WO2020181163A1

WO2020181163A1 - Lipid-based formulation of cenicriviroc

Info

Publication number: WO2020181163A1
Application number: PCT/US2020/021315
Authority: WO
Inventors: Yi-Ling Hsieh; Hovhannes John Gukasyan; Pushpa Chandrasekar
Original assignee: Tobira Therapeutics, Inc.
Priority date: 2019-03-06
Filing date: 2020-03-06
Publication date: 2020-09-10

Abstract

The described invention provides pharmaceutical formulations comprising cenicriviroc (CVC) and either a lipid, a surfactant, a co-solvent or a combination thereof and methods of using the same.

Description

LIPID-BASED FORMULATION OF CENICRIVIROC

CROSS-REFERENCE TO RELATED APPLICATIONS

[00001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62/814,436, filed March 6, 2019, and U.S. Provisional Patent

Application No. 62/982,901 , filed February 28, 2020, the contents of each are

incorporated by reference herein in their entireties.

FIELD OF THE INVENTION

[00002] The described invention generally relates to pharmaceutical formulations and therapeutic methods of use.

BACKGROUND OF THE INVENTION

[00003] Nonalcoholic Fatty Liver Disease (NAFLD)

[00004] Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat is stored in the liver not caused by heavy alcohol use. NAFLD is associated with increased morbidity and mortality worldwide, mainly attributable to cardiovascular and chronic liver diseases (Lefebvre E. et al. , Clin Transl Sci. 2016 Jun; 9(3): 139-148;

Zhang Q.Q. et al., J. Clin. Transl. Hepatol. 3, 78-84 (2015). Two types of NAFLD exist: (i) simple fatty liver also called nonalcoholic fatty liver (NAFL); and (ii) nonalcoholic steatohepatitis (NASH). NAFL is characterized by excess fat in the liver but little or no inflammation or liver cell damage. NASH is a form of NAFLD characterized by hepatitis (i.e. , inflammation of the liver) and liver cell damage, in addition to fat in the liver.

Inflammation and liver cell damage can lead to fibrosis, or scarring, of the liver. NASH may ultimately lead to cirrhosis or liver cancer. While disease progression for people with liver steatosis is typically slow, those with NASH and hepatic fibrosis can progress to cirrhosis and hepatocellular carcinoma (Lefebvre E. et al., Clin Transl Sci. 2016 Jun; 9(3): 139-148; Vernon G. et al., Aliment. Pharmacol. Ther. 34, 274-285 (2011 ); Matteoni C.A. et al., Gastroenterology 116, 1413-1419 (1999)). NASH is the second indication for liver transplant in the United States and is predicted to become the first by the year 2020 (Lefebvre E. et al., Clin Transl Sci. 2016 Jun; 9(3): 139-148; Wong R.J. et al., Gastroenterology 148, 547-555 (2015)). There are currently no approved agents to treat NASH, but several classes of medication (e.g., insulin sensitizers, fatty acid-bile acid conjugates, antifibrotic agents, and C-C chemokine receptor types 2 and 5 (CCR2/CCR5) antagonists) are currently being investigated (Lefebvre E. et al. , Clin Transl Sci. 2016 Jun; 9(3): 139-148; Ratziu V. et al., J. Hepatol. 62, S65-S75 (2015)).

[00005] CCR2/CCR5 Antagonists

[00006] CCR2/CCR5 antagonists disrupt the interactions between CCR2/CCR5 and their ligands, which mediate the inflammatory immune response that can lead to fibrogenesis (Lefebvre E. et al., Clin Transl Sci. 2016 Jun; 9(3): 139-148; Seki E. et al.,

J. Clin. Invest. 119, 1858-1970 (2009); Seki E. et al., Hepatology 50, 185-197 (2009)).

Following hepatocyte injury, hepatic macrophages (Kupffer cells) secrete C-C chemokine ligand type 2 (CCL2, a.k.a. monocyte chemoattractant protein-1 (MCP-1 )), driving the recruitment and migration of proinflammatory monocytes to the liver where they mature into macrophages (Lefebvre E. et al., Clin Transl Sci. 2016 Jun; 9(3): 139-

148; Karlmark K.R. et al., Hepatology 50, 261 -274 (2009); Miura K. et al., Am. J.

Physiol. Gastrointest. Liver Physiol. 302, G1310-G1321 (2012)). These macrophages secrete proinflammatory cytokines (e.g., transforming growth factor-b [TGF-b], platelet- derived growth factor [a potent myofibroblast growth factor], interleukin(IL)-1 b, and adipose tissue proinflammatory mediators, such as IL-6 and tumor necrosis factor-a

[TNF-a]) that activate hepatic stellate cells (HSCs) and further aggravate hepatocyte injury (Lefebvre E. et al., Clin Transl Sci. 2016 Jun; 9(3): 139-148; Pradere J.P et al.,

Hepatology 58, 1461 -1473 (2013); Bataller R. & Brennar D.A., J. Clin. Invest. 115,

2019-218 (2005)). Activated HSCs differentiate into myofibroblast-like cells that produce collagen, the basis of the extracellular matrix that deposits in the liver, resulting in fibrosis and, eventually, cirrhosis (Lefebvre E. et al., Clin Transl Sci. 2016 Jun; 9(3):

139-148; Pradere J.P. et al., Hepatology 58, 1461-1473 (2013); Bataller R. & Brennar

D.A., J. Clin. Invest. 115, 2019-218 (2005)). This process is further exacerbated by increased bacterial translocation observed in liver disease. Bacterial products such as lipopolysaccharide enhance hepatic inflammation and fibrosis via Toll-like receptor

(TLR) 4-mediated activation of Kupffer cells and HSCs (Lefebvre E. et al., Clin Transl

Sci. 2016 Jun; 9(3): 139-148; Seki E. et al., Nat. Med. 13, 1324-1332 (2007)). TLR5 activation by flagellin (a marker of bacterial translocation) has also been shown to cause hepatic injury in mice; flagellin induces CCL4 (a.k.a. macrophage inflammatory protein-1 b) and CCL5 (a.k.a. regulated on activation normal T-cell expressed and secreted [RANTES]) expression in H IV- 1 -infected lymphoid tissue (Lefebvre E. et al., Clin Transl Sci. 2016 Jun; 9(3): 139-148; Xiao Y. et al., Cell Mol. Immunol. 12, 729-742 (2015); Brichacek B. et al., PLoS One 5, e12831 (2010)).

[00007] Cenicriviroc (CVC)

[00008] Cenicriviroc (also known as CVC) is the common name of (S,E)-8-[4-(2- butoxyethoxy)phenyl]-1 -(2-methylpropyl)-N-[4-[(3-propylimidazol-4- yl)methylsulfinyl]phenyl]-3,4-dihydro-2FI-1 -benzazocine-5-carboxamide. CVC is a Biopharmaceutics Classification System (BCS) class 4, oral, dual CCR2/CCR5 antagonist with the chemical structure:

cenicriviroc

[00009] CVC has demonstrated potent anti-inflammatory and antifibrotic activity in animal models of peritonitis, liver, and kidney diseases and has shown decreases in aspartate aminotransferase (AST)-to-platelet ratio index (APRI), noninvasive hepatic fibrosis index (FIB-4), and enhanced liver fibrosis score in humans (Lefebvre E. et al. , Clin Transl Sci. 2016 Jun; 9(3): 139-148). Decreases in both APRI and FIB-4 correlated with reductions in soluble CD14 (sCD14, a marker of monocyte activation) levels. In addition, twice as many NASFI patients receiving 1 year of CVC treatment achieved improvement in fibrosis and no worsening of steatohepatitis compared with placebo (Friedman SL et al., Hepatology. 2018 May; 67(5): 1754-1767).

[00010] Presently, CVC is formulated as a mesylate salt administered as an immediate release (IR) tablet. Administering the IR tablet with food has been shown to increase CVC bioavailability (i.e. , positive food effect) (Lefebvre E. et al., Clin Transl Sci. 2016 Jun; 9(3): 139-148; Palleja S. et al., J. Int. AIDS Soc. Conf. HIV Pathogenesis Treat. 2009 5 Abs. WEPEB252). As such, the current CVC formulation requires administration with food. However, the need to administer CVC with food encompasses several disadvantages. For example, bioavailability is influenced by both the quantity and composition of food which may result in individual variability in CVC exposure based on an individual’s diet. Similarly, NASH patients are often placed on dietary restrictions as part of their treatment regimen. Such restrictions may interfere with a patient’s CVC drug compliance or may eliminate CVC as a treatment option.

[00011] Proton pump inhibitors (PPIs) have also been shown to reduce the bioavailability of the CVC IR tablet. Because PPIs act to inhibit gastric acid secretion and in turn increase gut pH, the reduction in CVC bioavailability is likely due to the low solubility of CVC at neutral pH.

[00012] Thus, a need exists for improved pharmaceutical formulations of CVC.

The described invention provides pharmaceutical lipid-based formulations (LBFs) comprising CVC. These pharmaceutical LBFs may eliminate the need to administer CVC with food which may result in reduced individual variability in CVC bioavailability and improved patient compliance. The pharmaceutical lipid-based formulations of the described invention may also prevent the reduction in CVC bioavailability caused by PPIs.

SUMMARY OF THE INVENTION

[00013] According to one aspect, the described invention provides a

pharmaceutical formulation comprising Cenicriviroc and a pharmaceutically acceptable excipient selected form the group consisting of a lipid, a surfactant, a co-solvent and a combination thereof. [00014] According to another aspect, the described invention provides a pharmaceutical formulation comprising Cenicriviroc; 20% v/v oleic acid; 70% v/v ethoxylated castor oil (Cremophor^® EL); and 10% v/v ethanol.

[00015] According to another aspect, the described invention provides a pharmaceutical formulation comprising Cenicriviroc; 60% v/v oleic acid; 30% v/v ethoxylated castor oil (Cremophor^® EL); and 10% v/v ethanol.

[00016] According to another aspect, the describe invention provides a

pharmaceutical formulation comprising Cenicriviroc; 80% v/v glycerol/glyceryl monooleate (Peceol^™); and 20% v/v polysorbate-80 (Tween^®-80).

[00017] According to another aspect, the described invention provides a pharmaceutical formulation comprising 12.5% w/w Cenicriviroc dissolved in 87.5% of a mixture comprising 49% w/w propylene glycol monolaurate type II (Lauroglycol^™ 90); 40% w/w polysorbate-80 (Tween^®-80); 10% propylene glycol; and 1 % vitamin E.

[00018] According to another aspect, the described invention provides a pharmaceutical formulation comprising 12.5% w/w Cenicriviroc dissolved in 87.5% of a mixture comprising 45.5% w/w vitamin E TPGS; 45.5% w/w polysorbate-80 (Tween^®- 80); and 9% propylene glycol.

[00019] According to another aspect, the described invention provides a method of treating fibrosis in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising a therapeutically effective amount of Cenicriviroc; oleic acid; ethoxylated castor oil (Cremophor^® EL); and ethanol.

[00020] According to another aspect, the described invention provides a method of treating non-alcoholic steatohepatitis (NASH) in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising a therapeutically effective amount Cenicriviroc; oleic acid; ethoxylated castor oil

(Cremophor^® EL); and ethanol.

[00021] According to another aspect, the described invention provides a method of treating fibrosis in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising a therapeutically effective amount of Cenicriviroc; 80% v/v glycerol/glyceryl monooleate (Peceol^™); and 20% v/v polysorbate-80 (Tween^®-80).

[00022] According to another aspect, the described invention provides a method of treating non-alcoholic steatohepatitis (NASH) in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising a therapeutically effective amount of Cenicriviroc; 80% v/v glycerol/glyceryl monooleate (Peceol^™); and 20% v/v polysorbate-80 (Tween^®-80).

[00023] According to another aspect, the described invention provides a method of treating fibrosis in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising a therapeutically effective amount of Cenicriviroc; 49% w/w propylene glycol monolaurate type II (Lauroglycol^™ 90); 40% w/w polysorbate-80 (Tween^®-80); 10 % w/w propylene glycol; and 1 % w/w vitamin E.

[00024] According to another aspect, the described invention provides a method of treating non-alcoholic steatohepatitis (NASH) in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising a therapeutically effective amount of Cenicriviroc; 49% w/w propylene glycol monolaurate type II (Lauroglycol^™ 90); 40 % w/w polysorbate-80 (Tween^®-80); 10% w/w propylene glycol; and 1 % vitamin E.

[00025] According to another aspect, the described invention provides a method of treating fibrosis in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising a therapeutically effective amount of Cenicriviroc; 45.5% w/w vitamin E TPGS; 45.5% w/w polysorbate-80 (Tween^®-80); and 9% propylene glycol.

[00026] According to another aspect, the described invention provides a method of treating non-alcoholic steatohepatitis (NASH) in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising a therapeutically effective amount of Cenicriviroc; 45.5% w/w vitamin E TPGS; 45.5 % w/w polysorbate-80 (Tween^®-80); and 9% propylene glycol. [00027] According to one embodiment, the Cenicriviroc is amorphous free base.

[00028] According to one embodiment, the lipid is selected from the group consisting of propylene glycol monolaurate type I (Lauroglycol™ FCC), propylene glycol monolaurate type II (Lauroglycol™ 90), propylene glycol monocaprylate (Capryol™ 90), glycerol caprylate/caprate (Capmul^® MCM), castor oil, glycerol/glyceryl monooleate (Peceol™), glyceryl monolinoleate (Maisine^® CC), glycerol/glyceryl monolinoleate (Maisine™ 35-1 ), propylene glycol dicaprylocaprate (Labrafac™ PG), medium chain triglycerides (Labrafac™ lipophile WL1349), olive oil, flaxseed oil, a mixture of phosphatidyl choline and propylene glycol (Phosal^® 50PG), a mixture of phosphatidyl choline and medium chain triglycerides (Phosal^® 53 MCT) and a combination thereof.

