HK1214171B - Cenicriviroc compositions and methods of making and using the same - Google Patents

Description

Cenicvir compositions and methods of preparation and use thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Application No. 61/823,766, filed May 15, 2013, and entitled “CENICRIVIROC COMPOSITIONS AND METHODS OF MAKING AND USING THE SAME,” the contents of which are hereby incorporated by reference herein in their entirety for all purposes.

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field

The present disclosure relates to pharmaceutical compositions containing Cenicvir or its salts; methods of preparing the same; and their use in treating diseases or conditions, particularly viruses such as human immunodeficiency virus (HIV).

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Cenicriviroc is the common name for (S,E)-8-(4-(2-butoxyethoxy)phenyl)-1-(2-methylpropyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide, whose chemical structure is shown in Figure 1. Cenicriviroc is a weakly basic and poorly water-soluble drug that is effective against viruses, such as retroviruses, such as human immunodeficiency virus (HIV). However, the clinical use of Cenicriviroc can be limited due to bioavailability and stability issues associated with known Cenicriviroc compositions. Moreover, current Cenicriviroc formulations cannot accommodate the daily dose of Cenicriviroc in a single tablet, so subjects must take multiple tablets to obtain an adequate therapeutic effect. Therefore, there is a need for new compositions and formulations containing Cenicriviroc, as well as related methods of making and using the same. The present invention addresses some of these needs and provides other related advantages.

Brief Overview

The present disclosure provides, inter alia, pharmaceutical compositions containing sanicvir as a single active agent or as one of multiple active agents; methods for their preparation; and their use in treating diseases or conditions, particularly viruses such as human immunodeficiency virus (HIV). In certain embodiments, the compositions of the present invention are in solid dosage form. In certain embodiments, the compositions of the present invention are oral compositions.

In one embodiment, a composition of cenikvir or a salt thereof and fumaric acid is provided. In certain embodiments, cenikvir or a salt thereof is cenikvir mesylate.

In other embodiments, the weight ratio of zeneviroc or its salt to fumaric acid is about 7:10 to about 10:7, such as about 8:10 to about 10:8, about 9:10 to about 10:9, or about 95:100 to about 100:95, based on the weight of free zeneviroc.

In other embodiments, fumaric acid is present in an amount from about 15% to about 40%, such as from about 20% to about 30%, or about 25%, by weight of the composition.

In other embodiments, the cynicvir or salt thereof is present in an amount of about 15% to about 40%, such as about 20% to about 30%, or about 25% by weight of the composition based on the weight of free cynicvir.

In other embodiments, the composition comprises one or more pharmaceutically inactive ingredients, such as pharmaceutically acceptable excipients, eg, fillers, disintegrants, lubricants, and the like.

In other embodiments, the composition comprises one or more fillers. In more specific embodiments, the one or more fillers are selected from microcrystalline cellulose, calcium hydrogen phosphate, cellulose, lactose, sucrose, mannitol, sorbitol, starch, and calcium carbonate. For example, in certain embodiments, the one or more fillers are microcrystalline cellulose. In specific embodiments, the weight ratio of the one or more fillers to the one or more fillers or its salt is about 25:10 to about 10:8, such as about 20:10 to about 10:10, or about 15:10, based on the weight of the free cynicvir. In other specific embodiments, the one or more fillers are present in an amount of about 25% to about 55%, such as about 30% to about 50% or about 40% by weight of the composition.

In other embodiments, the composition further comprises one or more disintegrants. In more specific embodiments, the one or more disintegrants are selected from cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, and sodium starch glycolate. For example, in certain embodiments, the one or more disintegrants are cross-linked sodium carboxymethyl cellulose (croscarmellose sodium). In specific embodiments, the weight ratio of the one or more disintegrants to the one or more zenevir or its salt is about 10:10 to about 30:100, such as about 25:100, based on the weight of free zenevir. In other specific embodiments, the one or more disintegrants are present in an amount of about 2% to about 10%, such as about 4% to about 8%, or about 6% by weight of the composition.

In other embodiments, the composition further comprises one or more lubricants. In more specific embodiments, the one or more lubricants are selected from stearin, magnesium stearate, and stearic acid. For example, in certain embodiments, the one or more lubricants are magnesium stearate. In specific embodiments, the one or more lubricants are present in an amount of about 0.25% to about 5%, such as about 0.75% to about 3%, or about 1.25% by weight of the composition.

In other embodiments, the composition further comprises one or more anti-adherents, such as, for example, talc. In other embodiments, the composition further comprises one or more flow aids, such as, for example, silicon dioxide.

In other embodiments, the compositions are substantially similar to those described in Tables 3a and 3b.

In other embodiments, the composition is substantially similar to that of Example 2b of Table 3a.

In other embodiments, any of the above-mentioned embodiments are produced by a process involving dry granulation.For example, any of the above-mentioned embodiments can be produced by a process involving dry granulation of a blend of Cenicvir or a salt thereof and fumaric acid.

In other embodiments, any of the above-mentioned compositions have a water content of up to about 4% by weight, such as up to 2% by weight, after exposure to about 40° C. at about 75% relative humidity for six weeks when packaged with a desiccant in a container, such as a closed bottle configuration, e.g., an induction sealed bottle.

In other embodiments, any of the above-mentioned compositions have a total impurity and degradant level of at most about 2.5%, such as at most 1.5%, after exposure to about 40° C. at 75% relative humidity for 12 weeks when packaged with a desiccant in a container, such as a closed bottle configuration, e.g., an induction sealed bottle.

In other embodiments, the saenicvir or its salt of any of the above-mentioned compositions has an average absolute bioavailability after oral administration that is substantially similar to the average absolute bioavailability of saenicvir or its salt in solution after oral administration. In other embodiments, saenicvir or its salt has an average absolute bioavailability of about 10% to about 50%, about 10% to about 30%, about 10% to about 25%, about 15% to about 20%, including all ranges and subranges therebetween. In a specific embodiment, saenicvir or its salt has an average absolute bioavailability of about 15% to about 20%, including all ranges and subranges therebetween. In one embodiment, saenicvir or its salt has an average absolute bioavailability of about 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26% or 27%, including all ranges and subranges therebetween. In a specific embodiment, the saenicvir or its salt has an average absolute bioavailability of about 18%. In a specific embodiment, the above-mentioned bioavailability is for saenicvir or its salt of any of the above-mentioned compositions in a mammal. In a specific embodiment, the mammal is a dog, such as a beagle dog.

In one embodiment, the present invention provides a pharmaceutical composition comprising about 150 mg of zenikvir or a salt thereof, wherein after administration of the composition to a subject under fed conditions, the composition exhibits a steady-state AUC 0-last of about 7,000 h*ng/ml to about 11,000 h*ng/ml, such as about 7,500 h*ng/ml to about 9,500 h*ng/ml, or about 8,000 h*ng/ml to about 9,000 _h *ng/ml. In one embodiment, the present invention provides a pharmaceutical composition comprising about 150 mg of zenikvir or a salt thereof, wherein after administration of the composition to a subject under fed conditions, the composition exhibits a steady-state C _max of about 500 ng/ml to about 750 ng/ml, such as about 550 ng/ml to about 700 ng/ml. In one embodiment, the present invention provides a pharmaceutical composition comprising about 150 mg of cenikvir or a salt thereof, wherein following administration of the composition to a subject under fed conditions, the composition exhibits a steady-state _Cmin of about 100 ng/ml to about 230 ng/ml, such as about 130 ng/ml to about 200 ng/ml.

In another embodiment, the present invention provides a pharmaceutical composition comprising about 200 mg of cenikvir or a salt thereof, wherein following single-dose administration of the composition under fasting conditions, the composition exhibits an AUC _0-last of about 13200 h*ng/ml to about 14200 h*ng/ml and a C _max of about 550 ng/ml to about 700 ng/ml.

"Fasted state" or "fasting conditions" include, for example, a human subject who has not consumed any food overnight, such as a subject who wakes up from sleep but has not eaten around bedtime or has an empty stomach. A subject (particularly a human) in a fasting state may also be a subject who has not consumed any food other than water for at least 6 hours, specifically at least 8 hours, more specifically at least 10 hours, and even more specifically at least 12 hours. "Fed state" or "fed conditions" refers to a human subject who consumes one or more of a standard meal, a high-fat meal, a high-calorie meal, a rice meal, a low-calorie meal, a low-fat meal, a low-carbohydrate meal, with or without a drink or beverage such as coffee, tea, water, juice, soda, etc. A meal may be preceded by at least 6, 8 or 10 hours of fasting, such as 10, 11 or 12 hours of fasting, however, unless otherwise specified, this is not a requirement.

In other embodiments, after oral administration, any of the above-mentioned compositions exhibits a zeneviroc AUC _0-last that is about 175% or greater than 175%, such as about 200% or greater, or about 225% or greater, or about 250% or greater than 250% of the zeneviroc AUC _0-last exhibited by a reference solid formulation. In other embodiments, after oral administration, any of the above-mentioned compositions exhibits a zeneviroc C _max that is at least 40% higher, such as at least 50% higher, or at least 55% higher, than the zeneviroc C _max exhibited by the reference solid formulation. By reference solid formulation, it is meant a solid formulation comprising zeneviroc or a salt thereof and one or more pharmaceutically acceptable excipients in the formulation, but without an acid solubilizer or pH adjuster.

In other embodiments, any of the above-mentioned compositions further comprise one or more additional pharmaceutically active agents.

In more specific embodiments, the one or more additional pharmaceutically active agents are one or more antiretroviral drugs selected from the group consisting of CCR5 receptor antagonists, entry inhibitors, nucleoside reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and maturation inhibitors.

In other more specific embodiments, the one or more additional pharmaceutically active agents are selected from maraviroc, lamivudine, efavirenz, raltegravir, vivecon, bevirimat, interferon alpha, zidovudine, abacavir, lopinavir, ritonavir, tenofovir, tenofovir disoproxil, tenofovir prodrugs, emtricitabine, elvitegravir, cobicistat darunavir, atazanavir, rilpivirine, and dolutegravir.

In other more specific embodiments, the one or more other pharmaceutically active agents include one or more immune system suppressants. In other more specific embodiments, the one or more other pharmaceutically active agents are selected from the group consisting of cyclosporine, tacrolimus, prednisolone, hydrocortisone, sirolimus, everolimus, azathioprine, mycophenolic acid, methotrexate, basiliximab, daclizumab, rituximab, anti-thymocyte globulin, and anti-lymphocyte globulin. In other specific embodiments, the one or more other pharmaceutically active agents are one or more of tacrolimus or methotrexate.

In one embodiment, a composition comprising cynicvir or a salt thereof, fumaric acid, and lamivudine (3TC) is provided. In certain embodiments, cynicvir or a salt thereof is cynicvir mesylate. In other embodiments, the weight ratio of cynicvir or a salt thereof to lamivudine is from about 1:15 to about 1:1, such as from about 1:12 to about 2:3; about 1:12; about 1:4; or about 1:2, based on the weight of free cynicvir. In other embodiments, lamivudine is present in an amount of from about 25% to about 65%, such as from about 30% to about 60%, about 31.6%; about 33.3%; about 37.5%; about 40.0%; about 46.2%; or about 60% by weight of the composition. In another embodiment, the composition comprises about 15.8% cynicvir or a salt thereof and about 31.6% lamivudine, based on the weight of the composition and based on the weight of free cynicvir. In another embodiment, the composition comprises about 16.7% zenevir or a salt thereof and about 33.3% lamivudine, based on the weight of the composition and based on the weight of free zenevir. In another embodiment, the composition comprises about 18.8% zenevir or a salt thereof and about 37.5% lamivudine, based on the weight of the composition and based on the weight of free zenevir. In another embodiment, the composition comprises about 20% zenevir or a salt thereof and about 40.0% lamivudine, based on the weight of the composition and based on the weight of free zenevir. In another embodiment, the composition comprises about 11.5% zenevir or a salt thereof and about 46.2% lamivudine, based on the weight of the composition and based on the weight of free zenevir. In another embodiment, the composition comprises about 5% zenevir or a salt thereof and about 60% lamivudine, based on the weight of the composition and based on the weight of free zenevir.

In other embodiments, the above composition containing sanicvir or its salt, fumaric acid and 3TC may further comprise one or more pharmaceutically inactive ingredients, such as pharmaceutically acceptable excipients, for example, fillers, disintegrants, lubricants, etc.

