can be used in medicine, in particular for the treatment of viral infections such as HIV.

[0007] The inventors have discovered that solid oral dosage forms can be formulated that are intended to be pharmaceutically acceptable (i.e., pharmacologically effective and physically acceptable) while reducing the total amount of excipients required to achieve stability. Thus, in one aspect, the present invention provides a solid oral dosage form comprising 25 mg of tenofovir alafenamide or a pharmaceutically acceptable salt thereof and 200 mg of emtricitabine or a pharmaceutically acceptable salt thereof, wherein the dosage form has a total weight of less than 850 mg (e.g., less than 800 mg or less than 700 mg). In another aspect, a solid oral dosage form comprising 25 mg of tenofovir alafenamide or a pharmaceutically acceptable salt thereof and 200 mg of emtricitabine or a pharmaceutically acceptable salt thereof is provided, wherein the dosage form has a total weight of less than 500 mg (e.g., less than 400 mg). In another aspect, a solid oral dosage form comprising 10 mg of tenofovir alafenamide or a pharmaceutically acceptable salt thereof and 200 mg of emtricitabine or a pharmaceutically acceptable salt thereof is provided, wherein the dosage form has a total weight of less than 850 mg (e.g., less than 800 mg or less than 700 mg). In another aspect, a solid oral dosage form is provided comprising 10 mg of tenofovir alafenamide or a pharmaceutically acceptable salt thereof and 200 mg of emtricitabine or a pharmaceutically acceptable salt thereof, wherein the dosage form has a total weight of less than 500 mg (eg, less than 400 mg).

[0008] In one embodiment, the oral dosage form is a tablet.In some embodiments, the dosage forms and tablets of the present invention will contain two (and only two) active pharmaceutical ingredients: tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof.

[0009] The inventors have demonstrated that a stable composition comprising tenofovir alafenamide and emtricitabine that exhibits acceptable stability can be formulated. Therefore, in another aspect, the present invention provides a composition comprising (a) tenofovir alafenamide or a pharmaceutically acceptable salt thereof and (b) emtricitabine or a pharmaceutically acceptable salt thereof, wherein the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof is less than 3% after storage at 40°C / 75%RH for one month under open conditions. This composition may also comprise rilpivirine or a pharmaceutically acceptable salt thereof.

[0010] The inventors have also discovered the relationship between the stability of tenofovir alafenamide and the concentration of tenofovir alafenamide within a given composition. Therefore, in another aspect, the present invention provides a solid composition comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof, wherein the proportion of tenofovir alafenamide or a pharmaceutically acceptable salt thereof in the composition is about 2.5% to about 12% (by weight). Another aspect provides a solid composition comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof, wherein the proportion of tenofovir alafenamide or a pharmaceutically acceptable salt thereof in the composition is about 4% to about 12% (by weight). Another aspect provides a solid composition comprising about 5% to about 15% by weight of tenofovir alafenamide hemifumarate. Another aspect provides a solid composition comprising about 2% to about 4% by weight of tenofovir alafenamide hemifumarate.

[0011] In another aspect, provided is a dry granulated mixture of (a) tenofovir alafenamide or a pharmaceutically acceptable salt thereof and (b) emtricitabine or an acceptable salt thereof.

[0012] In another aspect, a kit is provided, comprising (a) a tablet comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof, and (b) a desiccant (e.g., silica gel). In another aspect, a kit is provided, comprising (a) a tablet comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof, and (b) a desiccant (e.g., silica gel), wherein the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof after storage at 30°C / 75%RH for 12 months is less than 2%. In another aspect, a kit is provided, comprising (a) a tablet comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof, and (b) a desiccant (e.g., silica gel), wherein the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof after storage at 40°C / 75%RH for three months is less than 2.5%.

[0013] Also provided are methods of producing solid oral dosage forms, such as tablets, as discussed in more detail below.

[0014] Additionally, methods for treating a patient are provided, which are also discussed in more detail below. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 Shown is the percentage of degradation of tenofovir alafenamide hemifumarate as a function of drug loading.

[0016] Figure 2is a flow chart illustrating the preparation of a monolayer tablet formulation of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide hemifumarate.

[0017] Figure 3A and 3B To illustrate the effect of the presence of (i) emtricitabine and (ii) emtricitabine and rilpivirine hydrochloride on the stability of tenofovir alafenamide hemifumarate. Figure 3A The total degradation of tenofovir alafenamide hemifumarate at 40°C / 75%RH under open conditions is shown. Figure 3B Shown is the overall degradation of tenofovir alafenamide hemifumarate at 60°C under closed conditions.

[0018] Figure 4 is a flow chart illustrating the preparation of a bilayer tablet formulation of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide hemifumarate.

[0019] Figure 5 Results of a study conducted on a bilayer tablet formulation of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide hemi-fumarate and a monolayer formulation of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide hemi-fumarate to evaluate the effects of and The dissolution rate of rilpivirine was compared with the dissolution rate of rilpivirine.

[0020] Fig. 6A A, B, and C show the results of studies conducted on bilayer tablet formulations to evaluate the dissolution of rilpivirine hydrochloride, emtricitabine, and tenofovir alafenamide hemifumarate, respectively, as a function of tablet hardness (ie, tablet hardness of 13, 16, and 19 kP).

[0021] Figure 7 Shown are the degradation products of total tenofovir alafenamide hemifumarate of various tablets containing rilpivirine hydrochloride, emtricitabine, and tenofovir alafenamide hemifumarate relative to the degradation products of tenofovir alafenamide hemifumarate from tablets containing only emtricitabine and tenofovir alafenamide hemifumarate as active pharmaceutical ingredients.

[0022] Fig. 8A A, B, and C show the results of studies conducted on a bilayer tablet formulation to evaluate whether the dissolution of rilpivirine hydrochloride, emtricitabine, and tenofovir alafenamide hemifumarate changes after storing the tablets under different conditions for 1 month, 3 months, and 6 months, respectively.

[0023] Fig. 9 The tensile strength of each of the rilpivirine hydrochloride and emtricitabine / tenofovir alafenamide hemifumarate powder blends is shown as a function of upper punch pressure.

[0024] Fig.10is a flow chart illustrating the preparation of a tablet formulation of emtricitabine and tenofovir alafenamide hemifumarate. DETAILED DESCRIPTION

[0025] In some embodiments, the oral dosage form disclosed herein comprises three active pharmaceutical ingredients: rilpivirine (or a pharmaceutically acceptable salt thereof), tenofovir alafenamide (or a pharmaceutically acceptable salt thereof) and emtricitabine (or a pharmaceutically acceptable salt thereof). In some embodiments, the oral dosage form consists of two (i.e., only two) active pharmaceutical ingredients: tenofovir alafenamide (or a pharmaceutically acceptable salt thereof) and emtricitabine (or a pharmaceutically acceptable salt thereof).

[0026] Rilpivirine

[0027] Rilpivirine (R or RPV), a diarylpyrimidine derivative, is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) that is active against wild-type HIV-1 and NNRTI-resistant mutants in vitro. It has the following formula (see WO2003 / 016306):

[0028]

[0029] Its IUPAC name is 4-{[4-({4-[(E)-2-cyanovinyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile. It is currently approved as (Rilpivirine hydrochloride 27.5mg, equivalent to 25mg Rilpivirine) and (Rilpivirine hydrochloride 27.5 mg, tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg).

[0030] Solid oral dosage forms disclosed herein include rilpivirine, typically in the form of a pharmaceutically acceptable salt. Rilpivirine may be present in the oral dosage form in a solvated or unsolvated form, and reference to "rilpivirine" includes both forms. Typically, rilpivirine is in the form of rilpivirine hydrochloride, which has the following formula:

[0031]

[0032] In certain specific embodiments, a solid oral dosage form is provided comprising 25 mg of rilpivirine, such as about 27.5 mg of rilpivirine hydrochloride.

[0033] As used herein, in the absence of specific reference to a particular pharmaceutically acceptable salt and / or solvate of rilpivirine (e.g., rilpivirine hydrochloride salt), any dosage, whether expressed in, for example, mg or weight %, should be understood to refer to the amount of rilpivirine free base, i.e., the amount of the formula:

[0034]

[0035] For example, therefore, reference to "25 mg of rilpivirine or a pharmaceutically acceptable salt and / or solvate thereof" refers to that amount of rilpivirine or a pharmaceutically acceptable salt and / or solvate thereof that provides the same amount of rilpivirine as 25 mg of rilpivirine free base.

[0036] Tenofovir alafenamide

[0037] Tenofovir alafenamide (TAF) is a nucleotide reverse transcriptase inhibitor having the following formula (see WO02 / 08241A2):

[0038]

[0039] Its IUPAC name is isopropyl (S)-2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate. It is also known as {9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine}.

[0040] The solid oral dosage form of the present invention comprises tenofovir alafenamide, usually in the form of a pharmaceutically acceptable salt. Tenofovir alafenamide may be present in the oral dosage form in a solvated or unsolvated form, and reference to "rilpivirine" includes both forms. In particular, tenofovir alafenamide may be associated with a fumarate, such as a butyrate or a hemifumarate. Typically, tenofovir alafenamide is in the form of tenofovir alafenamide hemifumarate, which has the following formula (see WO 2013 / 025788 A1):

[0041]

[0042] As used herein, in the absence of specific reference to a particular pharmaceutically acceptable salt and / or solvate of tenofovir alafenamide, any dose, whether expressed in, for example, mg or weight %, should be deemed to refer to the amount of tenofovir alafenamide, i.e., the amount of the following formula:

[0043]

[0044] For example, therefore, reference to "25 mg of tenofovir alafenamide or a pharmaceutically acceptable salt and / or solvate thereof" refers to an amount of tenofovir alafenamide or a pharmaceutically acceptable salt and / or solvate thereof that provides the same amount of tenofovir alafenamide as 25 mg of tenofovir alafenamide free base.

[0045] The amount of tenofovir alafenamide in the solid oral dosage form provided herein is generally 10 mg to 30 mg, for example 20 mg to 30 mg, and in some cases 24 mg to 28 mg. In certain embodiments, the solid oral dosage form comprises 10 mg of tenofovir alafenamide, such as about 11 mg of tenofovir alafenamide hemifumarate. In certain other specific embodiments, a solid oral dosage form comprising 25 mg of tenofovir alafenamide, such as about 28 mg of tenofovir alafenamide hemifumarate is provided.

[0046] Emtricitabine

[0047] Emtricitabine (FTC) is a nucleoside reverse transcriptase inhibitor with the following formula:

[0048]

[0049] Its IUPAC name is 4-amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one. It is also known as -5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. It is currently approved as (Emtricitabine 200mg), (Emtricitabine 200mg, Tenofovir disoproxil fumarate 300mg), (Emtricitabine 200mg, Efavirenz 600mg, Tenofovir disoproxil fumarate 300mg) and (Emtricitabine 200mg, Cobicistat 150mg, Tenofovir Disoproxil Fumarate 300mg, Elvitegravir 150mg) and part of.

[0050] Solid oral dosage forms disclosed herein include emtricitabine, optionally as a pharmaceutically acceptable salt thereof. Emtricitabine may be present in the oral dosage form in a solvated or unsolvated form, and reference to "emtricitabine" includes both forms. Typically, emtricitabine exists as a free base.

[0051] As used herein, in the absence of specific reference to a particular pharmaceutically acceptable salt and / or solvate of emtricitabine, any dosage, whether expressed in, for example, mg or weight %, should be considered to refer to the amount of emtricitabine, i.e., the amount of the formula:

[0052]

[0053] For example, therefore, reference to "200 mg emtricitabine or a pharmaceutically acceptable salt and / or solvate thereof" refers to an amount of emtricitabine or a pharmaceutically acceptable salt and / or solvate thereof that provides the same amount of emtricitabine as 200 mg emtricitabine free base.

[0054] The amount of emtricitabine in the solid oral dosage forms provided herein is typically 180 mg to 220 mg, such as 190 mg to 210 mg, and in some cases 195 mg to 205 mg. In certain specific embodiments, a solid oral dosage form comprising 200 mg emtricitabine is provided.

[0055] Solid oral dosage form

[0056] The present inventors have successfully formulated emtricitabine and tenofovir alafenamide into a single stable dosage form that is expected to be pharmacologically effective and physically acceptable. The present inventors have also successfully formulated rilpivirine, emtricitabine and tenofovir alafenamide into a single stable dosage form that is expected to be pharmacologically effective and physically acceptable. The solid oral dosage forms disclosed herein are intended for pharmaceutical use in human subjects. Therefore, in addition to being therapeutically effective, they must also have a size and weight that is appropriate for oral administration to humans (e.g., they should have a total weight of less than about 1.5 grams, preferably less than 1.0 g).

[0057] In addition to the above-mentioned clinical benefits that may result from the use of tenofovir alafenamide, the dosage forms of the present invention may also provide further advantages. In certain embodiments, the inventors have determined that emtricitabine and tenofovir alafenamide can be formulated into a solid oral dosage form having a total weight of less than about 850 mg, for example, less than about 750 mg, less than about 500 mg, or less than about 400 mg. In other embodiments comprising a third active ingredient (rilpivirine), the inventors have determined that the three active ingredients (i.e., rilpivirine, emtricitabine and tenofovir alafenamide) can be formulated into a solid oral dosage form having a total weight of less than about 1.0 g, for example, less than about 800 mg, or even less than about 700 mg. Taking into account The total weight is advantageously about 1200 mg. The total weight of the solid oral dosage form is about 1000 mg. Providing relatively small dosage forms, particularly tablets, represents a clinical advantage because it is expected to improve patient convenience, and thus compliance, compared to large dosage forms that are difficult for patients to swallow. In specific embodiments, the total weight of the solid oral dosage form of the present invention is 600-700 mg. In certain embodiments, particularly those comprising emtricitabine and tenofovir alafenamide without a third active ingredient, the total weight of the solid oral dosage form is about 300 mg to about 700 mg, or about 300 mg to about 500 mg. By comparison, Contains about 500mg excipients, while the dosage forms disclosed herein contain less than 300mg of excipients, such as less than 250mg of excipients, or less than 200mg of excipients or less. For example, in certain embodiments, the disclosed solid oral dosage forms include 100mg to 650mg of excipients, or 100mg to 500mg of excipients. In certain embodiments, the solid oral dosage forms disclosed herein contain 100mg to 200mg of excipients, or 100mg to 175mg of excipients, or 100mg to 150mg of excipients. In some cases, the solid oral dosage forms disclosed herein contain 120mg to 150mg of excipients. In such embodiments, the dosage form will generally contain (a) 10mg or 25mg of tenofovir alafenamide or a pharmaceutically acceptable salt thereof and (b) 200mg of emtricitabine or a pharmaceutically acceptable salt thereof as active ingredients. For example, the dosage form may contain as an active ingredient (a) 10 mg of tenofovir alafenamide or a pharmaceutically acceptable salt thereof and (b) 200 mg of emtricitabine or a pharmaceutically acceptable salt thereof. Alternatively, the dosage form may contain as an active ingredient (a) 25 mg of tenofovir alafenamide or a pharmaceutically acceptable salt thereof and (b) 200 mg of emtricitabine or a pharmaceutically acceptable salt thereof. In certain embodiments, the dosage form will typically contain as an active ingredient (a) 11 mg or 28 mg of tenofovir alafenamide hemifumarate and (b) 200 mg of emtricitabine. For example, the dosage form may contain as an active ingredient (a) 11 mg of tenofovir alafenamide hemifumarate and (b) 200 mg of emtricitabine. Alternatively, the dosage form may contain as an active ingredient (a) 28 mg of tenofovir alafenamide hemifumarate and (b) 200 mg of emtricitabine.

[0058] Similarly, in the presence of a third active ingredient, as a comparison, Contains more than 650 mg of excipients, while the dosage forms disclosed herein may contain less than 600 mg of excipients, such as less than 500 mg of excipients or less than 400 mg of excipients. For example, the solid oral dosage forms disclosed herein may contain 200-600 mg of excipients, or 250-550 mg of excipients or 300-500 mg of excipients. In some embodiments, the solid oral dosage forms disclosed herein contain 350-450 mg of excipients. In such embodiments, the dosage form will typically contain as active ingredients (a) 25 mg of rilpivirine or a pharmaceutically acceptable salt thereof, (b) 25 mg of tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (c) 200 mg of emtricitabine or a pharmaceutically acceptable salt thereof. In certain embodiments, the dosage form will generally comprise as active ingredients (a) 27.5 mg of rilpivirine hydrochloride, (b) 28 mg of tenofovir alafenamide hemifumarate, and (c) 200 mg of emtricitabine.

[0059] In certain embodiments, the solid oral dosage forms described herein will be in the form of tablets. In specific embodiments, they are in the form of monolayer tablets. In specific embodiments, especially when a third active ingredient is present in the composition, they can be in the form of multilayer tablets. This is because the inventors have found that the use of multilayer tablets can help optimize the properties of the dosage form, especially stability (e.g., stability of tenofovir alafenamide). They have also found that the use of multilayer tablets may affect the dissolution profile of one or more active ingredients in the dosage form, and therefore may have an effect on the in vivo pharmacokinetics of the dosage form. In particular, it was observed that the dissolution rate of rilpivirine varies depending on whether the tablet is a monolayer or multilayer tablet. Providing tablets with specific pharmacokinetic parameters, such as pharmacokinetic parameters that are bioequivalent to existing drugs (or drugs in the later stages of the procedure), has specific advantages that can be provided by the present invention. Achieving bioequivalence may require the use of multilayer tablets.

[0060] In one embodiment, a tablet is provided, comprising (a) tenofovir alafenamide or a pharmaceutically acceptable salt thereof and (b) emtricitabine or a pharmaceutically acceptable salt thereof. In one embodiment, the tablet is a single-layer tablet. In one embodiment, the tablet is substantially free of rilpivirine or a pharmaceutically acceptable salt thereof (e.g., the tablet comprises less than 1% by weight of rilpivirine or a pharmaceutically acceptable salt thereof). In one embodiment, the tablet is free of lactose and / or starch.

