pharmaceutical composition in the form of a tablet with a fixed dose combination of two antiviral co

专利摘要:
COMBINATION OF FORMULATION OF TWO ANTI-VIRAL COMPOUNDS Pharmaceutical compositions containing an effective amount of substantially amorphous ledipasvir and an effective amount of substantially crystalline sofosbuvir are described.
公开号:BR112014011938B1
申请号:R112014011938-4
申请日:2014-01-30
公开日:2021-03-16
发明作者:Ben Chal；Erik Mogalian；Reza Oliyai；Rowchanak Pakdaman；Dimitrios Stefanidis；Vahid Zia
申请人:Gilead Pharmasset Llc；
IPC主号:

专利说明:

CROSS REFERENCE WITH RELATED ORDER
[001] This claim claims the benefit under 35 USC § 119 (e) for US Provisional Application Number 61 / 759,320, filed on January 31, 2013, US Provisional Application Number 61 / 772,292, filed on March 4, 2013, Provisional US Order Number 61 / 828,899, filed on May 30, 2013, Provisional US Order Number 61 / 870,729, filed on August 27, 2013, Provisional US Order Number 61 / 897,793, filed on October 30, 2013 and US Order Provisional Number 61 / 907,332, deposited on November 21, 2013, the totalities of which are incorporated herein by reference. BACKGROUND OF THE INVENTION
[002] Hepatitis C is recognized as a chronic viral disease of the liver that is characterized by liver disease. Although drugs targeting the liver are in widespread use and have shown effectiveness, toxicity and other side effects have limited their usefulness. Inhibitors of the hepatitis C virus (HCV) are useful to limit the establishment and progression of HCV infection, as well as in diagnostic tests for HCV.
[003] Ledipasvir is a selective inhibitor of non-structural protein 5A (NS5A), which has been previously described (see, for example, WO 2010/132601). The chemical name of ledipasvir is acid methyl ester (1- {3- [6- (9,9-difluor-7- {2- [5- (2-methoxycarbonylamino-3-methyl-butyryl) -5-aza- spiro [2.4] hept-6-yl] -3H- imidazol-4-yl} -9H-fluoren-2-yl) -1H-benzoimidazol-2-yl] -2-aza-bicycle [2.2.1] heptane- 2-carbonyl} -2-methylpropyl) -carbamic.
[004] Sofosbuvir (SOF) is a selective inhibitor of non-structural protein 5B (NS5B) (see, for example, WO 2010/132601 and U.S. Patent 7,964,580). The chemical name of sofosbuvir is (S) -isopropyl 2 - (((S) - ((((2R, 3R, 4R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate. SUMMARY OF THE INVENTION
[005] The present disclosure provides, in some embodiments, a pharmaceutical composition comprising ledipasvir in a substantially amorphous form and sofosbuvir in a substantially crystalline form.
[006] Ledipasvir has the chemical name of methyl acid ester (1- {3- [6- (9,9-difluoro-7- {2- [5- (2- methoxycarbonylamino-3-methyl-butyryl) -5 -aza-spiro [2.4] hept-6-yl] -3H-imidazol-4-yl} -9H-fluoren-2-yl) -1H-benzoimidazol-2-yl] -2-aza-bicyclo [2.2.1 ] heptane-2-carbonyl} -2-methyl-propyl) -carbamic, and has the following chemical formula:

[007] Sofosbuvir (SOF) has the name (S) -isopropyl 2 - (((S) - ((((2R, 3R, 4R, 5R) -5- (2,4-dioxo-3,4-dihydropyrimidin - 1 (2H) -yl) -4-fluorine-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propanoate and has the following chemical formula:

[008] In some embodiments, a pharmaceutical composition is provided which comprises: a) an effective amount of ledipasvir, in which ledipasvir is substantially amorphous; and b) an effective amount of sofosbuvir, wherein sofosbuvir is substantially crystalline.
[009] Additional disclosure modalities are related to pharmaceutical dosage forms and tablets. The disclosure also provides methods for using the combination in the treatment of hepatitis C. BRIEF DESCRIPTION OF THE DRAWINGS
[010] FIG. 1 is an XRPD standard of the solid dispersion formulation of ledipasvir that comprises copovidone in a 1: 1 drug: polymer ratio. As shown by XRPD, the solid dispersion is in an amorphous state.
[011] FIG. 2 is a modulated differential scanning calorimetry (DSC) curve of the solid dispersion of ledipasvir that comprises copovidone in a drug: polymer ratio of 1: 1. The glass transition temperature of the solid dispersion is about 140 ° C.
[012] FIG. 3 shows a characterization of the solid state of the ledipasvir solid dispersion formulation which comprises copovidone in a drug: polymer ratio of 1: 1 by solid-state nuclear magnetic resonance (SS-RNM).
[013] FIG. 4 is a Fourier transformed Raman spectrum of the solid dispersion of ledipasvir that comprises copovidone in a drug: polymer ratio of 1: 1.
[014] FIG. 5 shows the dissolution of sofosbuvir in the combination of sofosbuvir (400 mg) / ledipasvir (90 mg) described in Example 7.
[015] FIG. 6 shows the dissolution of ledipasvir in the combination formulation of sofosbuvir (400 mg) / ledipasvir (90 mg) described in Example 3.
[016] FIG. 7A-D shows HCV RNA levels during 12 weeks of treatment and 24 weeks post-treatment for treatment naive (FIG. 7A) or non-responsive (FIG. 7B) patients treated with sofosbuvir (SOF) and ribavirin (RBV) and for treatment naive (FIG. 7C) or non-responsive (FIG. 7D) patients treated with sofosbuvir (SOF), ledipasvir and ribavirin (RBV). These data and the experimental method are further described in Example 5.
[017] FIG. 8A-B presents graphs to show that all three formulations had comparable dissolution performance, similar to that of single agent controls. This is described in more detail in Example 7.
[018] FIG. 9 presents the pH-solubility profile of ledipasvir at room temperature (RT). The line is the nonlinear least square regression adjustment using the equation ST = S0 [(1 + 10 (pKa1-pH) +10 (pKa1 + pKa2-2 ^ pH))] with an intrinsic solubility (S0) of 0 , 04 μg / ml and weakly basic pKal and pKa2 values of 5.0 and 4.0, respectively. This is described in more detail in Example 8.
[019] FIG. 10 shows the study design for treatment naive patients (non-cirrhotic) and for non-responsive patients (50% cirrhotic) treated with a fixed dose combination of sofosbuvir (SOF) and ledipasvir, with and without ribavirin (RBV) for 8 and 12 weeks. The data and experimental method are described in Example 9.
[020] FIG. 11 shows the results for treatment virgins (non-cirrhotic) and for non-responders (50% cirrhotic) for patients treated with a fixed dose combination of sofosbuvir (SOF) and ledipasvir, with and without ribavirin (RBV) for 8 and 12 weeks . These data and the experimental method are further described in Example 9. DETAILED DESCRIPTION 1. Definitions
[021] As used in this specification, the following words and phrases generally have the meanings presented below, except when the context in which they are used indicates otherwise.
[022] As used herein, the term “about” used in the context of quantitative measurements, means the indicated amount ± 10% or, alternatively, ± 5%, or ± 1%. For example, with a range of ± 10%, “about 2: 8” can mean 1.8-2.2: 7.2-8.8.
[023] The term "amorphous" refers to a state in which the material has no long-range order at the molecular level and, depending on the temperature, can exhibit the physical properties of a solid or liquid. Typically, these materials do not generate distinct X-ray diffraction patterns and, although they exhibit the properties of a solid, they are more formally described as a liquid. Upon heating, a change in the properties of solids to liquids occurs, which is characterized by a change in state, typically second order (glass transition).
[024] The term “crystalline” refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinct X-ray diffraction pattern with defined peaks. These materials, when heated sufficiently, will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically of the first order (melting point).
[025] The term "substantially amorphous", as used herein, means that more than 70%; or more than 75%; or more than 80%; or more than 85%; or more than 90%; or more than 95%, or more than 99% of the compound present in a composition is in amorphous form. The term "substantially amorphous" also refers to material that has a maximum of about 20% crystallinity, or a maximum of about 10% crystallinity, or a maximum of about 5% crystallinity, or a maximum of about 2% crystallinity. crystallinity.
[026] The term "substantially crystalline", as used herein, means that more than 70%; or more than 75%; or more than 80%; or more than 85%; or more than 90%; or more than 95%, or more than 99% of the compound present in a composition is in crystalline form. "Substantially crystalline" can also refer to the material that has a maximum of about 20%, or a maximum of about 10%, or a maximum of about 5%, or a maximum of about 2% in amorphous form.
[027] The term "polymer" refers to a chemical compound or mixture of compounds that consists of repetitive structural units created through a polymerization process. Suitable polymers useful in this invention will be described throughout.
[028] The term "polymer matrix", as used herein, is defined to mean compositions that comprise one or more polymers in which the active agent is dispersed or included within the matrix.
[029] The term “solid dispersion” refers to the dispersion of one or more active agents in a solid-state polymer matrix prepared by various methods, including atomization, the melting (melting), solvent, or melting method solvent.
[030] The term "amorphous solid dispersion", as used herein, refers to stable solid dispersions that comprise an amorphous active agent and a polymer. The term "amorphous active agent" means that the solid amorphous dispersion contains active agent in a substantially amorphous solid state form. In some respects, as shown by the XRPD in FIG. 1, the solid dispersion is in the amorphous state, and the glass transition temperature of the solid dispersion is about 140 ° C (see FIG. 2).
[031] The term “pharmaceutically acceptable” indicates that the material has no properties that would reasonably be expected by a reasonably prudent medical professional to avoid administering the material to a patient, taking into account the disease or conditions to be treated and the respective route of administration . For example, it is commonly necessary for this material to be basically sterile, for example, for injectables.
[032] The term "pharmaceutically acceptable polymer" refers to a polymer that does not have properties that would reasonably be expected by a reasonably prudent medical professional to avoid administering the material to a patient, taking into account the disease or conditions to be treated and the respective route of administration.
[033] The term "vehicle" refers to a glidant, diluent, adjuvant, excipient or carrier etc. with which the compound is administered, without limitation. Examples of vehicles are described herein and also in "Remington’s Pharmaceutical Sciences" by E.W. Martin.
[034] The term "diluent" refers to chemical compounds that are used to dilute the compound of interest prior to release. Diluents can also serve to stabilize compounds. Non-limiting examples of diluents include starch, saccharides, disaccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose, monohydrate lactose, dicalcium phosphate, cellulose, compressible sugars, dibasic calcium phosphate dehydrate, mannitol, microcrystalline cellulose and tribasic calcium phosphate.
[035] The term "binder", when used here, refers to any pharmaceutically acceptable film that can be used to bond together with the active and inert components of the vehicle together to maintain distinctive and cohesive portions. Non-limiting examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, copovidone and ethyl cellulose.
[036] The term "disintegrant" refers to a substance that, upon addition to a solid preparation, facilitates its breakdown or disintegration after administration and allows the release of an active ingredient as efficiently as possible to allow its rapid dissolution. Non-limiting examples of disintegrants include corn starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, povidone, pregelatinized starch and alginic acid.
[037] The term “lubricant” refers to an excipient that is added to a powder mixture to prevent the mass of compacted powder from sticking to the equipment during the process of producing tablets or encapsulation. It helps in ejecting the tablet form from the mold, and can increase the flow of dust. Non-limiting examples of lubricants include magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate or talc; and solubilizers such as, for example, fatty acids, including lauric acid, oleic acid and C8 / C10 fatty acid.
[038] The term “film coating” refers to a thin, uniform film on the surface of a substrate (eg, tablet). Film coatings are particularly useful for protecting the active ingredient from photolytic degradation. Non-limiting examples of film coatings include film coatings based on polyvinyl alcohol, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
[039] The term "glidant", as used herein, means agents used in tablet and capsule formulations to increase flow properties during tablet compression and to produce an anti-aging effect. Non-limiting examples of glidants include colloidal silicon dioxide, talc, vaporized silica, starch, starch derivatives and bentonite.
[040] The term "effective amount" refers to an amount that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on the patient being treated, the patient's weight and age, the severity of the disease condition, the form of administration and the like, which can be easily determined by those skilled in the art.
[041] The term "treatment" or "treating", when related to a disease or condition, includes preventing the occurrence of a disease or condition, inhibiting the disease or condition, eliminating the disease or condition and / or relieving one or more symptoms of the disease or condition.
[042] The term “sustained virological response” refers to the absence of detectable RNA (or where RNA is below the detection limit) of a virus (ie HCV) in a patient sample (ie, sample of blood) for a specific period of time after discontinuing treatment. For example, an SVR at 4 weeks indicates that RNA was not detected or was below the detection limit in the patient at 4 weeks after discontinuation of HCV therapy.
[043] The term "% w / w", as used herein, refers to the weight of a component based on the total weight of a composition that comprises the component. For example, if component A is present in an amount of 50% w / w in a 100 mg composition, component A is present in an amount of 50 mg. 2. Pharmaceutical compositions
[044] The pharmaceutical compositions comprise a combination of an effective amount of ledipasvir, in which ledipasvir is substantially amorphous, and an effective amount of sofosbuvir, in which sofosbuvir is substantially crystalline.
[045] Such a combined composition, as the experimental examples demonstrate, exhibits unexpected properties. Both sofosbuvir and ledipasvir have previously been shown to act as effective anti-HCV agents. Ledipasvir, when administered alone in a conventional formulation, however, exhibited a negative dietary effect, as evidenced by an approximately 2-fold decrease in exposure when given with a high-fat meal compared to fasting dosage (see, for example, example, Tables 10 and 11, Example 3). When ledipasvir is administered in a solid dispersion formulation and in combination with sofosbuvir, no negative food effect occurs (Table 12, Example 3).
[046] In the combined composition, ledipasvir is present in a substantially amorphous form. Compared with crystalline agents, amorphous agents are expected to be unstable and have non-linear solubility and exposure profiles. The data presented here, however, show that ledipasvir in the combined composition is stable under various conditions, both short term and long term, and maintains high and consistent solubility and exposure profiles (Example 6).
[047] Furthermore, according to conventional wisdom, it is not recommended to co-formulate an amorphous agent with a crystalline agent, as the crystals can serve as seeds to induce crystallization of the amorphous agent, leading to instability of the amorphous agent. Current data show that, however, whether co-granulated or co-mixed with sofosbuvir in the same layer or integrated as separate layers, ledipasvir remains stable and does not form crystals in the composition (Example 6).
[048] It has also been found that in tablet formations of the combined composition in which sofosbuvir and ledipasvir are co-granulated or co-mixed, drug-drug interaction does not occur (Example 7). A. Ledipasvir
[049] Ledipasvir has been previously described (see, for example, WO 2010/132601) and can be prepared by methods described herein. In one embodiment, the pharmaceutical composition comprises ledipasvir formulated as a solid dispersion dispersed within a polymer matrix formed by a pharmaceutically acceptable polymer. The starting material of the solid dispersion may consist of several forms of ledipasvir, including crystalline forms, amorphous forms, salts thereof, solvates thereof and the free base. For example, acetone solvate, D-tartrate salt, anhydrous crystalline free base, amorphous free base, ledipasvir solvates or desolvates can be used. Ledipasvir solvates include, for example, those described in US Publication No. 2013/0324740 (incorporated herein by reference) such as, for example, monoacetone solvate, diacetone solvate, ethyl acetone solvate, isopropyl acetate solvate, solvate methyl acetate, ethyl formate solvate, acetonitrile solvate, tetrahydrofuran solvate, methyl ethyl ketone solvate, tetrahydrofuran solvate, methyl ethyl ketone solvate and methyl tert-butyl ether solvate. Particular starting materials contemplated as being useful are monoacetone solvate, diacetone solvate, anhydrous crystalline free base, D-tartrate salt, anhydrous crystalline free base and amorphous free base. These forms are characterized and described in U.S. Publication No. 2013/0324496.
[050] After dispersion with the polymer, the solid dispersion is in amorphous form. FIGS. 1-4 characterizes the solid amorphous dispersion comprising ledipasvir. As shown by the XRPD in FIG. 1, the solid dispersion is in the amorphous state, and the glass transition temperature of the solid dispersion is about 140 ° C.
[051] Various methodologies are well known in the art for preparing solid dispersions including, without limitation, melt extrusion, atomization, lyophilization and solution-evaporation.
[052] Fusion extrusion is the process of mixing a compound in a thermoplastic vehicle. The mixture is processed at elevated temperatures and pressures, which disperses the compound in the matrix at a molecular level to form a solid solution. The extruded material can also be processed in several dosage forms, including capsules, tablets and transmucosal systems.
[053] For the solution-evaporation method, the solid dispersion can be prepared by dissolving the compound in a suitable liquid solvent and then incorporating the solution directly into a melted polymer, which is then evaporated until on a transparent film, free of solvent. The film is further dried to a constant weight.
[054] For the lyophilization technique, the compound and vehicle can be co-dissolved in a common solvent, frozen and sublimated to obtain a lyophilized molecular dispersion.
[055] For atomized solid dispersions, the solid dispersion can be made by: a) mixing the compound and polymer in a solvent to provide a feed solution; and b) atomizing the feed solution to provide the solid dispersion.
[056] Solid atomized dispersions of ledipasvir provide increased performance and fabricability / scalability in vivo and in vitro compared to other formulation approaches, for example, wet and dry granulation formulations. Ledipasvir can be supplied as the free base, D-tartrate salt, crystalline acetone solvate or other solvate as described herein.
[057] The selection of the polymer for the solid dispersion is based on the stability and physical characteristics of ledipasvir in the solution. Solid dispersions of hypromellose and copovidone showed adequate physical characteristics and stability. Consequently, in one embodiment, the polymer used in the solid dispersion is selected from hypromellose and copovidone. In addition, the copovidone-based dispersion increased in bioavailability more than the equivalent hypromellose-based formulation (F = 30% and 22%, respectively) when prepared in an API: polymer ratio of 2: 1. The bioavailability of the copovidone-based formulation was further increased by increasing the polymer fraction to a ratio of 1: 1, resulting in a 35% bioavailability in dogs pretreated with famotidine.
[058] In one embodiment, the polymer used in the solid dispersion of ledipasvir is hydrophilic. Non-limiting examples of hydrophilic polymers include polysaccharides, polypeptides, cellulose derivatives such as, for example, methyl cellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, ethyl cellulose, hydroxypropyl methylcellulose acetate-succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate, phthalate, phthalate, povidone copovidone, hypromellose, pyroxylin, polyethylene oxide, polyvinyl alcohol and methacrylic acid copolymers.
[059] In an additional embodiment, the polymer is non-ionic. Nonionic polymers exhibit benefits in solubility assessment experiments. Non-limiting examples of non-ionic polymers include hypromellose, copovidone, povidone, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, pyroxylin, polyethylene oxide, polyvinyl alcohol, polyethylene glycol, and polyvinyl caprolactam-polyvinyl acetate-polyethylene.
[060] In another modality, the polymer is ionic. Examples of ionic polymers include hydroxypropyl methylcellulose acetate-succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate and methacrylic acid copolymers.
[061] In an additional modality, the polymer is selected from the group consisting of hypromellose, copovidone and povidone. Solid dispersions of hypromellose and copovidone exhibited adequate physical characteristics and stability. Copovidone-based dispersion increased bioavailability more than the equivalent hypromellose-based formulation (F = 30% and 22%, respectively) when atomized in the ratio of ledipasvir: 2: 1 polymer (data not shown). Consequently, in a specific embodiment, the polymer is copovidone.
[062] In certain embodiments, the weight ratio of ledipasvir to polymer is about 5: 1 to about 1: 5. In additional embodiments, the weight ratio of ledipasvir to polymer is about 5: 1 to about 1: 4, or about 5: 1 to about 1: 3, or about 5: 1 to about 1 : 2, or from about 2: 1 to about 1: 2, or from about 2: 1 to about 1: 1. In a specific embodiment, the weight ratio of ledipasvir to polymer is about 1: 1. In another embodiment, the weight ratio of ledipasvir to polymer is about 2: 1. In additional embodiments, the weight ratio of ledipasvir to polymer is about 5: 1, 1: 4, 1: 3, or 1: 2. Increasing the polymer fraction to a 1: 1 ratio can, in some cases, result in increased bioavailability. For example, a 1: 1 ratio of ledipasvir: copovidone resulted in increased bioavailability (F = 35%) in dogs pretreated with famotidine.
[063] The solid dispersion comprising ledipasvir may be present in the pharmaceutical composition in a therapeutically effective amount. In some embodiments, the pharmaceutical compositions comprise from about 1% to about 50% w / w of the solid dispersion of ledipasvir. In additional embodiments, the composition comprises from about 5% to about 40% w / w, or from about 5% to about 35% w / w, or from about 5% to about 30% w / w , or from about 10% to about 30% w / w, or from about 10% to about 25% w / w, or from about 15% to about 20% w / w of the solid dispersion of ledipasvir . In additional embodiments, the pharmaceutical composition comprises about 1% w / w, about 5% w / w, about 10% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, or about 40% w / w of the solid dispersion of ledipasvir. In a specific embodiment, the pharmaceutical composition comprises about 18% w / w of the solid dispersion of ledipasvir.
[064] Ledipasvir may be present in the pharmaceutical composition in a therapeutically effective amount. In some embodiments, the pharmaceutical compositions comprise from about 1% to about 50% w / w of ledipasvir. In additional embodiments, the composition comprises from about 1% to about 40% w / w, or from about 1% to about 30% w / w, or from about 1% to about 20% w / w , or from about 5% to about 15% w / w, or from about 7% to about 12% w / w ledipasvir. In comprises about 1% w / w, about 3% w / w, about 5% w / w, about 7% w / w, about 11% w / w, about 13% w / w, about 15% w / w, about 17% w / w, about 20% w / w, about 23% w / w, about 25% w / w, or about 28% w / w, or about 30% w / w ledipasvir. In a specific embodiment, the pharmaceutical composition comprises about 9% w / w ledipasvir.
[065] As noted above, after the ledipasvir is mixed with the polymer, the mixture can then be solubilized in a solvent. It is part of the knowledge of those skilled in the art to select an appropriate solvent based on the properties of the drug and / or polymer, such as, for example, solubility, glass transition temperature, viscosity and molecular weight. Suitable solvents include, without limitation, water, acetone, methyl acetate, ethyl acetate, chlorinated solvents, ethanol, dichloromethane and methanol. In one embodiment, the solvent is selected from the group consisting of ethanol, dichloromethane and methanol. In an additional embodiment, the solvent is ethanol or methanol. In a specific embodiment, the solvent is ethanol.
[066] After the compound and polymer mixture has solubilized with the solvent, the mixture can then be atomized. Atomization is a well-known process by which a liquid raw material is dispersed in droplets in a drying chamber together with a jet of heated gas from the process to assist in solvent removal and to produce a powder product. Suitable atomization parameters are known in the art, and it is part of the knowledge of those skilled in the art to select appropriate parameters for atomization. The target concentration of the feed is generally about 10 to about 50% with a target of about 20% and a viscosity of about 15 to about 300 cP. The inlet temperature of the atomizing apparatus is typically about 50-190 ° C, while the outlet temperature is about 30-90 ° C. The two-fluid nozzle and the hydraulic pressure nozzle can be used for the atomization of ledipasvir. The gas flow from the two-fluid nozzle can be about 1-10 kg / h, the flow from the hydraulic pressure nozzle can be about 15-300 kg / h, and the gas flow from the chamber can be carcass of 25-2,500 kg / h. The atomized material typically has a particle size (D90) below 80 μm. In some cases, a crushing step can be used, if desired, to further reduce the particle size. Additional descriptions of atomization methods and other techniques for forming amorphous dispersions are provided in U.S. Patent No. 6,763,607 and U.S. Patent Publication No. 2006¬0189633, the entirety of which is incorporated herein by reference.
[067] Atomization with ethanol removal resulted in high yields (88, 90, 92, 95, 97, 98, 99%) across a wide range of atomization outlet temperatures (30-90 ° C) without accumulation of material in the atomization chamber, and the yields obtained by atomization with DCM removal were 60%, 78%, and 44%. In addition, ledipasvir demonstrated good chemical stability in the ethanolic feed solution. B. Sofosbuvir
[068] Sofosbuvir was previously described in U.S. Patent 7,964,580 and U.S. Publications Nos: 2010/0016251, 2010/0298257, 2011/0251152 and 2012/0107278. Sofosbuvir is supplied as substantially crystalline in the pharmaceutical compositions described herein. Examples of preparing crystalline forms of sofosbuvir are disclosed in U.S. Publications Nos: 2010/0298257 and 2011/0251152, both of which are incorporated herein by reference. Crystalline forms, Forms 1-6, of sofosbuvir are described in U.S. Publications Nos: 2010/0298257 and 2011/0251152, both of which are incorporated herein by reference. Forms 1-6 of sofosbuvir have the following 2θ values characteristic of X-ray powder diffraction (XRPD) pattern measured according to the XRPD methods disclosed here: (1) 2θ reflections (° ± 0.2θ) in about from: 7.5, 9.6 and 18.3 (Form 1); (2) 2θ reflections (° ± 0.2θ) in about: 5.0, 7.3 and 18.1 (Form 1); (3) 2θ reflections (° ± 0.2θ) in about: 6.9, 24.7 and 25.1 (Form 2); (4) 2θ reflections (° ± 0.2θ) in about: 19.7, 20.6 and 24.6 (Form 3); (5) 2θ reflections (° ± 0.2θ) in about: 5.0, 6.8 and 24.9 (Form 4); (6) Reflections 2θ (° ± 0.2θ) in about: 5.2, 6.6 and 19.1 (Form 5); and (7) Reflections 2θ (° ± 0.2θ) in about: 6.1, 20.1 and 20.8 (Form 6).
[069] Form 6, as described in the patent publications above, can be cited as Form 2 as, for example, by the "Food and Drug Administration" (American government agency that regulates and supervises the manufacture of edibles, drugs and cosmetics). Forms 1 and 6 are alternatively characterized by the following 2θ values characteristic of the XRPD standard, as measured according to the methods disclosed in US Patent Publications Nos: 2010/0298257 and 2011/0251152: (1) Reflections 2θ (° ) at about: 5.0 and 7.3 (Form 1); and (2) 2θ (°) reflections at about: 6.1 and 12.7 (Form 6).
[070] In one mode, the crystalline sofosbuvir has 2θ XRPD reflections (° ± 0.2θ) in about: (1) 7.5, 9.6 and 18.3; (Form 1A) (2) 5.0, 7.3 and 18.1; (Form 1B) (3) 6.9, 24.7 and 25.1; (Form 2) (4) 19.7, 20.6 and 24.6; (Form 3) (5) 5.0, 6.8 and 24.9; (Form 4) (6) 5.2, 6.6 and 19.1; (Form 5) or (7) 6.1, 20.1 and 20.8; (Form 6).
[071] In certain modalities, crystalline sofosbuvir has 2θ XRPD reflections (° ± 0.2θ) in about: (1) 5.2, 7.5, 9.6, 16.7, 18.3 and 22 , 2 (Form 1); (2) 5.0, 7.3, 9.4 and 18.1 (Form 1); (3) 4.9, 6.9, 9.8, 19.8, 20.6, 24.7, 25.1 and 26.1 (Form 2); (4) 6.9, 9.8, 19.7, 20.6 and 24.6 (Form 3); (5) 5.0, 6.8, 19.9, 20.6, 20.9 and 24.9 (Form 4); (6) 5.2, 6.6, 7.1, 15.7, 19.1 and 25.0 (Form 5); or (7) 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4, 19.8, 20.1, 20, 8, 21.8 and 3.3 (Form 6).
[072] In an additional modality, sofosbuvir crystalline has 2θ reflections of XRPD (° ± 0.2θ) in about: 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4, 19.8, 20.1, 20.8, 21.8 and 23.3. In yet another additional modality, crystalline sofosbuvir has 2θ XRPD reflections (° ± 0.2θ) in about: 6.1 and 12.7.
[073] Sofosbuvir may be present in the pharmaceutical composition in a therapeutically effective amount. In some embodiments, the pharmaceutical compositions comprise from about 10% to about 70% w / w of sofosbuvir. In additional embodiments, the composition comprises from about 15% to about 65% w / w, or from about 20% to about 60% w / w, or from about 25% to about 55% w / w , or from about 30% to about 50% w / w, or from about 35% to about 45% w / w of sofosbuvir. In additional embodiments, the pharmaceutical composition comprises about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 65% w / w, or about 70 % w / w, or about 75% w / w. In a specific embodiment, the pharmaceutical composition comprises about 40% w / w of sofosbuvir. C. Excipients