[00029] According to one embodiment, the surfactant is selected from the group consisting of caprylocaproyl macrogol-8 / polyoxyl-8 glycerides (Labrasol^®), linoleoyl polyoxyl-6 glycerides (Labrafil^® M 2125 CS), ethoxylated castor oil (Cremophor^® EL), ethoxylated hydrogenated castor oil (Cremophor^® RH40), polysorbate 80 (Tween^®-80), vitamin E TPGS and a combination thereof.

[00030] According to one embodiment, the pharmaceutical formulation comprises more than one surfactant. According to another embodiment, the more than one surfactant is a combination of a lipophilic surfactant and a hydrophilic surfactant.

[00031] According to one embodiment, the co-solvent is selected from the group consisting of ethanol, propylene glycol, PEG-400, glycerol and a combination thereof.

[00032] According to one embodiment, the pharmaceutical formulation further comprises one or more additional therapeutic agents.

[00033] According to one embodiment, the method of treating fibrosis further comprises administering to the subject one or more additional therapeutic agents.

According to another embodiment, the method of treating non-alcoholic steatohepatitis (NASH) further comprises administering to the subject one or more additional therapeutic agents. [00034] According to one embodiment, the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist. According to another embodiment, the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

[00035] According to one embodiment, the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist. According to another embodiment, the TFIR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5- isopropyl-6-oxo-1 ,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2, 3,4,5- tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5- dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]- dioxaphosphonane (MB07811L/K2809), (3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methylphosphonic acid (MB07344) and a combination of T3 and T4 (Armour^® Thyroid).

BRIEF DESCRIPTION OF THE DRAWINGS

[00036] Figure 1 is a graph depicting the particle size distribution of the in vitro dispersion of two CVC lipid-based formulations.

[00037] Figure 2 is a graph depicting parameter sensitivity analysis of the effect of particle size on percent absorption of CVC as predicted by GastroPlus^™ simulation software.

[00038] Figure 3 is a graph depicting the in vitro dissolution of a CVC lipid-based formulation and a solid CVC powder (“API”) in fed and fasted simulated intestinal fluid (SIF).

[00039] Figure 4 is a graph depicting the in vitro dissolution of a CVC lipid-based formulation (LBF) and a solid CVC powder (API) in fed, fasted pH 1.6 (“Fasted”) and fasted pH 4 (“Fasted-PPI”) simulated intestinal fluid (SIF).

[00040] Figure 5 is a graph depicting pharmacokinetic (PK) profiles of CVC tablet formulation (DP7A) in fasted and fed dogs.

[00041] Figure 6 is a graph depicting plasma concentration profiles for CVC lipid- based formulations Variant #1 (“LBF#1”), Variant #2 (“LBF#2”), Variant #3 (“LBF#3”) and Variant #4 (“LBF#4”) in fasted dogs; and CVC tablet formulation (“DP7A”) in both fasted and fed dogs.

[00042] Figure 7 is a graph depicting pharmacokinetic (PK) profiles for CVC lipid- based formulations Variant #3 (“LBF#3”), Variant #4 (“LBF#4”) and CVC tablet formulation (“DP7A”) in both fasted and fed dogs.

DETAILED DESCRIPTION OF THE INVENTION

[00043] Definitions

[00044] As used herein, the words or terms set forth below have the following definitions:

[00045] The terms“about” or“approximately” as used herein, refer to an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined (i.e. , the limitation of the measurement system). For example,“about” can mean within 1 or more than 1 standard deviation, per practice in the art. Alternatively,“about” with respect to the compositions of the described invention can mean plus or minus a range of up to 20%, up to 10%, or up to 5%. With respect to biological systems or processes, the terms can represent those amounts close to and including the stated amount that still perform a desired function or achieve a desired result, e.g.“about 1 mg” includes 1 mg and those amounts reasonably close to 1 mg that still perform a desired function or achieve a desired result. Where particular values are described, unless otherwise stated, the term“about” means with an acceptable error range for a particular value.

For example, when referring to a period of time, e.g., hours, the present values (+ 20%) are applicable. By way of example, 6 hours can be e.g., 4.8 hours, 5.5 hours, 6 hours, 6.5 hours and 7.2 hours.

[00046] The term "active" as used herein refers to the ingredient, component or constituent of the compositions of the present invention responsible for the intended therapeutic effect. The term "active ingredient" ("Al", "active pharmaceutical ingredient", "API", or "bulk active") is the substance in a drug that is pharmaceutically active. As used herein, the phrase "additional active ingredient" refers to an agent, other than a compound of the described composition, that exerts a pharmacological, or any other beneficial activity. [00047] The term "admixture" or "blend" as used herein generally refers to a physical combination of two or more different components.

[00048] The term "administer" or "administering" as used herein means to give or to apply, and includes in vivo administration, as well as administration directly to tissue ex vivo. Generally, administration may be systemic, e.g., orally, buccally, parenterally, topically, by inhalation or insufflation (i.e., through the mouth or through the nose), rectally in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired, or locally by means such as, but not limited to, injection, implantation, grafting, topical application, or parenterally.

[00049] The term "agent" as used herein refers generally to compounds that are contained in or on the formulation. "Agent" includes a single compound and is also intended to include a plurality of compounds.

[00050] The term "agonist" as used herein refers to a chemical substance capable of activating a receptor to induce a pharmacological response. Receptors can be activated or inactivated by either endogenous or exogenous agonists and antagonists, resulting in stimulating or inhibiting a biological response. A physiological agonist is a substance that creates the same bodily responses, but does not bind to the same receptor. An endogenous agonist for a particular receptor is a compound naturally produced by the body which binds to and activates that receptor. A superagonist is a compound that is capable of producing a greater maximal response than the

endogenous agonist for the target receptor, and thus has an efficiency greater than 100%. This does not necessarily mean that it is more potent than the endogenous agonist but is rather a comparison of the maximum possible response that can be produced inside a cell following receptor binding. Full agonists bind and activate a receptor, displaying full efficacy at that receptor. Partial agonists also bind and activate a given receptor but have only partial efficacy at the receptor relative to a full agonist.

An inverse agonist is an agent which binds to the same receptor binding-site as an agonist for that receptor and reverses constitutive activity of receptors. Inverse agonists exert the opposite pharmacological effect of a receptor agonist. An irreversible agonist is a type of agonist that binds permanently to a receptor in such a manner that the receptor is permanently activated. It is distinct from a mere agonist in that the association of an agonist to a receptor is reversible, whereas the binding of an irreversible agonist to a receptor is believed to be irreversible. This causes the compound to produce a brief burst of agonist activity, followed by desensitization and internalization of the receptor, which with long-term treatment produces an effect more like an antagonist. A selective agonist is specific for one certain type of receptor.

[00051] The term“antagonist” as used herein refers to a substance that interferes or counteracts the effects of another substance. Functional or physiological

antagonism occurs when two substances produce opposite effects on the same physiological function. Chemical antagonism or inactivation is a reaction between two substances to neutralize their effects. Dispositional antagonism is the alteration of the disposition of a substance (its absorption, biotransformation, distribution, or excretion) so that less of the agent reaches the target or its persistence there is reduced.

Antagonism at the receptor for a substance entails the blockade of the effect of an antagonist with an appropriate antagonist that competes for the same site.

[00052] The term“attenuate” as used herein means to render less virulent; to weaken or reduce in force, intensity, effect or quantity.

[00053] The term "bioactive agent" as used herein refers to a compound of interest contained in or on a pharmaceutical formulation or dosage form that is used for pharmaceutical or medicinal purposes to provide some form of therapeutic effect or elicit some type of biologic response or activity. "Bioactive agent" includes a single such agent and is also intended to include a plurality of bioactive agents including, for example, combinations of two or more bioactive agents.

[00054] The term "bioavailable" as used herein refers to the rate and extent to which an active ingredient is absorbed from a drug product and becomes available at the site of action.

[00055] The term "biocompatible" as used herein refers to a material that is generally non-toxic to the recipient and does not possess any significant untoward effects to the subject and, further, that any metabolites or degradation products of the material are non-toxic to the subject. Typically, a substance that is "biocompatible" causes no clinically relevant tissue irritation, injury, toxic reaction, or immunological reaction to living tissue. [00056] The term "biodegradable" as used herein refers to a material that will erode to soluble species or that will degrade under physiologic conditions to smaller units or chemical species that are, themselves, non-toxic (biocompatible) to the subject and capable of being metabolized, eliminated, or excreted by the subject.

[00057] The term“biomarker” (or "biosignature") as used herein refers to peptides, proteins, nucleic acids, antibodies, genes, metabolites, or any other substances used as indicators of a biologic state. It is a characteristic that is measured objectively and evaluated as a cellular or molecular indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. The term "indicator" as used herein refers to any substance, number or ratio derived from a series of observed facts that may reveal relative changes as a function of time; or a signal, sign, mark, note or symptom that is visible or evidence of the existence or presence thereof. Once a proposed biomarker has been validated, it may be used to diagnose disease risk, presence of disease in an individual, or to tailor treatments for the disease in an individual (choices of drug treatment or administration regimes). In evaluating potential drug therapies, a biomarker may be used as a surrogate for a natural endpoint, such as survival or irreversible morbidity. If a treatment alters the biomarker, and that alteration has a direct connection to improved health, the biomarker may serve as a surrogate endpoint for evaluating clinical benefit. Clinical endpoints are variables that can be used to measure how patients feel, function or survive. Surrogate endpoints are biomarkers that are intended to substitute for a clinical endpoint; these biomarkers are demonstrated to predict a clinical endpoint with a confidence level acceptable to regulators and the clinical community.

[00058] The term "carrier" as used herein refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the peptide of the composition of the described invention. Carriers must be of sufficiently high purity and of sufficiently low toxicity to render them suitable for administration to the mammal being treated. The carrier can be inert, or it can possess pharmaceutical benefits. The terms "excipient", "carrier", or "vehicle" are used interchangeably to refer to carrier materials suitable for formulation and administration of pharmaceutically acceptable compositions described herein. Carriers and vehicles useful herein include any such materials know in the art which are nontoxic and do not interact with other components.

[00059] The term "component" as used herein refers to a constituent part, element or ingredient.

[00060] The term "composition" as used herein refers to an aggregate material formed of two or more substances.

[00061] The term "condition", as used herein, refers to a variety of health states and is meant to include disorders or diseases caused by any underlying mechanism or disorder, injury, and the promotion of healthy tissues and organs.

[00062] The term "contact" and all its grammatical forms as used herein refers to a state or condition of touching or of immediate or local proximity.

[00063] The term "controlled release" as used herein refers to refer to any drug- containing formulation in which the manner and profile of drug release from the formulation are regulated. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including, but not limited to, sustained release and delayed release formulations.

[00064] The term“decrease” as used herein means to make or become smaller or fewer in size, amount, intensity, degree, etc.

[00065] The term "delayed release" as used herein in its conventional sense refers to a formulation in which there is a time delay between administration of the formulation and the release of the therapeutic agent therefrom. "Delayed release" may or may not involve gradual release of the therapeutic agent over an extended period of time, and thus may or may not be "sustained release."

[00066] The term "disease" or "disorder", as used herein, refers to an impairment of health or a condition of abnormal functioning.

[00067] The term "drug" as used herein refers to a therapeutic agent or any substance, other than food, used in the prevention, diagnosis, alleviation, treatment, or cure of disease. [00068] The term "effective amount" refers to the amount necessary or sufficient to realize a desired biologic effect.

[00069] The term "excipient" is used herein to include any other agent or compound that may be contained in a formulation that is not the bioactive agent. As such, an excipient should be pharmaceutically or biologically acceptable or relevant (for example, an excipient should generally be non-toxic to the subject). The term

"pharmaceutically acceptable excipient" means those excipients which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. "Excipient" includes a single such compound and is also intended to include a plurality of such compounds.

[00070] The term“food effect” as used herein refers to a food-drug interaction, or food-induced physiological changes in gastrointestinal state (such as luminal pH, secretions from gallbladder, venous-portal blood flow, gastric emptying time, etc.) associated with alterations in the pharmacokinetic (PK) and/or pharmacodynamic (PD) profile of a drug.

[00071] The term "formulation" as used herein refers to a mixture prepared according to a specific procedure, formula or rule.

[00072] The term“incidence” as used herein refers to the frequency with which a disease, condition, symptom, trait, etc. appears in a particular subject, population or area.

[00073] The term“induce” as used herein means to bring about or stimulate the occurrence of something (e.g., a pharmacological effect) or to initiate or increase the production of a protein at the level of genetic transcription.

[00074] The terms "inhibiting", "inhibit" or "inhibition" are used herein to refer to reducing the amount or rate of a process, to stopping the process entirely, or to decreasing, limiting, or blocking the action or function thereof. Inhibition may include a reduction or decrease of the amount, rate, action function, or process of a substance by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100%.

[00075] The term "inhibitor" as used herein refers to a second molecule that binds to a first molecule thereby decreasing the first molecule's activity. The binding of an inhibitor may stop substrate from entering the active site of an enzyme and/or hinder an enzyme from catalyzing its reaction. Inhibitor binding is either reversible or irreversible. Irreversible inhibitors usually react with a molecule and change it chemically, for example, by modifying key amino acid residues. In contrast, reversible inhibitors bind non-covalently and produce different types of inhibition.

[00076] The term "injury," as used herein, refers to damage or harm to a structure or function of the body caused by an outside agent or force, which may be physical or chemical.