[0061] In one embodiment, a multilayer tablet is provided, comprising (a) rilpivirine or a pharmaceutically acceptable salt thereof, (b) tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (c) emtricitabine or a pharmaceutically acceptable salt thereof. In some embodiments, each layer comprises at least one of (a), (b) and (c). For example, the tablet may comprise (a) a first layer comprising rilpivirine or a pharmaceutically acceptable salt thereof, (b) a second layer comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (c) further comprising emtricitabine or a pharmaceutically acceptable salt thereof. In such embodiments, typically, (a) the first layer is substantially free of tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and / or (b) the second layer is substantially free of rilpivirine or a pharmaceutically acceptable salt thereof. In one embodiment, (a) the first layer is substantially free of tenofovir alafenamide or a pharmaceutically acceptable salt thereof (e.g., the first layer comprises less than 1 weight % of tenofovir alafenamide or a pharmaceutically acceptable salt thereof), and (b) the second layer is substantially free of rilpivirine or a pharmaceutically acceptable salt thereof (e.g., the second layer comprises less than 1 weight % of rilpivirine or a pharmaceutically acceptable salt thereof).

[0062] Specific embodiments provide a tablet, wherein the first layer comprises rilpivirine or a pharmaceutically acceptable salt thereof and is substantially free of tenofovir alafenamide or a pharmaceutically acceptable salt thereof (e.g., the first layer comprises less than 1% by weight of tenofovir alafenamide or a pharmaceutically acceptable salt thereof), and (b) the second layer comprises tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof, and is substantially free of rilpivirine or a pharmaceutically acceptable salt thereof (e.g., the second layer comprises less than 1% by weight of rilpivirine or a pharmaceutically acceptable salt thereof). In a specific embodiment, the present invention provides a tablet, wherein (a) the first layer comprises 27.5 mg of rilpivirine hydrochloride and is substantially free of tenofovir alafenamide or a pharmaceutically acceptable salt thereof (e.g., the first layer comprises less than 1% by weight of tenofovir alafenamide or a pharmaceutically acceptable salt thereof), and (b) the second layer comprises 28 mg of tenofovir alafenamide hemifumarate and 200 mg of emtricitabine and is substantially free of rilpivirine or a pharmaceutically acceptable salt thereof (e.g., the second layer comprises less than 1% by weight of rilpivirine or a pharmaceutically acceptable salt thereof), wherein the first layer has a total weight of less than about 400 mg, e.g., about 300 mg, and the second layer has a total weight of less than about 450 mg, e.g., about 350 mg. In one embodiment, the layer comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof does not contain lactose and / or starch.

[0063] The tablets disclosed herein are generally immediate release tablets. In one embodiment, the present invention provides a tablet that releases at least 80% of (a) tenofovir alafenamide and / or (b) emtricitabine within 20 minutes, measured using USP apparatus II at 500 ml of 50 mM sodium citrate pH 5.5, 37° C. and a stirring speed of 75 rpm. Typically, the tablets disclosed herein release at least 90% of (a) tenofovir alafenamide and / or (b) emtricitabine within 20 minutes, measured using USP apparatus II at 500 ml of 50 mM sodium citrate pH 5.5, 37° C. and a stirring speed of 75 rpm. In some embodiments, a tablet is provided that releases less than 50% of rilpivirine within 60 minutes, measured using USP apparatus II in 1000 ml of sodium acetate pH 4.5 and 2% polysorbate 20, 37° C. and a stirring speed of 75 rpm.

[0064] The tablets disclosed herein generally have a hardness in the range of 13-19 kP (kilogram force), and in certain embodiments, have a hardness of 16 kP. The hardness can be conveniently determined by driving an anvil to compress the tablet at a constant load rate until it breaks, according to USP <1217> The evaluation is performed using a hardness tester (eg TBH 220, ERWEKA GmbH, Heusenstamm Germany).

[0065] The tablets of the present invention generally have a friability of <1% by weight. Friability can be determined according to USP <1216> to evaluate.

[0066] The core of the tablets provided herein can have a hardness of 13-19 kP, and a friability of <1 wt%.

[0067] Tablets usually include one or more excipients. Excipients should be compatible with other ingredients of the preparation and physiologically harmless to its subject. Examples of suitable excipients are well known to those skilled in the art of tablet formulations, and can be found, for example, in Handbook of Pharmaceutical Excipients (Rowe, Sheskey & Quinn) 2009, the 6th edition. The term "excipient" used herein refers to, among others, alkalizing agents, solubilizing agents, glidants, fillers, adhesives, lubricants, diluents, preservatives, surfactants, dispersants, etc. The term also includes agents such as sweeteners, flavoring agents, coloring agents and preservatives. These components are usually present in a mixture in tablets.

[0068] Examples of solubilizers include, but are not limited to, ionic surfactants (including ionic and nonionic surfactants) such as sodium lauryl sulfate, cetyltrimethylammonium bromide, polysorbates (such as polysorbate 20 or 80), poloxamers (such as poloxamer 188 or 207) and polyethylene glycol. In a specific embodiment, the tablet comprising rilpivirine or a pharmaceutically acceptable salt thereof includes polysorbates, particularly polysorbate 20. In certain specific embodiments, the amount of polysorbate 20 in the tablet of the present invention is less than about 5 mg, such as less than about 1 mg, or about 0.5 mg.

[0069] Examples of lubricants, glidants and flow aids include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, stearyl palmitin, glyceryl behenate, sodium stearyl fumarate, colloidal silicon dioxide and talc. The amount of lubricant in the tablet can generally be between 0.5-5% by weight. In certain specific embodiments, tablets of the present invention include magnesium stearate. In certain embodiments, tablets include less than about 20 mg magnesium stearate.

[0070] Examples of disintegrants include, but are not limited to, starch, cellulose, cross-linked PVP, sodium starch glycolate, sodium carboxymethylcellulose, and the like.

[0071] Examples of fillers (also referred to as extenders or diluents) include, but are not limited to, starch, maltodextrin, polyols (such as lactose) and cellulose. The tablet provided herein can contain lactose and / or microcrystalline cellulose. Lactose can be used in anhydrous form or hydrated form (e.g., monohydrate), and is typically prepared by spray drying, fluidized bed granulation or drum drying. In certain embodiments, the tablet provided herein contains less than about 250 mg of lactose, particularly less than about 200 mg of lactose, and / or less than about 250 mg of microcrystalline cellulose, particularly less than about 200 mg of microcrystalline cellulose. Lactose monohydrate is preferred.

[0072] Examples of binders include, but are not limited to, cross-linked PVP, HPMC, microcrystalline cellulose, sucrose, starch, and the like.

[0073] Tablets provided herein may be uncoated or coated (in which case they comprise a coating). Although uncoated tablets may be used, coated tablets are more commonly provided, in which case conventional non-enteric coatings may be used. Film coatings are known in the art and may be made of hydrophilic polymer materials, but are not limited to polysaccharide materials such as hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), poly(vinyl alcohol-co-glycol) and other water-soluble polymers. Although the water-soluble material contained in the film coating of the present invention may comprise a single polymer material, it may also be formed using a mixture of more than one polymer. The coating may be white or colored, such as gray. Suitable coatings include, but are not limited to, polymer film coatings, such as those comprising polyvinyl alcohol, for example (It comprises partially hydrolyzed PVA, titanium dioxide, polyethylene glycol 3350 and talc, optionally a colorant: such as iron oxide or indigo carmine or yellow iron oxide or FD&C Yellow #6). The amount of coating will generally be about 2-4% by weight of the core, and in certain embodiments about 3%. Unless otherwise indicated, in the case of a dosage form coating, it is understood that reference to the weight % of the tablet refers to the total tablet, i.e. including the coating.

[0074] Pharmacokinetics

[0075] The present inventors have discovered that rilpivirine (particularly rilpivirine hydrochloride), emtricitabine and tenofovir alafenamide (particularly tenofovir alafenamide hemifumarate) can be formulated into solid oral dosage forms that can demonstrate bioequivalence, i.e., equivalent systemic exposure (AUC) to each active ingredient when compared to a standard comparator. inf ,C max In particular, in some embodiments, the tablets of the present invention provide blood concentrations (AUC inf ,C max), which is related to (rilpivirine hydrochloride, 27.5 mg) and / or a fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide hemifumarate (E / C / F / TAF) (corresponding to 150 / 150 / 200 / 10 mg of the free base), the latter of which was the subject of a new drug application submitted to the U.S. Food and Drug Administration in November 2014 and approved in November 2015 as Achieve single-drug comparison with currently approved rilpivirine Bioequivalence of rilpivirine was initially a challenge because the dissolution rate of rilpivirine was found to vary depending on the nature of the dosage form in which rilpivirine is present. Based on the findings of the inventors and the present disclosure, one skilled in the art will be able to provide dosage forms that provide such bioequivalence (see, e.g., the examples below).

[0076] Thus, in one embodiment, there is provided a solid oral dosage form (particularly a tablet) as described herein, wherein the dosage form:

[0077] (a) releases emtricitabine in vivo in a human subject to provide a plasma C of about 1250 to about 2050 ng / mL max and / or an AUC of about 7650 to about 12050 h·ng / mL inf , and / or

[0078] (b) releases emtricitabine in vivo in a human subject administered thereto to provide a plasma C of about 90 to about 160 ng / mL. max and / or an AUC of about 3050 to about 4850 h·ng / mL inf , and / or

[0079] (c) releases tenofovir alafenamide in vivo in a human subject to provide a plasma C of about 150 to about 260 ng / mL. max and / or an AUC of about 200 to about 340 h·ng / mL inf .

[0080] In some embodiments, the solid oral dosage form exhibits properties (a) and (b). In other embodiments, the solid oral dosage form exhibits properties (a) and (c). In some embodiments, the solid oral dosage form exhibits properties (b) and (c). In some embodiments, the solid oral dosage form exhibits properties (a), (b), and (c).

[0081] In some embodiments, there is provided a solid oral dosage form (particularly a tablet) as described herein, wherein:

[0082] (a) Log-transformed C of rilpivirine in human subjects takingmax and log-transformed AUC inf The 90% confidence intervals completely fell within the log-transformed C max and log-transformed AUC inf in the range of 80-125% of ...

[0083] (b) Log-transformed C of emtricitabine in human subjects taking max and log-transformed AUC inf The 90% confidence intervals completely fell within the log-transformed C max and log-transformed AUC inf The reference tablets have (i) a core consisting of 150 mg elvitegravir, 60.8 mg lactose monohydrate, 241.5 mg microcrystalline cellulose, 7.5 mg hydroxypropyl cellulose, 11.3 mg sodium lauryl sulfate, 65.8 mg croscarmellose sodium, 200 mg emtricitabine, 11.2 mg tenofovir alafenamide hemifumarate, 288.5 mg cobicistat on silicon dioxide (equivalent to 150 mg cobicistat), 13.5 mg magnesium stearate; and (ii) a film coating consisting of 31.5 mg polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, indigo carmine, and iron oxide (such as Green); and / or

[0084] (c) Log-transformed C of tenofovir alafenamide in individuals taking max and logarithmically transformed AU C inf The 90% confidence intervals completely fell within the log-transformed C max and log-transformed AUC infThe reference tablets have (i) a core consisting of 150 mg elvitegravir, 60.8 mg lactose monohydrate, 241.5 mg microcrystalline cellulose, 7.5 mg hydroxypropyl cellulose, 11.3 mg sodium lauryl sulfate, 65.8 mg croscarmellose sodium, 200 mg emtricitabine, 11.2 mg tenofovir alafenamide hemifumarate, 288.5 mg cobicistat on silicon dioxide (equivalent to 150 mg cobicistat), 13.5 mg magnesium stearate; and (ii) a film coating consisting of 31.5 mg polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, indigo carmine, and iron oxide (such as Green) mixture.

[0085] In some embodiments, the solid oral dosage form exhibits properties (a) and (b). In other embodiments, the solid oral dosage form exhibits properties (a) and (c). In some embodiments, the solid oral dosage form exhibits properties (b) and (c). In some embodiments, the solid oral dosage form exhibits properties (a), (b), and (c).

[0086] C max

[0087] As used herein, C max is the maximum observed plasma / serum concentration of the drug.

[0088] In a specific embodiment, the solid oral dosage form of the invention provides a plasma C of rilpivirine of about 90 to about 160 ng / mL, such as about 120 ng / mL, in a patient taking the dosage form. max .

[0089] In certain specific embodiments, the solid oral dosage form of the present invention provides a plasma C of emtricitabine of about 1250 to about 2050 ng / mL, such as about 1600 ng / mL, in a patient taking the solid oral dosage form. max .

[0090] In certain specific embodiments, the solid oral dosage form of the present invention provides a tenofovir alafenamide plasma C of about 150 to about 260 ng / mL, such as about 200 ng / mL, in a patient taking the dosage form. max .

[0091] AUC inf

[0092] As used herein, AUC inf is the area under the plasma / serum concentration-time curve extrapolated to infinity, calculated as AUC 0-最终 +(C 最终 / λ z ).

[0093] In certain specific embodiments, the solid oral dosage form of the present invention provides a plasma AUC of rilpivirine of about 3050 to about 4850 h·ng / mL, such as about 3850 h·ng / mL, in a patient taking the solid oral dosage form. inf .

[0094] In certain specific embodiments, the solid oral dosage form of the present invention provides an emtricitabine plasma AUC of about 7650 to about 12050 h·ng / mL, such as about 9600 h·ng / mL, in a patient taking the solid oral dosage form. inf .

[0095] In certain specific embodiments, the solid oral dosage form of the present invention provides a plasma AUC of tenofovir alafenamide of about 200 to 340 h·ng / mL, such as about 260 h·ng / mL, in patients taking the solid oral dosage form. inf .

[0096] AUC last

[0097] As used herein, AUC last It is the area under the plasma / serum concentration-time curve from time zero to the last quantifiable concentration.

[0098] In certain specific embodiments, the solid oral dosage form of the present invention provides a plasma AUC of rilpivirine of about 2950 to about 4650 h·ng / mL, such as about 3700 h·ng / mL, in a patient taking the solid oral dosage form. last .

[0099] In certain specific embodiments, the solid oral dosage form of the present invention provides an emtricitabine plasma AUC of about 7500 to about 12000 h·ng / mL, such as about 9400 h·ng / mL, in a patient taking the solid oral dosage form. last .

[0100] In certain specific embodiments, the solid oral dosage form of the present invention provides a plasma AUC of tenofovir alafenamide of about 200 to 315 h·ng / mL, such as about 250 h·ng / mL, in a patient taking the solid oral dosage form. last .

[0101] C last

[0102] As used herein, C last is the last measurable plasma / serum concentration of drug observed.

[0103] C max , C last , AUC inf and AUC lastIt is a standard pharmacokinetic parameter, which can be estimated manually or by using modeling software well known in the art, such as Pharsight WinNonlin package using a non-compartmental model. The general basis for calculating these amounts is known (see Rowland & Tozer (2010) Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications ISBN 978-0781750097, or Jambhekar & Breen (2012) Basic Pharmacokinetics ISBN 978-0853699804). Typically, the parameter will be assessed as a mean value (e.g., geometric mean or arithmetic mean) within a group of at least 12 healthy adults (and typically 24 to 36). Parameters should be measured according to standards and practices acceptable to drug regulatory agencies such as FDA, EMA, MHLW or WHO. Values ​​can be based on measurements taken at appropriate intervals after tablet ingestion, such as every hour, or at increasingly sparse sampling intervals: such as 1, 3, 5, 7, 9, 11, 13, 15, 20, and 24 hours after ingestion. They can also be assessed after a single dose of the drug or at steady state, but are usually assessed after a single dose.

[0104] The present inventors have discovered that emtricitabine and tenofovir alafenamide (particularly tenofovir alafenamide hemifumarate) can be formulated into solid oral dosage forms that demonstrate bioequivalence, i.e., equivalent systemic exposure (AUC) to each active ingredient when compared to a standard comparator. inf ,C max In particular, in some embodiments, the tablets of the present invention provide a blood concentration (AUC inf ,C max ), which is bioequivalent to the blood concentrations produced by administering a fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide hemifumarate (E / C / F / TAF) (corresponding to 150 / 150 / 200 / 10 mg free base), the latter of which was the subject of a new drug application filed with the U.S. Food and Drug Administration in November 2014. In some embodiments, when co-administered with elvitegravir (EVG) 150 mg tablets and cobicistat (COBI) 150 mg tablets, the tablets of the invention provide blood concentrations (AUC inf ,C max), which is bioequivalent to the blood concentration produced by administering a fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide hemifumarate (E / C / F / TAF) (corresponding to 150 / 150 / 200 / 10 mg free base). In some embodiments, the tablets of the present invention provide blood concentrations of one or more active pharmaceutical ingredients that are comparable to those produced by co-administration The blood concentrations produced by emtricitabine 200 mg capsules and tenofovir alafenamide hemifumarate (TAF) 25 mg single-dose tablets are bioequivalent.

[0105] Based on the findings of the inventors and this disclosure, one skilled in the art will be able to provide dosage forms that provide such bioequivalence (see, e.g., the Examples below).

[0106] Thus, in one embodiment, there is provided a solid oral dosage form (particularly a tablet) as described herein, wherein the dosage form:

[0107] (a) releases emtricitabine in vivo in a human subject to provide a plasma C of about 1300 to about 2100 ng / mL max and / or an AUC of about 8200 to about 13200 h·ng / mL inf , and / or

[0108] (b) releases tenofovir alafenamide in vivo in a human subject to provide a plasma C of about 240 to about 390 ng / mL max and / or an AUC of about 280 to about 450 h·ng / mL inf .

[0109] In one embodiment, there is provided a solid oral dosage form (particularly a tablet) as described herein, wherein the dosage form:

[0110] (a) releases emtricitabine in vivo in a human subject to provide a plasma C of about 1250 to about 2050 ng / mL max and / or an AUC of about 8500 to about 13400 h·ng / mL inf , and / or

[0111] (b) releases tenofovir alafenamide in vivo in a human subject to provide a plasma C of about 200 to about 360 ng / mL max and / or an AUC of about 30 to about 500 h·ng / mL inf .

[0112] In one embodiment, there is provided a solid oral dosage form (particularly a tablet) as described herein, wherein the dosage form:

[0113] (a) releases emtricitabine in vivo in a human subject to provide a plasma C of about 1400 to about 2300 ng / mL max and / or an AUC of about 7400 to about 11600 h·ng / mL inf , and / or

[0114] (b) releases tenofovir alafenamide in vivo in a human subject to provide a plasma C of about 160 to about 270 ng / mL. max and / or an AUC of about 190 to about 320 h·ng / mL inf .