[074] The pharmaceutical compositions provided in accordance with the present disclosure are usually administered orally. This disclosure, therefore, provides pharmaceutical compositions comprising a solid dispersion comprising ledipasvir as described herein and one or more excipients or pharmaceutically acceptable vehicles including, without limitation, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof. These compositions are prepared in a manner known in the pharmaceutical art (see, for example, “Remington's Pharmaceutical Sciences”, Mace Publishing Co., Philadelphia, PA 17th Edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Edition (GS Banker & CT Rhodes, Eds.).
[075] The pharmaceutical compositions can be administered in single or multiple doses by oral administration. Administration can be by means of capsules, tablets, or the like. In one embodiment, ledipasvir is in the form of a tablet. In an additional embodiment, the tablet is a compressed tablet. In the production of pharmaceutical compositions that include the solid described herein, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier, which may be in the form of a capsule, tablet, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
[076] The pharmaceutical composition can be formulated for immediate release or for sustained release. A "sustained release formulation" is a formulation that is designed to slowly release a therapeutic agent into the body over an extended period of time, while an "immediate release formulation" is a formulation that is designed to quickly release a therapeutic agent in the body over a shortened period of time. In some cases, the immediate release formulation can be coated in such a way that the therapeutic agent is only released after reaching the desired target in the body (for example, in the stomach). In a specific embodiment, the pharmaceutical composition is formulated for immediate release.
[077] The pharmaceutical composition may further comprise pharmaceutical excipients such as, for example, diluents, binders, fillers, glidants, disintegrants, lubricants, solubilizers, and combinations thereof. Some examples of suitable excipients are described here. When the pharmaceutical composition is formulated into a tablet, the tablet may be uncoated or may be coated by known techniques, including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide sustained action over a longer period. . For example, a time-delaying material such as, for example, glyceryl monostearate or glyceryl distearate alone or with a wax, can be employed.
[078] In one embodiment, the pharmaceutical composition comprises a diluent selected from the group consisting of dicalcium phosphate, cellulose, compressible sugars, dibasic calcium phosphate dehydrate, lactose, lactose monohydrate, mannitol, microcrystalline cellulose, starch, calcium phosphate tribasic, and combinations of these.
[079] In additional embodiments, the pharmaceutical composition comprises lactose monohydrate in an amount of about 1 to about 50% w / w, or about 1 to about 45% w / w, or about 5 to about 40% w / w, or about 5 to about 35% w / w, or about 5 to about 25% w / w, or about 10 to about 20% w / w. In specific embodiments, lactose monohydrate is present at about 5% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25 % w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, or about 50% w / w . In an additional specific embodiment, the lactose monohydrate is in an amount of about 16.5% w / w.
[080] Still in additional embodiments, the pharmaceutical composition comprises microcrystalline cellulose in an amount of about 1 to about 40% w / w, or about 1 to about 35% w / w, or about 1% up to about 25% w / w, or from about 5 to about 25% w / w, or from about 10 to about 25% w / w, or from about 15 to about 20% w / w . In specific embodiments, microcrystalline cellulose is present in an amount of about 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40% w / w. In an additional specific embodiment, microcrystalline cellulose is in an amount of about 18% w / w.
[081] In other embodiments, the pharmaceutical composition comprises a disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, povidone, pregelatinized starch, sodium starch glycolate, and combinations thereof.
[082] In certain embodiments, the pharmaceutical composition comprises croscarmellose sodium in an amount of about 1 to about 20% w / w, or about 1 to about 15% w / w, or from about 1 to about from 10% w / w, or from about 1 to about 8% w / w, or from about 2 to about 8% w / w. In specific embodiments, croscarmellose sodium is present in an amount of about 1%, or about 3%, or about 6%, or about 8%, or about 10%, or about 13%, or about 15% w / w. In an additional specific embodiment, croscarmellose sodium is in an amount of about 5% w / w.
[083] In other embodiments, the pharmaceutical composition comprises a glidant selected from the group consisting of colloidal silicon dioxide, talc, starch, starch derivatives, and combinations thereof.
[084] In additional embodiments, the pharmaceutical composition comprises colloidal silicon dioxide in an amount of about 0.1 to about 5% w / w, or about 0.1 to about 4.5% w / w , or from about 0.1 to about 4% w / w, or from about 0.5 to about 5.0% w / w, or from about 0.5 to about 3% w / w , or from about 0.5 to about 2% w / w, or from about 0.5 to about 1.5% w / w. In specific embodiments, colloidal silicon dioxide is present in an amount of about 0.1% w / w, 0.5% w / w, 0.75% w / w, 1.25% w / w, 1 , 5% w / w, or 2% w / w. In an additional specific embodiment, colloidal silicon dioxide is present in an amount of about 1% w / w.
[085] In other embodiments, the pharmaceutical composition comprises a lubricant selected from the group consisting of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, and combinations thereof.
[086] In additional embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of about 0.1 to about 3% w / w, or from about 0.1 to about 2.5% w / w, or from about 0.5 to about 3% w / w, or from about 0.5 to about 2.5% w / w, or from about 0.5 to about 2% w / w, or from about 1 to about 3% w / w, or from about 1 to about 2% w / w. In specific embodiments, magnesium stearate is present in an amount of about 0.1%, or about 0.5, or about 1%, or about 2%, or about 2.5%, or about 3% w / w. In an additional specific embodiment, the magnesium stearate is in an amount of about 1.5% w / w.
[087] In one embodiment, the pharmaceutical composition comprises a) about 30 to about 50% w / w of sofosbuvir and b) about 5 to about 35% w / w of the solid dispersion comprising ledipasvir. In a related embodiment, the composition comprises a) about 40% w / w of sofosbuvir and b) about 18% w / w of the solid dispersion comprising ledipasvir. In yet another related embodiment, the composition further comprises a) about 5 to about 25% w / w of lactose monohydrate, b) about 5 to about 25% w / w of microcrystalline cellulose, c) about 1 up to about 10% w / w croscarmellose sodium, d) about 0.5 to about 3% w / w colloidal silicon dioxide, and e) about 0.1 to about 3% w / w stearate magnesium. In an additional embodiment, the pharmaceutical composition comprises a) about 40% w / w of sofosbuvir, b) about 18% w / w of the solid dispersion comprising ledipasvir, c) about 16.5% w / w of monohydrate lactose, d) about 18% w / w microcrystalline cellulose, e) about 5% w / w croscarmellose sodium, f) about 1% w / w colloidal silicon dioxide, eg) about 1, 5% w / w of magnesium stearate. 3. Pharmaceutical dosage forms
[088] The disclosure provides tablets, pills, and the like, which comprise the pharmaceutical compositions or dosage forms described herein. The tablets or pills of the present disclosure can be provided to provide a dosage form that has the advantage of prolonged action or to protect against acidic stomach conditions. The tablets can also be formulated for immediate release, as previously described. In certain embodiments, the tablet comprises a film coating. A film coating is useful for limiting photolytic degradation. Suitable film coatings are selected by routine selection of commercially available preparations. In one embodiment, the film coating is a coating based on polyvinyl alcohol.
[089] The tablets can be formulated into a monolayer or bilayer tablet. Typically, monolayer tablets comprise the active ingredients (ie ledipasvir and sofosbuvir) co-mixed in a single uniform layer. For the production of monolayer tablets, exemplary methods include, without limitation, co-mixing (or bigranulation) and co-drying granulation. Co-mixing granulation is a multi-step process consisting of separate dry granulations for each active ingredient with excipients, followed by mixing the two granulations together. Co-dry granulation consisted of granulating both active ingredients and excipients together.
[090] Bilayer tablets comprise the active ingredients (ie ledipasvir and sofosbuvir) in separate layers and can be made by producing a blend that comprises excipients and an active ingredient (ie ledipasvir), and producing a separate blend that comprises the second active ingredient (ie sofosbuvir) and excipients. One blend can then be pre-compressed, and the second blend can then be added on top of the first pre-compressed blends. The resulting tablet comprises two separate layers, each layer comprising a different active ingredient.
[091] In one embodiment, the tablet comprises a) about 30 to about 50% w / w of sofosbuvir and b) about 10 to about 40% w / w of the solid dispersion comprising ledipasvir. In a related embodiment, the tablet comprises a) about 40% w / w of sofosbuvir and b) about 18% w / w of the solid dispersion comprising ledipasvir. In an additional embodiment, the tablet comprises a) about 300 to about 500 mg of sofosbuvir and b) about 50 to about 130 mg of ledipasvir. In another additional embodiment, the tablet comprises a) about 400 mg of sofosbuvir and b) about 90 mg of ledipasvir. In a related embodiment, the tablet further comprises a) about 5 to about 25% w / w of lactose monohydrate, b) about 5 to about 25% w / w of microcrystalline cellulose, c) about 1 to about 10% w / w croscarmellose sodium, d) about 0.5 to about 3% w / w colloidal silicon dioxide, and e) about 0.1 to about 3% w / w stearate magnesium.
[092] In some embodiments, the pharmaceutical compositions as described herein are formulated in a unit dosage or pharmaceutical dosage form. The term "unit dosage forms" or "pharmaceutical dosage forms" refers to physically distinct units suitable as unit dosages for human patients and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient (for example, a tablet or capsule). The compounds are generally administered in a pharmaceutically effective amount. In some embodiments, each dosage unit contains from 3 mg to 2 g of ledipasvir. In other embodiments, the pharmaceutical dosage form comprises from about 3 to about 360 mg, or about 10 to about 200 mg, or about 10 to about 50 mg, or about 20 to about 40 mg, or about 25 to about 35 mg, or about 40 to about 140 mg, or about 50 to about 130 mg, or about 60 to about 120 mg, or about 70 to about 110 mg, or about 80 to about 100 mg. In specific embodiments, the pharmaceutical dosage form comprises about 40, or about 45, or about 50, or about 55, or about 60, or about 70, or about 80, or about 100, or about 120, or about 140, or about 160, or about 180, or about 200, or about 220 mg of ledipasvir. In an additional specific embodiment, the pharmaceutical dosage form comprises about 90 mg of ledipasvir. In yet another specific specific modality, the pharmaceutical dosage form comprises about 30 mg of ledipasvir.
[093] In other embodiments, the pharmaceutical dosage form comprises from about 1 mg to about 3 g of sofosbuvir. In other embodiments, the pharmaceutical dosage form comprises from about 1 to about 800 mg, or about 100 to about 700 mg, or about 200 to about 600 mg, or about 300 to about 500 mg, or about 350 to about 450 mg, of sofosbuvir. In specific embodiments, the pharmaceutical dosage form comprises about 50, or about 100, or about 150, or about 200, or about 250, or about 300, or about 350, or about 450, or about 500, or about 550, or about 600, or about 650, or about 700, or about 750, or about 800 mg of sofosbuvir. In an additional specific embodiment, the pharmaceutical dosage form comprises about 400 mg of sofosbuvir. It will be understood, however, that the amount of ledipasvir and / or sofosbuvir actually administered will normally be determined by a doctor, in the light of the relevant circumstances, including the condition to be treated, the route of administration chosen, the actual compound administered and its activity relative, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.
[094] In a specific embodiment, the pharmaceutical dosage form comprises about 400 mg of sofosbuvir and about 90 mg of ledipasvir.
[095] In one embodiment, the pharmaceutical composition, or alternatively, the pharmaceutical dosage form or the tablet comprises about 90 mg of amorphous ledipasvir formulated in a solid dispersion comprising a ratio of polymer: ledipasvir of 1: 1, about 400 mg of crystalline sofosbuvir, lactose monohydrate in an amount of about 5 to about 25% w / w, microcrystalline cellulose in an amount of about 5 to about 25% w / w, croscarmellose sodium in an amount of about from 1 to about 10% w / w, colloidal silicon dioxide in an amount of about 0.5 to about 3% w / w and magnesium stearate in an amount of about 0.1 to about 3% w /P. In one embodiment, the polymer is copovidone.
[096] In additional embodiments, the pharmaceutical composition, the pharmaceutical dosage form or the tablet as described herein is free of negative drug-drug interactions. In a related embodiment, the pharmaceutical composition, the pharmaceutical dosage form or the tablet is free of negative drug-drug interactions with acid suppressive therapies. In an additional embodiment, the pharmaceutical composition, the pharmaceutical dosage form or the tablet as described herein is manageable without regard to food and with or without regard to whether the patient is on acid suppressive therapy. 4. Methods of use
[097] Solid dispersions, pharmaceutical compositions, pharmaceutical dosage forms and tablets of ledipasvir and sofosbuvir as described herein are administered to a patient suffering from hepatitis C virus (HCV) in a daily dose by oral administration. In one embodiment, the patient is human.
[098] Ledipasvir has previously been shown to have a negative dietary effect when administered alone. Unexpectedly, the combined treatment of ledipasvir and sofosbuvir does not have a negative food effect. Consequently, the administration of the pharmaceutical composition comprising sofosbuvir and ledipasvir can be done unrelated to food.
[099] In some embodiments, the combined composition had a reduced dietary effect. In some respects, the composition obtains a first exposure when administered to a patient after a meal, that is, at most 25% or, alternatively, at most 20%, 15% or 10%, less than a second exposure when administered to the patient not after a meal. The exposures can be measured as Cmax, AUClast or AUCinf. In some respects, administration is performed within four, three, two or one hour after a meal.
[100] In one embodiment, solid dispersions, pharmaceutical compositions, pharmaceutical dosage forms and tablets of ledipasvir and sofosbuvir as described herein are effective in treating one or more of patients infected with HCV genotype 1, patients infected with HCV genotype 2, HCV genotype 3 infected patients, HCV genotype 4 infected patients, HCV genotype 5 infected patients and / or HCV genotype 6 infected patients. In one embodiment, solid dispersions, pharmaceutical compositions, pharmaceutical dosage forms and ledipasvir tablets and sofosbuvir as described herein are effective in treating patients infected with HCV genotype 1, including genotype 1a and / or genotype 1b. In another embodiment, solid dispersions, pharmaceutical compositions, pharmaceutical dosage forms and tablets of ledipasvir and sofosbuvir as described herein are effective in treating patients infected with HCV genotype 2, including genotype 2a, genotype 2b, genotype 2c and / or genotype 2d . In another embodiment, solid dispersions, pharmaceutical compositions, pharmaceutical dosage forms and tablets of ledipasvir and sofosbuvir as described herein are effective in treating patients infected with HCV genotype 3, including genotype 3a, genotype 3b, genotype 3c, genotype 3d, genotype 3e and / or genotype 3f. In another embodiment, solid dispersions, pharmaceutical compositions, pharmaceutical dosage forms and tablets of ledipasvir and sofosbuvir as described herein are effective in treating patients infected with HCV genotype 4, including genotype 4a, genotype 4b, genotype 4c, genotype 4d, genotype 4e, genotype 4f, genotype 4g, genotype 4 h, genotype 4i and / or genotype 4j. In another embodiment, solid dispersions, pharmaceutical compositions, pharmaceutical dosage forms and tablets of ledipasvir and sofosbuvir as described herein are effective in treating patients infected with HCV genotype 5, including genotype 5a. In another embodiment, solid dispersions, pharmaceutical compositions, pharmaceutical dosage forms and tablets of ledipasvir and sofosbuvir as described herein are effective in treating patients infected with HCV genotype 6, including genotype 6a. In one embodiment, the compositions are pangenotypical, which means that they are useful across all genotypes and their drug-resistant mutants.
[101] In some embodiments, the pharmaceutical composition, the pharmaceutical dosage form or the ledipasvir and sofosbuvir tablet as described herein is administered, alone or in combination with one or more therapeutic agents for the treatment of HCV (for example, an inhibitor of NS3 HCV protease or an NS5B HCV polymerase inhibitor), for about 24 weeks, for about 16 weeks, or for about 12 weeks, or less. In additional embodiments, the pharmaceutical composition, the pharmaceutical dosage form or the ledipasvir and sofosbuvir tablet is administered, alone or in combination with one or more therapeutic agents for the treatment of HCV (for example, an HCV NS3 protease inhibitor or an NS5B HCV polymerase inhibitor), for about 24 weeks or less, about 22 weeks or less, about 20 weeks or less, about 18 weeks or less, about 16 weeks or less, about 12 weeks or less, about 10 weeks or less, about 8 weeks or less, or about 6 weeks or less or about 4 weeks or less. The pharmaceutical composition, pharmaceutical dosage form or tablet can be administered once daily, twice daily, once every other day, twice a week, three times a week, four times a week or five times a week.
[102] In additional modalities, a sustained virological response is obtained in about 4 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks, or in about 20 weeks, or in about 24 weeks, or in about 4 months, or about 5 months, or about 6 months, or about 1 year, or about 2 years.
[103] In one embodiment, the daily dose is 90 mg of ledipasvir and 400 mg of sofosbuvir given as a tablet. In an additional embodiment, the daily dose is a tablet comprising a) about 30 to about 50% w / w of sofosbuvir, b) about 10 to about 40% w / w of the solid dispersion comprising ledipasvir, c ) about 5 to about 25% w / w of lactose monohydrate, d) about 5 to about 25% w / w of microcrystalline cellulose, e) about 1 to about 10% w / w of croscarmellose sodium , f) about 0.5 to about 3% w / w of colloidal silicon dioxide, eg) about 0.1 to about 3% w / w of magnesium stearate.
[104] In additional modalities, the patient also suffers from cirrhosis. In yet another additional modality, the patient does not suffer from cirrhosis. 5. Combination therapy
[105] In the methods described herein, the method may further comprise the administration of another therapeutic agent for the treatment of HCV and other conditions such as, for example, HIV infections. In one embodiment, non-limiting examples of suitable additional therapeutic agents include one or more interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectors, nucleoside or nucleotide inhibitors of HCV HCV polymerase, inhibitors non-nucleoside NS5B HCV polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs or therapeutic agents for the treatment of HCV.
[106] More specifically, the additional therapeutic agent can be selected from the group consisting of: 1) interferons, for example, pegylated rIFN-alpha 2b (PEG-Intron), pegylated rIFN-alpha 2a (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon alfa (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subalin), interferon alfacon-1 (Infergen), interferon alfa-n1 (Wellferon) , interferon alfa-n3 (Alferon), interferon¬beta (Avonex, DL-8234), interferon-omega (omega DUROS, Biomed 510), albinterferon alfa-2b (Albuferon), IFN alfa-2b XL, BLX-883 (Locteron ), DA-3021, glycosylated interferon alpha-2b (AVI-005), PEG-Infergen, PEGylated interferon lambda-1 (PEGylated IL-29) and bellerophon; 2) ribavirin and its analogs, for example, ribavirin (Rebetol, Copegus) and taribavirin (Viramidine); 3) HCV NS3 protease inhibitors, for example, boceprevir (SCH-503034, SCH-7), telaprevir (VX-950), TMC435350, BI-1335, BI-1230, MK-7009, VBY-376, VX- 500, GS-9256, GS-9451, BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531, ABT-450, ACH-1625, ITMN-191, MK5172, MK6325 and MK2748; 4) alpha-glycosidase 1 inhibitors, for example, celgosivir (MX-3253), Miglitol and UT-231B; 5) hepatoprotectors, for example, emericasan (IDN-6556), ME-3738, GS-9450 (LB-84451), silibilin and MitoQ; 6) nucleoside or nucleotide inhibitors of NS5B HCV polymerase, for example, R1626, R7128 (R4048), IDX184, IDX-102, BCX-4678, valopicitabine (NM-283), MK-0608 and INX-189 (now BMS986094) ; 7) non-nucleoside inhibitors of NS5B HCV polymerase, for example, PF-868554, VCH-759, VCH-916, JTK-652, MK-3281, GS-9190, VBY-708, VCH-222, A848837, ANA- 598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir), GSK625433, BILN-1941, XTL-2125, ABT-072, ABT-333, GS-9669 , PSI-7792 and GS-9190; 8) HCV NS5A inhibitors, for example, AZD-2836 (A-831), BMS-790052, ACH-3102, ACH-2928, MK8325, MK4882, MK8742, PSI-461, IDX719, ABT-267 and A- 689; 9) TLR-7 agonists, for example, imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD-8848 (DSP-3025) and SM-360320; 10) cyclophilin inhibitors, for example, DEBIO-025, SCY-635 and NIM811; 11) HCV IRES inhibitors, for example, MCI-067; 12) pharmacokinetic enhancers, for example, BAS-100, SPI-452, PF-4194477, TMC-41629, GS-9350, GS-9585 and roxithromycin; and 13) other drugs for the treatment of HCV, for example, thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101) , GS-9525, KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, tarvacina, EHC-18, VGX-410C, EMZ- 702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106 (ONO-4538), Oglufanide and VX-497 (merimepodib).
[107] More specifically, the additional therapeutic agent can be combined with one or more compounds selected from the group consisting of non-nucleoside HCV NS5B polymerase inhibitors (ABT-072 and ABT-333), HCV NS5A inhibitors (ACH- 3102 and ACH-2928) and HCV NS3 protease inhibitors (ABT-450 and ACH-125).
[108] In another embodiment, the therapeutic agent used in combination with the pharmaceutical compositions as described herein can be any agent that has a therapeutic effect when used in combination with the pharmaceutical compositions as described herein. For example, the therapeutic agent used in combination with the pharmaceutical compositions as described herein may be interferons, ribavirin analogs, NS3 protease inhibitors, NS5B polymerase inhibitors, alpha glucosidase 1 inhibitors, hepatoprotectors, non-nucleoside HCV inhibitors, and other drugs for the treatment of HCV.
[109] In another embodiment, the additional therapeutic agent used in combination with the pharmaceutical compositions as described herein is a cyclophilin inhibitor, including, for example, a cyclophilin inhibitor disclosed in WO 2013/185093. Non-limiting examples include one or more compounds selected from the group consisting of:
and stereoisomers and mixtures of stereoisomers thereof.
[110] In another embodiment, the additional therapeutic agent used in combination with the pharmaceutical compositions as described herein is a non-nucleoside inhibitor of NS5B HCV polymerase. A non-limiting example includes Compound E (as described below).
[111] Examples of additional anti-HCV agents that can be combined with the compositions provided herein include, without limitation, the following: A. Interferons, for example, pegylated rIFN-alpha 2b (PEG-Intron), pegylated rIFN-alpha 2a (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon alfa (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subalin), interferon alfacon-1 (Infergen) , interferon alfa-n1 (Wellferon), interferon alfa-n3 (Alferon), interferon¬beta (Avonex, DL-8234), interferon-omega (omega DUROS, Biomed 510), albinterferon alfa-2b (Albuferon), IFN alfa XL , BLX-883 (Locteron), DA-3021, glycosylated interferon alfa-2b (AVI-005), PEG-Infergen, PEGylated interferon lambda (PEGylated IL-29), or bellerophon, IFN alfa-2b XL, rIFN-alpha 2a , consensus IFN alpha, infergen, rebif, pegylated IFN-beta, oral interferon alfa, feron, reaferon, intermax alfa, r-IFN-beta, and infergen + actimune-ribavirin and ribavirin analogues, for example, rebetol, copegus, VX ¬497 and saw idine (taribavirin); B. NS5A inhibitors, for example, Compound B (described below), Compound C (described below), ABT-267, Compound D (described below), JNJ-47910382, daclatasvir (BMS-790052), ABT-267, MK -8742, EDP-239, IDX-719, PPI-668, GSK-2336805, ACH-3102, A-831, A-689, AZD-2836 (A-831), AZD-7295 (A-689) and BMS -790052; C. NS5B polymerase inhibitors, for example, Compound E (described below), Compound F (described below), ABT-333, Compound G (described below), ABT-072, Compound H (described below), tegobuvir (GS- 9190), GS-9669, TMC647055, setrobuvir (ANA-598), filibuvir (PF-868554), VX-222, IDX-375, IDX-184, IDX-102, BI-207127, valopicitabine (NM-283), PSI-6130 (R1656), PSI-7851, BCX-4678, nesbuvir (HCV-796), BILB 1941, MK-0608, NM-107, R7128, VCH-759, GSK625433, XTL- 2125, VCH-916, JTK -652, MK-3281, VBY-708, A848837, GL59728, A-63890, A-48773, A-48547, BC-2329, BMS-791325 and BILB-1941; D. NS3 protease inhibitors, for example, Compound I, Compound J, Compound K, ABT-450, Compound L (described below), simeprevir (TMC-435), boceprevir (SCH-503034), narlaprevir (SCH-900518) , vaniprevir (MK-7009), MK-5172, damageprevir (ITMN-191), sovaprevir (ACH-1625), neceprevir (ACH-2684), Telaprevir (VX-950), VX-813, VX-500, faldaprevir ( BI-201335), asunaprevir (BMS-650032), BMS-605339, VBY-376, PHX-1766, YH5531, BILN-2065 and BILN-2061; E. Alpha-glycosidase 1 inhibitors, for example, celgosivir (MX-3253), Miglitol and UT-231B; F. Hepatoprotectors, for example, IDN-6556, ME 3738, MitoQ and LB-84451; G. Non-nucleoside HCV inhibitors, for example, benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives and phenylalanine derivatives; and H. Other anti-HCV agents, for example, zadaxin, nitazoxanide (Alinea), BIVN-401 (Virostat), DEBIO-025, VGX-410C, EMZ-702, AVI 4065, bavituximab, oglufanide, PYN-17, KPE02003002 , actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18 and NIM811.
[112] Compound B is an NS5A inhibitor and is represented by the following chemical structure:

[113] Compound C is an NS5A inhibitor and is represented by the following chemical structure:

[114] Compound D is an NS5A inhibitor and is represented by the following chemical structure:

[115] See U.S. Publication No. 2013/0102525 and references cited therein.
[116] Compound E is an NS5B Thumb II polymerase inhibitor and is represented by the following chemical structure:

[117] Compound F is a nucleotide inhibitor prodrug designed to inhibit viral RNA replication by the NS5B HCV polymerase, and is represented by the following chemical structure:

[118] Compound G is an HCV polymerase inhibitor and is represented by the following structure:

[119] See U.S. Publication No. 2013/0102525 and references cited therein.
[120] Compound H is an HCV polymerase inhibitor and is represented by the following structure:

[121] See U.S. Publication No. 2013/0102525 and references cited therein.
[122] Compound I is an HCV protease inhibitor and is represented by the following chemical structure:

[123] See U.S. Publication No. 2014/0017198 and references cited therein.
[124] Compound J is an HCV protease inhibitor and is represented by the following chemical structure:

[125] See U.S. Patent No. 8,178,491 and references cited therein.
[126] Compound K is an HCV protease inhibitor and is represented by the following chemical structure:

[127] Compound L is an HCV protease inhibitor and is represented by the following chemical structure:

[128] See U.S. Publication No. 2013/0102525 and references cited therein.
[129] In one embodiment, the additional therapeutic agent used in combination with the pharmaceutical compositions as described herein is an HCV NS3 protease inhibitor. Non-limiting examples include one or more compounds selected from the group consisting of:

[130] In another embodiment, a method of treating hepatitis C in a needy human patient is provided in the present application which comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition as described herein and an additional therapeutic substance selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, IFN alpha-2b XL, rIFN-alpha 2a, consensus IFN alpha, infergen, rebif, locteron, AVI-005, PEG-infergen, Pegylated IFN-beta, oral interferon alpha, feron, reaferon, intermax alfa, r-IFN-beta, infergen + actimune, IFN-omega with HARD, albuferon, rebetol, copegus, levovirin, VX-497, viridine (taribavirin), A -831, A-689, NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, MK-0608, NM-107, R7128, VCH-759, PF-868554, GSK625433, XTL -2125, SCH- 503034 (SCH-7), VX-950 (Telaprevir), ITMN-191 and BILN-2065, MX-3253 (celgosivir), UT-231B, IDN-6556, ME 3738, MitoQ, and LB- 84451, derivatives benzimidazole, benzo-1,2,4-thiadiazine derivatives and phenylalanine, zadaxine, nitazoxanide (Alinea), BIVN-401 (Virostat), DEBIO-025, VGX-410C, EMZ-702, AVI 4065, bavituximab, oglufanide, PYN-17, KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975 (Isatoribine), XTL-6865, ANA 971, NOV-205, tarvacine, EHC-18 and NIM811 and a pharmaceutically acceptable vehicle or excipient.
[131] In yet another embodiment, the present application provides a combined pharmaceutical agent comprising: a) a first pharmaceutical composition comprising an effective amount of ledipasvir in which ledipasvir is substantially amorphous; and an effective amount of sofosbuvir, wherein sofosbuvir is substantially crystalline as described herein and b) a second pharmaceutical composition comprising at least one additional therapeutic agent selected from the group consisting of HIV protease inhibitory compounds, non-nucleoside reverse transcriptase inhibitors. HIV, HIV nucleoside reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors , alpha-glycosidase 1 inhibitors, hepatoprotectors, non-nucleoside HCV inhibitors, and other drugs for the treatment of HCV, and combinations thereof.
[132] The additional therapeutic agent may be one that treats other conditions, such as HIV infections. Consequently, the additional therapeutic agent can be a useful compound in the treatment of HIV, for example, HIV protease inhibitor compounds, non-nucleoside HIV reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, nucleotide HIV reverse transcriptase inhibitors , HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors, NS5b polymerase inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectors, non-inhibitors HCV nucleosides, and other drugs for the treatment of HCV.
[133] More specifically, the additional therapeutic agent can be selected from the group consisting of: 1) HIV protease inhibitors, for example, amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, lopinavir + ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), AG1859, DG35, L-756423, RO0334649, KNI-272, DPC-681, DPC-684 and GW640385X, DG17, PPL-100. 2) A non-nucleoside HIV reverse transcriptase inhibitor, for example, capravirin, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150 , and TMC-120, TMC-278 (rilpivirine), efavirenz, BILR 355 BS, VRX 840773, UK-453,061, RDEA806. 3) A nucleoside inhibitor of HIV reverse transcriptase, for example, zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, eoxovir, elvucitabine, alovudine, MIV-210, racivir (± -FTC), Dtricit , phosphatide, fozivudine ,idoxil, fosalvudine ,idoxil, apricitibine (AVX754), eoxovir, KP-1461, abacavir + lamivudine, abacavir + lamivudine + zidovudine, zidovudine + lamivudine. 4) A nucleotide inhibitor of HIV reverse transcriptase, for example, tenofovir, tenofovir disoproxil fumarate + emtricitabine, tenofovir disoproxil fumarate + emtricitabine + efavirenz and adefovir. 5) An HIV integrase inhibitor, for example, curcumin, curcumin derivatives, chicory acid, chicory acid derivatives, 3,5-Dicafeoylquinic acid derivatives, 3,5-Dicafeoylquinic acid derivatives, Aurintricarboxylic acid, Aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tirfostine, tirfostine derivatives, quercetin, quercetin derivatives, S-1360, zintevir (AR-177), L-870812, and L-870810, MK-0518 ( raltegravir), BMS-707035, MK-2048, BA-011, BMS-538158, GSK364735C. 6) A gp41 inhibitor, for example, enfuvirtide, sifuvirtide, FB006M, TRI-1144, SPC3, DES6, Locus gp41, CovX and REP 9. 7) A CXCR4 inhibitor, for example, AMD-070. 8) An entry inhibitor, for example, SP01A, TNX-355. 9) A gp120 inhibitor, for example, BMS-488043 and BlockAide / CR. 10) An inhibitor of G6PD and NADH-oxidase, for example, immunitin. 11) A CCR5 inhibitor, for example, aplaviroc, vicriviroc, INCB9471, PRO-140, INCB15050, PF-232798, CCR5mAb004 and maraviroc. 12) An interferon, for example, pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, IFN alpha-2b XL, rIFN-alpha 2a, consensus IFN alpha, infergen, rebif, locteron, AVI-005 , PEG-infergen, pegylated IFN-beta, oral interferon alfa, feron, reaferon, intermax alfa, r- IFN-beta, infergen + actimune, IFN-omega with HARD and albuferon. 13) Analogs of ribavirin, for example, rebetol, copegus, levovirin, VX-497 andramidine (taribavirin). 14) NS5a inhibitors, for example, A-831, A-689 and BMS-790052. 15) NS5b polymerase inhibitors, for example, NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, MK-0608, NM-107, R7128, VCH-759, PF-868554, GSK625433 and XTL-2125. 16) NS3 protease inhibitors, for example, SCH-503034 (SCH-7), VX-950 (Telaprevir), ITMN-191 and BILN-2065. 17) Alpha-glucosidase 1 inhibitors, for example, MX¬3253 (celgosivir) and UT-231B. 18) Hepatoprotectors, for example, IDN-6556, ME 3738, MitoQ and LB-84451. 19) Non-nucleoside HCV inhibitors, for example, benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives and phenylalanine derivatives. 20) Other drugs for the treatment of Hepatitis C, for example, zadaxin, nitazoxanide (Alinea), BIVN-401 (Virostat), DEBIO-025, VGX-410C, EMZ-702, AVI 4065, bavituximab, oglufanide, PYN-17 , KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975 (isatoribine), XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18 and NIM811. 21) Pharmacokinetic enhancers, for example, BAS-100 and SPI452. 22) RNAse H inhibitors, for example, ODN-93 and ODN-112, and 23) Other anti-HIV agents, for example, VGV-1, PA-457 (bevirimat), ampligen, HRG214, citoline, polimun, VGX - 410, KD247, AMZ 0026, CYT 99007, A-221 HIV, BAY 50-4798, MDX010 (iplimumab), PBS119, ALG889 and PA-1050040.
[134] In one embodiment, the additional therapeutic agent is ribavirin. Accordingly, the methods described herein include a method of treating hepatitis C in a needy human patient which comprises administering to the patient a therapeutically effective amount of ribavirin and a therapeutically effective amount of a pharmaceutical composition, pharmaceutical dosage form or tablet as herein. described. In an additional embodiment, ribavirin and pharmaceutical composition, pharmaceutical dosage form or tablet comprising sofosbuvir and ledipasvir is administered for about 12 weeks or less. In additional modalities, ribavirin and pharmaceutical composition, pharmaceutical dosage form or tablet comprising sofosbuvir and ledipasvir is administered for about 8 weeks or less, for about 6 weeks or less, or for about 4 weeks or less.
[135] It is contemplated that the additional therapeutic agent will be administered in a form that is known in the art and the dosage can be selected by those skilled in the art. For example, the additional agent can be administered at a dose of about 0.01 milligrams up to about 2 grams per day. EXAMPLES
[136] In the following examples and throughout this disclosure, the abbreviations used here have the respective meanings presented below.