In other embodiments, the above-described composition containing ZENICVIROC or a salt thereof, fumaric acid, and 3TC may further comprise one or more fillers. In more specific embodiments, the one or more fillers are selected from microcrystalline cellulose, calcium hydrogen phosphate, cellulose, lactose, sucrose, mannitol, sorbitol, starch, and calcium carbonate. For example, in certain embodiments, the one or more fillers are microcrystalline cellulose. In specific embodiments, the weight ratio of the one or more fillers to the ZENICVIROC or a salt thereof, based on the weight of free ZENICVIROC, is from about 5:1 to about 1:5, such as from about 1:4 to about 1:5; or from about 2:3 to about 1:2; or from about 2:1 to about 4:3; or from about 5:1 to about 5:2. In other specific embodiments, the one or more fillers are present in an amount of from about 5% to about 30% of the composition, such as from about 5.8%; about 6.6%; about 12%; about 20.5%; about 22.2%; about 23.4%; or about 24.8% by weight. In another embodiment, the composition comprises about 15.8% zenevir or a salt thereof, about 31.6% lamivudine, and 24.8% one or more fillers, based on the weight of the composition and based on the weight of free zenevir. In another embodiment, the composition comprises about 16.7% zenevir or a salt thereof, about 33.3% lamivudine, and 23.4% one or more fillers, based on the weight of the composition and based on the weight of free zenevir. In another embodiment, the composition comprises about 18.8% zenevir or a salt thereof, about 37.5% lamivudine, and 12.0% one or more fillers, based on the weight of the composition and based on the weight of free zenevir. In another embodiment, the composition comprises about 20% zenevir or a salt thereof, about 40.0% lamivudine, and 5.8% one or more fillers, based on the weight of the composition and based on the weight of free zenevir. In another embodiment, the composition comprises about 20% zenevir or a salt thereof, about 40.0% lamivudine, and 6.6% of one or more fillers, based on the weight of the composition and based on the weight of free zenevir. In another embodiment, the composition comprises about 11.5% zenevir or a salt thereof, about 46.2% lamivudine, and 20.5% of one or more fillers, based on the weight of the composition and based on the weight of free zenevir. In another embodiment, the composition comprises about 5% zenevir or a salt thereof, about 60% lamivudine, and 22.2% of one or more fillers, based on the weight of the composition and based on the weight of free zenevir.

In other embodiments, the above-described composition comprising zenevir or a salt thereof, fumaric acid, and 3TC may further comprise one or more disintegrants. In more specific embodiments, the one or more disintegrants are selected from cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, and sodium starch glycolate. For example, in certain embodiments, the one or more disintegrants is cross-linked sodium carboxymethyl cellulose. In specific embodiments, the weight ratio of the one or more disintegrants to zenevir or a salt thereof, based on the weight of free zenevir or a salt thereof, is from about 1:4 to about 3:2, such as about 1:3; about 2:5; about 1:2; or about 1:1. In other specific embodiments, the one or more disintegrants are present in an amount of from about 3% to about 9% by weight of the composition.

In other embodiments, the above-mentioned composition containing cenikvir or its salt, fumaric acid and 3TC may further comprise one or more lubricants. In more specific embodiments, the one or more lubricants are selected from stearin, magnesium stearate and stearic acid. For example, in certain embodiments, the one or more lubricants are magnesium stearate. In specific embodiments, the one or more lubricants are present in an amount of about 0.5% to about 4%, such as about 0.75% to about 3% by weight of the composition. In other embodiments, the composition further comprises one or more anti-adherents, such as, for example, talc. In other embodiments, the composition further comprises one or more flow aids, such as, for example, silicon dioxide.

In other embodiments, the above-described compositions containing Cenicvir or a salt thereof, fumaric acid, and 3TC are substantially similar to those described in Tables 18, 19, 20, 21, 22, 23, and 24.

In other embodiments, any of the above compositions containing Cenicvir or a salt thereof, fumaric acid, and 3TC have a water content of up to about 4% by weight, such as up to 2% by weight, after exposure to about 40°C at about 75% relative humidity for four weeks when packaged with a desiccant.

In other embodiments, any of the above compositions containing Cenicvir or a salt thereof, fumaric acid, and 3TC have a total impurity and degradant level of no more than about 4%, such as no more than 2%, after exposure to 40°C at 75% relative humidity for 9 weeks when packaged with a desiccant.

In other embodiments, any of the above compositions containing zenevir or a salt thereof, fumaric acid, and 3TC may further comprise efavirenz. In other embodiments, the weight ratio between zenevir or a salt thereof, lamivudine, and efavirenz is about 1:2:4, based on the weight of free zenevir. In other embodiments, any composition comprises approximately 10.3% zenevir or a salt thereof, approximately 18.2% lamivudine, and approximately 36.4% efavirenz, based on the weight of the composition and based on the weight of free zenevir. In other embodiments, any composition comprises approximately 9.5% zenevir or a salt thereof, approximately 19.1% lamivudine, and approximately 38.1% efavirenz, based on the weight of the composition and based on the weight of free zenevir. In other embodiments, any composition is substantially similar to the examples described in Tables 28 or 29. In other embodiments, any of the compositions have a water content of at most about 4.0% by weight, such as at most about 2.0%, when packaged with a desiccant in a container, such as a sealed bottle, e.g., an induction sealed bottle, after exposure to about 40° C. at about 75% relative humidity for about four weeks. In other embodiments, any of the compositions have a total impurity and degradant level of at most about 4.0%, such as at most about 2.0%, when packaged with a desiccant in a container, such as a sealed bottle, e.g., an induction sealed bottle, after exposure to about 40° C. at about 75% relative humidity for nine weeks.

In one embodiment, the present invention provides a pharmaceutical formulation comprising any of the above-mentioned compositions. In one embodiment, the present invention provides a pharmaceutical formulation comprising saenicvir or a salt thereof, lamivudine (3TC) and one or more pharmaceutically acceptable excipients. In another embodiment, the present invention provides a pharmaceutical formulation comprising saenicvir or a salt thereof, efavirenz (EFV) and one or more pharmaceutically acceptable excipients. In another embodiment, the present invention provides a pharmaceutical formulation comprising saenicvir or a salt thereof, 3TC, EFV and one or more pharmaceutically acceptable excipients. In any of the previous embodiments, saenicvir or a salt thereof is saenicvir mesylate.

In one embodiment of the pharmaceutical formulation, the composition is in the form of a granulate. In other embodiments, the saenicvir or its salt is present in a pharmaceutical composition in the form of a granulate. In some embodiments, the granulate may contain an acid solubilizer, such as fumaric acid. For example, in one embodiment, saenicvir or its salt and fumaric acid are blended with a suitable excipient and granulated to obtain granules containing saenicvir or its salt. Granules containing saenicvir or its salt and fumaric acid can be combined with other excipients to prepare the composition of the present invention. Components present within the granules of saenicvir are referred to as "intragranular" components, while components outside the granules are referred to as "extragranular" components. In one embodiment, the "intragranular" components include saenicvir or its salt and fumaric acid; while the "extragranular" components include one or more pharmaceutically active agents, such as 3TC and/or EFV. In other embodiments, the "intragranular" component includes saenicvir or a salt thereof, fumaric acid, and one or more pharmaceutically active agents, such as 3TC and/or EFV, while the "extragranular" component includes one or more pharmaceutically active agents other than saenicvir or a salt thereof, such as 3TC and/or EFV. In other embodiments, the "intragranular" component includes saenicvir or a salt thereof, fumaric acid, and one or more pharmaceutically active agents, such as 3TC and/or EFV, while the "extragranular" component does not include any pharmaceutically active agent.

In another embodiment, a pharmaceutical formulation comprising the composition of any of the above-mentioned embodiments is provided. In other embodiments, the composition of the formulation is placed in a capsule. In other embodiments, the composition of the formulation is placed in a sachet. In other embodiments, the composition of the formulation is a tablet or a component of a tablet.

In other embodiments, the composition of the formulation is in one or more layers of a multilayer tablet. In other embodiments, the composition of the formulation is in a monolayer tablet.

In one embodiment of the multilayer tablet, the composition is in a bilayer tablet comprising a single core and a layer external to the single core. In one embodiment of the bilayer tablet, saenicvir or its salt and fumaric acid are present in the core; while lamivudine is present in a layer external to the single core. In another embodiment of the bilayer tablet, saenicvir or its salt, fumaric acid, and lamivudine are present in the core, while efavirenz is present in a layer external to the single core.

In other embodiments, any of the compositions in the above-mentioned pharmaceutical formulations are substantially similar to the examples described in Tables 3a, 36, 18, 19, 20, 21, 22, 23, 24, 28, or 29. In other embodiments, the pharmaceutical formulation is in an oral dosage form, such as a tablet, containing a composition substantially similar to that in Tables 3a, 36, 18, 19, 20, 21, 22, 23, 24, 28, or 29.

In other embodiments, any of the above-mentioned compositions, any of the above-mentioned pharmaceutical formulations, or any of the above-mentioned tablets is a coating matrix.

In another embodiment, a method for preparing any of the above-mentioned embodiments is provided. In other embodiments, the method comprises blending zenevir or a salt thereof and fumaric acid to form a blend, and dry granulating the blend. In other embodiments, the method further comprises blending one or more fillers with zenevir or a salt thereof and fumaric acid to form a blend. In more specific embodiments, the one or more fillers are selected from microcrystalline cellulose, calcium hydrogen phosphate, cellulose, lactose, sucrose, mannitol, sorbitol, starch, and calcium carbonate. For example, in certain embodiments, the one or more fillers are microcrystalline cellulose. In other embodiments, the method further comprises blending one or more disintegrants with zenevir or a salt thereof and fumaric acid to form a blend. In more specific embodiments, the one or more disintegrants are selected from cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, and sodium starch glycolate. For example, in certain embodiments, the one or more disintegrants are cross-linked sodium carboxymethyl cellulose. In other embodiments, the method further comprises blending one or more lubricants with zenevir or a salt thereof and fumaric acid to form a blend. In more specific embodiments, the one or more lubricants are selected from stearin, magnesium stearate, and stearic acid. For example, in certain embodiments, the one or more lubricants are magnesium stearate. In other embodiments, the method further comprises compressing the dry granulated blend into tablets. In other embodiments, the method comprises filling a capsule with the dry granulated blend.

In other embodiments, the method further comprises mixing the dry granulation blend with one or more extragranular substances. In more specific embodiments, the one or more extragranular substances are one or more other pharmaceutically active agents. In other more specific embodiments, the one or more pharmaceutically active agents are one or more other antiretroviral drugs. In other more specific embodiments, the one or more other antiretroviral drugs are selected from CCR5 receptor antagonists, entry inhibitors, nucleoside reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and maturation inhibitors. In other more specific embodiments, the one or more other antiretroviral drugs are selected from one or more of the following: maraviroc, lamivudine, efavirenz, raltegravir, vilavirenz, bevirimab, interferon alpha, zidovudine, abacavir, lopinavir, ritonavir, tenofovir disoproxil fumarate, tenofovir prodrug, emtricitabine, elvitegravir, cobicistat, atazanavir, rilpivirine, and dolutegravir. In other more specific embodiments, the one or more other pharmaceutically active agents include one or more immune system suppressants. In other more specific embodiments, the one or more other pharmaceutically active agents are selected from the group consisting of cyclosporine, tacrolimus, prednisolone, hydrocortisone, sirolimus, everolimus, azathioprine, mycophenolic acid, methotrexate, basiliximab, daclizumab, rituximab, anti-thymocyte globulin, and anti-lymphocyte globulin. In other specific embodiments, the one or more other pharmaceutically active agents are one or more of tacrolimus or methotrexate.

In certain embodiments, a portion of other pharmaceutically active agents may be added intragranularly along with Cenicvir or a salt thereof.

In another embodiment, a method of administering cenikvir or a salt thereof is provided, comprising administering a composition, formulation, tablet, or composition produced by the methods of any of the above-mentioned embodiments. In another embodiment, a method of treating a disease, disorder, or condition is provided, comprising administering a therapeutically effective amount of a composition, formulation, tablet, or composition produced by any of the above-mentioned embodiments. In other embodiments, the disease, disorder, or condition is a viral infection. In other embodiments, the viral infection is a retroviral infection. In other embodiments, the disease, disorder, or condition is hepatitis, human immunodeficiency virus, or sarcoma virus. In certain embodiments, the disease, disorder, or condition is human immunodeficiency virus. In other embodiments, the disease, disorder, or condition is inflammation. In other embodiments, the disease, disorder, or condition is graft-versus-host disease, diabetic inflammation, cardiovascular inflammation, or fibrosis.

Other embodiments of the present invention will be apparent to those of ordinary skill in the art from the following description and examples.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is the chemical formula of Cynicavir.

2 is a graph comparing the absolute bioavailability of ZENICVIROC mesylate formulated as an oral solution in beagle dogs with the absolute bioavailability of ZENICVIROC mesylate prepared by wet granulation and mixed with various acid solubilizer excipients.

3 is a graph of total impurity and degradant levels of various Cenicvir formulations subjected to accelerated stability testing at 40° C. and 75% relative humidity when packaged in induction sealed bottles with a desiccant.

Figure 4 shows the dissolution profile of Ceniveroc from tablets after storage at 40°C and 75% relative humidity.

FIG5 shows the dynamic vapor sorption isotherms of different senevin formulations.

FIG6 shows the absorption of sanicvir from different formulations in beagle dogs under three pretreatment conditions.

Figures 7 and 8 show the dissolution profiles and disintegration profiles of the tablets of Examples 2a-2e, respectively.

FIG. 9 shows the absolute bioavailability of the tablets of Examples 2a-2e in beagle dogs.

FIG. 10 shows the compressibility curves of the abrasive particles of Examples 14 and 15.

FIG. 11 shows the compressibility curves of the ground granules of Example 14 when compacted using different roller presses.

FIG12 shows the compressibility curves of the powder blends of Examples 17, 19, and 20.

Figure 13 shows the dissolution profiles of the tablets of Example 28 after storage at 40°C/75% RH for 4 weeks. Panel A shows the dissolution profile of 3TC, Panel B shows the dissolution profile of CVC, and Panel C shows the dissolution profile of EFV.