[00077] The term "particle" as used herein refers to an extremely small

constituent, e.g., a nanoparticle or microparticle) that may contain in whole or in part at least one therapeutic agent as described herein. The term "microparticle" is used herein to refer generally to a variety of structures having sizes from about 10 nm to 2000 microns (2 millimeters) and includes a microcapsule, microsphere, nanoparticle, nanocapsule, nanosphere as well as particles, in general, that are less than about 2000 microns (2 millimeters). The particles may contain therapeutic agent(s) in a core surrounded by a coating. Therapeutic agent(s) also may be dispersed throughout the particles. Therapeutic agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, etc., and any combination thereof. The particle may include, in addition to therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, non-erodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules that contain the active agent in a solution or in a semi-solid state. The particles may be of virtually any shape.

[00078] The term“particle size distribution” or“PSD” as used herein refers to the distribution of solid particles or liquid droplets of different sizes in a sample. The most commonly used metric to describe particle size distributions are D-values (e.g., D10, D50, D90). D-values represent the intercepts for 10% (D10), 50% (D50) and 90%

(D90) of the cumulative particle mass in a sample. For example, if D90 is 200nm, then 90% of the particles in a sample have a size of 200nm or smaller. If D10, for example, is 200nm, then 10% of the particles in a sample have a size of 200nm or smaller. If D50, for example, is 200nm, then 50% of the particles in a sample have a size of 200nm or smaller. D50 is also referred to as mass median diameter as it divides a sample equally by mass.

[00079] The term "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.

[00080] The terms "pharmaceutical formulation" or "pharmaceutical composition" as used herein refer to a formulation or a composition that is employed to prevent, reduce in intensity, cure or otherwise treat a target condition or disease.

[00081] The term "prevent" as used herein refers to the keeping, hindering or averting of an event, act or action from happening, occurring, or arising.

[00082] The term“protect” as used herein means to defend, preserve, or guard from attack, invasion, loss, insult, injury or harm.

[00083] The term“pure” as used herein means not mixed or adulterated with any other substance or material, for example, free from contaminants or pollutants.

[00084] The term "reduce", "reduced", "to reduce" or "reducing" as used herein refer to a diminution, a decrease, an attenuation or abatement of the degree, intensity, extent, size, amount, density or number.

[00085] The term "similar" is used interchangeably with the terms analogous, comparable, or resembling, meaning having traits or characteristics in common.

[00086] The term "stability" of a pharmaceutical product as used herein refers to the capability of a particular formulation to remain within its physical, chemical, microbiological, therapeutic and toxicological specifications. [00087] The term“suppress” as used herein means to curtail or inhibit a biological activity (e.g., the immune system or a gene) or to reduce the incidence or severity of a condition or symptom.

[00088] The term "susceptible" as used herein refers to a member of a population at risk.

[00089] The terms "subject" or "individual" or "patient" are used interchangeably to refer to a member of an animal species of mammalian origin, including but not limited to, a mouse, a rat, a cat, a goat, a sheep, a horse, a hamster, a ferret, a platypus, a pig, a dog, a guinea pig, a rabbit and a primate, such as, for example, a monkey, an ape, or a human.

[00090] The phrase "subject in need thereof" as used herein refers to a patient that (i) will be administered a formulation containing at least one therapeutic agent, (ii) is receiving a formulation containing at least one therapeutic agent; or (iii) has received a formulation containing at least one therapeutic agent, unless the context and usage of the phrase indicates otherwise.

[00091] The term“substantially” as used herein means to a great degree in identity, amount, activity, etc.

[00092] As used herein, the term“substantially pure” refers purity of at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% pure as determined by an analytical protocol. Such protocols may include, without limitation, FACS, HPLC, gel electrophoresis, chromatography, and the like.

[00093] The term "sustained release" (also referred to as "extended release") is used herein in its conventional sense to refer to a drug formulation that provides for gradual release of a therapeutic agent over an extended period of time, and that preferably, although not necessarily, results in constant levels of the agent over an extended time period.

[00094] The term "symptom" as used herein refers to a phenomenon that arises from and accompanies a particular disease or disorder and serves as an indication of it. [00095] The term "syndrome," as used herein, refers to a pattern of symptoms indicative of some disease or condition.

[00096] The term "therapeutic agent" as used herein refers to a drug, molecule, nucleic acid, protein, composition or other substance that provides a therapeutic effect. The terms "therapeutic agent" and "active agent" are used interchangeably.

[00097] The term "therapeutic component" as used herein refers to a

therapeutically effective dosage (i.e. , dose and frequency of administration) that eliminates, reduces, or prevents the progression of a particular disease manifestation in a percentage of a population. An example of a commonly used therapeutic component is the E D50 which describes the dose in a particular dosage that is therapeutically effective for a particular disease manifestation in 50% of a population.

[00098] The term "therapeutic effect" as used herein refers to a consequence of treatment, the results of which are judged to be desirable and beneficial. A therapeutic effect may include, directly or indirectly, the arrest, reduction, or elimination of a disease manifestation. A therapeutic effect may also include, directly or indirectly, the arrest reduction or elimination of the progression of a disease manifestation.

[00099] The terms "therapeutically effective amount",“therapeutic amount” and "amount effective" of one or more of the active agents is an amount that is sufficient to provide the intended benefit of treatment. Dosage levels are based on a variety of factors, including the type of injury, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular active agent employed. Thus, the dosage regimen may vary widely, but can be routinely determined using standard methods.

[00100] The term "treat" or "treating" includes abrogating, substantially inhibiting, slowing or reversing the progression of a disease, condition, disorder or injury, substantially ameliorating clinical or esthetical symptoms of a disease, condition, disorder or injury, substantially preventing the appearance of clinical or esthetical symptoms of a disease, condition, disorder or injury, and protecting from harmful or annoying symptoms. The term "treat" or "treating" as used herein further refers to accomplishing one or more of the following: (a) reducing the severity of the disease, condition, disorder or injury; (b) limiting development of symptoms characteristic of the disease, condition, disorder or injury being treated; (c) limiting worsening of symptoms characteristic of the disease, condition, disorder or injury being treated; (d) limiting recurrence of the disease, condition, disorder or injury in patients that have previously had the disease, condition, disorder or injury; and (e) limiting recurrence of symptoms in patients that were previously symptomatic for the disease, condition, disorder or injury.

[00101] The term "vehicle" as used herein refers to a substance that facilitates the use of a drug or other material that is mixed with it.

[00102] According to some embodiments, the described invention provides a pharmaceutical formulation. According to some embodiments, the pharmaceutical formulation comprises a lipid. According to some embodiments, the pharmaceutical formulation comprises a surfactant. According to some embodiments, the

pharmaceutical formulation comprises a co-solvent. According to some embodiments, the pharmaceutical formulation comprises a lipid and a surfactant. According to some embodiments, the pharmaceutical formulation comprises a lipid and a co-solvent.

According to some embodiments, the pharmaceutical formulation comprises a surfactant and a co-solvent. According to some embodiments, the pharmaceutical formulation comprises more than one surfactant. According to some embodiments, the pharmaceutical formulation comprises a lipid and more than one surfactant. According to some embodiments, the pharmaceutical formulation comprises a co-solvent and more than one surfactant. According to some embodiments, the pharmaceutical formulation comprises a lipid, a surfactant and a co-solvent. According to some embodiments, the pharmaceutical formulation comprises a lipid, more than one surfactant, and a co-solvent. According to some embodiments, the more than surfactant is a combination of a lipophilic surfactant and a hydrophilic surfactant.

According to some embodiments, the more than one surfactant is a combination of lipophilic surfactants. According to some embodiments, the more than one surfactant is a combination of hydrophilic surfactants.

[00103] According to some embodiments, the lipid is a long chain fatty acid. Long chain fatty acids include, but are not limited to, fatty acids having twelve (12) or more carbon atoms. Non-limiting examples of long chain fatty acids include gadoleic, gondoic, lauric, myristic, palmitic, palmitooleic, margaric, moroctic, stearic, 9,10 dihydrostearic, ricinooleic, oleic, linoleic, linolenic, linolenic a, arachidic, eicosenoic, eicosatetraenoic acid, heneicosapentaenoic acid, eicosapentaenoicic acid, docosahexaenoic acid, erucic, lignoceric, nervonic, vanenic, timnodonic, cetoleic, clupanodonic, cervonic, behenic, 9,10-dihydroxy-stearic, 12-oxostearic, 12- hydroxystearic and the like. According to some embodiments, the lipid is a medium chain fatty acid. Medium chain fatty acids, include, but are not limited to, fatty acids having six (6) to twelve (12) carbon atoms. Non-limiting examples of medium chain fatty acids include caproil, caprylic and capric. According to some embodiments, the lipid is an ester of a long chain fatty acid. According to some embodiments, the lipid is an ester of a medium chain fatty acid. Esters of fatty acids include, but are not limited to, triglycerides, phospholipids and cholesterol esters.

[00104] According to some embodiments, the pharmaceutical formulation comprises oleic acid, propylene glycol, propylene glycol monocaprylate (Capryol^™ 90; Capryol^™ PGMC), glycerol caprylate/caprate (Capmul^® MCM), castor oil,

glycerol/glyceryl monooleate (Peceol^™), glyceryl monolinoleate (Maisine^® CC), glycerol/glyceryl monolinoleate (Maisine^™ 35-1 ), propylene glycol dicaprylocaprate (Labrafac^™ PG), medium chain triglycerides (Labrafac^™ lipophile WL1349), olive oil, flaxseed oil, sesame oil, a mixture of phosphatidyl choline and propylene glycol (e.g., Phosal^® 50PG), a mixture of phosphatidyl choline and medium chain triglycerides (e.g., Phosal^® 53 MCT) or a combination thereof.

[00105] According to some embodiments, the amount of lipid in the

pharmaceutical formulation is less than (<) 1 % volume/volume (v/v). According to some embodiments, the amount of lipid is greater than (>) 1 % v/v. According to some embodiments, the amount of lipid ranges from about 0.1 % v/v to about 100% v/v.

According to some embodiments, the amount of lipid ranges from about 0.5% v/v to about 50% v/v. According to some embodiments, the amount of lipid ranges from about 1 % v/v to about 10% v/v. According to some embodiments, the amount of lipid is about 0.1 % v/v. According to some embodiments, the amount of lipid is about 0.5% v/v.

According to some embodiments, the amount of lipid is about 1 % v/v. According to some embodiments, the amount of lipid is about 2% v/v. According to some

embodiments, the amount of lipid is about 3% v/v. According to some embodiments, the amount of lipid is about 4% v/v. According to some embodiments, the amount of lipid is about 5% v/v. According to some embodiments, the amount of lipid is about 6% v/v. According to some embodiments, the amount of lipid is about 7% v/v. According to some embodiments, the amount of lipid is about 8% v/v. According to some

embodiments, the amount of lipid is about 9% v/v. According to some embodiments, the amount of lipid is about 10% v/v. According to some embodiments, the amount of lipid is about 15% v/v. According to some embodiments, the amount of lipid is about 20% v/v. According to some embodiments, the amount of lipid is about 25% v/v. According to some embodiments, the amount of lipid is about 30% v/v. According to some embodiments, the amount of lipid is about 35% v/v. According to some embodiments, the amount of lipid is about 40% v/v. According to some embodiments, the amount of lipid is about 45% v/v. According to some embodiments, the amount of lipid is about 50% v/v. According to some embodiments, the amount of lipid is about 55% v/v.

According to some embodiments, the amount of lipid is about 60% v/v. According to some embodiments, the amount of lipid is about 65% v/v. According to some embodiments, the amount of lipid is about 70% v/v. According to some embodiments, the amount of lipid is about 75% v/v. According to some embodiments, the amount of lipid is about 76% v/v. According to some embodiments, the amount of lipid is about 77% v/v. According to some embodiments, the amount of lipid is about 78% v/v.

According to some embodiments, the amount of lipid is about 79% v/v. According to some embodiments, the amount of lipid is about 80% v/v. According to some embodiments, the amount of lipid is about 85% v/v. According to some embodiments, the amount of lipid is about 86% v/v. According to some embodiments, the amount of lipid is about 87% v/v. According to some embodiments, the amount of lipid is about 88% v/v. According to some embodiments, the amount of lipid is about 89% v/v.

According to some embodiments, the amount of lipid is about 90% v/v. According to some embodiments, the amount of lipid is about 95% v/v. According to some embodiments, the amount of lipid is about 96% v/v. According to some embodiments, the amount of lipid is about 97% v/v. According to some embodiments, the amount of lipid is about 98% v/v. According to some embodiments, the amount of lipid is about 99% v/v. According to some embodiments, the amount of lipid is about 100% v/v.

[00106] According to some embodiments, the amount of lipid in the

pharmaceutical formulation is less than (<) 1 % weight/weight (w/w). According to some embodiments, the amount of lipid is greater than (>) 1 % w/w. According to some embodiments, the amount of lipid ranges from about 0.1 % w/w to about 100% w/w. According to some embodiments, the amount of lipid ranges from about 0.5% w/w to about 50% w/w. According to some embodiments, the amount of lipid ranges from about 1 % w/w to about 10% w/w. According to some embodiments, the amount of lipid is about 0.1 % w/w. According to some embodiments, the amount of lipid is about 0.5% w/w. According to some embodiments, the amount of lipid is about 1 % w/w. According to some embodiments, the amount of lipid is about 2% w/w. According to some embodiments, the amount of lipid is about 3% w/w. According to some embodiments, the amount of lipid is about 4% w/w. According to some embodiments, the amount of lipid is about 5% w/w. According to some embodiments, the amount of lipid is about 6% w/w. According to some embodiments, the amount of lipid is about 7% w/w. According to some embodiments, the amount of lipid is about 8% w/w. According to some embodiments, the amount of lipid is about 9% w/w. According to some embodiments, the amount of lipid is about 10% w/w. According to some embodiments, the amount of lipid is about 15% w/w. According to some embodiments, the amount of lipid is about

20% w/w. According to some embodiments, the amount of lipid is about 25% w/w.