[0115] In some embodiments, a solid oral dosage form (particularly a tablet) as described herein is provided, wherein: the logarithmic transformed C of emtricitabine and tenofovir alafenamide hemifumarate in a human subject taking the max and log-transformed AUC inf The 90% confidence intervals completely fell within the log-transformed C max and log-transformed AUC inf The reference tablets have (i) a core consisting of 150 mg elvitegravir, 60.8 mg lactose monohydrate, 241.5 mg microcrystalline cellulose, 7.5 mg hydroxypropyl cellulose, 11.3 mg sodium lauryl sulfate, 65.8 mg croscarmellose sodium, 200 mg emtricitabine, 11.2 mg tenofovir alafenamide hemifumarate, 288.5 mg cobicistat on silicon dioxide (equivalent to 150 mg cobicistat), 13.5 mg magnesium stearate; and (ii) a film coating consisting of 31.5 mg polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, indigo carmine, and iron oxide (such as Green) mixture.

[0116] In some embodiments, a solid oral dosage form (particularly a tablet) as described herein is provided, wherein when co-administered with 150 mg tablets of elvitegravir (EVG) and 150 mg tablets of cobicistat (COBI), the log-transformed C of emtricitabine and tenofovir alafenamide hemifumarate in a human subject taking the drug is max and log-transformed AUC inf The 90% confidence intervals completely fell within the log-transformed C max and log-transformed AUC infThe reference tablets have (i) a core consisting of 150 mg elvitegravir, 60.8 mg lactose monohydrate, 241.5 mg microcrystalline cellulose, 7.5 mg hydroxypropyl cellulose, 11.3 mg sodium lauryl sulfate, 65.8 mg croscarmellose sodium, 200 mg emtricitabine, 11.2 mg tenofovir alafenamide hemifumarate, 288.5 mg cobicistat on silicon dioxide (equivalent to 150 mg cobicistat), 13.5 mg magnesium stearate; and (ii) a film coating consisting of 31.5 mg polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, indigo carmine, and iron oxide (such as Green) mixture.

[0117] In some embodiments, a solid oral dosage form (particularly a tablet) as described herein is provided, wherein: the logarithmic transformed C of emtricitabine and tenofovir alafenamide hemifumarate in a human subject taking the max and log-transformed AUC inf The 90% confidence intervals completely fall within the log-transformed C of the reference treatment. max and log-transformed AUC inf within the range of 80-125% of, wherein the reference therapy consists of administering: (i) tenofovir alafenamide hemifumarate tablets, consisting of 25 mg tenofovir alafenamide (as hemifumarate), lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, wherein the tablets are film-coated with polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and yellow iron oxide; and (ii) emtricitabine hard gelatin capsules, consisting of 200 mg emtricitabine, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, titanium dioxide, gelatin, and blue #2 / indigo carmine aluminum lake.

[0118] C max

[0119] In certain specific embodiments, the solid oral dosage form of the present invention provides a plasma C of emtricitabine of about 1300 to about 2100 ng / mL, such as about 1660 ng / mL, in a patient taking the solid oral dosage form. max .

[0120] In certain specific embodiments, the solid oral dosage form of the present invention provides a plasma C of emtricitabine of about 1250 to about 2050 ng / mL, such as about 1600 ng / mL, in a patient taking the solid oral dosage form. max .

[0121] In certain specific embodiments, the solid oral dosage form of the present invention provides a plasma C of emtricitabine of about 1400 to about 2300 ng / mL, such as about 1800 ng / mL, in a patient taking the solid oral dosage form. max .

[0122] In certain specific embodiments, the solid oral dosage form of the present invention provides a tenofovir alafenamide plasma C of about 240 to about 390 ng / mL, such as about 300 ng / mL, in a patient taking the solid oral dosage form. max .

[0123] In certain specific embodiments, the solid oral dosage form of the present invention provides a tenofovir alafenamide plasma C of about 200 to about 360 ng / mL, such as about 280 ng / mL, in a patient taking the dosage form. max .

[0124] In certain specific embodiments, the solid oral dosage form of the present invention provides a tenofovir alafenamide plasma C of about 160 to about 270 ng / mL, such as about 200 ng / mL, in a patient taking the solid oral dosage form. max .

[0125] AUC inf

[0126] In certain specific embodiments, the solid oral dosage form of the present invention provides an emtricitabine plasma AUC of about 8200 to about 132000 h·ng / mL, such as about 10500 h·ng / mL, in a patient taking the solid oral dosage form. inf .

[0127] In certain specific embodiments, the solid oral dosage form of the present invention provides an emtricitabine plasma AUC of about 8500 to about 13400 h·ng / mL, such as about 9700 h·ng / mL, in a patient taking the solid oral dosage form. inf .

[0128] In certain specific embodiments, the solid oral dosage form of the present invention provides an emtricitabine plasma AUC of about 7400 to about 11600 h·ng / mL, such as about 9300 h·ng / mL, in a patient taking the solid oral dosage form. inf .

[0129] In certain specific embodiments, the solid oral dosage form of the present invention provides a plasma AUC of tenofovir alafenamide of about 280 to 450 h·ng / mL, such as about 350 h·ng / mL, in patients taking the solid oral dosage form. inf .

[0130] In certain specific embodiments, the solid oral dosage form of the present invention provides a plasma AUC of tenofovir alafenamide of about 300 to 500 h·ng / mL, such as about 400 h·ng / mL, in a patient taking the solid oral dosage form. inf .

[0131] In certain specific embodiments, the solid oral dosage form of the present invention provides a tenofovir alafenamide plasma AUC of about 190 to 320 h·ng / mL, such as about 250 h·ng / mL, in patients taking the dosage form. inf .

[0132] AUC last

[0133] In certain specific embodiments, the solid oral dosage form of the present invention provides an emtricitabine plasma AUC of about 8000 to about 13000 h·ng / mL, such as about 10200 h·ng / mL, in a patient taking the solid oral dosage form. last .

[0134] In certain specific embodiments, the solid oral dosage form of the present invention provides an emtricitabine plasma AUC of about 7500 to about 11800 h·ng / mL, such as about 9400 h·ng / mL, in a patient taking the solid oral dosage form. last .

[0135] In certain specific embodiments, the solid oral dosage form of the present invention provides an emtricitabine plasma AUC of about 7200 to about 11400 h·ng / mL, such as about 9000 h·ng / mL, in a patient taking the solid oral dosage form. last .

[0136] In certain specific embodiments, the solid oral dosage form of the present invention provides a tenofovir alafenamide plasma AUC of about 260 to 430 h·ng / mL, such as about 340 h·ng / mL, in patients taking the solid oral dosage form. last .

[0137] In certain specific embodiments, the solid oral dosage form of the present invention provides a tenofovir alafenamide plasma AUC of about 280 to 470 h·ng / mL, such as about 370 h·ng / mL, in patients taking the solid oral dosage form. last .

[0138] In certain specific embodiments, the solid oral dosage form of the present invention provides a tenofovir alafenamide plasma AUC of about 170 to 310 h·ng / mL, such as about 250 h·ng / mL, in patients taking the solid oral dosage form. last .

[0139] C last

[0140] How to determine whether any particular tablet meets the regulatory requirements for equivalent bioavailability and pharmacokinetic bioequivalence is well known in the bioavailability and bioequivalence fields, see, for example: Niazi (2014) Handbook of Bioequivalence Testing, 2nd Edition, ISBN 978-1482226379; Guidance for Industry Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations FDA March 2003; and Guideline On The Investigation Of Bioequivalence, EMEA 2010 CPMP / EWP / QWP / 1401 / 98Rev.1 / Corr**. To ensure statistical power, C will be measured in multiple individuals, for example in a group of at least 12 (usually 24-36) healthy adults. max , AUC last and AUC inf Value research.

[0141] Because it is determined that C max , AUC last and AUC inf The values ​​are necessarily destructive and therefore these parameters will not be determined directly for the dosage form in question (particularly tablets), but rather for dosage forms made with the same components by the same manufacturing process. Thus, a batch of dosage forms (e.g., tablets) may be prepared by a particular process and C values ​​assessed on a sample of these tablets. max , AUC last and AUC inf If these values ​​meet the 80-125% requirement as described above, then the tablet produced by the manufacturing process in question is a tablet of the invention.

[0142] stability

[0143] As described above and as explained in more detail in the examples below, the stability of tenofovir alafenamide deteriorates in the presence of emtricitabine. The degradation of tenofovir alafenamide is further accelerated in the presence of rilpivirine. Known degradation products of tenofovir alafenamide include PMPA and PMPA anhydride. Similarly, the stability of emtricitabine in the presence of tenofovir alafenamide and optional rilpivirine hydrochloride is a challenge in formulating a composition containing these three active ingredients. Known degradation products of emtricitabine include cyclic FTU-1 and FTU.

[0144] The inventors have found that the solid oral dosage forms of the present invention are stable, i.e., they have an acceptable shelf life, even for dosage forms comprising tenofovir alafenamide and emtricitabine and optionally rilpivirine. Therefore, a solid oral dosage form that does not contain a pharmaceutically unacceptable amount of tenofovir alafenamide degradation products is provided. Also provided is a composition comprising (a) tenofovir alafenamide or a pharmaceutically acceptable salt thereof and (b) emtricitabine or a pharmaceutically acceptable salt thereof, wherein after storage under closed conditions at 40°C / 75%RH for six months, the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof is less than 5% (e.g., less than about 4.2%; such as less than 4%). Also provided is a composition comprising (a) tenofovir alafenamide or a pharmaceutically acceptable salt thereof and (b) emtricitabine or a pharmaceutically acceptable salt thereof, wherein the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof is less than 2.5% (e.g., less than 2%, e.g., about 1.7% or about 1.8%) after storage under closed conditions at 40°C / 75%RH for three months. Also provided is a composition comprising (a) tenofovir alafenamide or a pharmaceutically acceptable salt thereof and (b) emtricitabine or a pharmaceutically acceptable salt thereof, wherein the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof is less than 3% (e.g., less than 2%) after storage under open conditions at 40°C / 75%RH for one month. In a preferred embodiment, the composition is a tablet. In another embodiment, a kit is provided, comprising (a) a tablet comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof, and (b) a desiccant (e.g., silica gel). Optionally, the composition further comprises rilpivirine or a pharmaceutically acceptable salt thereof.

[0145] The inventors conducted drug loading studies and realized that the chemical stability of tenofovir alafenamide varies depending on the proportion of tenofovir alafenamide in a given composition. Therefore, in some embodiments, a solid composition comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof is provided, wherein the proportion of tenofovir alafenamide or a pharmaceutically acceptable salt thereof in the composition is about 2.5% by weight to about 12% by weight. In some embodiments, a solid composition comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof is provided, wherein the proportion of tenofovir alafenamide or a pharmaceutically acceptable salt thereof in the composition is about 4% by weight to about 12% by weight. In some embodiments, a solid composition comprising about 5% by weight to about 15% by weight of tenofovir alafenamide hemifumarate, for example about 7% by weight to about 9% by weight of tenofovir alafenamide hemifumarate, in particular about 8% by weight of tenofovir alafenamide hemifumarate is provided. In another embodiment, a solid composition comprising about 2-4% by weight of tenofovir alafenamide hemifumarate, such as 2.5% by weight of tenofovir alafenamide hemifumarate is provided. In some embodiments, a solid composition comprising about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, about 3.3%, about 3.4% or about 3.5% (weight) of tenofovir alafenamide hemifumarate is provided. The composition can take various forms. For example, it can be in powder form. In other embodiments, the composition is a compressed dosage form, such as a tablet.

[0146] In addition, tenofovir alafenamide undergoes solid-state hydrolysis, and therefore, the inclusion of a desiccant may help promote an acceptable shelf life. Therefore, a kit is provided, comprising: (a) a tablet containing tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof, and (b) a desiccant. In some embodiments, a kit is provided, comprising: (a) a tablet containing rilpivirine or a pharmaceutically acceptable salt thereof, tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof, and (b) a desiccant. The inventors have observed that the stability of tenofovir alafenamide in certain formulations depends on the level of desiccant. Therefore, in certain embodiments, the kit comprises silica gel as a desiccant. In certain specific embodiments, the kit comprises 3 grams of silica gel as a desiccant. The kit may also optionally comprise a polyester coil packaging material. In certain embodiments, after storage for 12 months at 30°C / 75%RH, the total amount of degradation products derived from tenofovir alafenamide or its pharmaceutically acceptable salt in the tablet is less than about 2%, for example, less than 1.5% or less than about 1%. In certain embodiments, after storage for 3 months at 40°C / 75%RH, the total amount of degradation products derived from tenofovir alafenamide or its pharmaceutically acceptable salt is less than 2.5% (e.g., less than 2%, for example, about 1.7% or about 1.8%). The kit of the present invention may comprise a bottle suitable for storing the oral dosage form described herein.

[0147] The use of multilayer tablets of the above type can also help optimize the stability of the dosage form. For example, a tablet is provided, comprising: (a) 25 mg of rilpivirine or a pharmaceutically acceptable salt thereof, (b) 25 mg of tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (c) 200 mg of emtricitabine or a pharmaceutically acceptable salt thereof, wherein (a) and (b) are isolated and the total weight of the tablet is less than about 1.5 g. The multilayer tablet is further described in detail in the above and following examples.

[0148] The present invention provides a multi-layer tablet comprising: (a) rilpivirine or a pharmaceutically acceptable salt thereof, (b) tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (c) emtricitabine or a pharmaceutically acceptable salt thereof.

[0149] In one embodiment, a multi-layer tablet disclosed herein comprises (a) a first layer comprising rilpivirine or a pharmaceutically acceptable salt thereof, (b) a second layer comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (c) further comprising emtricitabine or a pharmaceutically acceptable salt thereof.

[0150] In one embodiment of the multi-layer tablet disclosed herein, (a) the first layer is substantially free of tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and / or (b) the second layer is substantially free of rilpivirine or a pharmaceutically acceptable salt thereof.

[0151] In one embodiment of the multi-layer tablet disclosed herein, (a) the first layer comprises rilpivirine or a pharmaceutically acceptable salt thereof and is substantially free of tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and (b) the second layer comprises tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof, and is substantially free of rilpivirine or a pharmaceutically acceptable salt thereof.

[0152] In one embodiment of the multi-layer tablet disclosed herein, the first layer is substantially free of emtricitabine.

[0153] In one embodiment, a multilayer tablet disclosed herein comprises 25±3 mg of rilpivirine. In one embodiment, a multilayer tablet disclosed herein comprises 200±20 mg of emtricitabine. In one embodiment, a multilayer tablet disclosed herein comprises 25±3 mg of tenofovir alafenamide.

[0154] In one embodiment, the multilayer tablet disclosed herein comprises 27.5±3 mg of rilpivirine hydrochloride. In one embodiment, the multilayer tablet disclosed herein comprises 200±20 mg of emtricitabine. In one embodiment, the multilayer tablet disclosed herein comprises 28±3 mg of tenofovir alafenamide hemifumarate.

[0155] In one embodiment, the first layer of a multi-layer tablet disclosed herein comprises one or more excipients, such as one or more diluents, disintegrants, binders, or lubricants.

[0156] In one embodiment, the first layer of the multilayer tablet comprises an alkalizing agent. In one embodiment, the alkalizing agent is selected from the group consisting of croscarmellose sodium, calcium carbonate, sodium hydroxide, aluminum oxide, alkali metal hydroxides (such as sodium hydroxide, potassium hydroxide and lithium hydroxide), alkaline earth metal hydroxides (e.g., calcium hydroxide and magnesium hydroxide), aluminum hydroxide, aluminum dihydride, sodium carbonate, aluminum hydroxide magnesium sulfate, aluminum hydroxide magnesium carbonate, ammonium hydroxide, magnesium carbonate, magnesium stearate, piperazine, sodium acetate, sodium citrate, sodium tartrate, sodium maleate and sodium succinate, and mixtures thereof.

[0157] In one embodiment, the first layer of the multilayer tablet of the present invention comprises croscarmellose sodium and polysorbate 20. In one embodiment, the first layer of the multilayer tablet of the present invention comprises lactose monohydrate, povidone, croscarmellose sodium, polysorbate 20, microcrystalline cellulose and magnesium stearate.

[0158] In one embodiment, a tablet is provided wherein less than about 15% by weight of the first layer is rilpivirine hydrochloride. In one embodiment, a tablet is provided wherein less than about 12.2% by weight of the first layer is rilpivirine hydrochloride. In one embodiment, a tablet is provided wherein less than about 12% by weight of the first layer is rilpivirine hydrochloride.

[0159] In one embodiment, a tablet is provided wherein the first layer comprises 27.5±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 230 mg.

[0160] In one embodiment, a tablet is provided wherein the first layer comprises 27.5±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 240 mg.

[0161] In one embodiment, a tablet is provided wherein the first layer comprises 27.5±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 250 mg.

[0162] In one embodiment, a tablet is provided wherein the first layer comprises 27.5±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 260 mg.

[0163] In one embodiment, a tablet is provided wherein the first layer comprises 27.5±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 270 mg.

[0164] In one embodiment, a tablet is provided wherein the first layer comprises 27.5±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 280 mg.

[0165] In one embodiment, a tablet is provided wherein the first layer comprises 27.5±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 290 mg.

[0166] In one embodiment, a tablet is provided wherein the first layer comprises 27.5±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 300 mg.

[0167] In one embodiment, a tablet is provided wherein the first layer comprises 27.5±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 230 mg and less than about 325 mg.

[0168] In one embodiment, a tablet is provided wherein the first layer comprises 27.5±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 300 mg and less than about 325 mg.

[0169] In one embodiment, a tablet is provided wherein the first layer comprises 27.5±1.4 mg of rilpivirine hydrochloride and wherein the total weight of the first layer is at least about 290 mg and less than about 310 mg.

[0170] In one embodiment, the first layer of the multi-layer tablet of the invention has a total weight of 300±75 mg or 300±25 mg or 300±10 mg or 300 mg.