Figure 14 shows the dissolution profiles of the tablets of Example 29 after storage at 40°C/75% RH for 4 weeks. Panel A shows the dissolution profile of 3TC, Panel B shows the dissolution profile of CVC, and Panel C shows the dissolution profile of EFV.

Detailed description

Except where indicated, all terms are intended to have their ordinary meaning in the art and, when disclosed, are used as they would have been used by one of ordinary skill. It should be understood that throughout this application, singular forms such as "a", "an", and "the" are often used for convenience, however, unless otherwise specified, or unless the context clearly requires a singular, these singular forms are intended to encompass the plural. It should also be understood that all publications, patents, books, journal articles, etc. mentioned in this application are incorporated herein by reference in their entirety and for all purposes to the extent not inconsistent with this disclosure.

definition:

"Cenicvir" (also known as CVC) refers to the compound (S,E)-8-(4-(2-butoxyethoxy)phenyl)-1-(2-methylpropyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide, which also has the chemical name 8-[4-(2-butoxyethoxy)phenyl]-1,2,3,4-tetrahydro-1-(2-methylpropyl)-N-[4-[(S)-[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-1-benzoazocine-5-carboxamide. Cenicvir also has CAS Registry Number 497223-25-3. In certain embodiments, CVC forms acid addition salts, such as salts of methanesulfonic acid. In one embodiment, the compositions of the present invention contain cenikvir mesylate.

"Substantially similar" means that a composition or formulation is similar to a reference composition or formulation to a great extent, both in identity and quantity of the composition or formulation.

"About" means a value that is close enough to a reference value to have the same or substantially the same property as the reference value. Thus, "about" can mean, for example, ±5%, ±4%, ±3%, ±2%, ±1%, or ±less than 1%, as appropriate.

"Pharmaceutically acceptable" means that a substance or method can be used in medicine or pharmacy, including for veterinary purposes, for example, for administration to a subject.

"Salts" and "pharmaceutically acceptable salts" include both acid addition salts and base addition salts. "Acid addition salts" refer to those salts that retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and are formed with inorganic and organic acids. "Base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acid, which are not biologically or otherwise undesirable, and are prepared by adding an inorganic or organic base to the free acid.

"Pharmaceutical formulation" refers to a formulation of a compound of the present disclosure and a medium generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. The medium includes any pharmaceutically acceptable carriers, diluents, or excipients thereof. The pharmaceutical formulations described herein can be in various dosage forms, such as oral dosage forms or solid dosage forms, or both. In some embodiments, the pharmaceutical formulations of the present invention are in tablet or capsule dosage form.

"Treatment" includes ameliorating, alleviating, and relieving the condition of a disease or condition, or the symptoms of a disease or condition. Because many conditions of a disease or condition can be alleviated before the disease or condition manifests, treatment may also include prevention and treatment.

"Administering" includes any mode of administration, such as oral, subcutaneous, sublingual, transmucosal, parenteral, intravenous, intraarterial, buccal, sublingual, topical, vaginal, rectal, ocular, otic, nasal, inhalation, and transdermal. "Administering" may also include writing or filling a prescription for a dosage form containing a particular compound. "Administering" may also include providing instructions for performing a method involving a particular compound or a dosage form containing the compound.

"Therapeutically effective amount" means an amount of an active substance that, when administered to a subject to treat a disease, disorder, or other undesirable medical condition, is sufficient to have a beneficial effect with respect to that disease, disorder, or condition. The therapeutically effective amount will vary depending on the chemical identity and formulation form of the active substance, the disease or condition and its severity, and the age, weight, and other relevant characteristics of the patient to be treated. Determining a therapeutically effective amount of a given active substance is within the ordinary skill in the art and generally requires no more than routine experimentation.

As indicated above, the present disclosure provides a composition, such as a solid composition, containing cynicvir or a salt thereof and fumaric acid. Cynicvir or a salt thereof may be cynicvir or a salt thereof mesylate. Based on the weight of free cynicvir, the weight ratio between cynicvir or a salt thereof and fumaric acid may be from about 7:10 to about 10:7, such as from about 8:10 to about 10:8, from about 9:10 to about 10:9, or from about 95:100 to about 100:95. Fumaric acid may be present in an amount of from about 15% to about 40%, such as from about 20% to about 30%, or about 25% by weight of the composition. Based on the weight of free cynicvir, cynicvir or a salt thereof may be present in an amount of from about 15% to about 40%, such as from about 20% to about 30%, or about 25% by weight of the composition.

The fumaric acid in the composition can act as a solubilizer and impart beneficial properties to the composition. For example, fumaric acid can increase the bioavailability of the composition when compared to compositions using other solubilizers, particularly citric acid, maleic acid, and sodium bisulfate.

In some cases, the bioavailability of a composition comprising saenixvir mesylate and fumaric acid can approach that of an oral solution. Absorption of an oral solution is not impaired by the rate or extent of drug dissolution. Thus, absorption of the drug from the solution is limited only by interactions between the dissolved drug, the body, and ingested substances (such as food, beverages, and other medications). Therefore, a composition with a bioavailability approaching or equal to that of an oral solution may be particularly desirable.

This result is surprising and unexpected. As shown in Table 1, fumaric acid has a much slower dissolution time than other acids. Based on the theory that excipients should dissolve as quickly as or more quickly than the active pharmaceutical ingredient, it was previously believed that rapidly dissolving acidic excipients have a higher solubilizing power. Several journal articles have argued that fumaric acid should not be used in oral dosage forms due to its low solubility and long dissolution time. Therefore, it is surprising that the long dissolution time of fumaric acid is associated with a higher bioavailability of cynicvir.

The results described in Table 1 were achieved by adding 200 mg of acid to 90 mL of purified water at 250 rpm using a Mettler Toledo mixing chamber with an upward pumping four-blade impeller maintained at the specified temperature. The disappearance of particles undergoing dissolution was monitored by focused beam reflectometry (FBRM). The data were analyzed by reviewing individual 2-second measurement trends and average trends over 10 and 30 seconds.

Table 1

Without being bound by theory, the longer dissolution time of fumaric acid may be beneficial because, after administration, fumaric acid does not dissolve as quickly as other acid solubilizers. Therefore, fumaric acid can provide an acidic environment around Cenicvir or its salt for a longer period of time than other more soluble acid solubilizers, such as citric acid.

In addition to cenikvir and fumaric acid, the composition may also have one or more other ingredients, such as one or more fillers, one or more disintegrants, or one or more lubricants. Other ingredients may also be present, but it should be understood that specific other ingredients are not required unless otherwise specified.

When used, the one or more fillers may include at least one of microcrystalline cellulose, calcium hydrogen phosphate, cellulose, lactose, sucrose, mannitol, sorbitol, starch, and calcium carbonate. For example, the one or more fillers may be microcrystalline cellulose. The weight ratio of the one or more fillers (such as microcrystalline cellulose) to the one or more fillers or salts thereof may be from about 25:10 to about 10:8, such as from about 20:10 to about 10:10 or about 15:10, based on the weight of free cynicvir. The one or more fillers (such as microcrystalline cellulose) may be present in an amount of about 25% to about 55%, such as from about 30% to about 50%, or about 40% by weight of the composition.

When used, the one or more disintegrants may include at least one of cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, and sodium starch glycolate. For example, the one or more disintegrants may be cross-linked sodium carboxymethyl cellulose. The weight ratio of the one or more disintegrants (such as cross-linked sodium carboxymethyl cellulose) to the one or more zenevirorc or its salts may be about 10:100 to about 30:100, such as about 25:100, based on the weight of free zenevirorc. The one or more disintegrants may be present in an amount of about 2% to about 10%, such as about 4% to about 8%, or about 6% by weight of the composition.

When used, the one or more lubricants may include at least one of talc, silicon dioxide, stearin, magnesium stearate, or stearic acid. For example, the one or more lubricants may be magnesium stearate. The one or more lubricants may be present in an amount of about 0.25% to about 5%, such as about 0.75% to about 3%, or about 1.25% by weight of the composition.

Other ingredients that may be used are listed in Remington: The Science and Practice of Pharmacy, which is hereby incorporated by reference in its entirety for all purposes.

The composition can be in various forms. Examples of forms suitable for pharmaceutical use are listed in Remington: The Science and Practice of Pharmacy, which is hereby incorporated by reference in its entirety for all purposes. The composition can be, for example, a granulate, a matrix, a tablet or a portion of a tablet, such as one or more layers of a multilayer tablet. The composition can be a powder that can be filled into a capsule, a sachet, a bottle, a vial, an ampoule, etc. The composition can be a matrix of one or more coatings (such as drug coatings as known in the art) that can be applied to the composition. When the composition is a granulate, the average particle size can be about 75 microns or greater than 75 microns, such as about 300 microns or greater than 300 microns.

The composition can be made by blending cynicvir or a salt thereof (such as cynicvir mesylate) with fumaric acid to form a blend, and dry granulating the blend. Exemplary dry granulation methods include roller compaction, pre-compacting, and pelletizing. If necessary, the size of the dry granulated composition can be reduced by methods such as grinding. However, it should be understood that unless otherwise specified, no specific granulation, dry granulation, or size reduction method is required. One or more of the fillers, disintegrants, lubricants, and other additional ingredients discussed above may also be blended into the blend. The ratios or amounts of the various components of the blend may be the same as those discussed above with respect to the composition. The dry granulated blend may have an average particle size greater than 75 microns, such as greater than 300 microns.

Dry granulation can produce a composition that not only has a low moisture level, but is also not significantly hygroscopic, that is, does not absorb significant amounts of additional water from the surrounding environment. For example, when packaged with a desiccant, the water content of the composition can be up to about 4%, or up to about 2% by weight after exposure to about 40° C. at about 75% relative humidity for about six weeks.

After dry granulation, the composition can be formulated into one or more formulations. For example, the composition can be filled into a capsule or sachet. As another example, the dry granulated blend can be formulated into a matrix, a tablet, or one or more layers of a single or multilayer tablet, for example, by compression, or further formulated by methods known in the art for formulating pharmaceutical compositions, such as those described in Remington: The Science and Practice of Pharmacy, which is hereby incorporated by reference in its entirety for all purposes.

Compositions in the form of granulates, for example, can be mixed with other granulates or powders, however, for example, for the purpose of calculating the ratios or relative amounts of the various components, the extragranular material that is not granulated with the components of the composition is not part of the composition. However, one or more formulations comprising a composition in the form of a granulate and further comprising extragranular material are encompassed as part of the embodiments described herein.

As an example, a formulation may include a composition in the form of a granulate as described herein and one or more extragranular components, such as one or more other pharmaceutically active agents. The one or more other pharmaceutically active agents may include one or more antiretroviral drugs, such as one or more CCR5 receptor antagonists, entry inhibitors, nucleoside reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and maturation inhibitors, for example, one or more of maraviroc, lamivudine, efavirenz, raltegravir, vilvicon, bevirimab, alpha interferon, zidovudine, abacavir, lopinavir, ritonavir, tenofovir, tenofovir disoproxil fumarate, tenofovir prodrug, emtricitabine, elvitegravir, cobicistat, darunavir, atazanavir, rilpivirine, and dolutegravir. As another example, the one or more other pharmaceutically active agents may include one or more immune system suppressants, such as one or more of cyclosporine, tacrolimus, prednisolone, hydrocortisone, sirolimus, everolimus, azathioprine, mycophenolic acid, methotrexate, basiliximab, daclizumab, rituximab, antithymocyte globulin, and antilymphocyte globulin, for example, tacrolimus or methotrexate.

For example, a composition as described herein can be blended with one or more other pharmaceutically active agents and optionally one or more excipients and then compressed into a unitary fixed dose combination tablet. As another example, a composition as described herein and a second composition comprising another pharmaceutically active agent can be formed into a multilayer tablet using tableting equipment known in the art to be suitable for that purpose.

Current treatment guidelines for HIV prefer fixed-dose combination (FDC) single tablets. The main advantage of FDC products is the convenience and simplicity of administration, which leads to increased patient compliance and improved clinical outcomes. FDC products for HIV treatment fall into three categories: (1) matrix formulations, in which two agents are co-formulated in a single tablet, such as Truvada (emtricitabine/tenofovir disoproxil fumarate) and Epzicom (abacavir/lamivudine); (2) protease-boosted single-tablet products, such as Kaletra (lopinavir/ritonavir); and (3) single-tablet regimen (STR) products, which contain the entire treatment regimen in a single tablet and are taken once daily, such as Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate), Complera (emtricitabine/rilpivirine/tenofovir disoproxil fumarate), and Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate).

In one embodiment, the present invention provides a composition comprising saenicvir or a salt thereof and fumaric acid in combination with lamivudine (3TC). In another embodiment, the present invention provides a composition comprising saenicvir or a salt thereof and fumaric acid in combination with efavirenz (EFV). In another embodiment, the present invention provides a composition comprising saenicvir or a salt thereof and fumaric acid in combination with 3TC and EFV. In certain embodiments, the combination product containing saenicvir, 3TC, and/or EFV prepared according to the present invention is effective as a single tablet regimen for treating viral infections, specifically HIV infection.