According to some embodiments, the amount of lipid is about 30% w/w. According to some embodiments, the amount of lipid is about 35% w/w. According to some embodiments, the amount of lipid is about 40% w/w. According to some embodiments, the amount of lipid is about 45% w/w. According to some embodiments, the amount of lipid is about 50% w/w. According to some embodiments, the amount of lipid is about

55% w/w. According to some embodiments, the amount of lipid is about 60% w/w.

According to some embodiments, the amount of lipid is about 65% w/w. According to some embodiments, the amount of lipid is about 70% w/w. According to some embodiments, the amount of lipid is about 75% w/w. According to some embodiments, the amount of lipid is about 76% w/w. According to some embodiments, the amount of lipid is about 77% w/w. According to some embodiments, the amount of lipid is about

78% w/w. According to some embodiments, the amount of lipid is about 79% w/w.

According to some embodiments, the amount of lipid is about 80% w/w. According to some embodiments, the amount of lipid is about 85% w/w. According to some embodiments, the amount of lipid is about 86% w/w. According to some embodiments, the amount of lipid is about 87% w/w. According to some embodiments, the amount of lipid is about 88% w/w. According to some embodiments, the amount of lipid is about

89% w/w. According to some embodiments, the amount of lipid is about 90% w/w.

According to some embodiments, the amount of lipid is about 95% w/w. According to some embodiments, the amount of lipid is about 96% w/w. According to some embodiments, the amount of lipid is about 97% w/w. According to some embodiments, the amount of lipid is about 98% w/w. According to some embodiments, the amount of lipid is about 99% w/w. According to some embodiments, the amount of lipid is about 100% w/w.

[00107] According to some embodiments, the amount of lipid in the

pharmaceutical formulation is less than (<) 1 % weight/volume (w/v). According to some embodiments, the amount of lipid is greater than (>) 1 % w/v. According to some embodiments, the amount of lipid ranges from about 0.1 % w/v to about 100% w/v. According to some embodiments, the amount of lipid ranges from about 0.5% w/v to about 50% w/v. According to some embodiments, the amount of lipid ranges from about 1 % w/v to about 10% w/v. According to some embodiments, the amount of lipid is about 0.1 % w/v. According to some embodiments, the amount of lipid is about 0.5% w/v. According to some embodiments, the amount of lipid is about 1 % w/v. According to some embodiments, the amount of lipid is about 2% w/v. According to some embodiments, the amount of lipid is about 3% w/v. According to some embodiments, the amount of lipid is about 4% w/v. According to some embodiments, the amount of lipid is about 5% w/v. According to some embodiments, the amount of lipid is about 6% w/v. According to some embodiments, the amount of lipid is about 7% w/v. According to some embodiments, the amount of lipid is about 8% w/v. According to some

embodiments, the amount of lipid is about 9% w/v. According to some embodiments, the amount of lipid is about 10% w/v. According to some embodiments, the amount of lipid is about 15% w/v. According to some embodiments, the amount of lipid is about 20% w/v. According to some embodiments, the amount of lipid is about 25% w/v.

According to some embodiments, the amount of lipid is about 30% w/v. According to some embodiments, the amount of lipid is about 35% w/v. According to some embodiments, the amount of lipid is about 40% w/v. According to some embodiments, the amount of lipid is about 45% w/v. According to some embodiments, the amount of lipid is about 50% w/v. According to some embodiments, the amount of lipid is about 55% w/v. According to some embodiments, the amount of lipid is about 60% w/v.

According to some embodiments, the amount of lipid is about 65% w/v. According to some embodiments, the amount of lipid is about 70% w/v. According to some embodiments, the amount of lipid is about 75% w/v. According to some embodiments, the amount of lipid is about 76% w/v. According to some embodiments, the amount of lipid is about 77% w/v. According to some embodiments, the amount of lipid is about 78% w/v. According to some embodiments, the amount of lipid is about 79% w/v.

According to some embodiments, the amount of lipid is about 80% w/v. According to some embodiments, the amount of lipid is about 85% w/v. According to some embodiments, the amount of lipid is about 86% w/v. According to some embodiments, the amount of lipid is about 87% w/v. According to some embodiments, the amount of lipid is about 88% w/v. According to some embodiments, the amount of lipid is about 89% w/v. According to some embodiments, the amount of lipid is about 90% w/v.

According to some embodiments, the amount of lipid is about 95% w/v. According to some embodiments, the amount of lipid is about 96% w/v. According to some embodiments, the amount of lipid is about 97% w/v. According to some embodiments, the amount of lipid is about 98% w/v. According to some embodiments, the amount of lipid is about 99% w/v. According to some embodiments, the amount of lipid is about 100% w/v.

[00108] According to some embodiments, surfactants of the pharmaceutical formulations include, but are not limited to, anionic surfactants, cationic surfactants, non-ionic surfactants and amphoteric (Zwitterionic) surfactants. Non-limiting examples of anionic surfactants include carboxylates (e.g., alkyl carboxylates-fatty acid salts, carboxylate fluoro surfactants, etc.), sulfates (e.g., alkyl sulfates such as sodium lauryl sulfate; alkyl ether sulfates such as sodium laureth sulfate, etc.), sulfonates (e.g., docusates such as dioctyl sodium sulfosuccinate; alkyl benzene sulfonates; etc.) and phosphate esters (e.g., alkyl aryl ether phosphates; alkyl ether phosphates; etc.). Non limiting examples of cationic surfactants include amine salts such as alkyl amine salt and alkyl diamine salt, RN⁺H3CI (salt of a long-chain amine), ammonium salt (e.g., alkyl trimethyl ammonium salt), RN⁺(CH3)3CI (quaternary ammonium chloride also known as quats) and benzalkonium chloride (BAC). Non-limiting examples of non-ionic

surfactants include propylene glycol monolaurate type I (Lauroglycol™ FCC), propylene glycol monolaurate type II (Lauroglycol™ 90), caprylocaproyl macrogol-8 / polyoxyl-8 glycerides (Labrasol^®), linoleoyl polyoxyl-6 glycerides (Labrafil^® M 2125 CS), alkyl ethoxylate, nonylphenol ethoxylate, amine ethoxylate, alkyl poly (ethylene oxide), alkylphenol poly (ethylene oxide), copolymers of poly (ethylene oxide, poly (propylene oxide) (commercially referred to as poloxamers or poloxamines), fatty alcohols (e.g., cetyl alcohol; oleyl alcohol; etc.), cocaminde MEA, cocamide DEA, polysorbates (e.g., polysorbate (Tween^®) 20, polysorbate (Tween^®) 80, etc.), vitamin E D-a-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) and dodecyl dimethylamine oxide. Non-limiting examples of amphoteric (Zwitterionic) surfactants include quaternary amine group and carboxy group surfactants (e.g., alkyl betaine; alkyl imidazoline; etc.), quaternary amine group and sulfonic group containing surfactants (e.g., alkyl

sulphobetaine), phospholipid surfactants (e.g., phosphatidyl serine; phosphatidyl choline; phosphatidyl ethanolamine; etc.) including, but not limited to, a mixture of phosphatidyl choline/propylene glycol (e.g., Phosal^® 50PG), a mixture of phosphatidyl choline with medium chain triglycerides (e.g., Phosal^® 53 MCT) and carbohydrate- based surfactants (e.g., alkyl polyglucoside; alkyl glucamide; etc.).

[00109] According to some embodiments, surfactants of the pharmaceutical formulations include, but are not limited to, water-insoluble surfactants and water- soluble surfactants. Non-limiting examples of water-insoluble surfactants include sorbitan monolaurate (Span^®) 20, oleate esters such as polyoxyethylene (20) sorbitan tioleate (Tween®-85), polyoxyethylene (20) glyceryl troleate (Tagot-TO^®) and a blend of polysorbate (Tween^®) 80 and sorbitan monooleate (Span^®) 80. Non-limiting examples of water-soluble surfactants include ethoxylated hydrogenated castor oil (e.g.,

Cremophor^® RH40 and RH60) and ethoxylated castor oil (e.g., Cremophor^® EL).

[00110] According to some embodiments, surfactants of the pharmaceutical formulations include, but are not limited to, vitamin E and vitamin E tocopherol polyethylene glycol succinate (vitamin E TPGS).

[00111] According to some embodiments, the pharmaceutical formulation comprises caprylocaproyl macrogol-8 / polyoxyl-8 glycerides (Labrasol^®), linoleoyl polyoxyl-6 glycerides (Labrafil^® M 2125 CS), ethoxylated castor oil (e.g., Cremophor^® EL), ethoxylated hydrogenated castor oil (e.g., Cremophor^® RH40), polysorbate 80 (Tween^®-80), or a combination thereof.

[00112] According to some embodiments, the amount of surfactant in the pharmaceutical formulation is less than (<) 1 % volume/volume (v/v). According to some embodiments, the amount of surfactant is greater than (>) 1 % v/v. According to some embodiments, the amount of surfactant ranges from about 0.1 % v/v to about 100% v/v. According to some embodiments, the amount of surfactant ranges from about 0.5% v/v to about 50% v/v. According to some embodiments, the amount of surfactant ranges from about 1 % v/v to about 10% v/v. According to some embodiments, the amount of surfactant is about 0.1 % v/v. According to some embodiments, the amount of surfactant is about 0.5% v/v. According to some embodiments, the amount of surfactant is about 1 % v/v. According to some embodiments, the amount of surfactant is about 2% v/v. According to some embodiments, the amount of surfactant is about 3% v/v. According to some embodiments, the amount of surfactant is about 4% v/v. According to some embodiments, the amount of surfactant is about 5% v/v. According to some embodiments, the amount of surfactant is about 6% v/v. According to some embodiments, the amount of surfactant is about 7% v/v. According to some

embodiments, the amount of surfactant is about 8% v/v. According to some

embodiments, the amount of surfactant is about 9% v/v. According to some

embodiments, the amount of surfactant is about 10% v/v. According to some embodiments, the amount of surfactant is about 15% v/v. According to some embodiments, the amount of surfactant is about 20% v/v. According to some embodiments, the amount of surfactant is about 25% v/v. According to some embodiments, the amount of surfactant is about 30% v/v. According to some embodiments, the amount of surfactant is about 35% v/v. According to some embodiments, the amount of surfactant is about 40% v/v. According to some embodiments, the amount of surfactant is about 45% v/v. According to some embodiments, the amount of surfactant is about 46% v/v. According to some embodiments, the amount of surfactant is about 47% v/v. According to some embodiments, the amount of surfactant is about 48% v/v. According to some embodiments, the amount of surfactant is about 49% v/v. According to some embodiments, the amount of surfactant is about 50% v/v. According to some embodiments, the amount of surfactant is about 55% v/v. According to some embodiments, the amount of surfactant is about 60% v/v. According to some embodiments, the amount of surfactant is about 65% v/v. According to some embodiments, the amount of surfactant is about 70% v/v. According to some embodiments, the amount of surfactant is about 75% v/v. According to some embodiments, the amount of surfactant is about 76% v/v. According to some embodiments, the amount of surfactant is about 77% v/v. According to some embodiments, the amount of surfactant is about 78% v/v. According to some embodiments, the amount of surfactant is about 79% v/v. According to some embodiments, the amount of surfactant is about 80% v/v. According to some embodiments, the amount of surfactant is about 85% v/v. According to some embodiments, the amount of surfactant is about 86% v/v. According to some embodiments, the amount of surfactant is about 87% v/v. According to some embodiments, the amount of surfactant is about 88% v/v. According to some embodiments, the amount of surfactant is about 89% v/v. According to some embodiments, the amount of surfactant is about 90% v/v. According to some embodiments, the amount of surfactant is about 95% v/v. According to some embodiments, the amount of surfactant is about 96% v/v. According to some embodiments, the amount of surfactant is about 97% v/v. According to some embodiments, the amount of surfactant is about 98% v/v. According to some embodiments, the amount of surfactant is about 99% v/v. According to some embodiments, the amount of surfactant is about 100% v/v.