[0171] In one embodiment, the first layer of the multi-layer tablet comprises:

[0172] Element Mass (mg) Rilpivirine or its salt 20-35 Microcrystalline Cellulose 40-100 Croscarmellose Sodium 1-30 lactose 150-250 Povidone 1-10 Polysorbate 20 0.1-5 Magnesium Stearate 1-10

[0173] In one embodiment, the first layer of the multi-layer tablet comprises:

[0174] Element Mass(mg) Rilpivirine Hydrochloride 24-31 Microcrystalline Cellulose 50-80 Croscarmellose Sodium 2-20 lactose 130-230 Povidone 2-5 Polysorbate 20 0.1-2 Magnesium Stearate 2-6

[0175] In one embodiment, the first layer of the multi-layer tablet comprises:

[0176]

[0177]

[0178] In one embodiment, the first layer of the multi-layer tablet consists of:

[0179] Element Mass (mg) Rilpivirine Hydrochloride 27.5±2.8 Microcrystalline Cellulose 60.0±6.0 Croscarmellose Sodium 16.1±1.6 lactose 189.8±19.0 Povidone 3.3±0.3 Polysorbate 20 0.4±0.04 Magnesium Stearate 3.0±0.3

[0180] In one embodiment, the first layer of the multi-layer tablet consists of:

[0181] Element Mass(mg) Rilpivirine Hydrochloride 27.5±1.4 Microcrystalline Cellulose 60.0±3.0 Croscarmellose Sodium 16.1±0.8 lactose 189.8±9.5 Povidone 3.3±0.17 Polysorbate 20 0.4±0.02 Magnesium Stearate 3.0±0.15

[0182] In one embodiment, the first layer of the multi-layer tablet consists of:

[0183] Element Mass (mg) Rilpivirine Hydrochloride 27.5 Microcrystalline Cellulose 60.00 Croscarmellose Sodium 16.10 lactose 189.8 Povidone 3.25 Polysorbate 20 0.35 Magnesium Stearate 3.00

[0184] In one embodiment, the first layer of the multi-layer tablet consists of:

[0185]

[0186] In one embodiment, the second layer of the multi-layer tablet comprises one or more excipients, such as one or more diluents, disintegrants, binders, or lubricants.

[0187] In one embodiment, the second layer of the multilayer tablet comprises microcrystalline cellulose and croscarmellose sodium.

[0188] In one embodiment, the second layer of the multilayer tablet comprises microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0189] In one embodiment, the second layer of the multilayer tablet comprises 20-30 mg of croscarmellose sodium. In one embodiment, the second layer of the multilayer tablet comprises 80-90 mg of microcrystalline sodium. In one embodiment, the second layer of the multilayer tablet comprises 1-7 mg of magnesium stearate.

[0190] In one embodiment, the second layer of the multilayer tablet does not contain lactose. In one embodiment, the second layer of the multilayer tablet does not contain starch. In one embodiment, the second layer of the multilayer tablet does not contain lactose and starch.

[0191] In one embodiment, the second layer of the multilayer tablet has a total weight of less than 600 mg, or less than 500 mg, or less than 400 mg, or less than 375 mg. In one embodiment, the second layer of the multilayer tablet has a total weight of 350 mg ± 50 mg or 350 mg ± 25 mg or 350 mg ± 5 mg or 350 mg.

[0192] In one embodiment, more than 40% by weight of the second layer of the multilayer tablet is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof. In one embodiment, more than 50% by weight of the second layer of the multilayer tablet is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof. In one embodiment of the present invention, more than 60% by weight of the second layer of the multilayer tablet is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof. In one embodiment, more than 64% by weight of the second layer of the multilayer tablet is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof. In one embodiment of the present invention, more than 65% by weight of the second layer of the multilayer tablet is emtricitabine and tenofovir alafenamide hemifumarate.

[0193] In one embodiment, the second layer of the multi-layer tablet comprises less than 250 mg of excipient, such as less than 200 mg, or less than 150 mg, or less than 130 mg, or less than 120 mg of excipient.

[0194] In one embodiment, at least 50% by weight of the second layer of the multilayer tablet is emtricitabine. In one embodiment of the invention, at least 55% by weight of the second layer of the multilayer tablet is emtricitabine.

[0195] In one embodiment, at least 5% by weight of the second layer of the multilayer tablet is tenofovir alafenamide hemi-fumarate. In one embodiment, at least 7% by weight of the second layer of the multilayer tablet is tenofovir alafenamide hemi-fumarate. In one embodiment, at least 8% by weight of the second layer of the multilayer tablet is tenofovir alafenamide hemi-fumarate.

[0196] In one embodiment, less than 20% by weight of the second layer of the multilayer tablet is cross-linked sodium carboxymethylcellulose. In one embodiment, less than 10% by weight of the second layer of the multilayer tablet is cross-linked sodium carboxymethylcellulose. The use of cross-linked sodium carboxymethylcellulose can provide particular advantages in terms of stabilizing tenofovir alafenamide or a pharmaceutically acceptable salt thereof. For example, the inventors have found that the use of about 7-9% (e.g., about 8%) of the weight of the second layer of cross-linked sodium carboxymethylcellulose can provide enhanced stability relative to other amounts (e.g., 6% by weight) of cross-linked sodium carboxymethylcellulose and / or other disintegrants such as polyvinyl pyrrolidone.

[0197] In one embodiment, less than 40% by weight of the second layer of the multilayer tablet is microcrystalline cellulose. In one embodiment, less than 30% by weight of the second layer of the multilayer tablet is microcrystalline cellulose. In one embodiment, less than 26% by weight of the second layer of the multilayer tablet is microcrystalline cellulose.

[0198] In one embodiment, the total weight of the second layer is less than 200% of the total weight of the first layer. In one embodiment, the total weight of the second layer is less than 150% of the total weight of the first layer. In one embodiment, the total weight of the second layer is less than 130% of the total weight of the first layer. In one embodiment, the total weight of the second layer is less than 120% of the total weight of the first layer. In one embodiment, the total weight of the second layer is less than 117% of the total weight of the first layer.

[0199] In one embodiment, the second layer of the multi-layer tablet comprises:

[0200] Element Mass(mg) Emtricitabine or its salt 150-250 Tenofovir alafenamide or its salt 20-35 Croscarmellose Sodium 20-35 Microcrystalline Cellulose 70-100 Magnesium Stearate 1-7

[0201] In one embodiment, the second layer of the multi-layer tablet comprises:

[0202] Element Mass(mg) Emtricitabine 170-230 Tenofovir alafenamide hemifumarate 22-32 Croscarmellose Sodium 20-35 Microcrystalline Cellulose 70-100 Magnesium Stearate 1-7

[0203] In one embodiment, the second layer of the multi-layer tablet consists of:

[0204]

[0205]

[0206] In one embodiment, the second layer of the multi-layer tablet consists of:

[0207] Element Mass(mg) Emtricitabine 200±10 Tenofovir Alafenamide Hemifumarate 28±1.4 Croscarmellose Sodium 28±1.4 Microcrystalline Cellulose 89±4 Magnesium Stearate 5.2±0.5

[0208] In one embodiment, the second layer of the multi-layer tablet consists of:

[0209] Element Mass (mg) Emtricitabine 199.99 Tenofovir alafenamide hemifumarate 28.04 Croscarmellose Sodium 28.00 Microcrystalline Cellulose 88.69 Magnesium Stearate 5.20

[0210] In one embodiment, the second layer of the multi-layer tablet consists of:

[0211] Element Mass (mg) Intragranular Emtricitabine 199.99 Tenofovir Alafenamide Hemifumarate 28.04 Croscarmellose Sodium 28.00 Microcrystalline Cellulose 88.69 Magnesium Stearate 2.60 Extragranular Magnesium Stearate 2.60 Total layer weight 350

[0212] In one embodiment of the multilayer tablet of the present invention, the first layer is in contact with the second layer.

[0213] In one embodiment, the multilayer tablet further comprises a third layer located between and separating the first and second layers. In one embodiment, the third layer of the multilayer tablet comprises lactose monohydrate or microcrystalline cellulose or a mixture thereof.

[0214] In one embodiment, the multilayer tablet further comprises a film coating. In one embodiment, the film coating comprises polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and black iron oxide. In one embodiment, the film coating consists of 19.5±10 mg of Opadry II 85F17636 ash.

[0215] In one embodiment, a tablet is provided comprising a first layer consisting of:

[0216] Element Mass (mg) Rilpivirine Hydrochloride 27.5±3 Microcrystalline Cellulose 60.0±12 Croscarmellose Sodium 16±3 Lactose monohydrate 189±40 Povidone 3.3±1 Polysorbate 20 0.4±0.1 Magnesium Stearate 3.0±1

[0217] and the second layer consisting of:

[0218] Element Mass (mg) Emtricitabine 200±20 Tenofovir Alafenamide Hemifumarate 28±3 Croscarmellose Sodium 28±3 Microcrystalline Cellulose 89±9 Magnesium Stearate 5.2±1.1

[0219] In one embodiment, a tablet is provided comprising a first layer consisting of:

[0220]

[0221]

[0222] and the second layer consisting of

[0223] Element Mass (mg) Emtricitabine 200±10 Tenofovir alafenamide hemifumarate 28±1.4 Croscarmellose Sodium 28±1.4 Microcrystalline Cellulose 89±4 Magnesium Stearate 5.2±0.5

[0224] In one embodiment, a tablet is provided comprising a first layer consisting of:

[0225] Weight(mg) %w / w(in layer) Intragranular Rilpivirine Hydrochloride 27.50 9.2 Lactose monohydrate 55.10 18.4 Polysorbate 20 0.35 0.12 Povidone K29 / 32 3.25 1.1 Croscarmellose Sodium 1.10 0.37 Extragranular Lactose monohydrate 134.70 44.9 Croscarmellose Sodium 15.00 5.0 Microcrystalline Cellulose 60.00 20.0 Magnesium Stearate 3.00 1.0

[0226] and the second layer consisting of:

[0227]

[0228]

[0229] and optional film coating.

[0230] In one embodiment, a tablet is provided consisting of: a first layer consisting of:

[0231] Weight(mg) %w / w(in layer) Intragranular Rilpivirine Hydrochloride 27.50 9.2 Lactose Monohydrate 55.10 18.4 Polysorbate 20 0.35 0.12 Povidone K29 / 32 3.25 1.1 Croscarmellose Sodium 1.10 0.37 Extragranular Lactose Monohydrate 134.70 44.9 Croscarmellose Sodium 15.00 5.0 Microcrystalline Cellulose 60.00 20.0 Magnesium Stearate 3.00 1.0

[0232] and the second layer consisting of:

[0233] Weight(mg) %w / w(in layer) Intragranular Emtricitabine 199.99 57.1 Tenofovir Alafenamide Hemifumarate 28.04 8.01 Croscarmellose Sodium 28.00 8.0 Microcrystalline Cellulose 88.69 25.3 Magnesium Stearate 2.60 0.75 Extragranular Magnesium Stearate 2.60 0.75

[0234] and a film coating consisting of 19.5 mg of Opadry II 85F17636 gray (a combination of polyvinyl alcohol, polyethylene glycol (PEG), talc, titanium dioxide, and black iron oxide).

[0235] Another aspect of the present invention provides a solid oral dosage form comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof. In one embodiment, the solid oral dosage form is a tablet. In one embodiment, the solid oral dosage form is a coated tablet. In one embodiment, the coating is a film coating, such as Opadry II.

[0236] In one embodiment, the tablet comprises microcrystalline cellulose and croscarmellose sodium.

[0237] In one embodiment, the tablet comprises microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0238] In one embodiment, the tablet comprises 20-30 mg croscarmellose sodium. In one embodiment, the tablet comprises 80-90 mg microcrystalline sodium. In one embodiment, the tablet comprises 2-7 mg magnesium stearate.

[0239] In one embodiment, the tablet does not contain lactose. In one embodiment, the tablet does not contain starch. In one embodiment, the tablet does not contain lactose and starch.

[0240] In one embodiment, the total weight of the tablet is less than 600 mg, or less than 500 mg, or less than 400 mg, or less than 375 mg. In one embodiment, the total weight of the tablet is 350 mg ± 50 mg or 350 mg ± 25 mg or 350 mg ± 5 mg or 350 mg.

[0241] In one embodiment, the tablet is coated and the tablet has a total weight of less than 600 mg, such as less than 500 mg, less than 400 mg or less than 375 mg. In one embodiment, the tablet is coated and the total weight of the tablet is 360.5 mg ± 50 mg, such as 360.5 mg ± 25 mg, 360.5 mg ± 5 mg or 360.5 mg.

[0242] In one embodiment, more than 40% by weight of the tablet is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof. In one embodiment, more than 50% by weight of the tablet is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof. In one embodiment, more than 60% by weight of the tablet of the present invention is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof. In one embodiment, more than 64% by weight of the tablet is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof. In one embodiment, more than 65% by weight of the tablet is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof. In one embodiment of the present invention, more than 65% by weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate.

[0243] In one embodiment, about 40% to about 75% by weight of the tablet is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof. In one embodiment, about 50% to about 75% by weight of the tablet is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof. In one embodiment, about 50% to about 70% by weight of the tablet is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof. In one embodiment, about 60% to about 75% by weight of the tablet of the present invention is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof. In one embodiment, about 64% to about 75% by weight of the tablet is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof. In one embodiment, about 65% to about 75% by weight of the tablet is emtricitabine or a salt thereof and tenofovir alafenamide or a salt thereof.

[0244] In one embodiment, the tablet is coated and more than 40% by weight of the tablet is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In one embodiment, the tablet is coated and more than 50% by weight of the tablet is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In one embodiment, the tablet is coated and more than 58% by weight of the tablet of the present invention is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In one embodiment, the tablet is coated and more than 60% by weight of the tablet is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In one embodiment, the tablet is coated and more than 63% by weight of the tablet is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof.

[0245] In one embodiment, the tablet is coated and about 40% to about 75% by weight of the tablet is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In one embodiment, the tablet is coated and about 50% to about 75% by weight of the tablet is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In one embodiment, the tablet is coated and about 50% to about 70% by weight of the tablet is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In one embodiment, the tablet is coated and about 58% to about 70% by weight of the tablet of the present invention is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In one embodiment, the tablet is coated and about 60% to about 70% by weight of the tablet is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In one embodiment, the tablet is coated and about 63% to about 70% by weight of the tablet is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof.

[0246] In one embodiment of the invention, the tablet is coated and more than 50% by weight of the tablet is emtricitabine and tenofovir alafenamide hemi-fumarate. In one embodiment of the invention, the tablet is coated and more than 58% by weight of the tablet is emtricitabine and tenofovir alafenamide hemi-fumarate. In one embodiment of the invention, the tablet is coated and more than 63% by weight of the tablet is emtricitabine and tenofovir alafenamide hemi-fumarate.

[0247] In one embodiment of the invention, the tablet is coated and about 50% to about 75% by weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate. In one embodiment of the invention, the tablet is coated and about 58% to about 70% by weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate. In one embodiment of the invention, in one embodiment of the invention, the tablet is coated and about 63% to about 70% by weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate.

[0248] In one embodiment of the invention, the tablet comprises less than 250 mg of excipients, such as less than 200 mg, or less than 150 mg, or less than 130 mg, or less than 120 mg of excipients.

[0249] In one embodiment of the invention, at least 50% by weight of the tablet is emtricitabine. In one embodiment of the invention, at least 55% by weight of the tablet is emtricitabine.

[0250] In one embodiment of the invention, about 50% to about 65% by weight of the tablet is emtricitabine. In one embodiment of the invention, about 55% to about 60% by weight of the tablet is emtricitabine.

[0251] In one embodiment, at least 3% by weight of the tablet is tenofovir alafenamide hemifumarate. In one embodiment, at least 5% by weight of the tablet is tenofovir alafenamide hemifumarate. In one embodiment, at least 7% by weight of the tablet is tenofovir alafenamide hemifumarate. In one embodiment, at least 8% by weight of the tablet is tenofovir alafenamide hemifumarate. In one embodiment, the tablet comprises 3-4% by weight of tenofovir alafenamide hemifumarate, preferably about 3% tenofovir alafenamide hemifumarate. In another embodiment, the tablet comprises 7-9% by weight of tenofovir alafenamide hemifumarate, preferably about 8% by weight of tenofovir alafenamide hemifumarate.

[0252] In one embodiment, about 3% to about 15% by weight of the tablet is tenofovir alafenamide hemifumarate. In one embodiment, about 5% to about 10% by weight of the tablet is tenofovir alafenamide hemifumarate. In one embodiment, about 7% to about 9% by weight of the tablet is tenofovir alafenamide hemifumarate.

[0253] In one embodiment of the present invention, the tablet comprises: a) tenofovir alafenamide or a pharmaceutically acceptable salt thereof and b) emtricitabine or a pharmaceutically acceptable salt thereof, and the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof after storage at 40°C / 75%RH under closed conditions for 3 months is less than about 2.5%, such as less than 2%, for example about 1.7% or 1.8%.

[0254] In one embodiment of the invention, the tablet comprises: a) tenofovir alafenamide hemifumarate and b) emtricitabine, and the total amount of degradation products derived from tenofovir alafenamide hemifumarate after storage at 40°C / 75%RH under closed conditions for 3 months is less than about 2.5%, such as less than 2%, for example about 1.7% or 1.8%.

[0255] In one embodiment of the present invention, the tablet comprises 7-9% by weight of tenofovir alafenamide or a pharmaceutically acceptable salt thereof, preferably about 8% by weight of tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof after storage at 40°C / 75%RH under closed conditions for 3 months is less than about 2%, for example, about 1.7%.

[0256] In one embodiment of the present invention, the tablet comprises 7-9% by weight of tenofovir alafenamide hemifumarate, preferably about 8% by weight of tenofovir alafenamide hemifumarate, and the total amount of degradation products derived from tenofovir alafenamide hemifumarate after storage at 40°C / 75% RH under closed conditions for 3 months is less than about 2%, for example, about 1.7%.

[0257] In another embodiment of the present invention, the tablet comprises about 8% by weight of tenofovir alafenamide hemifumarate and at least 55% by weight of emtricitabine, wherein the total amount of degradation products derived from tenofovir alafenamide hemifumarate after storage under closed conditions at 40°C / 75% RH for 3 months is less than about 2%, for example about 1.7%.