In one embodiment, the dosage strength ratio of zeneviroc to 3TC in the combination formulation is from about 1:2 to about 1:12, such as about 1:2, 1:4, 1:10, or 1:12, based on the weight of free zeneviroc, including all ranges and subranges therebetween. For example, a single tablet comprising zeneviroc or its salt and 3TC may comprise a 25 mg dosage strength of zeneviroc free base and 300 mg of 3TC, thereby providing a dosage strength ratio of 1:12. Alternatively, a single tablet comprising zeneviroc or its salt and 3TC may comprise a 150 mg dosage strength of zeneviroc free base and 300 mg of 3TC, thereby providing a dosage strength ratio of 1:2.

In one embodiment, the dosage strength ratio of zeneviroc to EFV in the combination formulation is from about 1:2 to about 1:12, such as about 1:2, 1:3, 1:4, 1:5, 1:6, 1:8, 1:10, or 1:12, based on the weight of free zeneviroc, including all ranges and subranges therebetween. For example, a single tablet comprising zeneviroc or its salt and EFV may comprise a 150 mg dosage strength of zeneviroc free base and 600 mg of EFV, thereby providing a dosage strength ratio of 1:4. Alternatively, a single tablet comprising zeneviroc or its salt and EFV may comprise a 120 mg dosage strength of zeneviroc free base and 600 mg of EFV, thereby providing a dosage strength ratio of 1:2.

The present invention also provides a method for preparing a combination formulation comprising saenicvir, 3TC and/or EFV. In one embodiment, the method for preparing the combination formulation comprises blending saenicvir or a salt thereof, fumaric acid and other pharmaceutical excipients to form a blend, dry granulating the blend to obtain saenicvir granules, blending the saenicvir granules with 3TC and/or EFV and a suitable excipient, and compressing the resulting mixture into tablets to obtain a combination product. That is, in this embodiment, the other active agent is present extragranularly. In alternative embodiments, a portion or the entire amount of the other active agent may be present intragranularly. In another embodiment, a combination product comprising saenicvir, 3TC and EFV may be prepared in the form of a bilayer tablet, wherein one layer comprises saenicvir and 3TC and the other layer comprises EFV. In one embodiment of the bilayer tablet, saenicvir is present intragranularly and 3TC is present extragranularly.

Example

Example 1

A series of cenicvir mesylate compositions, identical except for the identity of the acid solubilizer, were prepared by wet granulation in a Key 1L drum granulator followed by pan drying, sieving, blending, and compression into tablets on a Carver tablet press. The compositions of the formulations are shown in Table 2.

Table 2

Tablets were administered to beagle dogs. An oral solution was also administered as a control. The absolute bioavailability of the formulations and the oral solution was determined and is shown in Figure 2. The results show that saenixvir mesylate, together with fumaric acid, had significantly higher bioavailability than any other solubilizer tested.

Examples 2a-2e

Zenixvir mesylate, fumaric acid, microcrystalline cellulose, croscarmellose sodium, cross-linked polyvinyl pyrrolidone (when used), and magnesium stearate were blended, dry granulated, milled, blended with extragranular microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, and compressed into tablets. In Example 2c, fumaric acid was not granulated with zenixvir mesylate and the other excipients; instead, it was blended with extragranular microcrystalline cellulose, and this blend was blended with the dry granulation and then compressed into tablets. In Example 2a, 39.00 mg of croscarmellose sodium was part of the dry granulation; the remainder was blended with extragranular microcrystalline cellulose, and this blend was blended with the dry granulation and then compressed into tablets. All tablets had a hardness greater than 10 kP and a friability less than 0.8% w/w. The tablets had the composition shown in Table 3a.

Table 3a

a. Equivalent to 150 mg of ceniciroc free base.

b. Added in the extragranular portion of the powder blend.

The concentration percentages (w/w) of the components of Example 2b and the mass per tablet are shown in Table 3b.

Table 3b

Components Concentration (% w/w) Mass per tablet (mg) Senevir mesylate 26.26 Fumaric acid 24.62 160.00 microcrystalline cellulose 41.87 272.18 Croscarmellose sodium 6.00 39.00 magnesium stearate 1.25 8.13 total 100.0 650.0

^aEquivalent to 150 mg of ceniciroc free base

Example 3

Cynicvir mesylate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate were blended, dry granulated, dried, milled, blended with extragranular microcrystalline cellulose, croscarmellose sodium, fumaric acid, colloidal silicon dioxide, and magnesium stearate, and compressed into tablets having a hardness greater than 10 kP and a friability less than 0.8% w/w. The resulting tablets had the composition shown in Table 4.

Table 4

Components Concentration (% w/w) Mass per tablet (mg) Senevir mesylate 26.26 Fumaric acid 24.62 26.67 microcrystalline cellulose 41.87 45.36 Croscarmellose sodium 6.00 39.00

magnesium stearate 1.25 1.35 total 100.0 108.3

^aEquivalent to 25 mg of cenikvir free base

It is noteworthy that the formulations of Table 4 have the same component ratios as the formulations of Table 3b and differ only in the total amount of the components used in each tablet. Thus, Table 3b shows tablets with 150 mg of cynicvir (calculated as free base), while Table 4 shows tablets with 25 mg of cynicvir (calculated as free base) having the same component ratios as the 150 mg tablets of Example 2b shown in Table 3b.

Example 4 - Reference

The citric acid-based formulations of Table 5 were prepared as follows. Zernicavir, hydroxypropylcellulose, mannitol, and croscarmellose sodium were blended, wet granulated, dried, milled, and blended with microcrystalline cellulose, croscarmellose sodium, citric acid, colloidal silicon dioxide, talc, and magnesium stearate. The resulting blend was compressed into tablets having a hardness greater than 10 kP and a friability less than 0.8% w/w. The tablets were yellow-coated with hydroxypropylmethylcellulose, polyethylene glycol 8000, titanium dioxide, and iron oxide. The resulting coated tablets were substantially the same as those disclosed in U.S. Patent Application Publication No. 2008/031942 (see, e.g., Table 3).

Table 5

Components mg/tablet %w/w Senevir mesylate 28.91 4.68 Mannitol 341.09 56.85 microcrystalline cellulose 80.00 12.94 Colloidal silica 12.00 2.00 Anhydrous citric acid 75.00 12.14 Hydroxypropyl cellulose 12.00 1.94 Croscarmellose sodium 30.00 4.85 talc 12.00 1.94 magnesium stearate 9.00 1.46 Hydroxypropyl methylcellulose 11.71 1.89 Polyethylene glycol 8000 2.69 0.44 Titanium dioxide 3.03 0.49 Iron oxide yellow 0.57 0.09

Example 5 - Reference

Example 5a:

Zynetox and hydroxypropylmethylcellulose acetate succinate were dissolved in methanol and spray-dried into a fine powder containing 25% zynetox by weight (based on the weight of zynetox free base). The powder was blended with colloidal silicon dioxide, microcrystalline cellulose, mannitol, sodium lauryl sulfate, croscarmellose sodium, and magnesium stearate. The blend was compressed into tablets having a hardness greater than 10 kP and a friability less than 0.8% w/w. The final composition of the tablets is shown in Table 6a.

Table 6a

Example 5b: Film coating composition of Example 5a

Cenicvir and hydroxypropyl methylcellulose acetate succinate were dissolved in methanol and spray-dried to a fine powder containing 25% of the CVC matrix by weight. The powder was blended with colloidal silicon dioxide, microcrystalline cellulose, mannitol, sodium lauryl sulfate, croscarmellose sodium, and magnesium stearate. The blend was compressed into tablets having a hardness greater than 10 kP and a friability less than 0.8% w/w. The tablets were then film-coated with Opadry Yellow 21K120001 (Colorcon) to achieve a theoretical weight gain of 3.5%. The final composition of the tablets is shown in Table 6b.

Table 6b

a. Adjust tablet weight to accommodate weight gain for purity and mesylate correction factor.

b. Opadry II Yellow 21K12001 (Colorcon) contains ethylcellulose; hydroxypropyl methylcellulose, USP; triacetin; titanium dioxide, USP; and yellow iron oxide.

c. Film coating weight is a theoretical weight increase of 3.5% w/w on tablet cores.

Example 6

The absolute bioavailability of the tablet of Example 3 in beagle dogs was compared with the absolute bioavailability of the tablets of Examples 4 and 5, and both the oral solution of cynicvir mesylate and the gelatin capsule containing cynicvir mesylate powder. The results are shown in Table 7.

Table 7

Components Absolute bioavailability (%) oral solution 25.8 Capsules containing powder 6.4 Example 3 26.6 Example 4 21.1

Example 5 12.4

This example demonstrates that the bioavailability of zenevir in dry-granulated tablets with fumaric acid (Example 3) is roughly similar to that of the oral solution, and significantly higher than the bioavailability of zenevir in wet-granulated tablets with citric acid (Example 4), and more than double the bioavailability of zenevir in tablets with amorphous zenevir in a spray-dried dispersion containing HPMC-AS (Example 5). These results are surprising because there is no reason to suspect that dry granulation of a crystalline API provides a significant increase in bioavailability over wet granulation and amorphous spray-dried dispersions. This is especially true because amorphous spray-dried dispersions are commonly used to increase the bioavailability of poorly water-soluble drugs. These results are also surprising because fumaric acid has a slower dissolution time than citric acid and was used at a lower mass ratio of acid to zenevir in the API (3:1 (citric acid:API) versus 1.06:1 (fumaric acid:API)). Therefore, the finding that fumaric acid is a more effective solubilizer for Cenicvirox than citric acid is surprising and unexpected.

Example 7

The stability of the tablets of Example 2b under accelerated stability testing was compared to the stability of the tablets of Examples 1b, 4, and 5 by exposing each of the tablets of Examples 2b, 1b, 4, and 5 to an environment of 75% relative humidity at 40°C. During the study, all tablets were packaged in induction-sealed bottles with a desiccant. As shown in Figure 3, the tablets of Example 2b were surprisingly much more stable than the other wet-granulated tablets and had a stability similar to that of the spray-dried dispersion tablets. This difference in stability between the tablets of Example 2b and Example 4 is particularly surprising because the only significant difference between the two is the method of preparing the formulation (dry granulation versus wet granulation). These results are also surprising because it was previously unknown that the granulation method could have an impact on both the bioavailability and tablet stability of Cenicvir.

Example 8

The stability of the tablets of Example 2b was tested under accelerated stability testing by exposing them to 75% relative humidity at 40°C for six weeks. During the study, all tablets were packaged in induction-sealed bottles with a desiccant. The tablets were tested for moisture content, strength, and total impurities. The results are shown in Table 8, which show that the tablets were extremely stable under these conditions.

Table 8

Time (week) Water content (%) strength(%) Total impurities (%) 0 1.5 99.1 1.2 2 1.4 99.2 1.1 4 1.4 98.0 1.0 6 1.4 98.6 1.0

The tablets of Examples 3, 4, and 5 were also tested for dissolution profiles of cenevir after storage under the above conditions. The results are shown in FIG4 , which shows that the wet-granulated citric acid-containing tablet of Example 4 was much less stable than the dry-granulated fumaric acid-containing tablet of Example 3 and the spray-dried dispersion tablet of Example 5.

Example 9

Dynamic vapor sorption isotherms at 25°C correlate with the stability of the tablets of Examples 2b and 4, as well as the stability of cenicirocco mesylate. Adsorption was performed at 5% intervals from 0% to 90% relative humidity. At each interval, each sample was allowed to equilibrate for no less than 10 minutes and no longer than 30 minutes. Equilibration was terminated when the rate of mass increase did not exceed 0.03% w/w per minute or after 30 minutes, whichever was shorter. The results presented in Figure 5 show that the tablets of Example 2b are significantly more stable than those of Example 4. This result is consistent with Example 2b being significantly less hygroscopic than Example 4. The increased hygroscopicity of Example 4 compared to Example 2b may be associated with a higher mobile water content, which in turn may lead to partial gelation of Example 4 and a subsequent decrease in stability.

Example 10

The bioavailability of the tablets of Example 3 under different gastric conditions in beagle dogs (n=5) was compared with that of Example 5 and gelatin capsules containing saenicvir mesylate powder. Bioavailability was tested under different pretreatment conditions, each of which altered gastric pH. Specifically, pentagastrin pretreatment provided the lowest pH, no treatment provided an intermediate pH, and famotidine treatment provided the highest pH. Pentagastrin is a synthetic polypeptide that stimulates gastric acid production, thereby lowering gastric pH.

The results presented in Figure 6 show that the tablets of Example 3 have high bioavailability under all test conditions. The bioavailability of Example 3 varies little between pentagastrin-treated and untreated dogs, while Example 5 shows a significant loss of bioavailability in fasted non-treated dogs (medium gastric pH) compared to the bioavailability in pentagastrin-treated dogs (lowest gastric pH). Pretreatment with famotidine (an H2 receptor agonist that inhibits gastric acidity and increases gastric pH) reduces the bioavailability of all samples, however, the reduction in Example 3 is much smaller than that in Example 5.