[00113] According to some embodiments, the amount of surfactant in the pharmaceutical formulation is less than (<) 1 % weight/weight (w/w). According to some embodiments, the amount of surfactant is greater than (>) 1 % w/w. According to some embodiments, the amount of surfactant ranges from about 0.1 % w/w to about 100% w/w. According to some embodiments, the amount of surfactant ranges from about

0.5% w/w to about 50% w/w. According to some embodiments, the amount of surfactant ranges from about 1 % w/w to about 10% w/w. According to some

embodiments, the amount of surfactant is about 0.1 % w/w. According to some embodiments, the amount of surfactant is about 0.5% w/w. According to some embodiments, the amount of surfactant is about 1 % w/w. According to some embodiments, the amount of surfactant is about 2% w/w. According to some embodiments, the amount of surfactant is about 3% w/w. According to some embodiments, the amount of surfactant is about 4% w/w. According to some embodiments, the amount of surfactant is about 5% w/w. According to some embodiments, the amount of surfactant is about 6% w/w. According to some embodiments, the amount of surfactant is about 7% w/w. According to some

embodiments, the amount of surfactant is about 8% w/w. According to some embodiments, the amount of surfactant is about 9% w/w. According to some embodiments, the amount of surfactant is about 10% w/w. According to some embodiments, the amount of surfactant is about 15% w/w. According to some embodiments, the amount of surfactant is about 20% w/w. According to some embodiments, the amount of surfactant is about 25% w/w. According to some embodiments, the amount of surfactant is about 30% w/w. According to some embodiments, the amount of surfactant is about 35% w/w. According to some embodiments, the amount of surfactant is about 40% w/w. According to some embodiments, the amount of surfactant is about 45% w/w. According to some embodiments, the amount of surfactant is about 46% w/w. According to some embodiments, the amount of surfactant is about 47% w/w. According to some embodiments, the amount of surfactant is about 48% w/w. According to some embodiments, the amount of surfactant is about 49% w/w. According to some embodiments, the amount of surfactant is about 50% w/w. According to some embodiments, the amount of surfactant is about 55% w/w. According to some embodiments, the amount of surfactant is about 60% w/w. According to some embodiments, the amount of surfactant is about 65% w/w. According to some embodiments, the amount of surfactant is about 70% w/w. According to some embodiments, the amount of surfactant is about 75% w/w. According to some embodiments, the amount of surfactant is about 76% w/w. According to some embodiments, the amount of surfactant is about 77% w/w. According to some embodiments, the amount of surfactant is about 78% w/w. According to some embodiments, the amount of surfactant is about 79% w/w. According to some embodiments, the amount of surfactant is about 80% w/w. According to some embodiments, the amount of surfactant is about 85% w/w. According to some embodiments, the amount of surfactant is about 86% w/w. According to some embodiments, the amount of surfactant is about 87% w/w. According to some embodiments, the amount of surfactant is about 88% w/w. According to some embodiments, the amount of surfactant is about 89% w/w. According to some embodiments, the amount of surfactant is about 90% w/w. According to some embodiments, the amount of surfactant is about 95% w/w. According to some embodiments, the amount of surfactant is about 96% w/w. According to some embodiments, the amount of surfactant is about 97% w/w. According to some embodiments, the amount of surfactant is about 98% w/w. According to some embodiments, the amount of surfactant is about 99% w/w. According to some embodiments, the amount of surfactant is about 100% w/w.

[00114] According to some embodiments, the amount of surfactant in the pharmaceutical formulation is less than (<) 1 % weight/volume (w/v). According to some embodiments, the amount of surfactant is greater than (>) 1 % w/v. According to some embodiments, the amount of surfactant ranges from about 0.1 % w/v to about 100% w/v. According to some embodiments, the amount of surfactant ranges from about 0.5% w/v to about 50% w/v. According to some embodiments, the amount of surfactant ranges from about 1 % w/v to about 10% w/v. According to some embodiments, the amount of surfactant is about 0.1 % w/v. According to some embodiments, the amount of surfactant is about 0.5% w/v. According to some embodiments, the amount of surfactant is about 1 % w/v. According to some embodiments, the amount of surfactant is about 2% w/v. According to some embodiments, the amount of surfactant is about 3% w/v. According to some embodiments, the amount of surfactant is about 4% w/v. According to some embodiments, the amount of surfactant is about 5% w/v. According to some embodiments, the amount of surfactant is about 6% w/v. According to some embodiments, the amount of surfactant is about 7% w/v. According to some

embodiments, the amount of surfactant is about 8% w/v. According to some

embodiments, the amount of surfactant is about 9% w/v. According to some

embodiments, the amount of surfactant is about 10% w/v. According to some

embodiments, the amount of surfactant is about 15% w/v. According to some

embodiments, the amount of surfactant is about 20% w/v. According to some

embodiments, the amount of surfactant is about 25% w/v. According to some

embodiments, the amount of surfactant is about 30% w/v. According to some

embodiments, the amount of surfactant is about 35% w/v. According to some

embodiments, the amount of surfactant is about 40% w/v. According to some

embodiments, the amount of surfactant is about 45% w/v. According to some

embodiments, the amount of surfactant is about 46% w/v. According to some

embodiments, the amount of surfactant is about 47% w/v. According to some

embodiments, the amount of surfactant is about 48% w/v. According to some

embodiments, the amount of surfactant is about 49% w/v. According to some

embodiments, the amount of surfactant is about 50% w/v. According to some

embodiments, the amount of surfactant is about 55% w/v. According to some embodiments, the amount of surfactant is about 60% w/v. According to some embodiments, the amount of surfactant is about 65% w/v. According to some embodiments, the amount of surfactant is about 70% w/v. According to some embodiments, the amount of surfactant is about 75% w/v. According to some embodiments, the amount of surfactant is about 76% w/v. According to some embodiments, the amount of surfactant is about 77% w/v. According to some embodiments, the amount of surfactant is about 78% w/v. According to some embodiments, the amount of surfactant is about 79% w/v. According to some embodiments, the amount of surfactant is about 80% w/v. According to some embodiments, the amount of surfactant is about 85% w/v. According to some embodiments, the amount of surfactant is about 86% w/v. According to some embodiments, the amount of surfactant is about 87% w/v. According to some embodiments, the amount of surfactant is about 88% w/v. According to some embodiments, the amount of surfactant is about 89% w/v. According to some embodiments, the amount of surfactant is about 90% w/v. According to some embodiments, the amount of surfactant is about 95% w/v. According to some embodiments, the amount of surfactant is about 96% w/v. According to some embodiments, the amount of surfactant is about 97% w/v. According to some embodiments, the amount of surfactant is about 98% w/v. According to some embodiments, the amount of surfactant is about 99% w/v. According to some embodiments, the amount of surfactant is about 100% w/v.

[00115] According to some embodiments, co-solvents of the pharmaceutical formulations include, but are not limited to, ethanol, glycerol (also known as glycerin), propylene glycol and polyethylene glycols (e.g., PEG-400).

[00116] According to some embodiments, the pharmaceutical formulation comprises ethanol, propylene glycol, PEG-400, glycerol or a combination thereof.

[00117] According to some embodiments, the amount of co-solvent in the pharmaceutical formulation is less than (<) 1 % volume/volume (v/v). According to some embodiments, the amount of co-solvent is greater than (>) 1 % v/v. According to some embodiments, the amount of co-solvent ranges from about 0.1 % v/v to about 100% v/v. According to some embodiments, the amount of co-solvent ranges from about 0.5% v/v to about 50% v/v. According to some embodiments, the amount of co-solvent ranges from about 1 % v/v to about 10% v/v. According to some embodiments, the amount of co-solvent is about 0.1 % v/v. According to some embodiments, the amount of co solvent is about 0.5% v/v. According to some embodiments, the amount of co-solvent is about 1 % v/v. According to some embodiments, the amount of co-solvent is about 2% v/v. According to some embodiments, the amount of co-solvent is about 3% v/v.

According to some embodiments, the amount of co-solvent is about 4% v/v. According to some embodiments, the amount of co-solvent is about 5% v/v. According to some embodiments, the amount of co-solvent is about 6% v/v. According to some

embodiments, the amount of co-solvent is about 7% v/v. According to some

embodiments, the amount of co-solvent is about 8% v/v. According to some

embodiments, the amount of co-solvent is about 9% v/v. According to some

embodiments, the amount of co-solvent is about 10% v/v. According to some embodiments, the amount of co-solvent is about 15% v/v. According to some embodiments, the amount of co-solvent is about 20% v/v. According to some embodiments, the amount of co-solvent is about 25% v/v. According to some embodiments, the amount of co-solvent is about 30% v/v. According to some embodiments, the amount of co-solvent is about 35% v/v. According to some embodiments, the amount of co-solvent is about 40% v/v. According to some embodiments, the amount of co-solvent is about 45% v/v. According to some embodiments, the amount of co-solvent is about 46% v/v. According to some embodiments, the amount of co-solvent is about 47% v/v. According to some embodiments, the amount of co-solvent is about 48% v/v. According to some embodiments, the amount of co-solvent is about 49% v/v. According to some embodiments, the amount of co-solvent is about 50% v/v. According to some embodiments, the amount of co-solvent is about 55% v/v. According to some embodiments, the amount of co-solvent is about 60% v/v. According to some embodiments, the amount of co-solvent is about 65% v/v. According to some embodiments, the amount of co-solvent is about 70% v/v. According to some embodiments, the amount of co-solvent is about 75% v/v. According to some embodiments, the amount of co-solvent is about 76% v/v. According to some embodiments, the amount of co-solvent is about 77% v/v. According to some embodiments, the amount of co-solvent is about 78% v/v. According to some embodiments, the amount of co-solvent is about 79% v/v. According to some embodiments, the amount of co-solvent is about 80% v/v. According to some embodiments, the amount of co-solvent is about 85% v/v. According to some embodiments, the amount of co-solvent is about 86% v/v. According to some embodiments, the amount of co-solvent is about 87% v/v. According to some embodiments, the amount of co-solvent is about 88% v/v. According to some embodiments, the amount of co-solvent is about 89% v/v. According to some embodiments, the amount of co-solvent is about 90% v/v. According to some embodiments, the amount of co-solvent is about 95% v/v. According to some embodiments, the amount of co-solvent is about 96% v/v. According to some embodiments, the amount of co-solvent is about 97% v/v. According to some embodiments, the amount of co-solvent is about 98% v/v. According to some embodiments, the amount of co-solvent is about 99% v/v. According to some embodiments, the amount of co-solvent is about 100% v/v.

[00118] According to some embodiments, the amount of co-solvent in the pharmaceutical formulation is less than (<) 1 % weight/weight (w/w). According to some embodiments, the amount of co-solvent is greater than (>) 1 % w/w. According to some embodiments, the amount of co-solvent ranges from about 0.1 % w/w to about 100% w/w. According to some embodiments, the amount of co-solvent ranges from about 0.5% w/w to about 50% w/w. According to some embodiments, the amount of co solvent ranges from about 1 % w/w to about 10% w/w. According to some

embodiments, the amount of co-solvent is about 0.1 % w/w. According to some embodiments, the amount of co-solvent is about 0.5% w/w. According to some embodiments, the amount of co-solvent is about 1 % w/w. According to some embodiments, the amount of co-solvent is about 2% w/w. According to some embodiments, the amount of co-solvent is about 3% w/w. According to some embodiments, the amount of co-solvent is about 4% w/w. According to some embodiments, the amount of co-solvent is about 5% w/w. According to some embodiments, the amount of co-solvent is about 6% w/w. According to some embodiments, the amount of co-solvent is about 7% w/w. According to some

embodiments, the amount of co-solvent is about 8% w/w. According to some embodiments, the amount of co-solvent is about 9% w/w. According to some

embodiments, the amount of co-solvent is about 10% w/w. According to some embodiments, the amount of co-solvent is about 15% w/w. According to some embodiments, the amount of co-solvent is about 20% w/w. According to some embodiments, the amount of co-solvent is about 25% w/w. According to some embodiments, the amount of co-solvent is about 30% w/w. According to some embodiments, the amount of co-solvent is about 35% w/w. According to some embodiments, the amount of co-solvent is about 40% w/w. According to some embodiments, the amount of co-solvent is about 45% w/w. According to some embodiments, the amount of co-solvent is about 46% w/w. According to some embodiments, the amount of co-solvent is about 47% w/w. According to some embodiments, the amount of co-solvent is about 48% w/w. According to some embodiments, the amount of co-solvent is about 49% w/w. According to some embodiments, the amount of co-solvent is about 50% w/w. According to some embodiments, the amount of co-solvent is about 55% w/w. According to some embodiments, the amount of co-solvent is about 60% w/w. According to some embodiments, the amount of co-solvent is about 65% w/w. According to some embodiments, the amount of co-solvent is about 70% w/w. According to some embodiments, the amount of co-solvent is about 75% w/w. According to some embodiments, the amount of co-solvent is about 76% w/w. According to some embodiments, the amount of co-solvent is about 77% w/w. According to some embodiments, the amount of co-solvent is about 78% w/w. According to some embodiments, the amount of co-solvent is about 79% w/w. According to some embodiments, the amount of co-solvent is about 80% w/w. According to some embodiments, the amount of co-solvent is about 85% w/w. According to some embodiments, the amount of co-solvent is about 86% w/w. According to some embodiments, the amount of co-solvent is about 87% w/w. According to some embodiments, the amount of co-solvent is about 88% w/w. According to some embodiments, the amount of co-solvent is about 89% w/w. According to some embodiments, the amount of co-solvent is about 90% w/w. According to some embodiments, the amount of co-solvent is about 95% w/w. According to some embodiments, the amount of co-solvent is about 96% w/w. According to some embodiments, the amount of co-solvent is about 97% w/w. According to some embodiments, the amount of co-solvent is about 98% w/w. According to some embodiments, the amount of co-solvent is about 99% w/w. According to some embodiments, the amount of co-solvent is about 100% w/w. [00119] According to some embodiments, the amount of co-solvent in the pharmaceutical formulation is less than (<) 1 % weight/volume (w/v). According to some embodiments, the amount of co-solvent is greater than (>) 1 % w/v. According to some embodiments, the amount of co-solvent ranges from about 0.1 % w/v to about 100% w/v. According to some embodiments, the amount of co-solvent ranges from about 0.5% w/v to about 50% w/v. According to some embodiments, the amount of co-solvent ranges from about 1 % w/v to about 10% w/v. According to some embodiments, the amount of co-solvent is about 0.1 % w/v. According to some embodiments, the amount of co-solvent is about 0.5% w/v. According to some embodiments, the amount of co solvent is about 1 % w/v. According to some embodiments, the amount of co-solvent is about 2% w/v. According to some embodiments, the amount of co-solvent is about 3% w/v. According to some embodiments, the amount of co-solvent is about 4% w/v.