Example 1: Synthesis of amorphous Ledipasvir
[137] Methods for producing various forms of ledipasvir can be found in U.S. Publications Nos. 2013/0324740 and 2013/0324496. Both of these requests are hereby incorporated by reference. Next, a method for isolation of ledipasvir amorphous free base will be presented.
[138] Combine ledipasvir acetone solvate (191.4 g) and acetonitrile (1356 g) in a reaction vessel and mix the contents until a solution is obtained. Add this ledipasvir in acetonitrile solution slowly to another reaction vessel containing vigorously stirred water (7870 g). Stir the contents at about 23 ° C for about 30 minutes. Filter the contents and dry at about 40-45 ° C until a constant weight is obtained to generate solid amorphous ledipasvir (146.4 g, 82% yield). Example 2: Tablet preparation and formulation A. Selection of tablet dose i. Sofosbuvir
[139] The dose of sofosbuvir selected for the tablet formulation is 400 mg once daily. Support for the 400 mg dose of sofosbuvir can be derived from PK / PD modeling of Emax with initial virological and human exposure data that also support the selection of a 400 mg dose of sofosbuvir over others tested.
[140] The average AUCtau of the main metabolite of sofosbuvir for the 400 mg dose of sofosbuvir is associated with approximately 77% of the maximum HCV RNA change from baseline that can be obtained as determined by that model, a value which is on the plateau cusp of the sigmoid exposure-response curve. In an Emax sigmoid model, there is a relatively linear exposure-response relationship in the range of 20 to 80% of the maximum effect. Therefore, considering that exposure to sofosbuvir with 200 mg tablets seems dose-proportional with single doses of up to 1,200 mg, it is expected that doses below 400 mg will generate considerable reductions in the magnitude of HCV RNA change in relation to the level of base. Similarly, in order to increase a 77% efficacy prediction on the plateau of the exposure-response curve, substantial increases in exposure (and therefore in dose) would be required for an appreciable increase in the antiviral effect.
[141] The sofosbuvir 400 mg once daily dose was associated with higher SVR rates in patients infected with HCV genotype 1 when compared to the 200 mg once daily dose when given in conjunction with additional therapeutic substances for HCV for 24 weeks. Safety and tolerability appeared similar across both dose levels. In addition, when 400 mg of sofosbuvir once daily plus other therapeutic substances for HCV were given to patients infected with HCV genotype 2 or 3, 100% SVR24 was observed. ii. Ledipasvir
[142] The median maximum log10 reduction in HCV RNA was 3 or more for all cohorts dosed with> 3 mg ledipasvir. A PK / PD model of Emax indicates that the exposures obtained after administration of the 30 mg dose provide> 95% of maximum antiviral response in patients infected with HCV genotype 1a. It was also observed that 30 mg or more of ledipasvir likely provided coverage for some drug-related mutations that doses less than 30 mg did not, based on an analysis of NS5A mutants that arose in response to exposure to ledipasvir. Therefore, 30 mg and 90 mg of ledipasvir were selected as the dose for the formulations described here.
[143] Additional studies suggest that when ledipasvir is administered in combination with other therapeutic agents, the penetration rate (BT) (the number of patients with HCV RNA> lower limit of quantification (LLOQ) after obtaining vRVR / total number of patients who obtained vRVR), is greater with doses of 30 mg (BT = 33%, 11/33; 30 mg ledipasvir), than with doses of 90 mg (BT = 12%, 9/74; 90 mg ledipasvir) . Therefore, the 90 mg dose of ledipasvir can provide greater antiviral coverage that prevents viral penetration. B. Solid dispersion comprising Ledipasvir
[144] To produce tablets comprising the combination of sofosbuvir and ledipasvir as described herein, a solid dispersion comprising ledipasvir has been co-formulated with crystalline sofosbuvir. The starting material of the solid dispersion can be various forms of ledipasvir, including crystalline forms, amorphous forms, salts thereof, solvates and free base, as described herein. Because of the high solubility in organic solvents and excipients and the ability to isolate the crystalline acetone solvate free from ledipasvir, this form was used in the amorphous solid dispersion of ledipasvir.
[145] The atomized solid dispersion approach achieved the most desirable characteristics over other formulation approaches, which included improved in vivo and in vitro performance and fabricability / scalability.
[146] The atomized feed solution was prepared by solubilizing ledipasvir acetone solvate and polymer in the feed solvent. Aggressive mixing or homogenization was used to prevent aggregation of the composition.
[147] Different polymers have been tested for the preferred characteristics in solid dispersions. Nonionic polymers, for example, solid dispersions of hypromellose and copovidone, showed stability and adequate physical characteristics.
[148] The feed solution was initially evaluated for the appropriate solvent with respect to solubility, stability and viscosity. Ethanol, methanol and dichloromethane (DCM) demonstrated excellent solubility (ledipasvir solubility> 500 mg / ml). Ethanol and DCM-based feed stocks were tested for ease of preparation and atomized over a range of inlet and outlet temperatures to assess the robustness of the atomization process. Both solvents generated rapid dissolution of ledipasvir and copovidone.
[149] Atomization with ethanol removal resulted in high yields (88, 90, 92, 94, 95, 97, 98, 99%) across a wide range of atomization outlet temperatures (49-70 ° C) without accumulation of material in the atomization chamber. Atomization with DCM removal resulted in yields of 60%, 78%, and 44%. Overall, the solid dispersion of ledipasvir (50% w / w) in a ratio of ledipasvir to copovidone of 1: 1 demonstrated good chemical stability in the ethanolic feed solution.
[150] An ethanol solution of 10% ledipasvir acetone solvate and 10% copovidone was prepared using homogenization. The viscosity of ethanolic solutions of ledipasvir: copovidone was low, measured by a solids content of 30% (approximately 65 cP).
[151] Atomization was performed using a two-fluid nozzle or a hydrolytic pressure nozzle. Table 1 shows the parameters of the atomization process evaluated at 100 g - 4,000 g of total feed solution using the anhydrous atomizer MS35, and Table 2 shows the parameters of the atomization process using the hydrolytic pressure nozzle. The particle size data suggested a sufficiently large particle size (average PS of 10-14 μm) and were minimally affected by using higher spray rates or a larger diameter spray nozzle. The gas flow from the nozzle has not been modulated to increase the particle size. Table 1. Ledipasvir atomization parameters in the MS35 anhydrous atomizer using a two fluid nozzle.

Table 2. Example of Ledipasvir atomization parameters using a hydrolytic pressure nozzle.

[152] Volatile organic impurities, including atomized ethanol solvent and residual acetone from ledipasvir acetone solvate, are rapidly removed during secondary drying at 60 ° C. Smaller scale production can be tray dried. In batches on a larger scale, a double cone dryer or agitated dryer can be used. Loss on drying (LOD) was proportionally slower and is attributable to water, which was later confirmed by Karl Fischer titration.
[153] Residual ethanol has been reduced below the 0.5% w / w ICH guidelines for 6 hours of drying (or 8 hours for larger scale). The ethanol content after drying was 0.08% w / w, and the residual acetone was 0.002%, indicating that the secondary drying process is suitable for removing residual solvent. C. Tablet preparation i. Monolayer tablet
[154] The solid dispersion of Ledipasvir: copovidone (1: 1) was made by dissolving ledipasvir and copovidone in ethanol, and then atomizing the mixture. The solid dispersion of Ledipasvir: atomized copovidone is further dried in a secondary dryer. The amorphous solid dispersion comprising ledipasvir was mixed with sofosbuvir and excipients and ground to facilitate mixing and uniformity of the mixture. A co-mixing or co-drying granulation process can be used. Co-mixing granulation is a multi-step process consisting of separate dry granulations for each active ingredient with excipients, followed by mixing the two granulations together. Co-dry granulation consisted of granulating both active ingredients and excipients together. The co-mixing and co-drying processes demonstrated comparable physical and chemical properties of the tablet. Exemplary co-mix and co-dry formulations are provided in Table 3 and Table 4 shown below. Table 3. Representative example composition of Sofosbuvir / Ledipasvir co-dried (co-granulated) tablets in various fill weights.

Table 4. Representative example composition of Sofosbuvir / Ledipasvir co-mix tablets (bigranules).


[155] The granules were then mixed with a lubricant before the tablet was compacted. The total core weight of the resulting tablet was 1,000 mg.
[156] The film coating of the tablets is provided to reduce photolytic degradation. The tablets were coated to a target weight gain of 3%. The film coating material was a polyvinyl alcohol based coating. An exemplary tablet formulation is provided in Table 5. Table 5. Representative example of the tablet composition comprising the solid dispersion of Ledipasvir and Sofosbuvir.

11. Bilayer tablet
[157] Tablets that comprise the co-formulation of a solid dispersion comprising ledipasvir and crystalline sofosbuvir can also be made as a bilayer tablet, with each active ingredient in a separate layer. To make the bilayer tablet, a solid dispersion of ledipasvir: copovidone (1: 1) is made by dissolving ledipasvir and copovidone in ethanol, and then atomizing the mixture. The solid dispersion of Ledipasvir: atomized copovidone is further dried in a secondary dryer. Next, the solid dispersion of Ledipasvir: atomized copovidone is then mixed with excipients. The mixture is crushed and then mixed with lubricant before dry granulation. The ledipasvir granules are mixed with extragranular lubricant. Separately, the pharmacological substance sofosbuvir is mixed with excipients, and then the mixture is crushed and then mixed with lubricant before dry granulation. The sofosbuvir granules are then mixed with extragranular lubricant. Finally, the sofosbuvir powder mixture and the ledipasvir powder mixture are compressed into bilayer tablet cores. The bilayer tablet cores are coated with film prior to packaging. A representative example composition of a bilayer tablet comprising the solid dispersion of ledipasvir and sofosbuvir is shown in Table 6. In that table, the solid dispersion comprises ledipasvir: copovidone in a 1: 1 ratio. Table 6. Representative example of the composition of bilayer tablets comprising the solid dispersion of Ledipasvir and Sofosbuvir.

Example 3: PK, stability and dissolution properties of Ledipasvir tablets as a single agent and Ledipasvir / Sofosbuvir tablets and reduction of the food effect and effects of gastric acid suppressants A. Bioavailability of Ledipasvir tablets as a single agent
[158] A series of in vivo experiments were carried out to assess the potential benefit of the solid dispersion approach over conventional formulations, as well as to optimize the solid dispersion by identifying the most beneficial polymer type and relative polymer concentration within the dispersal.
[159] Equivalent bioavailability was obtained between formulations comprising the amorphous free base form (4% w / w, 10 mg amorphous free base tablet) and formulations comprising the ledipasvir D-tartrate salt (5.85% w / w, 10 mg tablet of D-tartrate salt), both using conventional formulations, in the dog model pretreated with pentagastrin, as shown in Table 7. Pentagastrin is a synthetic polypeptide that stimulates the secretion of gastric acid , pepsin and intrinsic factor. Table 7. Average pharmacokinetic parameters (RSD) of Ledipasvir after oral administration of Tablets, 25 mg, in Beagle dogs (n = 6).

[160] As these formulations exhibited similar PK properties and the insulating properties of the D-tartrate salt were preferable to the free base amorphous form, the crystalline D-tartrate salt formulation was chosen to compare with the solid amorphous dispersion compositions. . For these studies, 30 mg tablets that comprise the ledipasvir crystalline D-tartrate salt and 30 mg or 90 mg tablets that comprise the solid amorphous dispersion of ledipasvir were used. The pharmacokinetic results in dogs for selected immediate-release ledipasvir tablets comprising solid dispersions of ledipasvir are shown in Table 8. Table 8. Average pharmacokinetic parameters (RSD) of Ledipasvir after oral administration of Ledipasvir tablets, fasting Beagle dogs (n = 6).