These results demonstrate another unexpected benefit of the dry-granulated ZENICVIROC composition with fumaric acid. Specifically, the pharmacokinetics of the formulation did not vary as much as the spray-dried dispersion formulation of Example 5 when administered across the full range of potential human gastric pH conditions. This result is unexpected and surprising, as the bioavailability of other weakly basic antiretroviral drugs, such as atazanavir, is greatly affected by gastric pH. For such drugs, changes in gastric pH, which can be caused by disease or medical conditions (such as patients without hydrochloric acid) or by co-administration of medications (such as antacids, proton pump inhibitors, or H2 receptor agonists), can reduce bioavailability to subtherapeutic levels. These results, showing that the bioavailability of the dry-granulated, fumaric acid-based ZENICVIROC mesylate formulation of Example 3 is less prone to change with changes in gastric pH, suggest that Example 3 is a more robust formulation that can be used in patients who have or may have varying gastric pH levels.

Example 11

The dissolution profiles of the formulations of Examples 2a-2e were measured in 0.1N HCl with 0.1% (w/w) CTAB using USP Apparatus 2 at a paddle speed of 50 rpm. The results are shown in Figure 7 . The disintegration profiles of the formulations of Examples 2a-2e were measured using FBRM. These results are shown in Figure 8 . In summary, Figures 7 and 8 demonstrate that compositions and formulations containing cenikvir mesylate and fumaric acid with different dissolution profiles can be obtained.

The absolute bioavailability of samples 2a-2e in beagle dogs (n=5) was also obtained, and the results are shown in Figure 9. The results show that although the absolute bioavailability can vary depending on the formulation, high bioavailability is obtained for all samples.

Example 12

In this study, tablets of Example 2 were coated with a commercially available film coating formulation, and the stability of the film-coated tablets was tested under accelerated conditions (40°C/75% RH).

The film coating step is typically used for taste masking or to establish a unique commercial appearance for the intended commercial formulation. The tablets of Example 2 were coated with three film coating formulations, each containing a different matrix polymer system. Specifically, Opadry II White 57U18539 containing hydroxypropyl methylcellulose (HPMC or Hydroxypropyl Methylcellulose), Opadry II White 85F18422 (Colorcon) containing polyethylene glycol (PEG) and partially hydrolyzed polyvinyl alcohol (PVA), and Opadry II White 200F280000 containing a methacrylic acid copolymer were used to coat the tablets.

Tablets are coated by spraying an aqueous suspension of the coating formulation onto the tablet surface in a perforated coating pan. The pan is continuously circulated with warm process air, which provides convective heat transfer to evaporate water from the tablet surface, leaving the coating formulation deposited as a thin film layer on the tablet surface. The compositions of the tablets coated with the above-mentioned polymers are shown in Tables 9-11 below. Analysis of the surfaces of the film-coated tablets is summarized in Table 12.

Example 12a-Table 9 (HPMC-coated CVC single dose)

Components Concentration (% w/w) Mass per tablet (mg) Senevir mesylate 26.26 Fumaric acid 24.62 160.00 microcrystalline cellulose 41.87 272.18 Croscarmellose sodium 6.00 39.00 magnesium stearate 1.25 8.13

total 100.0 650.0

a. Equivalent to 150 mg of ceniciroc free base.

b. Opadry II White 57U18539 contains hydroxypropyl methylcellulose, USP; maltodextrin, NF; medium chain triglycerides, NF; polydextrin, NF; talc, USP; and titanium dioxide, USP.

c. Film coating weight is a theoretical weight increase of 4.0% w/w on tablet cores.

Example 12b - Table 10 (PEG/PVA coated CVC single dose)

Components Concentration (% w/w) Mass per tablet (mg) Senevir mesylate 26.26 Fumaric acid 24.62 160.00 microcrystalline cellulose 41.87 272.18 Croscarmellose sodium 6.00 39.00 magnesium stearate 1.25 8.13 total 100.0 650.0

a. Equivalent to 150 mg of ceniciroc free base.

b. Opadry II White 85F18422 (Colorcon) contains polyethylene glycol 3350, NF; partially hydrolyzed polyvinyl alcohol, USP; talc, USP; and titanium dioxide, USP.

c. Film coating weight is a theoretical weight increase of 4.0% w/w on tablet cores.

Example 12c - Table 11 (Methacrylate-coated CVC single dose)

a. Equivalent to 150 mg of ceniciroc free base.

b. Opadry II White 200F280000 (Colorcon) contains methacrylic acid copolymer type C, USP; polyethylene glycol 3350, NF; partially hydrolyzed polyvinyl alcohol, USP; sodium bicarbonate, USP; talc, USP; and titanium dioxide, USP.

c. Film coating weight is a theoretical weight increase of 4.0% w/w on tablet cores.

Analysis of the surface of the film-coated tablets is summarized in Table 12 below. Because the coating with Opadry II White 200F28000 (tablets of Example 12c, Table 11) did not show uniform coverage, the stability of the tablets of Example 12c was not tested. The coatings of Examples 12a and 12b showed acceptable coverage and good adhesion to the tablet surface.

Table 12 - Surface Analysis of Film Coatings

The stability of the film-coated tablets of Examples 12a and 12b was compared to the stability of the uncoated tablets of Example 2 after exposure to 75% relative humidity at 40°C. During the study, all tablets were packaged in induction-sealed bottles with a desiccant. The results of the stability testing are shown in Table 13.

Table 13

N/D – Not Measured

As shown in Table 13, the tablets of Examples 12a and 12b exhibited acceptable stability profiles similar to that of the uncoated tablets of Example 2, with no substantial formation of impurities or degradants. These results are promising, as previous experiments have shown that processing of ciniclav tablets in the presence of an aqueous environment has a deleterious effect on the chemical and physical stability of the tablets.

Example 13

In this study, the pharmacokinetic (PK) profiles of the compositions of Example 2b (shown in Table 3b), Example 3 (shown in Table 4), and Example 5b (shown in Table 6b) were evaluated in human clinical trials. The composition of Example 5b was used as a reference.

A Phase 2b proof-of-concept study ("Study 202") was conducted using the composition of Example 5b to establish the PK profile of a 200 mg dose of the recommended Cenvironide taken with breakfast. In Study 202, patients were administered a 200 mg dose of the composition of Example 5b once daily for 10 consecutive days. Because the formulation of Example 5b is a 50 mg tablet, patients were required to take four tablets per dose to administer the 200 mg dose.

In Study 110, a multiple-dose regimen of the composition of Example 2b was evaluated. In this study, patients were administered a 150 mg dose of the composition of Example 2b once daily with breakfast for 10 consecutive days. Each time, the patient consumed a single tablet containing the 150 mg dose of the composition of Example 2b.

In Study 111, the PK profile of a 200 mg single dose regimen administered just before or at bedtime on an empty stomach was evaluated. The 200 mg dose was administered by taking one tablet of Example 2b (150 mg dose) and two tablets of Example 3 (25 mg dose/tablet). The administration of three tablets to provide a 200 mg dose was based solely on the availability of tablets of Examples 2b and 3, and not due to any limitations on the preparation of 200 mg cenicirocco tablets according to the present invention.

The PK profiles obtained in the above studies are summarized in Table 14 below.

Table 14

^aBased on Phase 2b data, DP6 at 200 mg taken with breakfast achieves exposures effective for clinical use with CVC for the treatment of HIV-1 infection.

The above data show that the AUC value obtained in study 110, in which the composition of the present invention was administered, was 1.6 times higher than the AUC value obtained in study 202, in which the reference composition was administered. Thus, under steady-state conditions (characterized by multiple dose exposure over 10 days), administration of 150 mg of cynicvir with breakfast as a composition of the present invention resulted in higher cynicvir bioavailability than administration of 200 mg of cynicvir with breakfast as a reference composition. This data demonstrates that the CVC compositions of the present invention, in which the microenvironment contains acid and the pH is therefore adjusted, have superior bioavailability to the spray-dried dispersion formulation. Thus, the compositions of the present invention make it possible to use lower amounts of CVC per patient per day, thereby reducing drug costs. Using lower amounts of CVC also reduces tablet size and improves ease of swallowing. The need for lower amounts of CVC also makes it possible to combine CVC with other antiretroviral agents in a single tablet.

Study 111 was conducted to evaluate PK parameters after administering the composition of the present invention immediately before or at bedtime. For the treatment of HIV, a combination of two or more active agents is preferred over a single active agent. For example, efavirenz (EFV) and lamivudine (3TC) are used in combination with each other or in combination with other active agents for the treatment of HIV. It is recommended that the EFV-containing composition be taken on an empty stomach at or around bedtime. This is because the PK profile of EFV is affected by the food content of the stomach, and the administration of EFV is accompanied by side effects, such as CNS toxicity (e.g., dizziness), that are primarily experienced around the time of maximum plasma concentration (Tmax). Bedtime administration is preferably used to manage these aspects of EFV administration. If cynicucovir is to be co-administered or co-formulated with EFV, it is important that the desired exposure level be achieved when administered on an empty stomach at bedtime. In addition, EFV is a metabolic inducer of P450 (specifically, CYP3A4 enzyme). Higher activity of CYP3A4 results in rapid metabolism of CVC and thus reduced absorption of CVC. Therefore, if Cenviron is to be administered in combination with EFV on an empty stomach around bedtime, it is estimated that higher amounts of CVC will be necessary to provide higher exposure levels to compensate for the metabolic effects of EFV on CVC.

The recommended exposure levels for the treatment of HIV were determined in Study 202 using a reference formulation containing 200 mg of Cenicvir in the form of a spray-dried dispersion administered with breakfast (see Table 14). Various other clinical trials based on different Cenicvir formulations have determined that due to the long half-life of CVC, which takes more than one dosing interval to accumulate to steady-state levels, the steady-state exposure levels (AUC) of Cenicvir (characterized by the 10-day exposure) are approximately 1.5 times higher than those obtained from a single dose. The expectation that higher amounts of CVC would be required for its combination with EFV is consistent with the above data on steady-state and single-dose exposure levels.

Unexpectedly, Study 111 showed that a 200 mg dose of Cenicvir, administered on an empty stomach near bedtime in the form of a composition of the present invention, achieved a single dose exposure level that was 2.6 times higher than the reference steady-state exposure level (Table 14). That is, a single 200 mg dose of the composition of the present invention near bedtime had a higher bioavailability than multiple 200 mg doses of the reference composition administered with breakfast. The CVC exposure levels achieved in Study 111 using a 200 mg dose of the composition of the present invention were far more than sufficient to offset the metabolic effects of EFV or the effects of food. Therefore, based on Study 111, it was inferred that less than 200 mg of CVC would be optimal for its co-formulation with EFV in a single tablet regimen (STR) product such as CVC/EFV/3TC. Therefore, further studies on the development of combination product prototypes used 150 mg of CVC for STR products containing CVC/EFV/3TC.

Example 14

Dry granulated CVC compositions were prepared using a custom-built laboratory-scale roller compactor with smooth stainless steel counter-rotating rollers (25 mm diameter, 125 mm width, and 0.5 to 3 mm gap width). Spunbond olefin sleeves were used to contain the pre- and post-rolling powders, providing adequate transport of the small amount of powder through the compaction zone.

In a container of suitable size, cynicvir mesylate, fumaric acid, microcrystalline cellulose and croscarmellose sodium are blended and blended by rolling action for a total of 40 turns over 2 minutes. Magnesium stearate is added and the mixture is blended again over 40 turns over 2 minutes. A Tyvek sheet having a size of 100 mm x 480 mm is folded to form a sleeve with a width of 50 mm to define a compaction zone that will contain the blended powder as it passes through a laboratory-scale roller compactor. Approximately 10 to 15 g of powder is added to the sleeve and evenly distributed. The powder-containing sleeve is fed into the roller compactor at a gap width of approximately 2 mm and at a speed of 45 rpm (linear speed = 0.06 m/s). The resulting strip is pressed into a thickness of approximately 1.0 to 1.5 mm (measured using a digital caliper). Repeat this process with more blended powder until the entire batch has completely passed through the roller compactor. The resulting compressed strips were then ground using a 6 inch diameter 20 mesh stainless steel rotary screen grinder to produce granules. The granules had the compositions shown in Table 15.

Table 15

Components Concentration (% w/w) Senevir mesylate 32.2 Fumaric acid 30.2 microcrystalline cellulose 33.0 Croscarmellose sodium 3.7 magnesium stearate 0.9 total 100.0

The granules prepared above were further blended with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate to prepare the CVC single-dose tablet formulations shown in Table 16. The strength of the single-dose tablets can be readily varied by simply adjusting the total tablet weight accordingly. For example, a tablet having a total mass of 325 mg can be prepared by using only half the amount of the components and will have a 75 mg CVC free base equivalent strength (using linear scaling of the co-blends) while maintaining the same inter-component ratios as in Table 16.

Table 16

Components Concentration (% w/w) Mass per tablet (mg) Senevir mesylate 26.26 Fumaric acid 24.62 160.00 microcrystalline cellulose 41.87 272.18 Croscarmellose sodium 6.00 39.00 magnesium stearate 1.25 8.13 total 100.0 650.0

a. Equivalent to 150 mg of ceniciroc free base.

Example 15

A single-dose CVC tablet formulation containing lower excipient levels, and thus lower overall tablet mass, was prepared using the method described in Example 14. The tablets had the composition shown in Table 17. This formulation contained a higher concentration of celecoxib for the purpose of combination with other antiretroviral agents and to avoid excessively large overall tablet size for the combination product.