According to some embodiments, the amount of co-solvent is about 5% w/v. According to some embodiments, the amount of co-solvent is about 6% w/v. According to some embodiments, the amount of co-solvent is about 7% w/v. According to some

embodiments, the amount of co-solvent is about 8% w/v. According to some

embodiments, the amount of co-solvent is about 9% w/v. According to some

embodiments, the amount of co-solvent is about 10% w/v. According to some embodiments, the amount of co-solvent is about 15% w/v. According to some embodiments, the amount of co-solvent is about 20% w/v. According to some embodiments, the amount of co-solvent is about 25% w/v. According to some embodiments, the amount of co-solvent is about 30% w/v. According to some embodiments, the amount of co-solvent is about 35% w/v. According to some embodiments, the amount of co-solvent is about 40% w/v. According to some embodiments, the amount of co-solvent is about 45% w/v. According to some embodiments, the amount of co-solvent is about 46% w/v. According to some embodiments, the amount of co-solvent is about 47% w/v. According to some embodiments, the amount of co-solvent is about 48% w/v. According to some embodiments, the amount of co-solvent is about 49% w/v. According to some embodiments, the amount of co-solvent is about 50% w/v. According to some embodiments, the amount of co-solvent is about 55% w/v. According to some embodiments, the amount of co-solvent is about 60% w/v. According to some embodiments, the amount of co-solvent is about 65% w/v. According to some embodiments, the amount of co-solvent is about 70% w/v. According to some embodiments, the amount of co-solvent is about 75% w/v. According to some embodiments, the amount of co-solvent is about 76% w/v. According to some embodiments, the amount of co-solvent is about 77% w/v. According to some embodiments, the amount of co-solvent is about 78% w/v. According to some embodiments, the amount of co-solvent is about 79% w/v. According to some embodiments, the amount of co-solvent is about 80% w/v. According to some embodiments, the amount of co-solvent is about 85% w/v. According to some embodiments, the amount of co-solvent is about 86% w/v. According to some embodiments, the amount of co-solvent is about 87% w/v. According to some embodiments, the amount of co-solvent is about 88% w/v. According to some embodiments, the amount of co-solvent is about 89% w/v. According to some embodiments, the amount of co-solvent is about 90% w/v. According to some embodiments, the amount of co-solvent is about 95% w/v. According to some embodiments, the amount of co-solvent is about 96% w/v. According to some embodiments, the amount of co-solvent is about 97% w/v. According to some embodiments, the amount of co-solvent is about 98% w/v. According to some embodiments, the amount of co-solvent is about 99% w/v. According to some embodiments, the amount of co-solvent is about 100% w/v.

[00120] According to some embodiments, the pharmaceutical formulation comprises 20% oleic acid; 70% ethoxylated castor oil (Cremophor^® EL); and 10% ethanol. According to some embodiments, the pharmaceutical formulation comprises 60% oleic acid; 30% ethoxylated castor oil (Cremophor^® EL); and 10% ethanol.

According to some embodiments, the percentage of oleic acid, ethoxylated castor oil (Cremophor^® EL) and ethanol in the pharmaceutical formulation is % v/v, % w/w, % w/v or a combination thereof.

[00121] According to some embodiments, the pharmaceutical formulation comprises 20% v/v oleic acid; 70% v/v ethoxylated castor oil (Cremophor^® EL); and 10% v/v ethanol. According to some embodiments, the pharmaceutical formulation comprises 60% v/v oleic acid; 30% v/v ethoxylated castor oil (Cremophor^® EL); and 10% v/v ethanol. [00122] According to some embodiments, the pharmaceutical formulation comprises 20% w/w oleic acid; 70% w/w ethoxylated castor oil (Cremophor^® EL); and 10% w/w ethanol. According to some embodiments, the pharmaceutical formulation comprises 60% w/w oleic acid; 30% w/w ethoxylated castor oil (Cremophor^® EL); and 10% w/w ethanol.

[00123] According to some embodiments, the pharmaceutical formulation comprises 20% w/v oleic acid; 70% w/v ethoxylated castor oil (Cremophor^® EL); and 10% w/v ethanol. According to some embodiments, the pharmaceutical formulation comprises 60% w/v oleic acid; 30% w/v ethoxylated castor oil (Cremophor^® EL); and 10% w/v ethanol.

[00124] According to some embodiments, the pharmaceutical formulation comprises 80% glycerol/glyceryl monooleate (Peceol™) and 20% polysorbate 80 (Tween^®-80). According to some embodiments, the percentage of glycerol/glyceryl monooleate (Peceol™) and polysorbate 80 (Tween^®-80) in the pharmaceutical formulation is % v/v, % w/w, % w/v or a combination thereof.

[00125] According to some embodiments, the pharmaceutical formulation comprises 80% v/v glycerol/glyceryl monooleate (Peceol™) and 20% v/v polysorbate 80 (Tween^®-80).

[00126] According to some embodiments, the pharmaceutical formulation comprises 80% w/w glycerol/glyceryl monooleate (Peceol™) and 20% w/w polysorbate 80 (Tween^®-80).

[00127] According to some embodiments, the pharmaceutical formulation comprises 80% w/v glycerol/glyceryl monooleate (Peceol™) and 20% w/v polysorbate 80 (Tween^®-80).

[00128] According to some embodiments, the pharmaceutical formulation comprises 99% propylene glycol monolaurate type II (Lauroglycol™ 90) and 1 % vitamin E. According to some embodiments, the percentage of propylene glycol monolaurate type II (Lauroglycol™ 90) and vitamin E in the pharmaceutical formulation is % v/v, % w/w, % w/v or a combination thereof. According to some embodiments, the pharmaceutical formulation comprises 79% propylene glycol monolaurate type II (Lauroglycol™ 90); 15.6% sorbitan monolaurate (Span^®) 20; 4.4% polysorbate 80 (Tween^®-80); and 1 % vitamin E. According to some embodiments, the percentage of propylene glycol monolaurate type II (Lauroglycol™ 90), sorbitan monolaurate (Span^®) 20, polysorbate 80 (Tween^®-80) and vitamin E in the pharmaceutical formulation is % v/v, % w/w, % w/v or a combination thereof. According to some embodiments, the pharmaceutical composition comprises 79% propylene glycol monolaurate type II (Lauroglycol™ 90); 5% sorbitan monooleate (Span^®) 80; 15% caprylocaproyl macrogol- 8 / polyoxyl-8 glycerides (Labrasol^®); and 1 % vitamin E. According to some

embodiments, the percentage of propylene glycol monolaurate type II (Lauroglycol™ 90), sorbitan monooleate (Span^®) 80, caprylocaproyl macrogol-8 / polyoxyl-8 glycerides (Labrasol^®) and vitamin E in the pharmaceutical formulation is % v/v, % w/w, % w/v or a combination thereof. According to some embodiments, the pharmaceutical formulation comprises 49% propylene glycol monolaurate type II (Lauroglycol™ 90); 40%

polysorbate 80 (Tween^®-80); 10% propylene glycol; and 1 % vitamin E. According to some embodiments, the percentage of propylene glycol monolaurate type II

(Lauroglycol™ 90), polysorbate 80 (Tween^®-80), propylene glycol and vitamin E in the pharmaceutical formulation is % v/v, % w/w, % w/v or a combination thereof.

[00129] According to some embodiments, the pharmaceutical formulation comprises 99% v/v propylene glycol monolaurate type II (Lauroglycol™ 90) and 1 % v/v vitamin E. According to some embodiments, the pharmaceutical formulation comprises 79% v/v propylene glycol monolaurate type II (Lauroglycol™ 90); 15.6% v/v sorbitan monolaurate (Span^®) 20; 4.4% v/v polysorbate 80 (Tween^®-80); and 1 % v/v vitamin E. According to some embodiments, the pharmaceutical composition comprises 79% v/v propylene glycol monolaurate type II (Lauroglycol™ 90); 5% v/v sorbitan monooleate (Span^®) 80; 15% v/v caprylocaproyl macrogol-8 / polyoxyl-8 glycerides (Labrasol^®); and 1 % v/v vitamin E. According to some embodiments, the pharmaceutical formulation comprises 49% v/v propylene glycol monolaurate type II (Lauroglycol™ 90); 40% v/v polysorbate 80 (Tween^®-80); 10% v/v propylene glycol; and 1 % v/v vitamin E.

[00130] According to some embodiments, the pharmaceutical formulation comprises 99% w/w propylene glycol monolaurate type II (Lauroglycol™ 90) and 1 % w/w vitamin E. According to some embodiments, the pharmaceutical formulation comprises 79% w/w propylene glycol monolaurate type II (Lauroglycol™ 90); 15.6% w/w sorbitan monolaurate (Span^®) 20; 4.4% w/w polysorbate 80 (Tween^®-80); and 1 % w/w vitamin E. According to some embodiments, the pharmaceutical composition comprises 79% w/w propylene glycol monolaurate type II (Lauroglycol™ 90); 5% w/w sorbitan monooleate (Span^®) 80; 15% w/w caprylocaproyl macrogol-8 / polyoxyl-8 glycerides (Labrasol^®); and 1 % w/w vitamin E. According to some embodiments, the pharmaceutical formulation comprises 49% w/w propylene glycol monolaurate type II (Lauroglycol™ 90); 40% w/w polysorbate 80 (Tween^®-80); 10% w/w propylene glycol; and 1 % w/w vitamin E.

[00131] According to some embodiments, the pharmaceutical formulation comprises 99% w/v propylene glycol monolaurate type II (Lauroglycol™ 90) and 1 % w/v vitamin E. According to some embodiments, the pharmaceutical formulation comprises 79% w/v propylene glycol monolaurate type II (Lauroglycol™ 90); 15.6% w/v sorbitan monolaurate (Span^®) 20; 4.4% w/v polysorbate 80 (Tween^®-80); and 1 % w/v vitamin E. According to some embodiments, the pharmaceutical composition comprises 79% w/v propylene glycol monolaurate type II (Lauroglycol™ 90); 5% w/v sorbitan monooleate (Span^®) 80; 15% w/v caprylocaproyl macrogol-8 / polyoxyl-8 glycerides (Labrasol^®); and 1 % w/v vitamin E. According to some embodiments, the pharmaceutical formulation comprises 49% w/v propylene glycol monolaurate type II (Lauroglycol™ 90); 40% w/v polysorbate 80 (Tween^®-80); 10% w/v propylene glycol; and 1 % w/v vitamin E.

[00132] According to some embodiments, the pharmaceutical formulation comprises 49% propylene glycol monocaprylate (Capryol™ 90); 40% polysorbate 80 (Tween^®-80); 10% propylene glycol; and 1 % vitamin E. According to some

embodiments, the percentage of propylene glycol monocaprylate (Capryol™ 90), polysorbate 80 (Tween^®-80), propylene glycol and vitamin E in the pharmaceutical formulation is % v/v, % w/w, % w/v or a combination thereof. According to some embodiments, the pharmaceutical formulation comprises 99% propylene glycol monocaprylate (Capryol™ 90) and 1 % vitamin E. According to some embodiments, the percentage of propylene glycol monocaprylate (Capryol™ 90) and vitamin E in the pharmaceutical formulation is % v/v, % w/w, % w/v or a combination thereof. [00133] According to some embodiments, the pharmaceutical formulation comprises 49% v/v propylene glycol monocaprylate (Capryol™ 90); 40% v/v polysorbate 80 (Tween^®-80); 10% v/v propylene glycol; and 1 % v/v vitamin E. According to some embodiments, the pharmaceutical formulation comprises 99% v/v propylene glycol monocaprylate (Capryol™ 90) and 1 % v/v vitamin E.

[00134] According to some embodiments, the pharmaceutical formulation comprises 49% w/w propylene glycol monocaprylate (Capryol™ 90); 40% w/w polysorbate 80 (Tween^®-80); 10% w/w propylene glycol; and 1 % w/w vitamin E.

According to some embodiments, the pharmaceutical formulation comprises 99% w/w propylene glycol monocaprylate (Capryol™ 90) and 1 % w/w vitamin E.

[00135] According to some embodiments, the pharmaceutical formulation comprises 49% w/v propylene glycol monocaprylate (Capryol™ 90); 40% w/v

polysorbate 80 (Tween^®-80); 10% w/v propylene glycol; and 1 % w/v vitamin E.

According to some embodiments, the pharmaceutical formulation comprises 99% w/v propylene glycol monocaprylate (Capryol™ 90) and 1 % w/v vitamin E.

[00136] According to some embodiments, the pharmaceutical formulation comprises 90% polysorbate 80 (Tween^®-80); 9% propylene glycol; and 1 % vitamin E. According to some embodiments, the pharmaceutical formulation comprises 45.5% polysorbate 80 (Tween^®-80); 9% propylene glycol; and 45.5% vitamin E. According to some embodiments, the percentage of polysorbate 80 (Tween^®-80), propylene glycol and vitamin E in the pharmaceutical formulation is % v/v, % w/w, % w/v or a

combination thereof.

[00137] According to some embodiments, the pharmaceutical formulation comprises 90% v/v polysorbate 80 (Tween^®-80); 9% v/v propylene glycol; and 1 % v/v vitamin E. According to some embodiments, the pharmaceutical formulation comprises 45.5% v/v polysorbate 80 (Tween^®-80); 9% v/v propylene glycol; and 45.5% v/v vitamin E.

[00138] According to some embodiments, the pharmaceutical formulation comprises 90% w/w polysorbate 80 (Tween^®-80); 9% w/w propylene glycol; and 1 % w/w vitamin E. According to some embodiments, the pharmaceutical formulation comprises 45.5% w/w polysorbate 80 (Tween^®-80); 9% w/w propylene glycol; and 45.5% w/w vitamin E.