[161] Compared to crystalline ledipasvir D-tartrate formulations, amorphous solid dispersion tablets exhibited greater bioavailability with less variability. In animals pretreated with pentagastrin, an approximately 40% increase in exposure and a 2-fold decrease in variability were observed. More importantly, in animals pretreated with famotidine, an increase of up to 3.5 times in bioavailability was observed, compared to the D-tartrate salt tablet formulations.
[162] A copovidone-based dispersion increased bioavailability more than the equivalent hypromellose-based formulation (F = 30% and 22%, respectively) when atomized in an API: polymer ratio of 2: 1. The bioavailability of the copovidone-based formulation was further increased by increasing the polymer fraction to a 1: 1 ratio, resulting in a 35% bioavailability in dogs pretreated with famotidine.
[163] Because of improved in vivo performance and acceptable physical properties and stability, a 1: 1 mixture of ledipasvir: copovidone was chosen as the atomized material.
[164] Formulations comprising solid amorphous dispersions have proven to be advantageous over formulations comprising free amorphous base or D-tartrate salt. It was observed that the bioavailability of amorphous free base formulations was similar to that of D-tartrate salt formulations. Additional data showed a decrease in bioavailability when ledipasvir was dosed with gastric acid suppressing agents (famotidine), indicating an unfavorable drug-drug interaction in formulations of amorphous free base and ledipasvir D-tartrate salt. A solid dispersion using atomization with a hydrophilic polymer has been identified as having acceptable stability, physical characteristics and in vivo performance. A rapidly disintegrating tablet was developed using a dry granulation process and commonly used excipients. A bioavailability study that compares formulations that comprise the D-tartrate salt with formulations that comprise the amorphous solid dispersion showed improved biopharmaceutical performance and that many of the negative drug-drug interactions have been overcome with acid suppressant therapies seen in D salt formulations. -treatment. B. Bioavailability of Ledipasvir + Sofosbuvir tablets
[165] The PK results for the combination of sofosbuvir with ledipasvir (where ledipasvir is in solid dispersion with a 1: 1 ratio of copovidone) are shown in Table 9 and demonstrate the absence of a significant interaction between sofosbuvir and ledipasvir. Table 9: Pharmacokinetic data for Sofosbuvir and Ledipasvir when administering Sofosbuvir and Ledipasvir alone or in combination.


[166] Sofosbuvir plasma exposure was increased approximately 2.3-fold by ledipasvir. The effect of ledipasvir on sofosbuvir is probably caused by the inhibition of P-gp, of which Sofosbuvir is a known substrate. The increase in sofosbuvir was not considered significant because of its very low and transient exposure in relation to the exposure of material related to the total drug (DRM) (DRM, calculated as the sum of the AUCs for each of the analytes, corrected for the molecular weight ). Based on this calculation, the AUC of sofosbuvir with ledipasvir is only approximately 5.7% of the DRM AUC. The exposure of metabolite II, the main circulating metabolite of sofosbuvir, was not impacted by the administration of ledipasvir, and demonstrates the absence of significant interaction between sofosbuvir and ledipasvir. C. Reduction of the food effect in solid dispersions of Ledipasvir and Ledipasvir / Sofosbuvir tablets
[167] Ledipasvir alone in a conventional formulation (not in solid dispersion) has been shown to have a negative food effect. Table 10 summarizes the PK parameters of ledipasvir after a single dose of ledipasvir, 30 mg, under fasting and postprandial conditions. The PK profile of ledipasvir was altered in the presence of food. Specifically, the high-fat meal seemed to delay the absorption of ledipasvir, prolong the Tmax (median Tmax of 8 hours) and decrease the plasma exposure of ledipasvir (decrease of approximately 45% each in Cmax, AUClast and AUCinf, averages, respectively). Table 10: PK parameters of plasma Ledipasvir after administration of a single dose of Ledipasvir by state of concomitant food intake.


[168] Table 11 shows the proportion of GLSMs (30 mg ledipasvir under fasting conditions / 30 mg ledipasvir under postprandial conditions) for each of the primary PK parameters. Table 11: Statistical evaluations of Ledipasvir PK parameters regarding the food effect.

[169] Similar median half-lives of ledipasvir were observed regardless of administration under fasting or postprandial conditions (t1 / 2 of 39.82 hours under fasting conditions vs. 36.83 hours under postprandial conditions) indicating that the food decreased the bioavailability of ledipasvir by reducing its solubility and / or absorption.
[170] As ledipasvir has been shown to have a negative food effect, the composition comprising both sofosbuvir and ledipasvir (as a solid dispersion in copovidone (1: 1)) has been tested for a food effect. These results are shown in Table 12. Food slowed the absorption rate of sofosbuvir (median Tmax: 1.00 vs. 2.00 hours) with only a modest change in bioavailability, as evidenced by 2-fold or less increases in plasma exposure of sofosbuvir and the sofosbuvir metabolite I. For the sofosbuvir II metabolite, an approximately 20-30% lower Cmax was observed after administration of sofosbuvir with food, with no change in AUC. The% GMR and the associated 90% confidence interval (90% CI) (fasting / postprandial treatments) for sofosbuvir II metabolite AUC were within the 70% to 143% equivalence limits. As the decrease in Cmax of the sofosbuvir II metabolite was modest and the AUC parameters met the equivalence criteria, the effect of food on the sofosbuvir II metabolite was not considered significant.
[171] Plasma exposures (AUC and Cmax) of similar ledipasvir were obtained after administration of ledipasvir under fasting or postprandial conditions. The% GMR and the associated 90% CIs (fasting / postprandial treatments) were within the 70-143% equivalence limits. Although a “negative” dietary effect was previously observed in ledipasvir when administered alone (as the amorphous free base, not as a solid dispersion), the pharmacokinetics of ledipasvir (solid amorphous dispersion; copovidone (1: 1)) administered in combination with sofosbuvir not appears to be altered by food. Thus, the combination of sofosbuvir and ledipasvir can be administered without considering food intake. Table 12: Pharmacokinetic data for Sofosbuvir, metabolites of Sofosbuvir I and II, and Ledipasvir in the administration of Sofosbuvir / Ledipasvir tablets on an empty stomach or with a meal with moderate fat content or with a high-calorie meal with a high fat content.



D. Reduction of the effects of gastric acid suppressants in Ledipasvir / Sofosbuvir tablets
[172] Ledipasvir, 30 mg, alone, both in a conventional formulation (such as the D-tartrate salt) and as a solid dispersion, has been shown to have a decrease in bioavailability when administered with some gastric acid suppressant; more significantly still, proton pump inhibitors (PPIs, for example, omeprazole), but also including histamine-2 antagonists (H2RAs, for example, famotidine, data not included). Table 12A summarizes the PK parameters of ledipasvir after administration of conventional ledipasvir tablets as a single agent, 30 mg, ledipasvir tablets as a solid dispersion (ledipasvir: copovidone 1: 1), 30 mg, and sofosbuvir / ledipasvir FDC tablets ( 90 mg of ledipasvir solid dispersion comprising 1: 1 copovidone) with and without omeprazole. The bioavailability of ledipasvir as single agent tablets has been reduced approximately 2 times when administered with omeprazole; however, administration of ledipasvir as part of the sofosbuvir / ledipasvir FDC tablet with omeprazole resulted in no significant decrease in ledipasvir exposure (AUC and Cmax) compared to administration of sofosbuvir / ledipasvir FDC tablet in the absence of omeprazole. Table 12A. Pharmacokinetic data for Ledipasvir in the administration of Ledipasvir tablets as a single agent or Sofosbuvir / Ledipasvir tablets with and without Omeprazole.

E. Dissolution of Ledipasvir / Sofosbuvir tablets
[173] Dissolution studies have been carried out comparing sofosbuvir 400 mg / ledipasvir 90 mg tablets (ledipasvir: copovidone (1: 1)). Sofosbuvir / ledipasvir (LOT 1-5) tablets exhibit more than 85% sofosbuvir (FIG. 5) and ledipasvir (FIG. 6) dissolved in 30 minutes for both tablet formulations. These results are shown in FIGS. 5 and 6. Example 4: Sofosbuvir / Ledipasvir co-formulation stability
[174] The compatibility of the anhydrous crystalline pharmacological substance of sofosbuvir was assessed with the solid dispersion of Ledipasvir: copovidone. A mixture of the solid dispersion of sofosbuvir and ledipasvir: copovidone (1: 1) was prepared in a representative proportion of the final 400 mg sofosbuvir / 90 mg ledipasvir tablets. The mixture was compressed in pellets and placed in stability chambers at 40 ° C / 75% relative humidity and 60 ° C / ambient humidity and tested after two and four weeks of storage in open glass bottles. The results summarized in Table 13 show that no degradation was observed for sofosbuvir or ledipasvir, demonstrating the chemical compatibility of sofosbuvir and the solid dispersion of Ledipasvir: copovidone with each other. Table 13: Potency and impurity content of the solid dispersion mixture of Sofosbuvir and Ledipasvir: copovidone stored at 40 ° C / 75% relative humidity and 60 ° C.

Example 5: Effectiveness of Sofosbuvir / Ledipasvir / Ribavirin treatment in patients with HCV infections
[175] Patients with HCV infections were treated with the combination of sofosbuvir, ledipasvir and ribavirin or with the combination of sofosbuvir and ribavirin. The patients used in the study included those who were treatment naïve, that is, they had not been previously treated for HCV, and those who were unresponsive, that is, they had been previously treated for HCV, but did not respond to treatment. Standard doses (90 mg of ledipasvir, 400 mg of sofosbuvir and 1,000 mg of ribavirin, for example) of each drug were given to patients for a duration of 12 weeks. Throughout the treatment, HCV RNA was measured, and the sustained virological response (SVR) was measured after treatment was stopped. Within four weeks of treatment, almost all patients had obtained a measurement of HCV RNA below the detection limit (LOD of 15 IU / ml) and, at the end of treatment, 100% of patients achieved a level of HCV RNA below of the LOD (Table 14). Table 14: Patients with HCV RNA below the detection limit over time.


[176] Surprisingly, 100% of patients receiving the combination of sofosbuvir, ledipasvir and ribavirin achieved a sustained virological response at four and twelve weeks after treatment. In contrast, only 88% of treatment-naïve patients and 10% of non-responsive patients treated with the combination of sofosbuvir and ribavirin achieved an SVR at four weeks post-treatment, and only 84% of treatment-naïve patients and 10% of patients Non-responsive patients treated with the combination of sofosbuvir and ribavirin achieved SVR at twelve weeks post treatment (Table 15). Table 15: Sustained virological response.

[177] These results are revealed graphically as FIG. 7A-D and demonstrate that adding ledipasvir to the treatment regimen generated 100% SVR at weeks 4 and 12. Example 9, below, shows that similar results are obtained with treatment regimens of less than twelve weeks (ie , treatment regimens of about 8 or 6 weeks), and similar results are obtained with treatment regimens of sofosbuvir and ledipasvir without the addition of ribavirin. Example 6. Stability of combined fixed-dose tablets of 400 mg SOF / 90 mg Ledipasvir
[178] This example summarizes the physical and chemical stability of blue tablets packaged with 400 mg Sofosbuvir (SOF) fixed dose combination film (SOF) / ledipasvir 90 mg at 25 ° C / 60% relative humidity ( RH) and 40 ° C / 75% relative humidity due to desiccant. The ledipasvir portion of the tablet comprised ledipasvir: copovidone in a 1: 1 ratio. In addition, the chemical and physical stability of SOF / ledipasvir FDC tablets was assessed at 40 ° C / 75% relative humidity under open condition for up to 4 weeks.
[179] The physicochemical properties that were assessed included appearance, potency, degradant formation, dissolution rate and water content. The physical stability of the tablets in the absence of desiccant was assessed after 24 weeks using FT-Raman spectroscopy and differential modulated scanning calorimetry (mDSC).
[180] Blue FDC 400 mg SOF / 90 mg ledipasvir film-coated tablets exhibited satisfactory stability at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for up to 24 weeks in the presence of 0, 1 and 3 g of desiccant. There were no significant changes in potency, impurity content or dissolution rate. However, a ledipasvir photodegradant was present at 0.1% for all conditions. FT-Raman analysis for tablets stored in the absence of desiccant showed no detectable crystallization after 24 weeks. Materials and methods Materials
[181] Table 16 lists the physico-chemical properties for the pharmacological substance of SOF and solid dispersion of ledipasvir used to produce tablets. The amounts of SOF pharmacological substance and ledipasvir solid dispersion were adjusted based on their respective drug content factor (DCF) with concomitant adjustment in the amount of lactose monohydrate. The DCFs used for SOF and ledipasvir solid dispersion powder, 50% w / w, were 0.997 and 0.497 (0.994 when adjusted for the amount of copovidone), respectively. Table 16. Physico-chemical properties of SOF pharmacological substance and Ledipasvir solid dispersion, 50% w / w, bulk powder used to produce FDC tablets coated with 400 mg SOF / 90 mg Ledipasvir film.