[0258] In one embodiment of the present invention, the tablet comprises 3-4% by weight of tenofovir alafenamide or a pharmaceutically acceptable salt thereof, preferably about 3% by weight of tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof after storage at 40°C / 75%RH under closed conditions for 3 months is less than about 2.5%, for example less than 2%, for example about 1.8%.

[0259] In one embodiment of the present invention, the tablet comprises 3-4% by weight of tenofovir alafenamide hemifumarate, preferably about 3% by weight of tenofovir alafenamide hemifumarate, and the total amount of degradation products derived from tenofovir alafenamide hemifumarate after storage at 40°C / 75%RH under closed conditions for 3 months is less than about 2.5%, for example less than 2%, for example about 1.8%.

[0260] In a preferred embodiment of the present invention, the tablet comprises about 3% by weight of tenofovir alafenamide hemifumarate and at least 55% by weight of emtricitabine, wherein the total amount of degradation products derived from tenofovir alafenamide hemifumarate after storage at 40°C / 75% RH for 3 months under closed conditions is less than about 2.5%, such as less than 2%, such as about 1.8%. In one embodiment of the present invention, the tablet comprises: a) tenofovir alafenamide or a pharmaceutically acceptable salt thereof and b) emtricitabine or a pharmaceutically acceptable salt thereof, and the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof after storage at 30°C / 75% RH for 12 months under closed conditions is less than about 2%, such as less than 1.5% or less than 1%.

[0261] In one embodiment of the invention, the tablet comprises: a) tenofovir alafenamide hemifumarate and b) emtricitabine, and the total amount of degradation products derived from tenofovir alafenamide hemifumarate after storage at 30°C / 75%RH for 12 months under closed conditions is less than about 2%, such as less than 1.5% or less than 1%.

[0262] In one embodiment of the present invention, the tablet comprises 7-9% by weight of tenofovir alafenamide or a pharmaceutically acceptable salt thereof, preferably about 8% by weight of tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof after storage at 30°C / 75% RH under closed conditions for 12 months is less than about 2%, for example less than 1.5% or less than 1%.

[0263] In one embodiment of the present invention, the tablet comprises 7-9% by weight of tenofovir alafenamide hemifumarate, preferably about 8% by weight of tenofovir alafenamide hemifumarate, and the total amount of degradation products derived from tenofovir alafenamide hemifumarate after storage at 30°C / 75% RH for 12 months under closed conditions is less than about 2%, for example less than 1.5%, for example about 1%.

[0264] In another embodiment of the present invention, the tablet comprises about 8% by weight of tenofovir alafenamide hemifumarate and at least 55% by weight of emtricitabine, wherein the total amount of degradation products derived from tenofovir alafenamide hemifumarate after storage under closed conditions at 30°C / 75% RH for 12 months is less than about 2%, such as less than 1.5% or less than 1%.

[0265] In one embodiment of the present invention, the tablet comprises 3-4% by weight of tenofovir alafenamide or a pharmaceutically acceptable salt thereof, preferably about 3% by weight of tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof after storage at 30°C / 75%RH under closed conditions for 12 months is less than about 2%, for example less than 1.5%.

[0266] In one embodiment of the present invention, the tablet comprises 3-4% by weight of tenofovir alafenamide hemifumarate, preferably about 3% by weight of tenofovir alafenamide hemifumarate, and the total amount of degradation products derived from tenofovir alafenamide hemifumarate after storage at 30°C / 75% RH for 12 months under closed conditions is less than about 2%, for example less than 1.5%.

[0267] In a preferred embodiment of the present invention, the tablet comprises about 3% by weight of tenofovir alafenamide hemifumarate and at least 55% by weight of emtricitabine, wherein the total amount of degradation products derived from tenofovir alafenamide hemifumarate after storage under closed conditions at 30°C / 75% RH for 12 months is less than about 2%, for example less than 1.5%.

[0268] In one embodiment of the invention, less than 20% by weight of the tablet is croscarmellose sodium. In one embodiment of the invention, less than 10% by weight of the tablet is croscarmellose sodium.

[0269] In one embodiment of the invention, less than 40% by weight of the tablet is microcrystalline cellulose.In one embodiment of the invention, less than 30% by weight of the tablet is microcrystalline cellulose.In one embodiment of the invention, less than 26% by weight of the tablet is microcrystalline cellulose.

[0270] In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 11.2 mg tenofovir alafenamide hemifumarate, wherein at least 50% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate. In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 11.2 mg tenofovir alafenamide hemifumarate, wherein at least 50% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate, wherein the excipients consist of cross-linked sodium carboxymethylcellulose, microcrystalline cellulose and magnesium stearate. In one embodiment of the invention, the tablet is coated with a film coating, optionally wherein the film coating is The amount of and / or coating is 2-4% of the core weight of the tablet. In one embodiment of the present invention, the total weight of the tablet is 350 mg. In one embodiment of the present invention, the tablet is coated and the total weight of the tablet is 360.5 mg.

[0271] In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 11.2 mg tenofovir alafenamide hemifumarate, wherein at least 58% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate. In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 11.2 mg tenofovir alafenamide hemifumarate, wherein at least 58% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate, wherein the excipients consist of cross-linked sodium carboxymethylcellulose, microcrystalline cellulose and magnesium stearate. In one embodiment of the invention, the tablet is coated with a film coating, optionally wherein the film coating is The amount of and / or coating is 2-4% of the core weight of the tablet. In one embodiment of the present invention, the total weight of the tablet is 350 mg. In one embodiment of the present invention, the tablet is coated and the total weight of the tablet is 360.5 mg.

[0272] In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 11.2 mg tenofovir alafenamide hemifumarate, wherein at least 60% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate. In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 11.2 mg tenofovir alafenamide hemifumarate, wherein at least 60% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate, wherein the excipients consist of cross-linked sodium carboxymethylcellulose, microcrystalline cellulose and magnesium stearate. In one embodiment of the invention, the tablet is coated with a film coating, optionally wherein the film coating is The amount of and / or coating is 2-4% of the core weight of the tablet. In one embodiment of the present invention, the total weight of the tablet is 350 mg. In one embodiment of the present invention, the tablet is coated and the total weight of the tablet is 360.5 mg.

[0273] In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 11.2 mg tenofovir alafenamide hemifumarate, wherein at least 65% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate. In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 11.2 mg tenofovir alafenamide hemifumarate, wherein at least 65% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate, wherein the excipients consist of cross-linked sodium carboxymethylcellulose, microcrystalline cellulose and magnesium stearate. In one embodiment of the invention, the tablet is coated with a film coating, optionally wherein the film coating is The amount of and / or coating is 2-4% of the core weight of the tablet. In one embodiment of the present invention, the total weight of the tablet is 350 mg. In one embodiment of the present invention, the tablet is coated and the total weight of the tablet is 360.5 mg.

[0274] In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 28 mg tenofovir alafenamide hemifumarate, wherein at least 50% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate. In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 28 mg tenofovir alafenamide hemifumarate, wherein at least 50% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate, wherein the excipients consist of cross-linked sodium carboxymethylcellulose, microcrystalline cellulose and magnesium stearate. In one embodiment of the invention, the tablet is coated with a thin film coating, optionally wherein the film coating is The amount of and / or coating is 2-4% of the core weight of the tablet. In one embodiment of the present invention, the total weight of the tablet is 350 mg. In one embodiment of the present invention, the tablet is coated and the total weight of the tablet is 360.5 mg.

[0275] In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 28 mg tenofovir alafenamide hemifumarate, wherein at least 60% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate. In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 28 mg tenofovir alafenamide hemifumarate, wherein at least 60% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate, wherein the excipients consist of cross-linked sodium carboxymethylcellulose, microcrystalline cellulose and magnesium stearate. In one embodiment of the invention, the tablet is coated with a film coating, optionally wherein the film coating is The amount of and / or coating is 2-4% of the core weight of the tablet. In one embodiment of the present invention, the total weight of the tablet is 350 mg. In one embodiment of the present invention, the tablet is coated and the total weight of the tablet is 360.5 mg.

[0276] In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 28 mg tenofovir alafenamide hemifumarate, wherein at least 63% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate. In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 28 mg tenofovir alafenamide hemifumarate, wherein at least 63% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate, wherein the excipients consist of cross-linked sodium carboxymethylcellulose, microcrystalline cellulose and magnesium stearate. In one embodiment of the invention, the tablet is coated with a film coating, optionally wherein the film coating is The amount of and / or coating is 2-4% of the core weight of the tablet. In one embodiment of the present invention, the total weight of the tablet is 350 mg. In one embodiment of the present invention, the tablet is coated and the total weight of the tablet is 360.5 mg.

[0277] In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 28 mg tenofovir alafenamide hemifumarate, wherein at least 65% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate. In one embodiment of the invention, the tablet comprises 200 mg emtricitabine and 28 mg tenofovir alafenamide hemifumarate, wherein at least 65% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate, wherein the excipients consist of croscarmellose sodium, microcrystalline cellulose and magnesium stearate. In one embodiment of the invention, the tablet is coated with a film coating, optionally wherein the film coating is The amount of and / or coating is 2-4% of the core weight of the tablet. In one embodiment of the present invention, the total weight of the tablet is 350 mg. In one embodiment of the present invention, the tablet is coated and the total weight of the tablet is 360.5 mg.

[0278] In another embodiment of the present invention, the tablet disclosed herein is part of a kit comprising (a) a tablet comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof, and (b) a desiccant (e.g., silica gel).

[0279] In one embodiment of the invention, the tablet comprises:

[0280] Element Mass (mg) Emtricitabine or its salt 150-250 Tenofovir alafenamide or its salt 5-35 Croscarmellose Sodium 20-35 Microcrystalline Cellulose 70-120 Magnesium Stearate 1-7

[0281] In one embodiment of the invention, the tablet of the invention comprises:

[0282] Element Mass(mg) Emtricitabine 170-230 Tenofovir Alafenamide Hemifumarate 10-32 Croscarmellose Sodium 20-35 Microcrystalline Cellulose 70-120 Magnesium Stearate 1-7

[0283] In one embodiment of the present invention, the tablet of the present invention consists of:

[0284] Element Mass (mg) Emtricitabine 200±20 Tenofovir alafenamide hemifumarate 18±10 Croscarmellose Sodium 28±3 Microcrystalline Cellulose 100±13 Magnesium Stearate 5.2±1.1

[0285] and optional film coating.

[0286] In one embodiment of the invention, the tablet comprises:

[0287]

[0288]

[0289] In one embodiment of the invention, the tablet of the invention comprises:

[0290] Element Mass (mg) Emtricitabine 170-230 Tenofovir alafenamide hemifumarate 10-15 Croscarmellose Sodium 20-35 Microcrystalline Cellulose 90-120 Magnesium Stearate 1-7

[0291] In one embodiment of the present invention, the tablet of the present invention consists of:

[0292] Element Mass (mg) Emtricitabine 200±20 Tenofovir alafenamide hemifumarate 11±1 Croscarmellose Sodium 28±3 Microcrystalline Cellulose 106±11 Magnesium Stearate 5.2±1.1

[0293] and optional film coating.

[0294] In one embodiment of the present invention, the tablet of the present invention consists of:

[0295] Element Mass (mg) Emtricitabine 200±10 Tenofovir alafenamide hemifumarate 11±0.6 Croscarmellose Sodium 28±1.4 Microcrystalline Cellulose 106±5 Magnesium Stearate 5.2±0.5

[0296] and optional film coating.

[0297] In one embodiment of the present invention, the tablet of the present invention consists of:

[0298] Element Mass (mg) Emtricitabine 200 Tenofovir alafenamide hemifumarate 11.2 Croscarmellose Sodium 28.0 Microcrystalline Cellulose 105.56 Magnesium Stearate 5.25

[0299] and an optional film coating, for example a film coating comprising Opadry II gray 85F97517 (a combination of polyvinyl alcohol, polyethylene glycol (PEG), talc, titanium dioxide, black iron oxide). In one embodiment of the invention, the tablet of the invention consists of:

[0300] Element Mass (mg) Intragranular Emtricitabine 200 Tenofovir alafenamide hemifumarate 11.2 Croscarmellose Sodium 28 Microcrystalline Cellulose 105.56 Magnesium Stearate 2.625 Extragranular Magnesium Stearate 2.625 Total core weight 350

[0301] and a film coating consisting of Opadry II gray 85F97517 (which contains 40.0% w / w polyvinyl alcohol-partially hydrolyzed, 24.74% w / w titanium dioxide, 20.2% w / w polyethylene glycol / PEG 3350, 14.8% w / w talc and 0.26% w / w black iron oxide).

[0302] In one embodiment of the invention, the tablet comprises:

[0303] Element Mass (mg) Emtricitabine or its salt 150-250 Tenofovir alafenamide or its salt 20-35 Croscarmellose Sodium 20-35 Microcrystalline Cellulose 70-100 Magnesium Stearate 1-7

[0304] In one embodiment of the invention, the tablet of the invention comprises:

[0305] Element Mass (mg) Emtricitabine 170-230 Tenofovir alafenamide hemifumarate 22-32 Croscarmellose Sodium 20-35 Microcrystalline Cellulose 70-100 Magnesium Stearate 1-7

[0306] In one embodiment of the present invention, the tablet of the present invention consists of:

[0307] Element Mass (mg) Emtricitabine 200±20 Tenofovir alafenamide hemifumarate 28±3 Croscarmellose Sodium 28±3 Microcrystalline Cellulose 89±9 Magnesium Stearate 5.2±1.1

[0308] and optional film coating.

[0309] In one embodiment of the present invention, the tablet of the present invention consists of:

[0310] Element Mass (mg) Emtricitabine 200±10 Tenofovir alafenamide hemifumarate 28±1.4 Croscarmellose Sodium 28±1.4 Microcrystalline Cellulose 89±4 Magnesium Stearate 5.2±0.5

[0311] and optional film coating.

[0312] In one embodiment of the present invention, the tablet of the present invention consists of:

[0313] Element Mass (mg) Emtricitabine 200 Tenofovir alafenamide hemifumarate 28 Croscarmellose Sodium 28 Microcrystalline Cellulose 89 Magnesium Stearate 5.3

[0314] and an optional film coating, such as one comprising Opadry II Blue 85F105057 (a combination of polyvinyl alcohol, polyethylene glycol (PEG), talc, titanium dioxide, FD&C Blue #2).

[0315] In one embodiment of the present invention, the tablet of the present invention consists of:

[0316] Element Mass (mg) Emtricitabine 200.00 Tenofovir alafenamide hemifumarate 28.00 Croscarmellose Sodium 28.00 Microcrystalline Cellulose 88.70 Magnesium Stearate 5.25

[0317] and an optional film coating, such as one comprising Opadry II Blue 85F105057 (a combination of polyvinyl alcohol, polyethylene glycol (PEG), talc, titanium dioxide, FD&C Blue #2).

[0318] In one embodiment of the present invention, the tablet of the present invention consists of:

[0319] Element Mass (mg) Intragranular Emtricitabine 200.00 Tenofovir alafenamide hemifumarate 28.00 Croscarmellose Sodium 28.00 Microcrystalline Cellulose 88.70 Magnesium Stearate 2.625 Extragranular Magnesium Stearate 2.625 Total core weight 350

[0320] and a film coating consisting of Opadry II Blue 85F105057 (which contains 40.0% w / w polyvinyl alcohol-partially hydrolyzed, 23.32% w / w titanium dioxide, 20.2% w / w polyethylene glycol / PEG 3350, 14.8% w / w talc, and 1.68% w / w FD&C Blue #2 / Indigo Carmine Aluminum Lake).

[0321] In one embodiment of the present invention, the tablet of the present invention consists of:

[0322]

[0323]

[0324] and a film coating consisting of Opadry II Blue 85F105057 (which contains 40.0% w / w polyvinyl alcohol-partially hydrolyzed, 23.32% w / w titanium dioxide, 20.2% w / w polyethylene glycol / PEG 3350, 14.8% w / w talc, and 1.68% w / w FD&C Blue #2 / Indigo Carmine Aluminum Lake).

[0325] Preparation method

[0326] Also provided are methods for producing the compositions and dosage forms described herein (particularly tablets). In some embodiments, the method comprises mixing emtricitabine and tenofovir alafenamide hemifumarate with an excipient, followed by compression. In some embodiments, emtricitabine and tenofovir alafenamide hemifumarate are first blended and granulated with an excipient, for example by dry granulation. In certain embodiments, this step involves rolling and / or milling. In some embodiments, the blended particles of emtricitabine and tenofovir alafenamide hemifumarate are further combined with an extragranular excipient and then compressed, and the extragranular excipient includes but is not limited to magnesium stearate.

[0327] In some embodiments, the method comprises (a) compressing rilpivirine or a pharmaceutically acceptable salt thereof as a first layer, and (b) compressing tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof as a second layer. The first layer and the second layer can be compressed separately and then combined. However, more typically, the first layer is formed by compression and then the second layer is compressed onto the first layer. The inventors have found that the choice of layer sequence during the tableting process of a multilayer tablet can affect the properties of the tablet (e.g., the adhesion of the inner layer of the tablet). Therefore, it is advantageous to compress rilpivirine or a pharmaceutically acceptable salt thereof as a first layer, for example, a first layer having a weight of about 300 mg, and then compress tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof as a second layer, for example, a second layer having a weight of about 350 mg, because the compressibility and fluidity of the first layer are enhanced. This is in contrast to commercially produced In contrast to the method of , the rilpivirine-containing layer is compressed as a second layer.

[0328] In some embodiments, a tablet is provided, wherein the first layer can be obtained by the following method: (a) compressing rilpivirine or a pharmaceutically acceptable salt thereof as the first layer and (b) compressing tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof as the second layer. In other embodiments, a tablet of the present invention is provided, wherein the second layer can be obtained by the following method: (a) compressing rilpivirine or a pharmaceutically acceptable salt thereof as the first layer and (b) compressing tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof as the second layer.

[0329] Typically, the process will include a step of coating the tablet core after compression, for example with a film coating as described above.

[0330] Tablet preparation methods are generally well known in the pharmaceutical art. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA), the entire contents of which are incorporated herein by reference.

[0331] Tablets may be prepared by compression or molding, optionally with one or more excipients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient.

[0332] Treatment

[0333] The solid oral dosage forms (particularly tablets) disclosed herein can be used to treat or prevent HIV (eg HIV-1). In some embodiments, the solid oral dosage forms (particularly tablets) disclosed herein can be used to treat or prevent HIV-1 or HIV-2.