[00139] According to some embodiments, the pharmaceutical formulation comprises 90% w/v polysorbate 80 (Tween^®-80); 9% w/v propylene glycol; and 1 % w/v vitamin E. According to some embodiments, the pharmaceutical formulation comprises 45.5% w/v polysorbate 80 (Tween^®-80); 9% w/v propylene glycol; and 45.5% w/v vitamin E.

[00140] According to some embodiments, the pharmaceutical formulation comprises 99% phosphatidyl choline/propylene glycol (Phosal^® 50PG) and 1 % vitamin E. According to some embodiments, the percentage of phosphatidyl choline/propylene glycol (Phosal^® 50PG) and vitamin E in the pharmaceutical formulation is % v/v, % w/w, % w/v or a combination thereof.

[00141] According to some embodiments, the pharmaceutical formulation comprises 99% v/v phosphatidyl choline/propylene glycol (Phosal^® 50PG) and 1 % v/v vitamin E.

[00142] According to some embodiments, the pharmaceutical formulation comprises 99% w/w phosphatidyl choline/propylene glycol (Phosal^® 50PG) and 1 % w/w vitamin E.

[00143] According to some embodiments, the pharmaceutical formulation comprises 99% w/v phosphatidyl choline/propylene glycol (Phosal^® 50PG) and 1 % w/v vitamin E.

[00144] According to some embodiments, the pharmaceutical formulation comprises 99% castor oil and 1 % vitamin E. According to some embodiments, the percentage of castor oil and vitamin E in the pharmaceutical formulation is % v/v, % w/w, % w/v or a combination thereof.

[00145] According to some embodiments, the pharmaceutical formulation comprises 99% v/v castor oil and 1 % v/v vitamin E. [00146] According to some embodiments, the pharmaceutical formulation comprises 99% w/w castor oil and 1 % w/w vitamin E.

[00147] According to some embodiments, the pharmaceutical formulation comprises 99% w/v castor oil and 1 % w/v vitamin E.

[00148] According to some embodiments, the pharmaceutical formulation comprises 49% propylene glycol monolaurate type II (Lauroglycol™ 90); 40% polysorbate-80 (Tween^®-80); 10% propylene glycol; and 1 % vitamin E. According to some embodiments, the percentage of propylene glycol monolaurate type II

(Lauroglycol™ 90), polysorbate-80 (Tween^®-80), propylene glycol and vitamin E in the pharmaceutical formulation is % v/v, % w/w, % w/v or a combination thereof.

[00149] According to some embodiments, the pharmaceutical formulation comprises 49% v/v propylene glycol monolaurate type II (Lauroglycol™ 90); 40% v/v polysorbate-80 (Tween^®-80); 10% v/v propylene glycol; and 1 % v/v vitamin E.

[00150] According to some embodiments, the pharmaceutical formulation comprises 49% w/w propylene glycol monolaurate type II (Lauroglycol™ 90); 40% w/w polysorbate-80 (Tween^®-80); 10% w/w propylene glycol; and 1 % w/w vitamin E.

[00151] According to some embodiments, the pharmaceutical formulation comprises 49% w/v propylene glycol monolaurate type II (Lauroglycol™ 90); 40% w/v polysorbate-80 (Tween^®-80); 10% w/v propylene glycol; and 1 % w/v vitamin E.

[00152] According to some embodiments, the pharmaceutical formulation comprises 45.5% vitamin E TPGS; 45.5% polysorbate-80 (Tween^®-80); and

9% propylene glycol. According to some embodiments, the percentage of vitamin E TPGS, polysorbate-80 (Tween^®-80) and propylene glycol in the pharmaceutical formulation is % v/v, % w/w, % w/v or a combination thereof.

[00153] According to some embodiments, the pharmaceutical formulation comprises 45.5% v/v vitamin E TPGS; 45.5% v/v polysorbate-80 (Tween^®-80); and 9% v/v propylene glycol. [00154] According to some embodiments, the pharmaceutical formulation comprises 45.5% w/w vitamin E TPGS; 45.5% w/w polysorbate-80 (Tween^®-80); and 9% w/w propylene glycol.

[00155] According to some embodiments, the pharmaceutical formulation comprises 45.5% w/v vitamin E TPGS; 45.5% w/v polysorbate-80 (Tween^®-80); and 9% w/v propylene glycol.

[00156] According to some embodiments, the pharmaceutical formulations are oral formulations. According to some embodiments, the oral formulations are liquid formulations. According to some embodiments, the oral formulations are soft gelatin capsules. According to some embodiments, the oral formulations are hard gelatin capsules. According to some embodiments, the oral formulations are

hydroxypropylmethyl cellulose (HPMC) capsules.

[00157] According to some embodiments, the pharmaceutical formulations of the described invention comprise appropriate adjuvants, including, without limitation, preservative agents, wetting agents, emulsifying agents, and dispersing agents.

Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It also may be desirable to include isotonic agents, for example, sugars, sodium chloride and the like.

[00158] According to some embodiments, the pharmaceutical formulations of the described invention comprise additives. Such additives include, but are not limited to, anti-oxidants. Non-limiting examples of anti-oxidants include a-tocopherol, b-carotene, propyl gallate, butylated hydroxyl toluene (BHT), butylated hydroxyanisole (BHA), vitamin E and the like.

[00159] According to some embodiments, the pharmaceutical formulations of the described invention can be prepared by methods known in the art. Such methods include, without limitation, spray congealing, spray drying, adsorption onto a solid carrier, melt granulation and supercritical fluid-based method. [00160] In the spray congealing method, a drug solution (drug in organic solvent or water) along with lipid excipient(s) is sprayed into a hot air chamber where the organic solvent or water evaporates, giving rise to solid microparticles containing the drug.

[00161] The adsorption of drug onto a solid carrier is a simple and economical process in which a liquid-lipid formulation is adsorbed onto a solid carrier such as, for example, silicon dioxide, calcium silicate or magnesium aluminometasilicate. Generally, a lipid-based formulation is added to a carrier by mixing in a blender. Advantages of this method include good content uniformity and high lipid exposure.

[00162] Melt granulation, also referred to as palletization, transforms a powder mixture containing a drug into granules or pellets. A melt able binder in a molten state is sprayed onto a powder mixture in the presence of high-shear mixing. Alternatively, the melt able binder is blended with a powder mixture and, due to friction of particles during high-shear mixing, the binder melts to form liquid bridges between powder particles. Small granules are formed which transform into spheronized pellets under certain controlled conditions.

[00163] The supercritical fluid-based method uses lipids for coating drug particles to produce solid dispersions. A drug and lipid-based excipient(s) are dissolved in an organic solvent and supercritical fluid (carbon dioxide) by elevating temperature and pressure. The coating process is facilitated gradual reduction in temperature and pressure in order to reduce the solubility of the coating material in the fluid and thus precipitate onto the drug particles to form a coating.

[00164] According to some embodiments, the pharmaceutical formulations of the described invention may be characterized by techniques known in the art. Such techniques include, but are not limited to, appearance (e.g, color and uniformity), odor, taste, density, pH, self-dispersion, dispersion size, droplet size, surface charge, viscosity, in vitro studies, in vivo studies and in vitro-in vivo correlation (IVIVC) studies.

[00165] Appearance of a pharmaceutical formulation may be evaluated by visual inspection of the formulation for color and uniformity. [00166] Odor and taste characteristics may be determined through the use of animal or human studies. Alternatively, artificial sensors may be substituted for the animal or human palate. These artificial sensory devices typically are arrays of sensors called“electronic noses” for arrays of gas sensors and“electronic tongues” for arrays of liquid sensors. In general, these devices are designed to analyze the levels of various ingredients that compose a fluid mixture.

[00167] Density, also referred to as specific gravity, is considered to be an essential parameter of a pharmaceutical formulation. For example, a decrease in density often indicates the entrapment of air within the structure of a formulation.

Density measurements at a given temperature may be made using a high precision hydrometer. A hydrometer is an instrument used to measure the specific gravity (or relative density) of liquids. That is, the ratio of the density of the liquid to the density of water. Hydrometers are usually made of glass and consist of a cylindrical stem and a bulb weighted with mercury or a lead shot to make it float upright. The liquid to be tested is poured into a tall container, often a graduated cylinder or a specially designed hydrometer cylinder, and the hydrometer is gently lowered into the liquid until it floats freely. The point at which the surface of the liquid touches the stem of the hydrometer is noted. Hydrometers usually contain a scale inside the stem so that the specific gravity can be directly measured.

[00168] The pH value of a liquid formulation is directly related to the ratio of hydrogen ion concentration ([H+]) to hydroxyl ion concentration ([OH-]). Higher H+ ion concentrations result in an acidic pH (i.e. , pH<7). Higher OH- ion concentrations result in a basic pH (i.e., pH>7). Equal amounts of H+ and OH- ions result in a neutral pH (pH=7). The pH of a formulation may be determined by using, for example, pH papers or indicators or a pH meter.

[00169] Particle size measurements may be performed by optical microscopy using a compound microscope for particles with measurements within microns.

Alternatively, a particle size analyzer may be used. Particle size analyzers work on the principle that when a beam a light (e.g., a laser) is scattered by a group particles, the angle of light scattering is inversely proportional to particle size (i.e., the smaller the particle, the larger the angle of light scattering). [00170] Droplet size distribution may be determined by electron microscopy or light-scattering techniques. Dynamic light-scattering measurements are taken at 90° in a dynamic light-scattering spectrophotometer which uses a neon laser of wavelength 632 nm. Data processing is performed by a computer built-in to the light-scattering instrument.

[00171] Surface charge may be determined using a zeta potential analyzer. Zeta potential (ZP) characterizes the surface charge of particles and thus provides information related to repulsive forces between particles and droplets. For example, to obtain a stable nano-emulsion by preventing flocculation and coalescence of nanodroplets, a ZP should typically reach a value greater than (+) 30 mV.

[00172] Viscosity of a lipid-based formulation may be measured by a viscometer. Types of viscometers include, but are not limited to, capillary viscometers, rotational viscometers, rolling ball viscometers, falling ball viscometers, sphere viscometers and piston viscometers. Capillary viscometers (also known as u-tube or glass viscometers) measure viscosity by timing how long it takes a fluid to flow between two points of a capillary tube. Capillary viscometers may be manual or automatic. Automatic capillary viscometers use either infrared optical sensors (for transparent samples) or thermal sensors (for opaque samples). Rotational viscometers (Brookfield type viscometers) use a torsion spring to measure the torque required to rotate a spindle within a sample material. Changing rotor speed and size allows for measurement of different ranges of viscosity. A rolling ball viscometer operates by rolling a ball through a closed, sample- filled capillary inclined at a defined angle. Inductive sensors are used to determine the ball’s rolling time between two marks. Similarly, falling ball or sphere viscometers measure the time it takes for a ball or a sphere to fall under gravity through a sample- filled tube inclined at an angle. Falling piston viscometers operate in a similar manner by measuring the resistance to a piston falling through a sample material.

[00173] In order to assess the performance of an excipient during formulation development and to predict in vivo performance, it may be necessary to design in vitro dissolution testing models. Such models consist of a temperature-controlled vessel (e.g., 37 + 1 °C), which contains a model intestinal fluid composed of digestion buffer, bile salt and phospholipid. A fluid lipid-based formulation is added followed by pancreatic lipase and colipase to initiate the digestion process. As digestion of the formulation begins, fatty acids are liberated, causing a transient drop in pH. This drop in pH is quantified by a pH electrode coupled with a pH-stat meter controller and auto burette. An equimolar quantity of sodium hydroxide is added by the auto burette in order to titrate the liberated fatty acids and prevent a change in pH of the digestion medium from a preset pH value. By quantifying the rate of sodium hydroxide addition and considering the stoichiometric relationship between fatty acids and sodium hydroxide, the extent of digestion can be quantified. During this process, samples may be separated into a poorly dispersed oil phase, a highly dispersed aqueous phase and a precipitated pellet phase by centrifugation. This separation may be indicative of the in vivo performance of the lipid-based formulation. For example, quantification of drug in the highly dispersed aqueous phase indicates that the drug has not precipitated.

Alternatively, the impact of excipients on the bioavailability and pharmacokinetic profile of drugs may be estimated by designing appropriate in vivo studies.

[00174] Developing experimental models that correlate in vitro data with in vivo data may aid in maximizing development potential and commercialization, shorten drug development periods and improve product quality of lipid-based formulations. By way of example, experimental models that correlate in vitro data with in vivo data include, but are not limited to, enterocytes in vivo and CaCo-2 cells cultured in vitro. Both enterocytes in vivo and CaCo-2 cells cultured in vitro produce and secrete chylomicrons upon exposure to lipids.

[00175] According to some embodiments, the pharmaceutical formulations of the described invention are pure. According to some embodiments, the pharmaceutical formulations of the describe invention are substantially pure. According to some embodiments, the pharmaceutical formulations are about 50% pure. According to some embodiments, the pharmaceutical formulations are about 55% pure. According to some embodiments, the pharmaceutical formulations are about 60% pure. According to some embodiments, the pharmaceutical formulations are about 65% pure. According to some embodiments, the pharmaceutical formulations are about 70% pure. According to some embodiments, the pharmaceutical formulations are about 75% pure. According to some embodiments, the pharmaceutical formulations are about 80% pure. According to some embodiments, the pharmaceutical formulations are about 85% pure. According to some embodiments, the pharmaceutical formulations are about 90% pure. According to some embodiments, the pharmaceutical formulations are about 95% pure. According to some embodiments, the pharmaceutical formulations are about 99% pure.

[00176] Methods of determining purity and/or detecting impurities include, but are not limited to, high-performance liquid chromatography (HPLC), enzyme-linked immunosorbent assay (ELISA), Western blot, polymerase chain reaction (PCR) and the like.