Equipment
[182] The primary equipment used to manufacture FDC tablets coated with 400 mg SOF / 90 mg Ledipasvir film included a 12 qt “V” Blender, a screen grinder (Comil 197S, Quadro, Waterloo, Canada ) equipped with a 2,388 mm graduated screen, a roller compactor / granulator (MiniPactor, Gerteis, Jona, Switzerland) equipped with a 1.0 mm grinding screen and a smooth / smooth cylinder configuration, a rotary tablet press instrumented 12 stations (XM-12, Korsch, Berlin, Germany), and a tablet coating apparatus (LabCoat, O'Hara Technologies Inc., Ontario, Canada). The diamond-shaped tablet modeling tool (Elizabeth Carbide Die Co., Inc., McKeesport, PA, USA) consisted of standardized concave D-type diamond punches, with dimensions of 19.43 mm x 10.20 mm. A 38.1 cm perforated film coating apparatus was used to coat the tablet cores. Container closure
[183] Sofosbuvir / Ledipasvir FDC tablets are packaged in 100 ml white high density polyethylene (HDPE) bottles. Each bottle contained 30 tablets and a bag or sachet of 0, 1 or 3 g of silica gel desiccant and polyester packaging material. Each bottle was closed with a white screw cap, resistant to children, with a lining with an induction sealed aluminum face.
[184] A selected number of bottles were left open and packaged without desiccant to assess physical and chemical stability at 40 ° C / 75% relative humidity under accelerated heat and humidity conditions. General study design
[185] The solid state and chemical stability of the packaged batch were evaluated in the following configurations: 1) At 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity due to desiccant. The samples were stored under closed condition for a minimum of 24 weeks. 2) At 40 ° C / 75% relative humidity under open condition for up to 4 weeks.
[186] The samples were examined at predetermined time points. The chemical stability test for appearance, potency, degradant formation, dissolution rate and water content was carried out. Additional physical stability tests were performed to monitor potential crystallization and phase separation. Assessment of physical stability
[187] Physical stability tests included appearance and FT-Raman. Visual inspection was performed on stressed film-coated tablets to identify changes in the color of the tablet and integrity of the coating. FT-Raman spectroscopy was used to detect potential crystalline ledipasvir (Form III) in film-coated tablets.
[188] The tablets were visually inspected for changes in appearance at all time points and storage conditions. In contrast, FT-Raman was only performed on tablets with 0 g of desiccant in 24 weeks (25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity). Appearance
[189] At all time points, the tablets were examined for physical integrity (ie color, shape, coating integrity and scaling). FT-Raman
[190] FT-Raman experiments were carried out. The 24-week film-coated FDC SOF / ledipasvir tablets stored in closed containers at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity were analyzed using FT-Raman spectroscopy to detect the formation of crystalline ledipasvir (Form III). Briefly, the tablet liner was carefully removed using a XactoTM knife, followed by crushing the tablet in a pestle and mortar. The tablet powder was then placed in bowls and spectra were collected using backscatter geometry. Chemical stability assessment
[191] Chemical stability tests were carried out which included the measurement of water content by Karl Fischer (KF), potency, formation of impurity / degradation products and dissolution rate. Water content of KF
[192] The water content was recorded for FDC 400 mg SOF / 90 mg ledipasvir film-coated tablets according to USP <921>. Power and impurity / degradation formation by UPLC
[193] The potency and degradation product formation of SOF / ledipasvir film-coated FDC tablets were evaluated by analyzing a sample solution composed of 10 tablets according to STM-2542 [5]. The standard reference concentration for SOF and ledipasvir is 2.0 mg / ml and 0.45 mg / ml, respectively. The power and degradation product content of SOF and ledipasvir were determined by UPLC using an external reference standard and area normalization at wavelengths of 262 nm and 325 nm, respectively. Dissolution methodology
[194] The dissolution test was performed on SOF / ledipasvir film-coated FDC tablets. A USP type 2 dissolution apparatus with 900 ml of dissolution medium and a vane speed of 75 rpm was used. The medium was 1.5% polysorbate 80 in 10 mM potassium phosphate buffer at pH 6.0 and the temperature was maintained at 37 ° C for the duration of the test. The extent of SOF and ledipasvir released as a function of time was monitored by UPLC using area normalization and an external reference standard at a wavelength of 250 nm. RESULTS A. Physical stability Appearance
[195] Samples in all conditions of stability and desiccant levels were visually inspected for all time points and found to look like blue film-coated diamond-shaped tablets. FT-Raman
[196] FT-Raman analysis was performed on powder extracted from tablets stored in the absence of desiccant after 24 weeks. Calculations of% crystallinity using the PLS model did not show signs of crystalline ledipasvir (Form III) above the LOD of 3% under any storage condition. This was consistent with the original sample (t = 0) in which ledipasvir (Form III) was also below the LOD. Spectra of selected samples were included in the graph, from 1,577 cm-1 to 1,514 cm-1 with the baselines artificially adjusted for clarity. This region is in one of the four spectral regions used to estimate the% ledipasvir (Form III) in tablets using the PLS model.
[197] The top two spectra (used as standards in the PLS model) in the graph were tablets speckled with 10% w / w and 3% w / w crystalline ledipasvir (Form III). The following two spectra represent stressed tablets stored for 24 weeks at 40 ° C / 75% relative humidity and 25 ° C / 60% relative humidity. The last spectrum represents the starting time point (t = 0). Ledipasvir (Form III) has a distinct peak at 1,552 cm-1, which can be clearly seen in the splashed tablets with an increasing intensity of 3% to 10%. The intensity in this region for stressed samples stored for 24 weeks does not increase in relation to the crystallinity sample. Ledipasvir (Form III) in the sample of t = 0 and in the samples of 24 weeks is below that present in the tablets speckled with 3% Ledipasvir Form III, the current detection limit for this analytical technique. 8. Chemical stability B.1 KF water content
[198] The water content of stressed samples stored for 4 weeks under open condition increased from 2.28% to 5.23%. The amount of water content of stressed samples stored at 25 ° C / 60% relative humidity decreased to 1.91%, 1.58% and 1.65% for tablets without desiccant, with 1 g of desiccant and 3 g of desiccant. desiccant, respectively. At 40 ° C / 75% relative humidity, the amount of water content decreased to 2.03%, 1.79% and 1.46% for tablets without desiccant, with 1 g of desiccant and 3 g of desiccant, respectively . B.2 Power and formation of impurities / degradation product
[199] The potency and impurity / degradation content for FDC 400 mg SOF / 90 mg ledipasvir film-coated tablets were determined at 25 ° C / 60% relative humidity and 40 ° C / 75% humidity relative. Chromatograms representative of stability samples stored at 40 ° C / 75% relative humidity were obtained. The data showed that SOF and ledipasvir remained chemically stable in 400 mg SOF / 90 mg film-coated ledipasvir FDC tablets stored for 24 weeks at 25 ° C / 60% relative humidity and 40 ° C / 75% humidity relative. The label power for SOF and ledipasvir remains unchanged at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity. Dissolution
[200] The dissolution profiles of SOF and ledipasvir in 400 mg SOF / 90 mg film-coated ledipasvir FDC tablets were obtained. At the 24-week time point, the tablets varied between 99% and 100% dissolution in 45 minutes for SOF, and between 99% and 98% for ledipasvir at either 25 ° C / 60% relative humidity or 40 ° C / 75% relative humidity for all tested desiccant levels.
[201] Considering what was presented earlier, this example shows that FDC 400 mg SOF / 90 mg ledipasvir film-coated tablets exhibited satisfactory stability at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for up to 24 weeks in the presence of 0, 1 and 3 g of desiccant. In addition, crystalline ledipasvir (Form III) was not detected by FT-Raman analysis after 24 weeks of storage. Example 7. Development of a 400 mg SOF / 90 mg Ledipasvir fixed dose combination tablet (FDC) formulation
[202] This example shows the development of a 400 mg SOF / 90 mg ledipasvir fixed dose combination tablet (FDC) comprising ledipasvir: copovidone (1: 1). Difficulties with this development were already expected, one of them was the expected low powder flow and the other is related to the inhomogeneous mixture, considering the existing formulations of each individual agent.
[203] Three tablet formulations were tested, including: (1) a monolayer co-granulated tablet formulation, (2) a monolayer co-mixed tablet formulation and (3) a bilayer tablet formulation. In all these formulations, SOF was in anhydrous crystalline form II and ledipasvir was in solid amorphous dispersion (ledipasvir: copovidone (1: 1)).
[204] Formulation (1) is typically associated with an increased risk of drug-drug interaction, but is the most cost-effective during manufacture. The bilayer formulation of (3), in contrast, has the lowest risk of drug-drug interaction.
[205] The dissolution performance of the formulations was tested in a dissolution medium that included 10 mM phosphate buffer at pH 6.0 (1.5% Tween® 80). As shown in FIG. 8A-B, all three formulations had comparable dissolution performance, similar to that of single agent controls.
[206] The pharmacokinetic performance (PK) of each formulation was also tested. The plasma concentration of SOF / ledipasvir after oral administration of FDC of SOF / ledipasvir and control tablets in fasting dogs was 100 mg / 22.5 mg fixed / dog. Table 17 below shows the PK results. Table 17. Pharmacokinetic performance of formulations in dogs pretreated with famotidine.


[207] Based on these results, the monolayer co-granulated tablet was selected for further analysis. The composition of this formulation is given in Table 18. Table 18. Composition of FDC tablets of 400 mg SOF / 90 mg Ledipasvir.


[208] A clinical bioavailability study was conducted with this formulation, with single agent tablets as a control, in 24 healthy patients under fasting conditions. The results are shown in Table 19. Table 19. Bioavailability of a fixed dose combination of SOF / Ledipasvir and with single agent primers.

[209] These results, therefore, show that the fixed dose combination of SOF / ledipasvir (co-granulated) and single agent tablets ARE bioequivalent. Example 8. Solubility studies for amorphous Ledipasvir
[210] This example examines the physicochemical properties of different forms of ledipasvir, including amorphous and crystalline free base, solvates and salts, with respect to solubility. A. Materials and methods pH-solubility profile
[211] The aqueous solubility of ledipasvir amorphous free base was determined using the pH range from 1 to 10. Excessive solid ledipasvir was added to a range of pH-adjusted aqueous solutions (titrated with HCl or NaOH) and stirred for 48 hours. hours at room temperature. The suspensions were then filtered through regenerated cellulose syringe filters. The pH value of the supernatant was measured, and the supernatant was diluted as appropriate with 50:50 H2O + 0.1% TFA: ACN and tested for ledipasvir content by the HPLC-UV method. Solubility in simulated intestinal media
[212] The solubility of ledipasvir amorphous free base was evaluated in three types of intestinal fluids simulated at pH 6.5 or pH 5.0; and simulated intestinal bile salt and lecithin mixture (SIBLM), pH 6.4. Excessive solid Ledipasvir was added to the respective SIFs and stirred for 48 hours at room temperature. The resulting suspensions were then filtered through regenerated cellulose syringe filters. The supernatant was diluted as appropriate with 50:50 H2O + 0.1% TFA: ACN and tested for ledipasvir content by the HPLC-UV method. Excipient solubility
[213] The solubility of the amorphous free base of ledipasvir and crystalline ledipasvir D-tartrate has been measured in a wide range of pharmaceutically acceptable solvents, including cosolvents, surfactants, fatty acids, triglycerides, or mixtures thereof. The material was weighed in scintillation flasks and stirred for up to 48 hours at room temperature. In many cases, the solubility was greater than the amount of solid used in the sample and, therefore, many results are reported as "greater than" or "more than or equal to", if the concentration was not quantitatively determined by HPLC-UV.
[214] In addition, aqueous solubility was measured as a function of time in the presence of 0.1% w / w surfactants and polymers at pH 2 (50 mM citrate) and pH 5 (50 mM citrate). The crystalline forms of ledipasvir (acetone solvate Form II; anhydrous FB Form III; D-tartrate) and the amorphous form were evaluated to identify differences in dissolution behavior. Excessive solid was added to buffered aqueous solutions; the samples were taken at predetermined intervals (2, 5, 8, 10, 15, 20, 30, 45, 60 minutes and 24 hours), filtered through regenerated cellulose filters, and diluted for concentration measurement using the HPLC- UV. B. Results Solubility and dissolution rate
[215] The pH-solubility profiles of all available ledipasvir forms were determined at room temperature and are shown graphically in FIG. 9. The flat portion of the solubility profile (pH> 5) represents the intrinsic aqueous solubility of the free base. The aqueous solubility of ledipasvir increases significantly as the pH of the solution is reduced below the pKa of the ionizable groups. All forms lose crystallinity, reverting to the free amorphous base in aqueous solution and, thus, show similar properties of aqueous solubility at equilibrium. However, the dissolution properties are form-dependent and are described in more detail below. Ledipasvir amorphous free base
[216] The intrinsic solubility of ledipasvir (FB) amorphous free base is approximately 0.04 μg / ml. Under acidic conditions, the solubility increases to 1 mg / ml at pH 2.3 and peaks at about 7 mg / ml at pH 1.6, as shown in Table 20 and FIG. 9. The solubility of ledipasvir in simulated intestinal fluids is governed both by the pH of the medium and by the presence of bile salts and lecithin. In simulated fasted intestinal fluids (FaSSIF) at pH 6.5 and room temperature, the solubility is 0.025 mg / ml, and it is increased approximately 10 times to 0.232 mg / ml in a simulated mixture of bile and lecithin (SIBLM , pH 6.5) due to the increased concentration of bile salts and lecithin. A similar increase in solubility to 0.230 mg / ml is seen in simulated intestinal fluid in the prandial state (FeSSIF, pH 5), which contains less mixtures of bile salt and lecithin than SIBLM. The increase in solubility in this mixture is predominantly attributed to the ionization state of the molecule at pH 5. Table 20. Ledipasvir amorphous free base solubility as a function of pH at room temperature.
1 FaSSIF is water with 3 mM sodium taurocholate and 0.75 mM lecithin, pH adjusted to 6.5 with phosphate buffer, ionic strength adjusted to 0.15 M with NaCl. 2 FeSSIF is water with 15 mM sodium taurocholate and 3.75 mM lecithin, pH adjusted to 6.5 with phosphate buffer, ionic strength adjusted to 0.15 M with NaCl. 3 SIBLM is water with 30 mM sodium glycocholate, 30 mM sodium glycochlodeoxycholate, 15 mM sodium glycodoxycholate, 10 mM sodium taurocholate, 10 mM sodium taurochenodeoxycholate, 5 mM sodium taurodeoxycholate, 50 mM sodium sodium chloride and 11 mM lecithin, pH adjusted to 6.4 with phosphate buffer, ionic strength adjusted to 0.15 M with NaCl.
[217] The rate of dissolution of the amorphous free base of ledipasvir at pH 3 and 6 was also tested. At pH 3, the dissolution of the amorphous free base form is faster than that of the crystalline free base forms and acetone solvate. However, at pH 6, all forms of free base show similar dissolution rate profiles.
[218] As shown in Table 21, ledipasvir's amorphous free base is freely soluble (> 500 mg / ml) in ethanol and other organic solvents such as propylene glycol and PEG 400. Its solubility is greater than 200 mg / ml in surfactants (eg polysorbate 80, Cremophor EL, Labrasol) and mixtures of lipids. Its solubility in oleic and octanoic acids is greater than 500 mg / ml. The solubility of ledipasvir in short-chain triglycerides (SCTs, tributyrin) is limited to 20 mg / ml, and decreases to less than 1 mg / ml in long-chain triglycerides (LCTs, soybean oil). It has a solubility of 25 mg / ml in the vehicle chosen for toxicological studies: propylene glycol 45%, caprilocaproil glycerides macrogol-8 15% (Solutol HS 15®) and water 40% (pH 2.5 per HCl). Table 21. Solubility of free base forms of Ledipasvir and Ledipasvir D-tartrate in solvents and organic excipients at room temperature.

1 RSSEDDS: Ethanol 10%, PG 10%, Solutol HS-15 40%, Labrasol 40%
[219] Diluted non-ionic surfactants generally increase the solubility of ledipasvir at both pH 2 and pH 5, as shown in Table 22. Similar effects have been observed with nonionic polymers, albeit to a lesser degree. Sodium lauryl sulfate (SLS), an anionic surfactant, increases the solubility of ledipasvir at pH 5. However, a significant decrease in solubility is noted in the presence of SLS under acidic conditions (pH 2). This observation is consistent with weakly basic compounds that have low intrinsic aqueous solubility, presumably forming an insoluble stolate salt. Table 22. Ledipasvir amorphous free base solubility in surfactant or polymeric excipients (0.1% w / w) diluted in aqueous media at pH 2 and 5 at room temperature.