[0334] In certain embodiments, the solid oral dosage forms disclosed herein (particularly tablets) can be used to treat HIV (eg, HIV-1). In some embodiments, the solid oral dosage forms disclosed herein (particularly tablets) can be used to treat HIV-1 or HIV-2.

[0335] In certain embodiments, the solid oral dosage forms disclosed herein (particularly tablets) can be used to prevent HIV (eg, HIV-1). In some embodiments, the solid oral dosage forms disclosed herein (particularly tablets) can be used to prevent HIV-1 or HIV-2.

[0336] Therefore, a method for treating an individual with HIV is provided, comprising administering to the individual a solid oral dosage form (particularly a tablet) of the present invention. Similarly, a solid oral dosage form (particularly a tablet) of the present invention is provided for use in such treatment methods. The present invention also provides the use of rilpivirine or a pharmaceutically acceptable salt thereof, tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and emtricitabine or a pharmaceutically acceptable salt thereof in the preparation of an oral dosage form (particularly a tablet) of the present invention for treating HIV. In some embodiments, the present invention provides the use of tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof in the preparation of an oral dosage form (particularly a tablet) of the present invention for treating HIV.

[0337] In certain embodiments, a method of treating HIV infection in a human suffering from an infection or at risk of infection is provided, wherein the method comprises administering to the human a solid oral dosage form disclosed herein. Similarly, a method of preventing HIV infection in a human suffering from an infection or at risk of infection is provided, wherein the method comprises administering to the human a solid oral dosage form disclosed herein.

[0338] In another embodiment, there is provided a use of a solid oral dosage form disclosed herein for treating HIV infection in a person suffering from an infection or at risk of infection. Similarly, there is provided a use of a solid oral dosage form disclosed herein for preventing HIV infection in a person suffering from an infection or at risk of infection.

[0339] In another embodiment, a method of using the solid oral dosage form disclosed herein in therapy is provided. In particular, a method of treating the proliferation of HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human, such as a male who has sex with a male or a transgender female who has sex with a male) is provided, comprising administering to the mammal a solid oral dosage form disclosed herein.

[0340] In a specific embodiment, there is provided a method for preventing HIV infection from being established and / or preventing the virus from establishing a permanent infection and / or preventing the appearance of disease symptoms and / or preventing the virus from reaching a monitorable level in the blood when the individual is exposed to the virus, for example, a solid oral dosage form disclosed herein for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Therefore, in certain embodiments, there is provided a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2). For example, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes administering a solid oral dosage form disclosed herein. In certain specific embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes administering a solid oral dosage form disclosed herein in combination with safe sex. In certain embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes administering to an individual at risk of acquiring HIV infection. Examples of individuals at high risk of acquiring HIV include, but are not limited to, individuals at risk of HIV sexual transmission.

[0341] In certain embodiments, the risk of acquiring HIV is reduced by at least about 40%, 50%, 60%, 70%, 80%, 90%, or 95%. To some extent, the risk of acquiring HIV is reduced by at least about 75%. In certain embodiments, the risk of acquiring HIV is reduced by about 80%, 85%, or 90%.

[0342] In another embodiment, disclosed is the use of a solid oral dosage form disclosed herein for preparing a medicament for treating HIV infection in a person suffering from an infection or at risk of infection. Similarly, in another embodiment, disclosed is the use of a solid oral dosage form disclosed herein for preparing a medicament for preventing HIV infection in a person suffering from an infection or at risk of infection.

[0343] In another embodiment, an article of manufacture comprising a solid oral dosage form disclosed herein; and a packaging material comprising a label indicating that the solid oral dosage form can be used to treat HIV infection is disclosed. Similarly, in another embodiment, an article of manufacture comprising a solid oral dosage form disclosed herein; and a packaging material comprising a label indicating that the solid oral dosage form can be used to prevent HIV infection is disclosed.

[0344] The methods disclosed herein involve administering to an individual, typically a human, an oral dosage form disclosed herein, particularly a tablet, and typically involve repeated administration, typically once daily.The treatment may be prophylactic or therapeutic treatment.

[0345] In certain embodiments, the methods disclosed herein involve repeated administration at intervals less than once a day. For example, in certain embodiments, the methods disclosed herein involve administration of an oral dosage form disclosed herein every other day, five times a week, four times a week, three times a week, twice a week, or once a week.

[0346] In certain embodiments, the methods disclosed herein involve administration before and / or after an event in which an individual is exposed to HIV or otherwise increases the risk of an individual acquiring HIV, such as pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP). Examples of events that may increase the risk of an individual acquiring HIV include, but are not limited to, not using a condom during anal sex with an HIV-positive partner or a partner of unknown HIV status; having anal sex with more than 3 sexual partners; exchanging money, gifts, shelter, or drugs for anal sex; having sex with a male partner diagnosed with a sexually transmitted infection; not consistently using condoms with a sexual partner known to be HIV-positive.

[0347] In certain embodiments, for example, when used as PrEP, solid oral dosage forms disclosed herein are applied 2-72 hours, 2-48 hours, 2-24 hours or 2-12 hours before an event that increases the risk of HIV acquisition in an individual (for example, before sexual behavior or other situations exposed to HIV virus). In some embodiments, solid oral dosage forms disclosed herein are applied within 72 hours, 60 hours, 48 ​​hours, 24 hours, 12 hours, 9 hours, 6 hours, 4 hours, 3 hours, 2 hours or 1 hour before an event that increases the risk of HIV acquisition in an individual (for example, before sexual behavior or other situations exposed to HIV virus). In certain embodiments, when solid oral dosage forms disclosed herein are applied before an event that increases the risk of HIV acquisition in an individual, they are applied daily before the event. In certain embodiments, when solid oral dosage forms disclosed herein are applied before an event that increases the risk of HIV acquisition in an individual, they are applied once to three times before the event.

[0348] In certain embodiments, for example, when administered as part of a PrEP regimen or as PEP, a solid oral dosage form disclosed herein is administered 2-48 hours, 2-36 hours, 2-24 hours, or 2-12 hours after an event that increases the risk of an individual acquiring HIV (e.g., after sexual intercourse or other means of exposure to HIV virus). In certain embodiments, for example, when administered as PEP, a solid oral dosage form disclosed herein is administered 7 days, 14 days, 21 days, 28 days, 30 days, or 45 days after an event that increases the risk of an individual acquiring HIV (e.g., after sexual intercourse or other means of exposure to HIV virus). In certain embodiments, for example, when administered as PEP, a solid oral dosage form disclosed herein is administered 30 days after an event that increases the risk of an individual acquiring HIV (e.g., after sexual intercourse or other means of exposure to HIV virus). In certain embodiments, after the event that will increase the risk of HIV acquisition by individuals (such as sexual behavior or other ways of exposure to HIV virus), solid oral dosage forms disclosed herein are applied less than 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 12 hours, 18 hours, 24 hours, 36 hours or 48 hours. In certain other embodiments, after the event that will increase the risk of HIV acquisition by individuals (such as sexual behavior or other ways of exposure to HIV virus), solid oral dosage forms disclosed herein are applied for 1 day, 2 days, 3 days, 4 days or 5 days. In certain embodiments, when solid oral dosage forms disclosed herein are applied after the event that will increase the risk of HIV acquisition by individuals, they are applied daily after the event. In certain embodiments, when solid oral dosage forms disclosed herein are applied after the event that will increase the risk of HIV acquisition by individuals, they are applied once to three times after the event. In certain embodiments, when solid oral dosage forms disclosed herein are applied after the event that will increase the risk of HIV acquisition by individuals, they are applied once after the event.

[0349] In certain embodiments, for example, when used as PrEP, solid oral dosage forms disclosed herein are applied before or after an event (e.g., before sexual behavior) that increases the risk of HIV acquisition in an individual. For example, in certain embodiments, for example, when used as PrEP, solid oral dosage forms disclosed herein are applied 2-72 hours, 2-48 hours, 2-24 hours or 2-12 hours before an event (e.g., before sexual behavior) that increases the risk of HIV acquisition in an individual or 2-48 hours, 2-36 hours, 2-24 hours or 2-12 hours after the event. For example, in some embodiments, one or more (e.g., one, two or three) solid oral dosage forms disclosed herein are applied before (e.g., before sexual behavior) an event that increases the risk of HIV acquisition in an individual and one to five days, once a day, are applied after the event. In some embodiments, one or more (e.g., one, two or three) solid oral dosage forms disclosed herein are applied 2-24 hours before (e.g., before sexual behavior) an event that increases the risk of HIV acquisition in an individual and one or more (e.g., once, twice or three) solid oral dosage forms disclosed herein are applied 2-48 hours after the event. In some embodiments, solid oral dosage forms disclosed herein are administered once a week, twice a week, three times a week, four times a week, or five times a week, or once or more (e.g., once, twice, or three times) after an event (e.g., sexual behavior) that may increase the risk of an individual acquiring HIV. In one embodiment, solid oral dosage forms disclosed herein are administered twice a week (one composition (i.e., tablet) per day) and once (one composition) after an event (e.g., one tablet within 24 hours after exposure such as sexual behavior) that may increase the risk of an individual acquiring HIV.

[0350] generally

[0351] The term "fed" in relation to administration of a solid oral dosage form to a human subject means oral administration of the dosage form under oral conditions (a moderate fat meal), e.g., within about 30 minutes of a human consuming a standard meal of about 300-600 calories and about 10 to about 15 grams of fat.

[0352] The term "substantially free" in relation to the presence of a given component in, for example, a composition means that less than 5% by weight of the composition (e.g., less than 1% by weight of the composition) is the given component. The word "substantially" does not exclude "completely", for example, a composition "substantially free" of Y may be completely free of Y. Optionally, the word "substantially" may be omitted from the definition of the present invention.

[0353] The term "isolated" as used in connection with certain components (e.g., A and B) in a tablet means that those components are physically separated such that the presence of one component (e.g., A) does not substantially affect the stability of the other components (e.g., B) isolated therefrom during storage. Typically, when components are isolated in a tablet, they are present in separate layers of a multilayer tablet. By way of example, components A and B may be present in separate layers of a multilayer tablet, wherein (a) the layer comprising component A is substantially free of component B and (b) the layer comprising component B is substantially free of component A. The isolated layers may be in contact with each other or may be separated, for example, by one or more additional layers.

[0354] The term "comprising" and variations thereof such as "including" and "containing" are to be construed as having an open, inclusive meaning, ie, "including, but not limited to."

[0355] The term "between" with respect to two values ​​includes both values, for example, the range "between 10 mg and 20 mg" includes, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 mg.

[0356] The term "about" as used herein is understood by those skilled in the art to reflect the variability of the numerical value to which it is modified. The values ​​expressed herein are understood to include a range of variability. In order to reflect this variability, any resin used herein includes this variability. Thus, the numerical values ​​used herein encompass specified values ​​as well as values ​​modified with "about". In certain embodiments, the term "about" associated with a numerical value x is optional and refers to, for example, x ± 10%, x ± 5%, or x ± 1%.

[0357] "% w / w" refers to the weight of a component as a percentage of the total weight of, for example, a layer or dosage form in which the component is present. For example, a composition comprising "5% w / w of X" refers to a composition in which the weight of component X is 5% of the total weight of the composition.

[0358] Reference in this specification to "one embodiment" or "an embodiment" means that the particular features, structures, or characteristics described in connection with the embodiment are included in at least one embodiment provided herein. Thus, the phrases "in one embodiment" or "in an embodiment" appearing in various places in this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0359] The term "pharmaceutically acceptable" with respect to a "substance" means a substance that is generally regarded as safe and suitable without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio.

[0360] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and has (or can be converted to have the following form) the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; acid addition salts formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, etc.; and salts formed when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth metal ions or aluminum ions) or coordinated with organic bases (such as diethanolamine, triethanolamine, N-methylglucamine, etc.). This definition also includes ammonium and substituted or quaternized salts. Representative, non-limiting lists of pharmaceutically acceptable salts can be found in SM Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and in Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st ed., Lippincott, Williams & Wilkins, Philadelphia, PA, (2005) pp. 732, Table 38-5, both of which are incorporated by reference.

[0361] The term "salt" as used herein includes co-crystals. The term "co-crystal" refers to a crystalline compound comprising two or more molecular components, for example, wherein the proton transfer between the molecular components is partial or incomplete. Therefore, the term "pharmaceutically acceptable salt" as used herein includes salts and co-crystals as defined above.

[0362] The term "solvate" refers to a molecular complex comprising a compound and one or more pharmaceutically acceptable solvent molecules. Examples of solvent molecules include water and C 1-6 Alcohols, such as ethanol. When the solvate is water, the term "hydrate" may be used.

[0363] "Treatment" of illnesses includes the following:

[0364] (1) Prevent or reduce the risk of developing a disease, i.e., prevent clinical symptoms of the disease from developing in individuals who may be exposed to or susceptible to the disease but who do not yet experience or show symptoms of the disease;

[0365] (2) inhibiting the disease, i.e., preventing or reducing the development of the disease or its clinical symptoms; and

[0366] (3) Relieve the disease, that is, cause the disease or its clinical symptoms to disappear.

[0367] The term "effective amount" refers to an amount that may effectively induce a desired biological or medical response, including an amount of a compound that is sufficient to effectively treat a disease when administered to an individual for treating a disease. The effective amount varies depending on the compound, the disease and its severity and age, weight, etc. of the individual to be treated. The effective amount may include a range of amounts.

[0368] Example

[0369] The invention will now be illustrated by the following non-limiting examples.

[0370] Example 1 - Emtricitabine / Tenofovir Alafenamide Hemifumarate Tablets

[0371] The emtricitabine / tenofovir alafenamide hemifumarate formulations were initially developed with 200 mg of target emtricitabine per tablet and 25 mg and 40 mg of target tenofovir alafenamide per tablet. Antiviral activity was measured by baseline changes in HIV-1 RNA and DAVG11. Statistically greater reductions in HIV-1 RNA and DAVG11 were observed for 25 mg tenofovir alafenamide single-dose tablets and 40 mg tenofovir alafenamide single-dose tablets compared to tenofovir disoproxil fumarate single-dose tablets, supporting further clinical studies of 25 mg and 40 mg tenofovir alafenamide.

[0372] Tablets of fixed-dose combinations of emtricitabine / tenofovir alafenamide 200 / 25 mg and emtricitabine / tenofovir alafenamide 200 / 40 mg were developed and manufactured for Phase I clinical studies, containing 200 mg emtricitabine and 25 mg (tablet A) or 40 mg emtricitabine / tenofovir alafenamide (tablet B) as emtricitabine formulations / tenofovir alafenamide. The fixed-dose combinations of emtricitabine / tenofovir alafenamide 200 / 25 mg and 200 / 40 mg were evaluated as follows:

[0373]

[0374] The emtricitabine / tenofovir alafenamide 200 / 25 mg (tablet A) and 200 / 40 mg (tablet B) tablets evaluated were prepared using a dry granulation / tablet compression / film coating process chain. Dry granulation by roller compaction was selected as a means of combining emtricitabine and tenofovir alafenamide to minimize the exposure of tenofovir alafenamide to moisture during the granulation process. The entire manufacturing process consists of blending and lubricating emtricitabine and tenofovir alafenamide with intragranular excipients, followed by roller compaction and grinding. The resulting emtricitabine / tenofovir alafenamide granules are then mixed and lubricated with extragranular excipients to produce the final powder mixture of emtricitabine / tenofovir alafenamide, which is compressed into 450 mg cores and subsequently film-coated with Opadry II White 85F18422.

[0375] Example 2 - Stability of Emtricitabine / Tenofovir Alafenamide Hemifumarate Tablets

[0376] The stability of Tablets A and B of Example 1 was evaluated for 24 months under long-term storage conditions at 25°C / 60% RH and for 6 months under accelerated conditions at 40°C / 75% RH. The stability results of emtricitabine and tenofovir alafenamide hemifumarate indicated that limited emtricitabine degradation occurred under any storage conditions regardless of the strength of the emtricitabine / tenofovir alafenamide hemifumarate tablets. After 6 months at 40°C / 75% RH, 4.2% of the total tenofovir alafenamide hemifumarate impurity products were observed in Tablet A, and 3.0% of the total tenofovir alafenamide hemifumarate impurity products were observed in Tablet B.

[0377] The dissolution of emtricitabine and tenofovir alafenamide hemifumarate from these tablets did not change. Tablets stored under all conditions showed a release of ≥98% of both active ingredients over the entire storage time (monitored using USP apparatus II, in 500 ml of 50 mM sodium citrate, pH 5.5, 37°C and a paddle speed of 75 RPM). During the stability study, the moisture content of these tablets ranged from 1.3-2.5%. In summary, these stability data demonstrate that Tablets A and Tablets B packaged in HDPE bottles with 2 g of desiccant remain physically and chemically stable after 6 months under accelerated conditions (40°C / 75% RH) and up to 24 months under long-term storage conditions (25°C / 60% RH).

[0378] Example 3 - Excipient Range Study

[0379] A formulation development study was conducted by designing, manufacturing, and testing eleven prototype monolayer co-dried granulated emtricitabine / tenofovir alafenamide hemi-fumarate tablet formulations.

[0380] The effects of excipient identity and relative composition in these formulations on the chemical stability of tenofovir alafenamide hemifumarate were evaluated. The compositions of the eleven formulations are summarized in the table below:

[0381]

[0382]

[0383] 30 tablets are packed in 60 ml HDPE bottle with 2g desiccant and polyester roll. The bottle is induction sealed with PP cap.

[0384] "-" excipient is not included in the composition.

[0385] The following preparations were examined for their properties:

[0386] - Filler type and excipient matrix composition: microcrystalline cellulose, microcrystalline cellulose and lactose monohydrate, microcrystalline cellulose and mannitol, or microcrystalline cellulose and anhydrous calcium dibasic phosphate.

[0387] -Disintegrant type and level: Croscarmellose sodium or crospovidone.

[0388] - Drug loading of tenofovir alafenamide hemifumarate: The concentrations of tenofovir alafenamide hemifumarate are 2.49% w / w and 3.20% w / w for emtricitabine / tenofovir alafenamide hemifumarate 200 / 10 mg tablets, and the concentrations of tenofovir alafenamide hemifumarate are 6.23% w / w and 8.01% w / w for emtricitabine / tenofovir alafenamide 200 / 25 mg tablets.