Table 17

Components Concentration (% w/w) Senevir mesylate 40.5 Fumaric acid 37.9 microcrystalline cellulose 15.6 Croscarmellose sodium 5.0 magnesium stearate 1.0 total 100.0

Example 16

The compressibility of the milled granules prepared by the laboratory-scale roller compactor in Examples 14 and 15 was measured using a standard compressibility test and is shown in FIG10 . Specifically, compression profiles of the tablet blends were generated using an instrumented compacting apparatus (Texture Analyzer) with 1/4" flat B-type tooling. Three replicates of 100 mg of compacts were compressed at four forces ranging from 100 kg to 700 kg. The ejected compacts were immediately weighed on a four-position balance, and the compact thickness was measured with a precision caliper. The compacts were tested by a radial compression test to induce tensile fracture. The tensile strength (TS) of the compacts was determined by the following equation:

TS＝2·F/(π·D·T)

Where F is the force required to produce a tensile fracture in the compact, D is the diameter of the compact, and T is the thickness of the compact. The solid fraction (SF) of the compact is calculated by the following equation:

SF＝m/(V· _ρabsolute )＝m/[(π·(D/2) ² ·T)· _ρabsolute ]

where m is the mass of the compact, V is the tablet volume, and pabs is the absolute density of the tablet blend as measured with a helium pycnometer.

The compressibility of the ground granules prepared by the laboratory-scale roller compactor in Example 14 was compared to the compressibility of granules prepared by large-scale processing equipment available from commercial suppliers. The results are shown in Figure 11. The compressibility of the granules from Example 14 was found to be similar to that of granules produced using a Vector-Freund TF-220 at a roller pressure of 500 psi (Example 16a) and a Gerteis Minipactor at a roller pressure of 4 kN/cm (Example 16b). These results demonstrate the utility of the laboratory-scale roller compactor in generating compaction pressures similar to those of large-scale processing equipment.

Example 17

A portion of the granulation from Example 14 (Cenicvir mesylate, fumaric acid, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate) was blended with extragranular lamivudine (3TC), microcrystalline cellulose, croscarmellose sodium, and magnesium stearate and compressed into tablets having a hardness greater than 6 kP and a friability less than 0.8% w/w. The resulting powder blend and tablets had the compositions shown in Table 18.

Table 18 (25/300CVC/3TC)

Element Concentration (% w/w) Mass per tablet (mg) Senevir mesylate 5.69 Lamivudine 60.00 300.00 Fumaric acid 5.33 26.67

microcrystalline cellulose 22.16 110.82 Croscarmellose sodium 5.65 28.25 magnesium stearate 1.16 5.81 total 100.0 500.0

a. Equivalent to 25 mg of ceniciroc free base.

Example 18

A portion of the granules from Example 14 (Cenicvir mesylate, fumaric acid, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate) were blended with extragranular lamivudine, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate and compressed into tablets. The resulting powder blends and tablets had the compositions shown in Table 19.

Table 19 (75/300CVC/3TC)

Element Concentration (% w/w) Mass per tablet (mg) Senevir mesylate 13.13 Lamivudine 46.15 300.00 Fumaric acid 12.31 80.00 microcrystalline cellulose 20.54 133.46 Croscarmellose sodium 6.50 42.25 magnesium stearate 1.38 8.94 total 100.0 650.0

a. Equivalent to 75 mg of cenikvir free base.

Example 19

A portion of the granules from Example 14 (cenikvir mesylate, fumaric acid, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate) was blended with extragranular lamivudine, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate and compressed into tablets having a hardness greater than 10 kP and a friability less than 0.8% w/w. The resulting tablets had the composition shown in Table 20.

Table 20 (150/300CVC/3TC)

Element Concentration (% w/w) Mass per tablet (mg)

Senevir mesylate 17.97 Lamivudine 31.58 300.00 Fumaric acid 16.84 160.00 microcrystalline cellulose 24.78 235.43 Croscarmellose sodium 7.31 69.50 magnesium stearate 1.51 14.38 total 100.0 950.0

a. Equivalent to 150 mg of ceniciroc free base.

Example 20

A portion of the granulation from Example 15 (cenikvir mesylate, fumaric acid, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate) was blended with extragranular lamivudine, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate and compressed into tablets having a hardness greater than 10 kP and a friability less than 0.8% w/w. The resulting tablets had the composition shown in Table 21.

Table 21 (150/300 CVC (concentrated)/3TC)

Element Concentration (% w/w) Mass per tablet (mg) Senevir mesylate 21.34 Lamivudine 37.50 300.00 Fumaric acid 20.00 160.00 microcrystalline cellulose 12.01 96.01 Croscarmellose sodium 7.64 61.10 magnesium stearate 1.53 12.20 total 100.0 800.0

a. Equivalent to 150 mg of ceniciroc free base.

Example 21: Composition containing intragranular (IG) cenikvir and half IG/half extragranular (EG) lamivudine

In this example, granules were prepared as described in Example 14, except that the granules also contained half the required amount of lamivudine. The granules were blended with the remaining amount of lamivudine, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, and the powder blend was compressed into tablets. That is, half the amount of lamivudine was present in the intragranular portion, and the remaining half was present in the extragranular portion. The resulting powder blend and tablets had the compositions shown in Table 22.

Table 22

Element Concentration (% w/w) Mass per tablet (mg) Senevir mesylate 22.76 Lamivudine 40.00 300.00 Fumaric acid 21.33 160.00 microcrystalline cellulose 5.82 43.66 Croscarmellose sodium 8.55 64.15 magnesium stearate 1.53 11.15 total 100.0 750.0

a. Equivalent to 150 mg of ceniciroc free base.

Example 22

In this example, granules were prepared as described in Example 14, except that the granules contained the entire amount of lamivudine. That is, the lamivudine was present only in the IG fraction. The granules were blended with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate and compressed into tablets. The resulting powder blend and tablets had the compositions shown in Table 23.

Table 23

Element Concentration (% w/w) Mass per tablet (mg) Senevir mesylate 22.76 Lamivudine 40.00 300.00 Fumaric acid 21.33 160.00 microcrystalline cellulose 6.60 49.51 Croscarmellose sodium 7.61 57.10 magnesium stearate 1.69 12.70 total 100.0 750.0

a. Equivalent to 150 mg of ceniciroc free base.

Example 23

A portion of the granules from Example 14 (cenikvir mesylate, fumaric acid, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate) was blended with extragranular microcrystalline cellulose, croscarmellose sodium, and magnesium stearate to obtain a powder blend containing cenikvir granules. Lamivudine was separately blended with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate to obtain a powder blend containing lamivudine. The powder blend containing cenikvir granules and the powder blend containing lamivudine were used to prepare bilayer tablets. The resulting bilayer tablets had the composition shown in Table 24.

Table 24

Element Concentration (% w/w) Mass per tablet (mg) CVC layer Senevir mesylate 18.96 Fumaric acid 17.78 160.00 microcrystalline cellulose 20.53 184.78 Croscarmellose sodium 4.34 39.00 magnesium stearate 1.17 10.53 3TC layer Lamivudine 33.33 300.00 microcrystalline cellulose 2.85 25.62 Croscarmellose sodium 0.74 6.70 magnesium stearate 0.30 2.68 total 100.0 900.0

a. Equivalent to 150 mg of ceniciroc free base.

Example 24

Tablets of Examples 18-23 (combinations containing saenicvir and 3TC) and Example 14 (combinations containing saenicvir as a single active agent) were tested for absolute bioavailability in fasted, untreated beagle dogs. All tablets were scaled down to deliver a constant dose of 25 mg saenicvir, with lamivudine correspondingly scaled down to 100 mg (for Example 18) or 50 mg (for Examples 19-23). The absolute bioavailability results are summarized in Table 25. The bioavailability of the tablets of Example 14 (saenicvir as a single agent) and Examples 19-20 (combinations of saenicvir and 3TC) was also tested under pentagastrin pretreatment conditions, which induces a minimum gastric pH similar to the pH conditions of the human stomach.

Table 25

a.50mg dose of celecoxib.

Absolute bioavailability data show that the CVC exposure achieved using the combined formulation of Examples 19 and 21 is similar to that achieved with the single-dose CVC formulation of Example 14. The bioavailability data from Example 19, with and without pentagastrin pretreatment, show that CVC exposure levels are similar regardless of gastric pH conditions. Importantly, the data also demonstrate that the acidic microenvironment functionality of the CVC formulation is maintained in this combination product formulation. Data from Example 21 (1/2IG 1/2EG 3TC) show that even when half the amount of weakly basic 3TC is in direct contact with the CVC/fumaric acid granules (IG), the CVC and 3TC exposures achieved are similar to those of Example 19, where 3TC is entirely external to the granules (EG) and has less intimate contact with the CVC/fumaric acid. This data indicates that highly water-soluble 3TC dissolves at a rate faster than that of fumaric acid, the slow-dissolving solubilizing agent used as CVC in the present invention, thereby eliminating the possibility that the weakly basic 3TC will neutralize the fumaric acid. The data also confirm that the acidic microenvironmental profile of the present invention, based on the slow-dissolving fumarate excipient, provides the desired CVC in vivo release profile despite the presence of the weakly basic drug 3TC. Example 20, which utilizes granules prepared using a concentrated CVC formulation, exhibited only 12.0% CVC exposure without pretreatment and 22.1% CVC exposure under lower gastric pH conditions. The exposure values of Examples 18, 20, 22, and 23 remain acceptable, and if administered to human subjects for comparison of relative bioavailability, dose adjustment may or may not be necessary. The absolute bioavailability of lamivudine, greater than 90% for all formulations, is acceptable and appears independent of formulation composition and manufacturing methods.

Example 25

The disintegration properties of the CVC/3TC tablets were characterized by placing a single tablet of each sample prepared for dog pharmacokinetic evaluation in approximately 250 mL of water and observing the disintegration pattern and rate.

Table 26 summarizes the disintegration results for Examples 18 and 20-22. Tablets of Examples 18 and 20, containing the entire amount of lamivudine extragranularly, exhibited rapid disintegration similar to that of the lamivudine active ingredient compressed into tablets. Examples 21-22, in which half or all of the lamivudine was present intragranularly, exhibited unexpected disintegration patterns. Specifically, Example 21, in which half of the lamivudine was present intragranularly, disintegrated slowly over a period of several minutes. Example 22, in which the entire amount of lamivudine was present intragranularly, did not disintegrate at all. These results are unexpected given the high aqueous solubility of lamivudine at 70 mg/mL. It is possible that interactions between intragranular components prevented proper wetting and disintegration of the tablet and granules. While adding lamivudine to the intragranular portion of the Cernicvir granulation is a strategy for maintaining tablet quality, special considerations regarding biopharmaceutical performance must be given due to variations in tablet disintegration characteristics.

Table 26

Example 26

The total impurities of the CVC/3TC tablets of Examples 17, 19, and 20 and the CVC single-dose tablet of Example 14 were tested under accelerated stability conditions by exposing the tablets to an environment of 75% relative humidity at 40°C. During the study, all tablets were packaged in HDPE bottles under induction sealing and desiccant. As summarized in Tables 27a and 27b, the CVC/3TC tablets of Examples 17, 19, and 20 were as stable as the CVC single-dose tablet of Example 14 and the commercial 3TC single-dose tablet Epivir, with no increase of impurities or degradants exceeding 0.1% over 9 weeks of accelerated storage. This indicates that the active ingredient is fully chemically compatible and stable in the above-described formulation and method. No lamivudine impurities or degradants were observed in any of the Examples as shown in Table 27b.

Table 27a

N/D – Not Measured

Table 27b

BLQ – below the limit of quantitation (<0.05%)

Example 27

The compression profiles of the CVC/3TC powder blends of Examples 17, 19, and 20 were measured and are shown in FIG12. Although the addition of 3TC reduced the compressibility of the CVC single-dose powder blends shown in FIG10, all CVC/3TC powder blends still exhibited acceptable compressibility characteristics required for commercial product purposes. Lamivudine is a highly crystalline, brittle material with large, discrete particles that can disrupt the powder matrix during compression. Examples 17 and 20, which have higher concentrations of lamivudine, exhibited lower compressibility than Example 19, which contained 150 mg more excipient mass than Example 20.

Example 28

A bilayer tablet containing a combination of three active agents, CVC, 3TC, and efavirenz (EFV), was prepared for a single-tablet regimen (STR) treatment study for HIV. In the bilayer tablet, the CVC/3TC combination was present as a single layer, while the third active agent, EFV, was present as a second layer. The CVC/3TC layer of the tablet was prepared using the concentrated composition of Example 20. However, any of the CVC/3TC combinations disclosed above, or related variations, can be similarly used in this STR tablet configuration.

The EFV layer was prepared by conventional high-shear wet granulation using a 5L stainless steel granulator drum. EFV, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and hydroxypropyl cellulose were blended in a high-shear mixer at speed setting 2 for 2 minutes to prepare a 300g batch. 238ml of purified water was added to the blend over approximately 6 minutes to achieve suitable granulation, and further blending was performed as necessary. The granules were milled using a forward hammer mill with paddle blades and dried in a tray dryer at 80°C. The dried granules were further milled and blended with magnesium stearate. The EFV layer weight of the bilayer tablets was 850mg, corresponding to 600mg of EFV active ingredient and 250mg of excipients. The separate CVC/3TC layers and the EFV layer were compressed into bilayer tablets having a hardness greater than 15kP and a friability less than 0.8% w/w. The bilayer tablets had the composition shown in Table 28.