Ledipasvir crystalline acetone solvate
[220] Ledipasvir acetone solvate (Ledipasvir-03) showed steady state solubility similar to other forms. Ledipasvir-03 has the lowest dissolution of all tested forms. Its dissolution at pH 6 was indistinguishable from that of other forms due to the low intrinsic solubility (<0.1 μg / ml).
[221] Ledipasvir-03 is soluble in many organic solvents and in pharmaceutically acceptable solvents, and the solubilities are comparable to those listed for the ledipasvir amorphous free base, as also shown in Table 21. Ledipasvir crystalline free base (Form III)
[222] Form III of the Ledipasvir crystalline free base showed steady state solubility similar to the other forms (FIG. 9). This form dissolves more slowly than the free amorphous base, but faster than Ledipasvir-03. The dissolution at pH 6 was indistinguishable from that of the other forms due to the low intrinsic solubility (<0.1 μg / ml). Solubility in a wider range of organic vehicles has not been explored, although it is expected to be similar to other forms of free base. Ledipasvir crystalline D-tartrate salt (Ledipasvir-02)
[223] Ledipasvir crystalline D-tartrate salt (Ledipasvir-02) showed steady state solubility similar to other forms (FIG. 9). The dissolution behavior of Ledipasvir-02 is improved in relation to all forms of free base. At pH 3, Ledipasvir-02 shows an initial dissolution rate approximately 5 to 10 times faster than the free base forms, and approximately doubled the amount of ledipasvir in solution for 60 minutes, compared to the amorphous form. At pH 6, the increased dissolution rate was also apparent. However, the rapid dissociation of the salt at this pH resulted in solubility values equivalent to other forms within minutes.
[224] Ledipasvir-02 is not soluble in various organic media, as shown in Table 21. The maximum solubility of Ledipasvir-02 in any organic vehicle is 20 mg / ml in methanol; this limits the use of Ledipasvir-02 in solubilized formulations or processes that require solubilization in organic media.
[225] Ledipasvir has low aqueous solubility and high permeability, and is considered a BCS Class 2 compound. The data presented in this example indicate that in water, all forms of ledipasvir, that is, the amorphous free base, acetone solvate crystalline free base (Ledipasvir-03), the anhydrous crystalline free base (Form III) and the crystalline D-tartrate salt (Ledipasvir-02), become the amorphous free base, and have similar aqueous solubility at equilibrium. The aqueous solubility of ledipasvir is less than 0.1 μg / ml in its neutral form (pH> 5), but increases substantially under acidic conditions due to the protonation of two basic portions. The aqueous dissolution rate of ledipasvir amorphous free base is faster than that of crystalline free base forms. However, all forms of free base have slower dissolution rates than the crystalline D-tartrate salt (Ledipasvir-02). Ledipasvir-02 also shows increased wetting in aqueous media. The ledipasvir free base forms, crystalline and amorphous, are highly soluble in a range of cosolvents and surfactants. In contrast, Ledipasvir-02 is poorly soluble in organic excipients, and this property potentially limits its usefulness.
[226] Ledipasvir's amorphous free base has been used in Phase 1 clinical studies, but the manufacture of the drug substance has been identified as a crucial form limitation. The Ledipasvir crystalline D-tartrate salt (Ledipasvir-02) was then identified as part of a more extensive selection of salt and form and was used in Phase 2, however, the low solubility in organic excipients limits its usefulness in non-formulations. conventional. Ledipasvir crystalline acetone solvate (Ledipasvir-03) is used to develop an atomized dispersion formulation to support future clinical studies due to its solubility in solvents and organic excipients in relation to Ledipasvir's crystalline D-tartrate salt and increased workability in relation to other forms of free base. Example 9: Efficacy of a fixed dose combination of Sofosbuvir and Ledipasvir with and without Ribavirin in patients with HCV infections
[227] Patients with HCV infections were treated with a fixed dose combination of sofosbuvir and ledipasvir, with and without ribavirin. Patients used in the studies include those who were treatment-naive (non-cirrhotic), that is, they had not been previously treated for HCV, and those who had protease inhibitor (PI) failures and were unresponsive (with and without cirrhosis), that is, they had been previously treated for HCV, but did not respond to treatment. Treatment-naive patients were treated for 6, 8 and 12 weeks and non-responsive patients were treated for 12 weeks. Study 1
[228] Cohort 1 of study 1 included patients of Genotype 1 without cirrhosis, treatment-naive. Patients were randomized 1: 1: 1 into three groups to receive: 1) fixed dose combination of SOF / ledipasvir for 8 weeks, 2) fixed dose combination of SOF / ledipasvir with ribavirin for 8 weeks, or 3) combination of fixed dose of SOF / ledipasvir for 12 weeks (FIG. 10).
[229] Cohort 2 of study 1 included patients of Genotype 1 undergoing treatment with a protease inhibitor (failures with previous treatment with a protease inhibitor, 50% of whom had compensated cirrhosis). Patients were randomized to receive 12 weeks of: 1) fixed dose combination of SOF / ledipasvir or 2) fixed dose combination of SOF / ledipasvir with ribavirin (FIG. 10). In Cohort 2, patients must not have discontinued prior therapy as a result of an adverse event.
[230] In study 1, there were broad inclusion criteria, specifically, there was no upper limit for age or BMI. Platelets were> 50,000 / mm3. Demographic data from study 1 is shown in Table 23, below. Table 23. Demographic data.

[231] Of 100 patients enrolled in study 1, 97% achieved sustained viral response. Of the failures, two patients presented recurrence (one from Group 1 (ie, SOF / Ledipasvir x 8 weeks) and one from Group 4 (ie, SOF / ledipasvir x 12 weeks), and one patient lost follow-up in Group 3 ( ie, SOF / ledipasvir x 12 Weeks), however, the patient who missed follow-up obtained SVR at week 8 and refused to participate in additional return visits.
[232] In cohort 1 of study 1 (ie, non-cirrhotic treatment naïve patients), 58 of 60 patients treated for 8 or 12 weeks obtained SVR. In cohort 2 of study 1 (that is, patients undergoing treatment, PI failure), 39 out of 40 patients treated for 12 weeks obtained SVR12. Twenty-one of the 21 cirrhosis patients obtained SVR12 (FIG. 11).
[233] In study 1, seven of the nine patients with variants associated with NS5A resistance (RAVs) achieved sustained viral response. In addition, all patients with variants associated with resistance to NS3 / 4A obtained a sustained viral response. Interestingly, the S282T mutation and multiple RAVs to NS5A were detected in relapse in the patient who experienced failure in Group 1 (Table 24). The safety summary and a reduction in adverse effects are shown in Tables 25 and 26, respectively. Table 24. Resistance analysis.
* number of patients in cohort 2 with previous exposure to a protease inhibitor. Table 25. Security summary.

* peptic ulcer, spinal compression fracture ** delirium, suicidal ideas Table 26. Adverse events (> 5% of total patients).

Study 2
[234] In study 2, treatment naive patients received fixed dose combination of SOF / ledipasvir with ribavirin and previous nonresponsive patients, all with cirrhosis, were randomized to receive twelve weeks of: 1) fixed dose combination of SOF / ledipasvir or 2) fixed dose combination of SOF / ledipasvir with ribavirin. Results of
[235] Of the 144 patients treated in both studies, 1 and 2, 136 of the 144 (94%) achieved SVR within four weeks of treatment. Of the 85 treatment naïve patients in these two studies, three out of 25 patients did not obtain SVR after 6 weeks of fixed dose combination of SOF / ledipasvir with ribavirin therapy, while 100% (60/60) of the patients obtained SVR after 8 or 12 weeks of fixed dose combination of SOF / ledipasvir with and without ribavirin therapy. Of the 59 previously treated patients in these two studies, three cirrhotic patients had relapse after receiving 12 weeks of fixed-dose SOF / ledipasvir combination without ribavirin. Conversely, no virological failure was observed in the treatment groups with fixed dose combination of SOF / ledipasvir with ribavirin, but two patients in these groups were not followed up. The fixed dose combination of SOF / ledipasvir with and without ribavirin was well tolerated, with few SAEs and minimal adverse events. Conclusion
[236] The fixed dose combination of SOF / ledipasvir +/- ribavirin can be given for even only 8 weeks to non-cirrhotic treatment naïve patients. Previously treated patients, even those with cirrhosis, obtained high rates of SVR with 12 weeks of the fixed dose combination of SOF / ledipasvir with and without ribavirin therapy. Example 10: Efficacy of multiple combined anti-HCV therapy in chronically infected hepatitis C patients
[237] To assess the safety, tolerability and efficacy of 4 to 12 weeks of SOF with ledipasvir, alone or in combination with Compound E and / or Compound J in HCV patients, HCV patients will be dosed as shown in Table 27. Table 27. Dosage.




[238] The primary analysis scheduled for safety analyzes will include patients who received at least one dose of the study drug. Treatment data will be analyzed and defined as data collected from the first dose of the study drug until the date of the last dose of the study drug plus 30 days. Patients who received study drug other than the one to which they were assigned will be analyzed according to the study drug received.
[239] The analysis scheduled for analyzes of antiviral activity will include patients who were included in the study and received at least one dose of the study drug.
[240] The scheduled pharmacokinetic analysis will include all patients who are included and received at least one dose of study medication.
[241] The patient will begin treatment of the study after confirmation of eligibility on Day 0 and after being fully informed about the rest of the study, and after signing the specific authorization for the treatment group (if not done previously). Blood will be collected to measure HCV viral loads, study drug levels, lipid levels for research, if the collection has not been done during selection, immunological studies and for storage before dosing as part of authorization in the selection . A pregnancy test will be done on women of childbearing potential and the pregnancy test must be negative on Day 0 before dosing with the study drugs. Patients will be asked to complete a basic compliance questionnaire, and an electronic pill bottle cap, which records the pill bottle openings, will be placed on all study drug bottles. Help will be provided to complete the questionnaire, if necessary. Patients in Arms B and H will also receive a diary on Day 0, Week 2, Week 4 (only in Arm B) to record gastrointestinal side effects.
[242] Upon arrival at the Clinic for scheduled study visits, patients will have their vital signs obtained, women will be subjected to a pregnancy test (if appropriate by the schedule and from fertile women), blood will be collected for laboratory clinical exams and a review of the study restrictions will be made.
[243] At each scheduled study visit (does not include Day 1, 3, 5, 10, Week 2, Week 3, Week 6 (not applicable for Arm F, G or H) or week 2 and 8 post-treatment that are for laboratory collection only), patients will be asked about their health status and use of any concomitant medication since the previous study visit. They will also be asked about adverse events and their adherence to the study restrictions. Vital signs, weight will be collected and an examination will be done according to the flow of the study. A complete list of study procedures and laboratory tests to be performed is in the Test Schedule, below. In addition, patients can be seen on unscheduled visits for a Grade 3 or 4 adverse event or any adverse event or potential unanticipated toxicity.
[244] Patients may be asked to complete a follow-up adherence questionnaire, and pill bottle openings can be recorded through the electronic bottle cap on Day 7 (Group A), Week 4 (Group A), Week 6 (Groups B and C), Week 8 (Group A), and Week 12 (Group A). Help will be provided to complete the questionnaire, if necessary.
[245] Patients in Groups B and H will be asked to bring their side effects diaries to visits at Week 2, 4, 6 (B only).
[246] Some of the visits will have a little flexibility as to when they should take place. Visits that occur during the interval at which the patient is receiving the study drug have limited flexibility, as they occur very frequently and, therefore, a missed visit during this period can be considered as a missed visit. The window period for scheduling visits is as shown in Table 28. Table 28. Window period for scheduling visits.


[247] During the week four visit, HCV RNA can be obtained to determine whether criteria for discontinuing treatment based on the virological response have been met. Patients who fail to achieve a> 2 log10 drop in HCV RNA (unless the> 2 log drop is below LLOQ) should be discontinued from therapy unless a review by the PI / LAI / Sponsor Medical Monitor determines otherwise form (see 9.3.1).
[248] At the end of the treatment duration as determined by the study group, patients can suspend the dosage of SOF and ledipasvir, Compound E and / or Compound J. In addition, if a patient's participation ends before the end of the duration pre-specified study drug, final treatment assessments can be performed at any end-of-treatment visit. An optional research liver biopsy for research purposes can now be performed on up to 10 patients in each study group. Additional liver biopsy data will serve to explore liver HCV RNA sequence analysis. If patients undergo a liver biopsy for optional research, they can have safety tests completed before the procedure and undergo imaging tests, as medically indicated. Patients who have an HCV VL <LLOQ may receive instructions on how to prevent HCV reinfection.
[249] All patients can be assessed for sustained virological response at the 12-week post-final treatment visit. Patients who have HCV VL <LLOD may receive instructions on how to prevent HCV reinfection.
[250] After study drug withdrawal, patients can be followed up at 2, 4, 8, 12, 24, 36 and 48 weeks post-final treatment. A serological pregnancy test can be done with each visit, as appropriate. Visits at the 2nd and 8th weeks after the end of treatment may only include collection for laboratory tests.
[251] Individuals (n = 18) received single doses of sofosbuvir (400 mg) alone or in combination with Compound E (500 mg QD) under postprandial conditions. Preliminary PK results for the combination of sofosbuvir with Compound E are shown in Table 29 and demonstrate the absence of a clinically significant interaction between sofosbuvir and Compound E. Table 29: Pharmacokinetic data for SOF, Compound E and ledipasvir alone and by co-administration.


[252] It should be understood that, although the present invention has been specifically disclosed by preferred modalities and optional features, the modification, enhancement and variation of the inventions disclosed herein can be used by those skilled in the art, and that these modifications, enhancements and variations are considered to be included in the scope of this invention. The materials, methods and examples provided herein are representative of preferred embodiments, are exemplary and are not intended to be limitations on the scope of the invention.
[253] The invention has been described here broadly and generically. Each of the narrower species and subgeneric groupings included in the generic disclosure also form part of the invention. This includes the generic description of the invention with the negative condition or limitation that removes any matter in question from the genre, regardless of whether or not the material removed is specifically cited here.
[254] Furthermore, when features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also described by them in terms of any individual member or subgroup of members of the Markush group.
[255] All publications, patent applications, patents and other references mentioned herein are expressly incorporated by reference in their entirety, to the same degree as if each were incorporated by reference individually. In the event of a conflict, this specification, including definitions, will prevail.

权利要求:
Claims (7)
[0001]
1. Pharmaceutical composition in the form of a tablet with a fixed dose combination, characterized by the fact that it comprises: a) from 10% to 25% of a solid dispersion comprising ledipasvir dispersed in a polymeric matrix formed by copovidone, in which the proportion by weight of ledipasvir to copovidone in the solid dispersion is 1: 1, where ledipasvir is amorphous and has the formula:
[0002]
2. Pharmaceutical composition according to claim 1, characterized by the fact that it comprises: a) 40% by weight of sofosbuvir, and b) 18% by weight of the solid dispersion.
[0003]
3. Pharmaceutical dosage form, characterized by the fact that it comprises the pharmaceutical composition defined in claim 1, comprising 90 mg of ledipasvir and 400 mg of sofosbuvir.
[0004]
4. Pharmaceutical composition in the form of a tablet with a fixed dose combination, characterized by the fact that it comprises: a) 18% by weight of a solid dispersion comprising ledipasvir dispersed in a polymeric matrix formed by copovidone, in which the proportion by weight from ledipasvir to copovidone in solid dispersion is 1: 1, where ledipasvir is amorphous and has the formula:
[0005]
Pharmaceutical composition according to claim 1, characterized in that it comprises a film coating.
[0006]
6. Use of the pharmaceutical composition defined in claim 1, characterized by the fact that it is for the preparation of a drug for the treatment of hepatitis C.
[0007]
7. Use according to claim 6, characterized by the fact that the hepatitis C virus is genotype 1a or 1b.

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法律状态:
2016-09-06| B65X| Notification of requirement for priority examination of patent application|

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2016-10-04| B65Y| Grant of priority examination of the patent application (request complies with dec. 132/06 of 20061117)|

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2016-10-25| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2017-01-31| B07D| Technical examination (opinion) related to article 229 of industrial property law|

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2018-04-17| B07E| Notice of approval relating to section 229 industrial property law|

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2018-08-14| B07A| Technical examination (opinion): publication of technical examination (opinion)|

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2019-04-24| B07A| Technical examination (opinion): publication of technical examination (opinion)|

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2020-01-28| B09B| Decision: refusal|

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2020-06-23| B12B| Appeal: appeal against refusal|

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2021-03-16| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 30/01/2014, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201361759320P| true| 2013-01-31|2013-01-31|

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US201361772292P| true| 2013-03-04|2013-03-04|

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US61/772.292|2013-03-04|

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US201361828899P| true| 2013-05-30|2013-05-30|

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US61/828.899|2013-05-30|

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US201361870729P| true| 2013-08-27|2013-08-27|

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US61/870.729|2013-08-27|

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US201361897793P| true| 2013-10-30|2013-10-30|

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US201361907332P| true| 2013-11-21|2013-11-21|

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