[0389] All film-coated tablets were packaged in 60 mL HDPE bottles with 2 g of silica gel desiccant and polyester rolls with 30 counts. The HDPE bottles were induction sealed using polypropylene (PP) caps with aluminum face liners. The chemical stability was monitored for 3 months at 40 ° C / 75% RH. For the 5 formulations tested (batches AE), the degradation products of total tenofovir alafenamide hemifumarate (relative to the initial) increased by 0.7-1.7% after one month and 2.3-2.7% after 3 months. Overall, the filler system did not significantly affect the degradation of tenofovir alafenamide hemifumarate after 3 months under accelerated conditions.

[0390] Example 4 - Effect of Tenofovir Alafenamide Hemifumarate Loading on Stability in Emtricitabine / Tenofovir Alafenamide Hemifumarate Tablets

[0391] The effect of drug loading of tenofovir alafenamide hemifumarate on the stability of tenofovir alafenamide hemifumarate in emtricitabine / tenofovir alafenamide 200 / 10 mg and 200 / 50 mg tablets was evaluated using drug loading of tenofovir alafenamide hemifumarate ranging from 2.49% to 8.01% with the accompanying adjustment of microcrystalline cellulose content. The emtricitabine / tenofovir alafenamide 200 / 10 mg tablet formulation contained 2.49% w / w of tenofovir alafenamide hemifumarate or 3.20% w / w of tenofovir alafenamide hemifumarate, while the emtricitabine / tenofovir alafenamide 200 / 25 mg tablet formulation contained 6.23% w / w of tenofovir alafenamide hemifumarate or 8.01% w / w of tenofovir alafenamide hemifumarate. Higher drug loading was achieved by reducing the total tablet weight from 450 mg to 350 mg.

[0392] The chemical stability of tenofovir alafenamide hemifumarate as a function of drug loading is summarized in the following table:

[0393]

[0394]

[0395] nd: Not detected (<0.025%)

[0396] tr: trace amount (0.025% < impurity < 0.05%)

[0397] a 30 tablets with 2g desiccant and polyester roll packed in 60ml HDPE bottle. Bottle is induction sealed with PP cap. b Represents the sum of all unspecified degradation products / impurities.

[0398] Emtricitabine / tenofovir alafenamide 200 / 10 mg tablets containing 2.49% w / w tenofovir alafenamide hemifumarate showed an increase of 0.7% and 2.4% of total tenofovir alafenamide hemifumarate degradation products after 1 month and 3 months, respectively. Emtricitabine / tenofovir alafenamide 200 / 10 mg tablets containing 3.20% w / w tenofovir alafenamide hemifumarate showed an increase of 0.3% and 1.1% of total tenofovir alafenamide hemifumarate degradation products after 1 month and 3 months, respectively. Increasing the tenofovir alafenamide hemifumarate drug load from 2.49% w / w to 3.20% w / w tenofovir alafenamide hemifumarate resulted in a 50% reduction in total tenofovir alafenamide hemifumarate degradation products after 3 months under accelerated conditions.

[0399] The emtricitabine / tenofovir alafenamide 200 / 25 mg tablets containing 8.01% w / w tenofovir alafenamide hemifumarate showed better chemical stability of tenofovir alafenamide hemifumarate than the tablets containing 6.23% w / w tenofovir alafenamide hemifumarate. After 3 months, the degradation products of total tenofovir alafenamide hemifumarate in the emtricitabine / tenofovir alafenamide 200 / 25 mg tablets increased by 1.5% for the 6.23% w / w tenofovir alafenamide hemifumarate formulation; and increased by 1.1% for the 8.01% w / w tenofovir alafenamide hemifumarate formulation. Based on the results of the drug loading study of tenofovir alafenamide hemifumarate, 3.20% and 8.01% w / w tenofovir alafenamide hemifumarate contents were selected for emtricitabine / tenofovir alafenamide 200 / 10 mg and 200 / 25 mg fixed-dose combination tablets, respectively.

[0400] Figure 1 A graph showing the increase in tenofovir alafenamide hemifumarate-related degradation products as a function of tenofovir alafenamide hemifumarate loading at 1 month and 3 months (at 40°C / 75%RH).

[0401] Example 5

[0402] As a result of the excipient and drug load evaluation, two formulations (emtricitabine / tenofovir alafenamide 200 / 10 mg tablet C; and emtricitabine / tenofovir alafenamide 200 / 25 mg tablet D) were developed for further study. The compositions of these formulations are shown in the following table:

[0403]

[0404] Emtricitabine and tenofovir alafenamide hemifumarate were blended with microcrystalline cellulose and croscarmellose sodium and then lubricated with magnesium stearate. The premix was then roller compacted and milled using an oscillating mill. The resulting granules were lubricated with magnesium stearate and compressed into 350 mg tablet cores, which were then film coated. Fig.10 A flow chart showing a method of making Tablets C and D.

[0405] Example 6

[0406] Tenofovir alafenamide hemifumarate undergoes solid-state hydrolysis and therefore a desiccant is included in the primary packaging to control the water content in the emtricitabine / tenofovir alafenamide hemifumarate tablets. Tablets C and D were packaged for development to evaluate the effect of the amount of desiccant on the chemical stability of tenofovir alafenamide hemifumarate during storage of emtricitabine / tenofovir alafenamide hemifumarate tablets.

[0407] Tablets C and D were packaged in 60 mL HDPE bottles at 30 count with 2 or 3 grams of desiccant and polyester rolls and sealed with an induction seal. Chemical stability was monitored at 40°C / 75%RH for up to 6 months.

[0408] The total degradation products related to tenofovir alafenamide hemifumarate in Tablet C after 6 months under accelerated conditions were 3.9% and 3.3% for bottles packed with 2 g and 3 g of desiccant, respectively. In comparison, the total degradation products related to tenofovir alafenamide hemifumarate in Tablet D were 2.3% and 2.4% for bottles packed with 2 g and 3 g of desiccant, respectively.

[0409] Example 7 - Bioequivalence study of emtricitabine / tenofovir alafenamide hemifumarate

[0410] A randomized, open-label, single-dose, two-way crossover study was conducted to determine:

[0411] Study 1: Bioequivalence of emtricitabine and TAF, administered as a F / TAF fixed-dose combination tablet (Tablet C) concomitantly with elvitegravir and cobicistat, or as an E / C / F / TAF fixed-dose combination tablet.

[0412] • Study 2: Bioequivalence of emtricitabine and TAF, administered as an F / TAF fixed-dose combination tablet (Tablet D) or as an E / C / F / TAF fixed-dose combination tablet.

[0413] Study 3: Bioequivalence of emtricitabine and TAF as a fixed-dose combination tablet of F / TAF (Tablet D) and from Emtricitabine and TAF were co-administered in the presence of (emtricitabine) capsules and TAF single-dose tablets.

[0414] Duration of treatment

[0415] Subjects were randomized to one of two treatment sequences (AB or BA) and received a single dose of one of the following treatments (A or B) on Days 1 and 7 (Studies 1 and 2) or Days 1 and 15 (Study 3):

[0416] Study 1

[0417] Treatment A: A single dose of F / TAF (200 / 10 mg) fixed-dose combination tablet (Tablet C) administered orally concurrently with EVG 150 mg and COBI 150 mg tablets under fed conditions.

[0418] Treatment B: A single dose of E / C / F / TAF (150 / 150 / 200 / 10 mg) fixed-dose combination tablet administered orally under fed conditions.

[0419] Study 2

[0420] Treatment A: A single dose of F / TAF (200 / 25 mg) fixed-dose combination tablet (Tablet D) administered orally under fed conditions.

[0421] Treatment B: A single dose of E / C / F / TAF (150 / 150 / 200 / 10 mg) fixed-dose combination tablet administered orally under fed conditions.

[0422] Study 3

[0423] Treatment A: A single dose of F / TAF (200 / 25 mg) fixed-dose combination tablet (Tablet D) administered orally under fed conditions.

[0424] Treatment B: A single dose of 200 mg capsule plus single TAF 25 mg tablet.

[0425] Studies 1 and 2: In each study, the total duration of the study was 22 days. There was a 6-day washout period between dosing on Days 1 and 7, and a 14-day follow-up period.

[0426] Study 3: The total duration of the study was 29 days. Doses were given on Days 1 and 15, with a 14-day follow-up period.

[0427] Evaluation Criteria

[0428] Calculate the following plasma pharmacokinetic parameters: C max , T max , C last ,t 1 / 2 , AUC last , AUC inf , %AUC exp 、V z / F, CL / F.

[0429] Statistical methods

[0430] Studies 1 and 2

[0431] Pharmacokinetics: Plasma concentrations and PK parameters were presented and summarized by treatment group using descriptive statistics. In addition, parametric analysis of variance was fitted to PK parameters (AUC inf ,AUC last and C max) were natural logarithm transformed. Two-sided 90% confidence intervals (CI) were constructed for the ratio of the geometric least square means (GLSM) of each PK parameter of emtricitabine and tenofovir alafenamide hemifumarate. If the 90% CI of the ratio of the GLSM (geometric least square means) of the pharmacokinetic parameters of each analyte between the two formulations fell within the predetermined bioequivalence margins of 80% to 125%, it was concluded that the emtricitabine and tenofovir alafenamide hemifumarate in the F / TAF fixed-dose combination (Tablet C / Tablet D) were bioequivalent to the emtricitabine and tenofovir alafenamide hemifumarate components in the E / C / F / TAF fixed-dose combination.

[0432] Study 3

[0433] Pharmacokinetics: Using descriptive statistics, plasma concentrations and PK parameters were listed and summarized by treatment group. In addition, geometric means, 95% confidence intervals (CI) and means and standard deviations (SD) of natural log-transformed values ​​for individual subject PK parameter data were presented.

[0434] For the bioequivalence evaluation of F / TAF and FTC+TAF, the PK parameters (natural log-transformed AUC inf , AUC last and C max ). Parameter analysis of variance using mixed effects models was fitted to the natural log-transformed values ​​of the PK parameters. 90% CIs were provided for the geometric mean ratios (GMRs) of the PK parameters between pairs of interest. If used for the selected PK parameters (i.e., AUC inf , AUC last and C max ) falls within the pre-specified bioequivalence margins of 80% to 125%, it can be concluded that the formulations are bioequivalent.

[0435] result

[0436] Study 1

[0437] A total of 100 patients were randomized and received at least one dose of study drug. 98 patients completed the study.

[0438] Statistical comparison of emtricitabine and TAF pharmacokinetic parameters between F / TAF 200 / 10 mg (Tablet C) and E / C / F / TAF co-administered with 150 mg EVG and 150 mg COBI is shown in the following table:

[0439]

[0440]

[0441] GLSM ratios and corresponding AUCs of emtricitabine and tenofovir alafenamide inf , AUC last and C max The 90% CI was contained within the 80% to 125% boundaries specified for bioequivalence.

[0442] Study 2

[0443] A total of 56 patients underwent randomization and received at least one dose of study drug. 54 patients completed the study.

[0444] The following table shows the statistical comparison of emtricitabine and TAF pharmacokinetic parameters between F / TAF 200 / 25 mg (Tablet D) and E / C / F / TAF:

[0445]

[0446]

[0447] GLSM ratios and corresponding AUCs of emtricitabine and tenofovir alafenamide inf , AUC last and C max The 90% CI was contained within the 80% to 125% boundaries specified for bioequivalence.

[0448] Study 3

[0449] A total of 116 patients were randomized, received at least one dose of study drug and completed the study.

[0450] The following table shows the F / TAF200 / 25 mg (Tablet D) and the co-administration with TAF 25 mg tablets. Statistical comparison of pharmacokinetic parameters of emtricitabine and TAF between 200 mg capsules:

[0451]

[0452]

[0453] GLSM ratios and corresponding AUCs of emtricitabine and tenofovir alafenamide inf , AUC last and C max The 90% CI was contained within the 80% to 125% boundaries specified for bioequivalence.

[0454] in conclusion

[0455] These studies show that:

[0456] • The exposure of emtricitabine and TAF from F / TAF 200 / 10 mg (Tablet C) co-administered with EVG and COBI monotherapy tablets was bioequivalent to that of emtricitabine and TAF from the reference treatment of E / C / F / TAF.

[0457] • Emtricitabine and TAF from F / TAF 200 / 25 mg (Tablet D) were bioequivalent to the emtricitabine and TAF exposures from the reference treatment of E / C / F / TAF.

[0458] Emtricitabine and TAF from F / TAF 200 / 25 mg (Tablet D) and co-administered with TAF single 25 mg tablet The exposure of emtricitabine and TAF to the co-administered reference treatment of 200 mg capsules was bioequivalent.

[0459] Example 8 - Emtricitabine / Rilpivirine Hydrochloride / Tenofovir Alafenamide Hemifumarate Monolayer Tablet

[0460] A monolayer formulation of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide hemifumarate was prepared by co-dry granulation (tablet F4). Figure 2 is a flow chart illustrating the preparation of the formulation. The composition of the co-granular formulation is shown in the following table:

[0461]

[0462]

[0463] Example 9 - Stability Study of Tenofovir Alafenamide Hemifumarate

[0464] A study was conducted to evaluate the stability of tenofovir alafenamide hemifumarate in the presence of (a) emtricitabine and (b) emtricitabine and rilpivirine hydrochloride. Figure 3A and Figure 3B Present this data. Figure 3A Shown is the overall degradation of tenofovir alafenamide hemifumarate under open conditions (ie, unsealed container without desiccant) at 40°C / 75%RH. Figure 3B The total degradation of tenofovir alafenamide hemifumarate under blocked conditions at 60° C. These data indicate that the degradation rate of tenofovir alafenamide hemifumarate increases in the presence of emtricitabine and further increases in the presence of both emtricitabine and rilpivirine hydrochloride.

[0465] Example 10 - Emtricitabine / Rilpivirine Hydrochloride / Tenofovir Alafenamide Hemifumarate Double-layer Tablet

[0466] A bilayer formulation of emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide hemifumarate (Tablet F1) was prepared using the method described in Example 15. Figure 4 is a flow chart illustrating the preparation of a bilayer tablet. The composition of the formulation is summarized in the following table:

[0467]

[0468]

[0469] Example 11 - Dissolution Study

[0470] A study was conducted to evaluate the dissolution profiles of tablets F1 and F4 and to compare these with and Dissolution profile of Rilpivirine HCl. The dissolution of Rilpivirine HCl was measured in 1000 mL of sodium acetate pH 4.5 with 2% polysorbate 20 at 37°C and a paddle speed of 75 RPM using USP Apparatus II. Figure 5 These data show that the bilayer formulation (tablet F1) has and Compared to the comparable dissolution rate of rilpivirine hydrochloride, the monolayer formulation (tablet F4) showed enhanced dissolution rate of rilpivirine hydrochloride.

[0471] Fig. 6A , B and C show the results of a study conducted in a bilayer formulation (F1) to evaluate how tablet hardness affects the dissolution of rilpivirine hydrochloride, emtricitabine and tenofovir alafenamide hemifumarate, respectively (i.e., at 13, 16 and 19 KP). The dissolution of rilpivirine hydrochloride in these experiments was measured using USP apparatus II in 1000 ml of 0.01N HCl with 0.5% polysorbate 20 at 37°C and a paddle speed of 75 RPM. The dissolution of emtricitabine and tenofovir alafenamide hemifumarate was monitored at 37°C and a paddle speed of 75 RPM in 500 ml of 50 mM sodium citrate, pH 5.5, using USP apparatus II. These data show that all tablets exhibit acceptable dissolution throughout the selected tablet hardness range (13-19 KP).

[0472] Example 12 - Emtricitabine / Rilpivirine / Tenofovir Alafenamide Tablet Formulation

[0473] The following tablets (Tablet E) were selected for the bioequivalence study:

[0474]

[0475] Example 13 - Stability Study

[0476] Three batches of Tablet E were tested. The results met the release and stability criteria and are shown in the following tables and Figure 7 middle:

[0477]

[0478] Trace = <0.10%; ND = Not Detected (<0.05%)

[0479] Figure 7 The stability of Rilpivirine HCl / Emtricitabine / Tenofovir Alafenamide Hemifumarate tablets (assessed at 40°C / 75%RH) relative to the Emtricitabine 200 mg / Tenofovir Alafenamide Hemifumarate 25 mg tablets of Batches 1, 2 and 3 (above) (assessment of total TANAF degradation products) is shown.

[0480] It was also observed that the dissolution of rilpivirine hydrochloride, emtricitabine, and tenofovir alafenamide hemifumarate from Tablet E did not change after storage at various temperature and humidity conditions for 1, 3, and 6 months (see Fig. 8A -C). The dissolution of rilpivirine hydrochloride in these studies was monitored in 1000 mL of 0.01 N HCl with 0.5% polysorbate 20 at 37°C and a paddle speed of 75 RPM using USP Apparatus II. The dissolution of emtricitabine and tenofovir alafenamide hemifumarate was monitored in 500 mL of 50 mM sodium citrate, pH 5.5, at 37°C and a paddle speed of 75 RPM using USP Apparatus II.

[0481] However, the stability of tenofovir alafenamide hemifumarate is sensitive to the water content of the tablets, as shown in the following table, which shows the total degradation of tenofovir alafenamide hemifumarate (Tablet E formulation) as a function of the initial moisture content of the tablets at time zero, 1 month, 3 months and 6 months at 40°C / 75%RH:

[0482]

[0483] For emtricitabine and tenofovir alafenamide hemifumarate described above, the stability of tenofovir alafenamide hemifumarate in tablet batch E packaged with various levels of desiccant was also studied. The data are shown in the table below.

[0484]

[0485] Example 14 - Bioequivalence study of rilpivirine hydrochloride / emtricitabine / tenofovir alafenamide hemifumarate

[0486] A randomized, open-label, single-dose, three-way, six-sequence crossover study was conducted to determine the bioequivalence of emtricitabine and tenofovir alafenamide hemifumarate, administered as elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide hemifumarate (E / C / F / TAF) fixed-dose combination tablets or as rilpivirine hydrochloride / emtricitabine / tenofovir alafenamide hemifumarate fixed-dose combination tablets (Tablet E), and the bioequivalence of rilpivirine hydrochloride administered as a single tablet of rilpivirine hydrochloride or as a fixed-dose combination tablet of rilpivirine hydrochloride / emtricitabine / tenofovir alafenamide hemifumarate (Tablet E).