Table 28 (CVC/EFV/3TC Single Tablet Regimen-1)

Element Concentration (% w/w) Mass per tablet (mg) CVC/3TC layer Senevir mesylate 10.34 Lamivudine 18.18 300.00 Fumaric acid 9.70 160.00 microcrystalline cellulose 5.82 96.01 Croscarmellose sodium 3.70 61.10 magnesium stearate 0.74 12.2 EFV layer Efavirenz 36.36 600.00 microcrystalline cellulose 7.97 131.50 Croscarmellose sodium 3.64 60.00 Sodium lauryl sulfate 0.73 12.00 Hydroxypropyl cellulose 2.30 38.00 magnesium stearate 0.52 8.50 total 100.0 1650.0

^a. Equivalent to 150 mg of ceniciroc free base.

Example 29

A bilayer tablet containing CVC, 3TC, and EFV as active agents was prepared as described in Example 28, except that the weight of the EFV layer was 775 mg. The CVC/3TC layer of the tablet was prepared using the concentrated composition of Example 20. However, any of the CVC/3TC combinations or related variations disclosed above can be similarly used in this STR tablet configuration. The tablet had a hardness greater than 15 kP and a friability less than 0.8% w/w. The bilayer tablet had the composition shown in Table 29.

Table 29 (CVC/EFV/3TC Single Tablet Regimen-2)

Element Concentration (% w/w) Mass per tablet (mg) CVC/3TC layer Senevir mesylate 10.84 Lamivudine 19.05 300.00

Fumaric acid October 16 160.00 microcrystalline cellulose 6.10 96.01 Croscarmellose sodium 3.88 61.10 magnesium stearate 0.77 12.2 EFV layer Efavirenz 38.09 600.00 microcrystalline cellulose 3.82 60.20 Croscarmellose sodium 3.81 60.00 Sodium lauryl sulfate 0.76 12.00 Hydroxypropyl cellulose 2.22 35.00 magnesium stearate 0.50 7.80 total 100.0 1575.0

a. Equivalent to 150 mg of ceniciroc free base.

Example 30

The absolute bioavailability of the CVC/3TC/EFV tablets of Examples 28-29 was measured in fasted, pentagastrin-pretreated beagle dogs and compared to the absolute bioavailability of a single dose of CVC tablet of Example 14. All tablets were scaled down to deliver a constant dose of 25 mg of cenavir free base, with lamivudine proportionally reduced to deliver a 50 mg dose and efavirenz proportionally reduced to deliver a 100 mg dose. The absolute bioavailability results are summarized in Table 30.

Table 30

a. 50mg dose of celecoxib

Absolute bioavailability data showed that CVC exposure was significantly reduced when administered in the presence of efavirenz. Efavirenz is a known inducer of the liver enzyme CYP3A4 and has been shown to increase the metabolism of ceftriaxone in humans, thereby reducing ceftriaxone plasma concentrations by approximately 2-fold.

Example 31

Tablets from Examples 28 and 29 were tested for total impurities under accelerated stability conditions by exposing the tablets to 75% relative humidity at 40°C. All tablets were packaged in induction-sealed HDPE bottles with a desiccant. As summarized in Table 31, the total impurities in CVC did not show significant changes over the four weeks of accelerated storage. Lamivudine impurities were not measured in any of the Examples, as shown in Table 31. Additionally, Table 17 shows no significant changes in efavirenz degradation products.

Table 31

BLQ – below the limit of quantitation (<0.05%).

Example 32

The tablets of Examples 28-29, as well as the tablets of Examples 17, 19, and 20, were tested for strength and water content under accelerated stability conditions by exposing the packaged tablets to an environment of 75% relative humidity at 40°C. As summarized in Tables 32-33 below, no significant changes in the strength of CVC and 3TC were observed for the tablets of Examples 19 and 20, as well as the STR tablets of Examples 28-29. The tablet of Example 17 did not show any significant changes after 2 weeks, but did show a numerical decrease in the strength of CVC and 3TC after 4 weeks. Additional testing confirmed that this decrease was not significant and occurred due to an artifact in the analytical testing method.

Table 32: Strength under accelerated conditions (40°C/75% RH)

Table 33: Strength under accelerated conditions (40°C/75%RH)

Table 34 shows that after 4 weeks of storage at 40°C/75% RH, no significant changes in the water content as determined by Karl Fischer were observed for any of the CVC/3TC tablets of Examples 17, 19, and 20, and the STR tablets of Examples 28-29.

Table 34: Water content under accelerated conditions (40°C/75%RH)

After storage at 40°C/75% RH for 9 weeks, the tablets of Examples 17, 19 and 20 were tested for dissolution. No significant changes in the dissolution profiles of 3TC and CVC were observed during storage at 40°C/75% RH for 9 weeks.

The tablets of Examples 28-29 were also tested for dissolution after storage at 40°C/75% RH for 4 weeks. The dissolution data are summarized in Figures 13-14.

Example 33

The tablets of Examples 17, 19, and 20 were also tested for related substance formation after storage at 40°C/75% RH for 9 weeks. For this test, a single tablet of Example 17 was placed in a 100 ml flask, 5 ml of MiliQ water was added, the flask was placed on a shaker at 200 rpm for 30 minutes, and then 65 ml of methanol was added. The flask was returned to the shaker for an additional 30 minutes at 200 rpm, and the contents were diluted to 100 ml with methanol. For the tablets of Examples 19 and 20, HPLC samples were prepared by placing a single tablet in a 500 ml flask, adding 25 ml of MiliQ water, the flask was placed on a shaker at 200 rpm for 30 minutes, 325 ml of methanol was added, the flask was placed on a shaker at 200 rpm for an additional 30 minutes, and the contents were diluted to 500 ml with methanol. The samples were analyzed for related substance formation using HPLC. After storage at 40°C/75%RH for 9 weeks, CVC-related substances increased from <LOQ (0.05%) to approximately 0.2%. After storage at 40°C/75%RH for 9 weeks, no 3TC-related substances were observed at levels greater than LOQ (0.05%).

The HPLC method parameters of related substances are listed in the table below:

Table 35

Example 34

The pharmacokinetic profile of the tablets of Example 28 (containing a combination of Cenicvir, 3TC, and EFV) was tested in fasting, pentagastrin-treated beagle dogs. All tablets were scaled down to deliver a constant dose of 25 mg CVC, 50 mg 3TC, and 100 mg EFV. The results are summarized in Table 36.

Table 36

It should be understood that although the above description provides guidance for those of ordinary skill in the art to carry out, use and implement the present disclosure, it is not intended to be restrictive. Various modifications may be made to this description without departing from the scope or spirit of the present disclosure. Those of ordinary skill may adopt the variations when appropriate, and the present disclosure may be implemented in a manner other than the manner clearly described herein. For example, although some embodiments have been described with respect to specific types of inactive ingredients (such as fillers, disintegrants, etc.), those of ordinary skill in the art will recognize that other inactive ingredients may also be used to achieve similar results. Therefore, the present disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as allowed by applicable law. In addition, unless otherwise indicated herein or otherwise clearly refuted by context, any combination of the above elements with all their possible variations is encompassed by the present disclosure.

Claims (135)