[0487] Duration of treatment

[0488] Three single doses were administered orally under fed conditions during a total study duration of up to 53 days: (a) emtricitabine / rilpivirine / tenofovir alafenamide fixed-dose combination tablet (200 / 25 / 25 mg) - Tablet E; (b) (rilpivirine, 25 mg, present in the tablet as 27.5 mg of rilpivirine hydrochloride); or (c) elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (E / C / F / TAF) (150 / 150 / 200 / 10 mg, wherein tenofovir alafenamide is present in the tablet as 11.2 mg of tenofovir alafenamide hemifumarate) fixed-dose combination tablets.

[0489] Evaluation Criteria

[0490] Calculate the following plasma pharmacokinetic parameters: C max , T max , C last ,t 1 / 2 , AUC last , AUC inf , %AUC exp 、V z / F, CL / F.

[0491] Statistical methods

[0492] Pharmacokinetics: Plasma concentrations and PK parameters were presented and summarized by analyte and treatment group using descriptive statistics. In addition, parametric analysis of variance was fitted to PK parameters (AUC inf , AUC last and C max) were natural logarithm transformed. Two-sided 90% confidence intervals (CI) were constructed for the ratios of the geometric least square means (GLSM) of each PK parameter for emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide hemifumarate. If the 90% CI of the ratio of the GLSM (geometric least square means) of the pharmacokinetic parameters of each analyte between the formulations fell within the predetermined bioequivalence margins of 80% to 125%, it was concluded that the emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide hemifumarate in the rilpivirine hydrochloride / emtricitabine / tenofovir alafenamide hemifumarate fixed-dose combination (Tablet E) were bioequivalent to the emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide hemifumarate components in the rilpivirine hydrochloride or elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide hemifumarate fixed-dose combination.

[0493] result

[0494] Individual Disposition and Demographics:

[0495] A total of 96 subjects were randomized and received at least 1 dose of study drug.

[0496] Pharmacokinetic results: PK parameters AUC of plasma rilpivirine hydrochloride, emtricitabine, and tenofovir alafenamide hemifumarate last , AUC inf and C max The statistical comparison is presented below:

[0497]

[0498]

[0499] GLSM ratios and AUC for emtricitabine, rilpivirine, and tenofovir alafenamide inf , AUC last and C max The corresponding 90% CI for was contained within the 80% to 125% boundaries specified for bioequivalence.

[0500] These values ​​are calculated based on the data given below for each active ingredient.

[0501] Emtricitabine

[0502] The following table shows the statistics of the pharmacokinetic parameters of emtricitabine:

[0503]

[0504] a Data are mean (%CV), except for T max and t 1 / 2Reported as median value (Q1, Q3).

[0505] The following table shows the pharmacokinetic parameters of emtricitabine AUC inf , AUC last and C max Statistical comparison of (when administered as emtricitabine / rilpivirine HCl / tenofovir alafenamide hemifumarate (tablet E) or elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide hemifumarate E / C / F / TAF):

[0506]

[0507] Rilpivirine Hydrochloride

[0508] The following table provides a summary of the pharmacokinetic parameters of rilpivirine hydrochloride following administration of rilpivirine hydrochloride / emtricitabine / tenofovir alafenamide hemifumarate (Tablet E) or rilpivirine hydrochloride:

[0509]

[0510] a Data are mean (%CV), except for T max and t 1 / 2 Reported as median value (Q1, Q3).

[0511] The following table shows the pharmacokinetic parameters of rilpivirine hydrochloride AUC last , AUC inf and C max Statistical comparison of (when administered as rilpivirine hydrochloride / emtricitabine / tenofovir alafenamide hemifumarate (Tablet E) or rilpivirine hydrochloride):

[0512]

[0513] Tenofovir alafenamide hemifumarate

[0514] The following table shows a statistical summary of the pharmacokinetic parameters of tenofovir alafenamide hemifumarate:

[0515]

[0516]

[0517] a Data are mean (%CV), except for T max and t 1 / 2 Reported as median value (Q1, Q3).

[0518] For AUC inf ,t 1 / 2, CL / F and Vz / F: for treatment A, n=82, for treatment C, n=85.

[0519] The following table shows the pharmacokinetic parameters of tenofovir alafenamide AUC last , AUC inf and C max Statistical comparison of (when administered as emtricitabine / rilpivirine hydrochloride / tenofovir alafenamide hemifumarate (Tablet E) or elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide hemifumarate):

[0520]

[0521] These studies show that:

[0522] 1. The emtricitabine and tenofovir alafenamide hemifumarate components of the fixed-dose combination of emtricitabine / rilpivirine hydrochloride / tenofovir alafenamide hemifumarate (200 / 25 / 25 mg by free base weight) (Tablet E) are bioequivalent to the fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide hemifumarate (150 / 150 / 200 / 10 mg by free base weight);

[0523] 2. The rilpivirine hydrochloride component of the fixed-dose combination of emtricitabine / rilpivirine hydrochloride / tenofovir alafenamide hemifumarate (200 / 25 / 25 mg free base weight) (Tablet E) and the rilpivirine hydrochloride 25 mg (based on free base weight) tablet are bioequivalent.

[0524] Example 15 - Manufacturing method

[0525] The manufacturing / packaging process of Rilpivirine Hydrochloride / Emtricitabine / Tenofovir Alafenamide Hemifumarate tablets is divided into five unit steps:

[0526] 1. Mixing the rilpivirine hydrochloride drug substance with the intragranular excipients, fluid bed granulation, grinding, and blending with the extragranular excipients to obtain a final powder mixture of rilpivirine hydrochloride;

[0527] 2. mixing the emtricitabine and tenofovir alafenamide hemifumarate drug substances with intragranular excipients, dry granulating, grinding, and blending with extragranular excipients to obtain a final powder mixture of emtricitabine / tenofovir alafenamide hemifumarate;

[0528] 3. Tablet compression to produce a bilayer core;

[0529] 4. film coating the tablets to produce film-coated tablets; and

[0530] 5. Packaging.

[0531] The following is a detailed description of the steps of the manufacturing process to produce the final drug product.

[0532] Final powder blend of Rilpivirine HCl (dosing, mixing, wet granulation, grinding, final blending)

[0533] 1. Weigh rilpivirine hydrochloride and excipients (lactose monohydrate and croscarmellose sodium). Correct the weight of rilpivirine hydrochloride for the drug content factor (DCF), with a decrease in the weight of lactose monohydrate.

[0534] 2. Weigh purified water, polysorbate 20 and polyvinyl pyrrolidone. Mix to form a granulation binder fluid until completely dissolved.

[0535] 3. Add Rilpivirine HCl, lactose monohydrate, croscarmellose sodium to the fluid bed granulator / dryer and fluidize to premix the components.

[0536] 4. Spray the entire volume of binder solution while keeping the powder bed fluidized.

[0537] 5. Dry the granules.

[0538] 6. Use a rotary impeller sifter to grind the particles.

[0539] 7. Add the dry milled granules along with extragranular lactose monohydrate, microcrystalline cellulose and croscarmellose sodium and mix in a mixer.

[0540] 8. Add extragranular magnesium stearate and mix.

[0541] Final powder blend of emtricitabine / tenofovir alafenamide hemifumarate (dosing, mixing, dry granulation, Grinding, final blending)

[0542] 9. Weigh the emtricitabine and tenofovir alafenamide hemifumarate drug substances and excipients (microcrystalline cellulose and croscarmellose sodium). Adjust the weights of the emtricitabine and tenofovir alafenamide hemifumarate drug substances according to their corresponding DCF, along with an adjustment for the weight of microcrystalline cellulose.

[0543] 10. Combine emtricitabine and tenofovir alafenamide hemifumarate drug substances, microcrystalline cellulose and croscarmellose sodium in a tumble mixer and mix.

[0544] 11. Add the intragranular portion of magnesium stearate into a tumble blender and mix.

[0545] 12. The resulting mixture was dry granulated using a roller compactor.

[0546] 13. Mix the extragranular portion of magnesium stearate.

[0547] Tablet pressing

[0548] 14. Compress the Rilpivirine HCl final powder blend as the first layer and the Emtricitabine / Tenofovir Alafenamide Hemifumarate final powder blend as the second layer to give a target Rilpivirine HCl layer weight of 300 mg, using a target total tablet weight of 650 mg with an appropriate main compression force to achieve a target hardness of 16 kP (range 13-19 kP).

[0549] Film coating

[0550] 15. Preparation The cores were film coated to achieve a target tablet weight gain of 3% (range 2-4%). ​​The film coated tablets were dried before cooling and discharge.

[0551] It was observed that the order of layers during tableting had an impact on compressibility and flowability, which is why Rilpivirine HCl was chosen as layer 1. Fig. 9 The tensile strength of tablets as a function of upper punch pressure in the final blend of rilpivirine hydrochloride and emtricitabine / tenofovir alafenamide hemifumarate is shown.

[0552] Based on studies conducted to evaluate the effect of tablet hardness on friability as reported in the table below, a hardness range of 13-19 kP with a target of 16 kP was selected to optimize friability:

[0553]

[0554]

[0555] a Average of five to nine tablets

[0556] Example 16 - Long-term stability study

[0557] The long term stability of Tablets C and D was measured at 30°C / 75% relative humidity (RH) over 12 months. The results of these studies are provided in the following table:

[0558]

[0559]

[0560]

[0561] These results indicate that TAF in tenofovir alafenamide hemi-fumarate tablets, which were packaged with 3 g of desiccant in induction-sealed 60 mL HDPE bottles (30 tablets / bottle), was stable under long-term storage conditions (30° C. 75% RH).

[0562] All publications, patents and patent applications are incorporated by reference in their entirety as if individually incorporated by reference. The present invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many changes and modifications may be made and still fall within the spirit and scope of the present invention.

Claims

1. A solid oral dosage form comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof.

2. The solid oral dosage form of claim 1, wherein the dosage form is substantially free of rilpivirine or a pharmaceutically acceptable salt thereof.

3. A solid composition comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof, wherein the proportion of tenofovir alafenamide or a pharmaceutically acceptable salt thereof in the composition is about 2.5% by weight to about 12% by weight.

4. The solid composition according to claim 3, wherein the proportion of tenofovir alafenamide or a pharmaceutically acceptable salt thereof in the composition is about 4% to about 12% by weight.

5. A solid composition comprising about 2 wt% to about 4 wt% of tenofovir alafenamide hemifumarate.

6. A solid composition comprising about 5% to about 15% by weight of tenofovir alafenamide hemifumarate.

7. A solid oral dosage form or composition according to any one of the preceding claims, wherein the dosage form or composition is a tablet.

8. The tablet according to claim 7, wherein the total weight of the tablet is about 350 mg.

9. The tablet according to claim 7, wherein the total weight of the tablet is 350 mg.

10. The tablet according to any one of claims 7 to 9, wherein the tablet is coated with a film coating.

11. The tablet of claim 10, wherein the film coating comprises Opadry II.

12. The tablet according to claim 10 or 11, wherein the amount of the coating is 2-4% by weight of the core of the tablet.

13. The tablet according to any one of claims 10-12, wherein the amount of the coating is about 3% by weight of the core of the tablet.

14. The tablet according to any one of claims 7 to 9, wherein the total weight of the tablet is 360.5 mg.

15. The tablet according to any one of claims 7-9, wherein more than 40% by weight of the tablet is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof.

16. The tablet according to any one of claims 7-9, wherein more than 60% by weight of the tablet is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof.

17. The tablet according to claim 16, wherein more than 60% by weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate.

18. The tablet according to any one of claims 10-14, wherein more than 40% by weight of the tablet is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof.

19. The tablet according to any one of claims 10-14, wherein more than 58% by weight of the tablet is emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof.

20. The tablet of claim 19, wherein more than 58% by weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate.

21. The tablet according to any one of claims 7-9, comprising 200 mg emtricitabine and 11.2 mg tenofovir alafenamide hemifumarate, wherein at least 50% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate.

22. The tablet according to any one of claims 10-14, comprising 200 mg emtricitabine and 11.2 mg tenofovir alafenamide hemifumarate, wherein at least 50% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate.

23. The tablet according to any one of claims 7-9, comprising 200 mg emtricitabine and 28 mg tenofovir alafenamide hemifumarate, wherein at least 50% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate.

24. The tablet according to any one of claims 10-14, comprising 200 mg emtricitabine and 28 mg tenofovir alafenamide hemifumarate, wherein at least 50% of the total weight of the tablet is emtricitabine and tenofovir alafenamide hemifumarate.

25. A composition comprising (a) tenofovir alafenamide or a pharmaceutically acceptable salt thereof and (b) emtricitabine or a pharmaceutically acceptable salt thereof, wherein the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof is less than 3% after storage at 40°C / 75%RH under open conditions for one month.

26. A composition comprising (a) tenofovir alafenamide or a pharmaceutically acceptable salt thereof and (b) emtricitabine or a pharmaceutically acceptable salt thereof, wherein the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof after storage under closed conditions at 40°C / 75%RH for three months is less than 2.5%.

27. A composition comprising (a) tenofovir alafenamide or a pharmaceutically acceptable salt thereof and (b) emtricitabine or a pharmaceutically acceptable salt thereof, wherein the total amount of degradation products derived from tenofovir alafenamide or a pharmaceutically acceptable salt thereof is less than 2% after storage under closed conditions at 30°C / 75%RH for 12 months.

28. The composition according to any one of claims 25-27, wherein the composition is a tablet.

29. The tablet according to claim 28, comprising 7-9% by weight of tenofovir alafenamide hemifumarate, preferably about 8% by weight of tenofovir alafenamide hemifumarate, wherein the total amount of degradation products derived from the hemifumarate tenofovir alafenamide after storage under closed conditions at 40°C / 75% RH for three months is less than about 2%, preferably about 1.7%.

30. The tablet of claim 29, comprising about 8% by weight of tenofovir alafenamide hemifumarate and further comprising at least 55% by weight of emtricitabine.

31. The tablet according to claim 28, comprising about 3-4% by weight of tenofovir alafenamide hemifumarate, preferably about 3% by weight of tenofovir alafenamide hemifumarate, wherein the total amount of degradation products derived from the hemifumarate tenofovir alafenamide after storage under closed conditions at 40°C / 75% RH for three months is less than about 2.5%, preferably about 1.8%.

32. The tablet of claim 31, comprising about 3 weight % of tenofovir alafenamide hemifumarate and at least 55 weight % of emtricitabine.

33. The tablet according to claim 28, wherein the tablet comprises tenofovir alafenamide hemifumarate and emtricitabine, and the total amount of degradation products derived from the tenofovir alafenamide hemifumarate after storage at 30°C / 75%RH for 12 months under closed conditions is less than about 2%.

34. The tablet according to claim 33, comprising 7-9% by weight of tenofovir alafenamide hemifumarate, preferably about 8% by weight of tenofovir alafenamide hemifumarate, wherein the total amount of degradation products derived from the hemifumarate tenofovir alafenamide after storage under closed conditions at 30°C / 75% RH for 12 months is less than about 2%, preferably less than 1%.

35. The tablet of claim 34, comprising about 8% by weight of tenofovir alafenamide hemifumarate and further comprising at least 55% by weight of emtricitabine.

36. The tablet according to claim 33, comprising about 3-4% by weight of tenofovir alafenamide hemifumarate, preferably about 3% by weight of tenofovir alafenamide hemifumarate, wherein the total amount of degradation products derived from the hemifumarate tenofovir alafenamide after storage under closed conditions at 30°C / 75%RH for 12 months is less than about 2%, preferably less than 1.5%.

37. The tablet of claim 36, comprising about 3 weight % of tenofovir alafenamide hemifumarate and at least 55 weight % of emtricitabine.

38. The solid oral dosage form, composition, or tablet of any one of claims 1-37, wherein the solid oral dosage form, composition, or tablet comprises an excipient consisting of croscarmellose sodium, microcrystalline cellulose, and magnesium stearate.

39. The solid oral dosage form, composition or tablet of any one of claims 1-37, wherein the solid oral dosage form, composition or tablet comprises 150-250 mg emtricitabine or a salt thereof, 5-35 mg tenofovir alafenamide or a salt thereof, 20-35 mg croscarmellose sodium, 70-120 mg microcrystalline cellulose and 1-7 mg magnesium stearate.

40. The solid oral dosage form, composition or tablet of claim 39, wherein the solid oral dosage form, composition or tablet comprises 200 mg emtricitabine, 11.2 mg tenofovir alafenamide hemifumarate, 28 mg croscarmellose sodium, 105.56 mg microcrystalline cellulose, 5.25 mg magnesium stearate, and a film coating consisting of Opadry II gray 85F97517.

41. The solid oral dosage form, composition or tablet of claim 39, wherein the solid oral dosage form, composition or tablet comprises 200 mg emtricitabine, 28 mg tenofovir alafenamide hemifumarate, 28 mg croscarmellose sodium, 88.70 mg microcrystalline cellulose, 5.25 mg magnesium stearate, and a film coating consisting of Opadry II Blue 85F105057.

42. A kit comprising (a) a tablet according to any one of claims 1 to 41, and (b) a desiccant, preferably wherein the desiccant is silica gel.

43. A method of producing a solid oral dosage form, composition or tablet according to any one of the preceding claims.

44. A dry particulate mixture of (a) tenofovir alafenamide or a pharmaceutically acceptable salt thereof and (b) emtricitabine or a pharmaceutically acceptable salt thereof.

45. A solid oral dosage form, composition or tablet according to any one of the preceding claims for use in the therapeutic treatment of HIV infection.

46. ​​A method of therapeutically treating HIV infection comprising administering to a subject a solid oral dosage form, composition or tablet as claimed in any one of the preceding claims.

47. A method of preventing HIV infection comprising administering to a subject the solid oral dosage form, composition or tablet of any one of the preceding claims.

48. The method of claim 46, wherein the solid oral dosage form, composition or tablet is administered at intervals less than once a day.

49. The method of claim 47 or 48, wherein the solid oral dosage form, composition or tablet is administered before and after an event that would increase the risk of an individual acquiring HIV.

Images