1. A composition comprising cineviro or a salt thereof and fumaric acid, produced by a dry granulation method, wherein the weight ratio of cineviro or a salt thereof to fumaric acid is 7:10 to 10:7 based on the weight of free cineviro. 2. The composition of claim 1, wherein the xenicovirol or its salt is xenicovirol methanesulfonate. 3. The composition of claim 1 or 2, wherein the weight ratio of xenicovirol or its salt to fumaric acid is 8:10 to 10:8 based on the weight of free xenicovirol. 4. The composition of claim 1 or 2, wherein the weight ratio of xenicovirol or its salt to fumaric acid is 9:10 to 10:9 based on the weight of free xenicovirol. 5. The composition of claim 1 or 2, wherein the weight ratio of xenicovirol or its salt to fumaric acid is 95:100 to 100:95 based on the weight of free xenicovirol. 6. The composition of claim 1 or 2, wherein the fumaric acid is present in an amount of 15% to 40% by weight of the composition. 7. The composition of claim 1 or 2, wherein the fumaric acid is present in an amount of 20% to 30% by weight of the composition. 8. The composition of claim 1 or 2, wherein the fumaric acid is present in an amount of 25% by weight of the composition. 9. The composition of claim 1 or 2, wherein the trinice or its salt is present in an amount of 15% to 40% by weight of the free trinice. 10. The composition of claim 1 or 2, wherein the trinice or its salt is present in an amount of 20% to 30% by weight of the free trinice. 11. The composition of claim 1 or 2, wherein the trinice or its salt is present in an amount of 25% by weight of the free trinice. 12. The composition of claim 1 or 2, further comprising one or more fillers. 13. The composition of claim 12, wherein one or more fillers are selected from microcrystalline cellulose, dicalcium phosphate, lactose, sucrose, mannitol, sorbitol, starch, and calcium carbonate. 14. The composition of claim 12, wherein one or more fillers are microcrystalline cellulose. 15. The composition of claim 12, wherein the weight ratio of the one or more fillers to the triniceviro or its salt is 25:10 to 10:8 based on the weight of free triniceviro. 16. The composition of claim 12, wherein the weight ratio of the one or more fillers to the triniceviro or a salt thereof is 20:10 to 10:10 based on the weight of free triniceviro. 17. The composition of claim 12, wherein the weight ratio of the one or more fillers to the triniceviro or a salt thereof is 15:10 based on the weight of free triniceviro. 18. The composition of claim 12, wherein the one or more fillers are present in an amount of 25% to 55% by weight of the composition. 19. The composition of claim 12, wherein the one or more fillers are present in an amount of 30% to 50% by weight of the composition. 20. The composition of claim 12, wherein the one or more fillers are present in an amount of 40% by weight of the composition. 21. The composition of claim 1 or 2, further comprising one or more disintegrants. 22. The composition of claim 21, wherein the one or more disintegrants are selected from croscarmellose, croscarmellose sodium carboxymethyl cellulose and sodium starch glycolate. 23. The composition of claim 21, wherein one or more disintegrants are croscarmellose sodium. 24. The composition of claim 21, wherein the weight ratio of the one or more disintegrants to the triniceviro or a salt thereof is from 10:100 to 30:100, based on the weight of free triniceviro. 25. The composition of claim 21, wherein the weight ratio of the one or more disintegrants to the trinicotinic acid or a salt thereof is 25:100 based on the weight of free trinicotinic acid. 26. The composition of claim 21, wherein the one or more disintegrants are present in an amount of 2% to 10% by weight of the composition. 27. The composition of claim 21, wherein the one or more disintegrants are present in an amount of 4% to 8% by weight of the composition. 28. The composition of claim 21, wherein the one or more disintegrants are present in an amount of 6% by weight of the composition. 29. The composition of claim 1 or 2, further comprising one or more lubricants. 30. The composition of claim 29, wherein one or more lubricants are selected from stearin, magnesium stearate and stearic acid. 31. The composition of claim 29, wherein one or more lubricants are magnesium stearate. 32. The composition of claim 29, wherein the one or more lubricants are present in an amount of 0.25% to 5% by weight of the composition. 33. The composition of claim 29, wherein the one or more lubricants are present in an amount of 0.75% to 3% by weight of the composition. 34. The composition of claim 29, wherein the one or more lubricants are present in an amount of 1.25% by weight of the composition. 35. The composition of claim 1 or 2, wherein the composition is selected from: 36. The composition of claim 1 or 2, wherein the composition comprises: 37. The composition of claim 1 or 2, wherein when packaged in a container with a desiccant, after exposure to 40°C at 75% relative humidity for six weeks, the composition has a water content of up to 4% by weight. 38. The composition of claim 1 or 2, wherein when packaged in a container with a desiccant, after exposure to 40°C at 75% relative humidity for six weeks, the composition has a water content of up to 2% by weight. 39. The composition of claim 1 or 2, wherein when packaged in a container with a desiccant, after exposure to 40°C at 75% for 12 weeks, the composition has a total impurity and degradation level of up to 2.5%. 40. The composition of claim 1 or 2, wherein when packaged in a container with a desiccant, after exposure to 40°C at 75% for 12 weeks, the composition has a total impurity and degradation level of up to 1.5%. 41. The composition of claim 1 or 2, wherein the cineviro or its salt has an average absolute bioavailability of 10% to 30% after oral administration. 42. The composition of claim 1 or 2, after oral administration, exhibits a trinicovir AUC that is 200% or greater than the trinicovir AUC exhibited by the reference solid dosage form. 43. The composition of claim 1 or 2, after oral administration, exhibits a Cmax of at least 50% higher than that of the reference solid dosage form of dextran. 44. The composition of claim 1 or 2, further comprising one or more other pharmaceutically active agents. 45. The composition of claim 44, wherein the one or more other pharmaceutically active agents are one or more other antiretroviral drugs selected from: CCR5 receptor antagonists, entry inhibitors, nucleoside reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and maturation inhibitors. 46. The composition of claim 44, wherein one or more other pharmaceutically active agents are selected from maraviro, lamivudine, efavirenz, retegvir, vevirica, bevirimilamide, interferon-alpha, zidovudine, abacavir, lopinavir, ritonavir, tenofovir, tenofovir alafenamide, emtricitabine, erticagvir, cobicistat, derenavir, atazanavir, rilpivirine, and dulutegravir. 47. The composition of claim 46, comprising: cineviro or a salt thereof and fumaric acid; and lamivudine. 48. The composition of claim 47, wherein the xenicovirol or a salt thereof is xenicovirol methanesulfonate. 49. The composition of claim 47 or 48, wherein the weight ratio of triniceviro or its salt to lamivudine is 1:15 to 1:1 based on the weight of free triniceviro. 50. The composition of claim 47, wherein the weight ratio of the free cineviro or its salt to lamivudine is 1:12 to 2:3 based on the weight of the free cineviro. 51. The composition of claim 47, wherein the weight ratio of the free cineviro or its salt to lamivudine is 1:12; 1:4; or 1:2, based on the weight of the free cineviro. 52. The composition of claim 47, wherein lamivudine is present in an amount of 25% to 65% by weight of the composition. 53. The composition of claim 47, wherein lamivudine is present in an amount of 30% to 60% by weight of the composition. 54. The composition of claim 47, wherein lamivudine is present in an amount of 31.6%; 33.3%; 37.5%; 40.0%; 46.2%; or 60% by weight of the composition. 55. The composition of claim 47, comprising... Based on the weight of the composition and the weight of free desnicerol, 15.8% desnicerol or its salt and 31.6% lamivudine; 16.7% Saneviro or its salts and 33.3% Lamivudine; 18.8% Saneviro or its salts and 37.5% Lamivudine; 20% cineviro or its salt and 40.0% lamivudine; 11.5% cineviro or its salt and 46.2% lamivudine; or 5% cineviro or its salt and 60% lamivudine. 56. The composition of claim 47, further comprising one or more fillers. 57. The composition of claim 56, wherein one or more fillers are selected from microcrystalline cellulose, dicalcium phosphate, lactose, sucrose, mannitol, sorbitol, starch, and calcium carbonate. 58. The composition of claim 56 or 57, wherein one or more fillers are microcrystalline cellulose. 59. The composition of claim 56, wherein the weight ratio of the one or more fillers to the triniceviro or a salt thereof is 5:1 to 1:5 based on the weight of free triniceviro. 60. The composition of claim 56, wherein the weight ratio of the one or more fillers to the triniceviro or its salt, based on the weight of free triniceviro, is 1:4 to 1:5; or 2:3 to 1:2; or 2:1 to 4:3; or 5:1 to 5:2. 61. The composition of claim 56, wherein the one or more fillers are present in an amount of 5% to 30% by weight of the composition. 62. The composition of claim 56, wherein the one or more fillers are present in an amount of 5.8%; 6.6%; 12%; 20.5%; 22.2%; 23.4%; or 24.8% by weight of the composition. 63. The composition of claim 56, comprising: Based on the weight of the composition and the weight of free desnicerol, 15.8% desnicerol or its salt, 31.6% lamivudine and 24.8% one or more fillers; 16.7% cineviro or its salt, 33.3% lamivudine and 23.4% one or more fillers; 18.8% cineviro or its salt, 37.5% lamivudine and 12.0% one or more fillers; 20% cineviro or its salt, 40.0% lamivudine and 5.8% one or more fillers; 20% cineviro or its salt, 40.0% lamivudine and 6.6% one or more fillers; 11.5% cineviro or its salts, 46.2% lamivudine, and 20.5% one or more fillers; or 5% cineviro or its salt, 60% lamivudine and 22.2% one or more fillers. 64. The composition of claim 47, further comprising one or more disintegrants. 65. The composition of claim 64, wherein one or more disintegrants are selected from croscarmellose, croscarmellose sodium carboxymethyl cellulose and sodium starch glycolate. 66. The composition of claim 64 or 65, wherein one or more disintegrants are croscarmellose sodium. 67. The composition of claim 64, wherein the weight ratio of the one or more disintegrants to the triniceviro or a salt thereof is 1:4 to 3:2 based on the weight of free triniceviro. 68. The composition of claim 64, wherein the weight ratio of the one or more disintegrants to the triniceviro or a salt thereof is 1:3; 2:5; 1:2; or 1:1, based on the weight of free triniceviro. 69. The composition of claim 64, wherein the one or more disintegrants are present in an amount of 3% to 9% by weight of the composition. 70. The composition of claim 47, further comprising one or more lubricants. 71. The composition of claim 70, wherein one or more lubricants are selected from stearin, magnesium stearate and stearic acid. 72. The composition of claim 70 or 71, wherein one or more lubricants are magnesium stearate. 73. The composition of claim 70, wherein the one or more lubricants are present in an amount of 0.5% to 4% by weight of the composition. 74. The composition of claim 47, wherein the composition is selected from: or or or or or or 75. The composition of claim 47, wherein when packaged together with a desiccant in a container and exposed to 40°C at 75% relative humidity for four weeks, the composition has a water content of up to 4.0% by weight. 76. The composition of claim 47, wherein when packaged together with a desiccant in a container and exposed to 40°C at 75% relative humidity for four weeks, the composition has a water content of up to 2.0% by weight. 77. The composition of claim 47, wherein when packaged in a container with a desiccant, after exposure to 40°C at 75% for 9 weeks, the composition has a total impurity and degradation level of up to 4.0%. 78. The composition of claim 47, wherein when packaged in a container with a desiccant, after exposure to 40°C at 75% for 9 weeks, the composition has a total impurity and degradation level of up to 2.0%. 79. The composition of claim 47, further comprising favorinol. 80. The composition of claim 79, wherein the weight ratio of triniceviro or its salt, lamivudine and efavirenz is 1:2:4 based on the weight of free triniceviro. 81. The composition of claim 79, comprising Based on the weight of the composition and the weight of free dextran, 10.3% dextran or its salt, 18.2% lamivudine and 36.4% efavirenz; or 9.5% sineviclor or its salt, 19.1% lamivudine and 38.1% efavirenz. 82. The composition of claim 79, wherein the composition is selected from: or 83. The composition of claim 79, wherein when packaged together with a desiccant in a container and exposed to 40°C at 75% relative humidity for four weeks, the composition has a water content of up to 4.0% by weight. 84. The composition of claim 79, wherein when packaged in a container with a desiccant, after being exposed to 40°C at 75% relative humidity for four weeks, the composition has a water content of up to 2.0% by weight. 85. The composition of claim 79, wherein when packaged in a container with a desiccant, after exposure to 40°C at 75% for 9 weeks, the composition has a total impurity and degradation level of up to 4.0%. 86. The composition of claim 79, wherein when packaged in a container with a desiccant, after exposure to 40°C at 75% for 9 weeks, the composition has a total impurity and degradation level of up to 2.0%. 87. A pharmaceutical preparation comprising the composition as described in any one of claims 1 to 86. 88. The formulation of claim 87, wherein the composition in the formulation is in granular form. 89. The formulation of claim 87 or 88, wherein the composition in the formulation is in capsule form. 90. The formulation of claim 87 or 88, wherein the composition in the formulation is in capsule form. 91. The formulation of claim 87 or 88, wherein the composition in the formulation is a tablet or a component of a tablet. 92. The formulation of claim 87 or 88, further comprising one or more pharmaceutically inactive ingredients. 93. The formulation of claim 87 or 88, wherein the composition is in one or more layers of a multilayer tablet. 94. The formulation of claim 87 or 88, wherein the composition is in a single-layer tablet. 95. The formulation of claim 93, wherein the composition is in a bilayer tablet comprising a single core and a layer outside the single core. 96. A pharmaceutical formulation comprising the composition of any one of claims 46 to 86, wherein the triniceviro or a salt thereof and fumaric acid are present in the core; and lamivudine is present in the layer outside the single core. 97. A pharmaceutical formulation comprising the composition of any one of claims 46 to 86, wherein the cyclophosphamide or its salt, fumaric acid and lamivudine are present in the core, and favoram is present in the layer outside the single core. 98. The formulation of claim 87 or 88, wherein the formulation is selected from: or or or or or or or or or or 99. A tablet comprising a composition selected from: or or or or or or or or or or 100. The composition of any one of claims 1 to 86, the formulation of any one of claims 87 to 98, or the tablet of claim 99, wherein the composition is a coating matrix. 101. A method for preparing a composition as described in any one of claims 1 to 86, a formulation as described in any one of claims 87 to 98, or a tablet as described in claim 99, the method comprising: Incorporating cinnickeril or its salts with fumaric acid to form a blend; and The blend is dry-granulated. 102. The method of claim 101, wherein the cineviro or a salt thereof is cineviro methanesulfonate. 103. The method of claim 101 or 102, further comprising incorporating one or more fillers with the cineviro or its salt and fumaric acid to form a blend. 104. The method of claim 101 or 102, wherein the one or more fillers are selected from microcrystalline cellulose, dicalcium phosphate, lactose, sucrose, mannitol, sorbitol, starch, and calcium carbonate. 105. The method of claim 101 or 102, wherein the one or more fillers are microcrystalline cellulose. 106. The method of claim 101 or 102, further comprising incorporating one or more disintegrants with the cineviro or a salt thereof and fumaric acid to form a blend. 107. The method of claim 106, wherein the one or more disintegrants are selected from croscarmellose, croscarmellose sodium carboxymethyl cellulose and sodium starch glycolate. 108. The method of claim 106, wherein one or more disintegrants are croscarmellose sodium. 109. The method of claim 101 or 102, further comprising blending one or more lubricants with the cineviro or its salt and fumaric acid to form a blend. 110. The method of claim 109, wherein the one or more lubricants are selected from stearin, magnesium stearate and stearic acid. 111. The method of claim 109, wherein one or more lubricants are magnesium stearate. 112. The method of claim 101 or 102, further comprising compressing the dry granulated blend into tablets. 113. The method of claim 101 or 102, further comprising filling capsules with a dry granulated blend. 114. The method of claim 101 or 102, further comprising mixing the dry granulation blend with one or more extra-particle substances. 115. The method of claim 114, wherein the one or more extraparticle substances are one or more other pharmaceutically active agents. 116. The method of claim 115, wherein the one or more other pharmaceutically active agents are one or more other antiretroviral drugs. 117. The method of claim 116, wherein the one or more other antiretroviral drugs are selected from CCR5 receptor antagonists, entry inhibitors, nucleoside reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and maturation inhibitors. 118. The method of claim 116 or 117, wherein the one or more other antiretroviral drugs are selected from maraviro, lamivudine, efavirenz, retigvir, veviricos, bevirimilamide, interferon-alpha, zidovudine, abacavir, lopinavir, ritonavir, tenofovir, tenofovir alafenamide, emtricitabine, erticavir, cobicistat, derenavir, atazanavir, rilpivirine, and dulutegravir. 119. The method of claim 116, wherein the other pharmaceutically active agent is lamivudine. 120. The method of claim 116, wherein one or more other pharmaceutically active agents are lamivudine and efavirenz. 121. The method of claim 115, wherein the one or more other pharmaceutically active agents are one or more immunosuppressants. 122. The method of any one of claims 115 or 121, wherein the one or more other pharmaceutically active agents are selected from the group consisting of: cyclosporine, tacrolimus, prednisolone, hydrocortisone, sirolimus, everolimus, azathioprine, mycophenolic acid, methotrexate, balithimab, dalizumab, rituximab, antithymocyte globulin, and antilymphocyte globulin. 123. The method of claim 115 or 121, wherein the one or more other pharmaceutically active agents are selected from the group consisting of tacrolimus and methotrexate. 124. Use of the composition of any one of claims 1 to 86, the formulation of any one of claims 87 to 98, the tablet of claim 99, or the composition produced by the method of any one of claims 109 to 123 in the preparation of a medicament for treating a disease, symptom, or condition of a subject, wherein the disease, symptom, or condition is selected from viral infections, hepatitis, fibrosis, and graft-versus-host disease. 125. The use of a composition of any one of claims 1 to 86, a formulation of any one of claims 87 to 98, a tablet of claim 99, or a composition produced by any one of claims 109 to 123 in the preparation of a medicament for treating a disease, symptom, or condition of a subject, wherein the disease, symptom, or condition is selected from retroviral infections and sarcoma viruses. 126. The use of a composition of any one of claims 1 to 86, a formulation of any one of claims 87 to 98, a tablet of claim 99, or a composition produced by any one of claims 109 to 123 in the preparation of a medicament for treating a disease, symptom, or condition of a subject, wherein the disease, symptom, or condition is inflammation. 127. The use as claimed in claim 124, wherein the disease, symptom, or condition is a viral infection. 128. The use as described in claim 125, wherein the disease, symptom, or condition is a retroviral infection. 129. The use as described in claim 124, wherein the disease, symptom, or condition is hepatitis. 130. The use as claimed in claim 125, wherein the disease, symptom, or condition is human immunodeficiency virus or sarcoma virus. 131. The use as described in claim 125 or 130, wherein the disease, symptom, or condition is human immunodeficiency virus. 132. The use as claimed in claim 124, wherein the disease, symptom, or condition is fibrosis. 133. The use as described in claim 124, wherein the disease, symptom, or condition is graft-versus-host disease. 134. The use as claimed in claim 126, wherein the disease, condition, or symptom is diabetic inflammation or cardiovascular inflammation. 135. The use as described in claim 125, wherein the disease, symptom, or condition is human immunodeficiency virus.