[00177] According to some embodiments, the pharmaceutical formulations of the described invention comprise a therapeutic agent. According to some embodiments, the therapeutic agent is cenicriviroc (CVC). According to some embodiments, CVC is in the form of an amorphous free base. According to some embodiments, CVC is in the form of a crystalline free base. According to some embodiments, CVC is in the form of a pharmaceutically acceptable salt. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may

conveniently be used to prepare pharmaceutically acceptable salts thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts may be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group. Pharmaceutically acceptable salts are well-known. For example, P. H. Stahl, et al.

describe pharmaceutically acceptable salts in detail in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley VCH, Zurich, Switzerland: 2002). The salts may be prepared in situ during the final isolation and purification of the compounds described within the described invention or may be prepared by separately reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate(isethionate), lactate, maleate, mesylate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil- soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid, citric acid and fumaric acid. Basic addition salts may be prepared in situ during the final isolation and purification of compounds described within the invention by reacting a carboxylic acid- containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine,

diethanolamine, piperidine, piperazine and the like. Pharmaceutically acceptable salts also may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium or magnesium) salts of carboxylic acids may also be made. According to some embodiments, CVC is cenicriviroc mesylate (S,E)-8-[4-(2-butoxyethoxy)phenyl]-1-(2-methylpropyl)-N-[4-[(3-propylimidazol- 4-yl)methylsulfinyl]phenyl]-3,4-dihydro-2H-1 -benzazocine-5-carboxamide;

methanesulfonic acid

[00178] According to some embodiments, the pharmaceutical formulations of the described invention comprise a therapeutic amount of CVC. According to some embodiments, the therapeutic amount of CVC is less than (<) 1 mg. According to some embodiments, the therapeutic amount of CVC is greater than (>) 1 mg. According to some embodiments, the therapeutic amount of CVC ranges from about 0.1 mg to about 1000 mg. According to some embodiments, the therapeutic amount of CVC ranges from about 0.5 mg to about 500 mg. According to some embodiments, the therapeutic amount of CVC ranges from about 0.15 mg to about 150 mg. According to some embodiments, the therapeutic amount of CVC is about 0.1 mg. According to some embodiments, the therapeutic amount of CVC is about 0.5 mg. According to some embodiments, the therapeutic amount of CVC is about 1 mg. According to some embodiments, the therapeutic amount of CVC is about 2 mg. According to some embodiments, the therapeutic amount of CVC is about 3 mg. According to some embodiments, the therapeutic amount of CVC is about 4 mg. According to some embodiments, the therapeutic amount of CVC is about 5 mg. According to some embodiments, the therapeutic amount of CVC is about 6 mg. According to some embodiments, the therapeutic amount of CVC is about 7 mg. According to some embodiments, the therapeutic amount of CVC is about 8 mg. According to some embodiments, the therapeutic amount of CVC is about 9 mg. According to some embodiments, the therapeutic amount of CVC is about 10 mg. According to some embodiments, the therapeutic amount of CVC is about 15 mg. According to some embodiments, the therapeutic amount of CVC is about 20 mg. According to some embodiments, the therapeutic amount of CVC is about 25 mg. According to some embodiments, the therapeutic amount of CVC is about 30 mg. According to some embodiments, the therapeutic amount of CVC is about 35 mg. According to some embodiments, the therapeutic amount of CVC is about 40 mg. According to some embodiments, the therapeutic amount of CVC is about 45 mg. According to some embodiments, the therapeutic amount of CVC is about 50 mg. According to some embodiments, the therapeutic amount of CVC is about 55 mg. According to some embodiments, the therapeutic amount of CVC is about 60 mg. According to some embodiments, the therapeutic amount of CVC is about 65 mg. According to some embodiments, the therapeutic amount of CVC is about 70 mg. According to some embodiments, the therapeutic amount of CVC is about 75 mg. According to some embodiments, the therapeutic amount of CVC is about 80 mg. According to some embodiments, the therapeutic amount of CVC is about 85 mg. According to some embodiments, the therapeutic amount of CVC is about 90 mg. According to some embodiments, the therapeutic amount of CVC is about 95 mg. According to some embodiments, the therapeutic amount of CVC is about 100 mg. According to some embodiments, the therapeutic amount of CVC is about 110 mg. According to some embodiments, the therapeutic amount of CVC is about 120 mg. According to some embodiments, the therapeutic amount of CVC is about 130 mg. According to some embodiments, the therapeutic amount of CVC is about 140 mg. According to some embodiments, the therapeutic amount of CVC is about 150 mg. According to some embodiments, the therapeutic amount of CVC is about 160 mg. According to some embodiments, the therapeutic amount of CVC is about 170 mg. According to some embodiments, the therapeutic amount of CVC is about 180 mg. According to some embodiments, the therapeutic amount of CVC is about 190 mg. According to some embodiments, the therapeutic amount of CVC is about 200 mg. According to some embodiments, the therapeutic amount of CVC is about 210 mg. According to some embodiments, the therapeutic amount of CVC is about 220 mg. According to some embodiments, the therapeutic amount of CVC is about 230 mg. According to some embodiments, the therapeutic amount of CVC is about 240 mg. According to some embodiments, the therapeutic amount of CVC is about 250 mg. According to some embodiments, the therapeutic amount of CVC is about 260 mg. According to some embodiments, the therapeutic amount of CVC is about 270 mg. According to some embodiments, the therapeutic amount of CVC is about 280 mg. According to some embodiments, the therapeutic amount of CVC is about 290 mg. According to some embodiments, the therapeutic amount of CVC is about 300 mg. According to some embodiments, the therapeutic amount of CVC is about 325 mg. According to some embodiments, the therapeutic amount of CVC is about 350 mg. According to some embodiments, the therapeutic amount of CVC is about 375 mg. According to some embodiments, the therapeutic amount of CVC is about 400 mg. According to some embodiments, the therapeutic amount of CVC is about 425 mg. According to some embodiments, the therapeutic amount of CVC is about 450 mg. According to some embodiments, the therapeutic amount of CVC is about 475 mg. According to some embodiments, the therapeutic amount of CVC is about 500 mg. According to some embodiments, the therapeutic amount of CVC is about 525 mg. According to some embodiments, the therapeutic amount of CVC is about 550 mg. According to some embodiments, the therapeutic amount of CVC is about 575 mg. According to some embodiments, the therapeutic amount of CVC is about 600 mg. According to some embodiments, the therapeutic amount of CVC is about 625 mg. According to some embodiments, the therapeutic amount of CVC is about 650 mg. According to some embodiments, the therapeutic amount of CVC is about 675 mg. According to some embodiments, the therapeutic amount of CVC is about 700 mg. According to some embodiments, the therapeutic amount of CVC is about 725 mg. According to some embodiments, the therapeutic amount of CVC is about 750 mg. According to some embodiments, the therapeutic amount of CVC is about 775 mg. According to some embodiments, the therapeutic amount of CVC is about 800 mg. According to some embodiments, the therapeutic amount of CVC is about 825 mg. According to some embodiments, the therapeutic amount of CVC is about 850 mg. According to some embodiments, the therapeutic amount of CVC is about 875 mg. According to some embodiments, the therapeutic amount of CVC is about 900 mg. According to some embodiments, the therapeutic amount of CVC is about 925 mg. According to some embodiments, the therapeutic amount of CVC is about 950 mg. According to some embodiments, the therapeutic amount of CVC is about 975 mg. According to some embodiments, the therapeutic amount of CVC is about 1000 mg.

[00179] According to some embodiments, the pharmaceutical formulations of the described invention comprise a therapeutic concentration of CVC. According to some embodiments, the therapeutic concentration of CVC is less than (<) 1 mg/mL.

According to some embodiments, the therapeutic concentration of CVC is greater than (>) 1 mg/mL. According to some embodiments, the therapeutic concentration of CVC ranges from about 0.1 mg/mL to about 1000 mg/mL. According to some embodiments, the therapeutic concentration of CVC ranges from about 0.5 mg/mL to about 500 mg/mL. According to some embodiments, the therapeutic concentration of CVC ranges from about 0.15 mg/mL to about 150 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 0.1 mg/mL. According to some

embodiments, the therapeutic concentration of CVC is about 0.5 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 1 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 2 mg/mL.

According to some embodiments, the therapeutic concentration of CVC is about 3 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 4 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 5 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 6 mg/mL. According to some embodiments, the therapeutic

concentration of CVC is about 7 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 8 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 9 mg/mL. According to some

embodiments, the therapeutic concentration of CVC is about 10 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 15 mg/mL.

According to some embodiments, the therapeutic concentration of CVC is about 20 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 25 mg/mL. According to some embodiments, the therapeutic concentration of

CVC is about 30 mg/mL. According to some embodiments, the therapeutic

concentration of CVC is about 35 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 40 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 45 mg/mL. According to some

embodiments, the therapeutic concentration of CVC is about 50 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 55 mg/mL.

According to some embodiments, the therapeutic concentration of CVC is about 60 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 65 mg/mL. According to some embodiments, the therapeutic concentration of

CVC is about 70 mg/mL. According to some embodiments, the therapeutic

concentration of CVC is about 75 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 80 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 85 mg/mL. According to some

embodiments, the therapeutic concentration of CVC is about 90 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 95 mg/mL.

According to some embodiments, the therapeutic concentration of CVC is about 100 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 110 mg/mL. According to some embodiments, the therapeutic concentration of

CVC is about 120 mg/mL. According to some embodiments, the therapeutic

concentration of CVC is about 130 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 140 mg/mL. According to some

embodiments, the therapeutic concentration of CVC is about 150 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 160 mg/mL.

According to some embodiments, the therapeutic concentration of CVC is about 170 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 180 mg/mL. According to some embodiments, the therapeutic concentration of

CVC is about 190 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 200 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 210 mg/mL. According to some

embodiments, the therapeutic concentration of CVC is about 220 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 230 mg/mL.

According to some embodiments, the therapeutic concentration of CVC is about 240 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 250 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 260 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 270 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 280 mg/mL. According to some

embodiments, the therapeutic concentration of CVC is about 290 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 300 mg/mL.

According to some embodiments, the therapeutic concentration of CVC is about 325 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 350 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 375 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 400 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 425 mg/mL. According to some

embodiments, the therapeutic concentration of CVC is about 450 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 475 mg/mL.

According to some embodiments, the therapeutic concentration of CVC is about 500 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 525 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 550 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 575 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 600 mg/mL. According to some

embodiments, the therapeutic concentration of CVC is about 625 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 650 mg/mL.

According to some embodiments, the therapeutic concentration of CVC is about 675 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 700 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 725 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 750 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 775 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 800 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 825 mg/mL.

According to some embodiments, the therapeutic concentration of CVC is about 850 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 875 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 900 mg/mL. According to some embodiments, the therapeutic

concentration of CVC is about 925 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 950 mg/mL. According to some

embodiments, the therapeutic concentration of CVC is about 975 mg/mL. According to some embodiments, the therapeutic concentration of CVC is about 1000 mg/mL.

[00180] According to some embodiments, the pharmaceutical formulations of the described invention comprise a drug load of CVC. According to some embodiments, the drug load of CVC is less than (<) 1 % by weight. According to some embodiments, the drug load of CVC is greater than (>) 1 % by weight. According to some

embodiments, the drug load of CVC ranges from about 0.1 % by weight to about 100% by weight. According to some embodiments, the drug load of CVC ranges from about 0.5% by weight to about 50% by weight. According to some embodiments, the drug load of CVC ranges from about 1 % by weight to about 15% by weight. According to some embodiments, the drug load of CVC ranges from about 1 % by weight to about 12.5% by weight. According to some embodiments, the drug load of CVC ranges from about 1 % by weight to about 10% by weight. According to some embodiments, the drug load of CVC is about 0.1 % by weight. According to some embodiments, the drug load of CVC is about 0.5% by weight. According to some embodiments, the drug load of CVC is about 1 % by weight. According to some embodiments, the drug load of CVC is about 1.5% by weight. According to some embodiments, the drug load of CVC is about 2% by weight. According to some embodiments, the drug load of CVC is about 2.5% by weight. According to some embodiments, the drug load of CVC is about 3% by weight. According to some embodiments, the drug load of CVC is about 3.5% by weight. According to some embodiments, the drug load of CVC is about 4% by weight. According to some embodiments, the drug load of CVC is about 4.5% by weight.

According to some embodiments, the drug load of CVC is about 5% by weight.

According to some embodiments, the drug load of CVC is about 5.5% by weight.

According to some embodiments, the drug load of CVC is about 6% by weight. According to some embodiments, the drug load of CVC is about 6.5% by weight.

According to some embodiments, the drug load of CVC is about 7% by weight.

According to some embodiments, the drug load of CVC is about 7.5% by weight.

According to some embodiments, the drug load of CVC is about 8% by weight.

According to some embodiments, the drug load of CVC is about 8.5% by weight.

According to some embodiments, the drug load of CVC is about 9% by weight.

According to some embodiments, the drug load of CVC is about 9.5% by weight.

According to some embodiments, the drug load of CVC is about 10% by weight.

According to some embodiments, the drug load of CVC is about 10.5% by weight.

According to some embodiments, the drug load of CVC is about 11 % by weight.

According to some embodiments, the drug load of CVC is about 11.5% by weight.

According to some embodiments, the drug load of CVC is about 12% by weight.

According to some embodiments, the drug load of CVC is about 12.5% by weight.

According to some embodiments, the drug load of CVC is about 13% by weight.

According to some embodiments, the drug load of CVC is about 13.5% by weight.

According to some embodiments, the drug load of CVC is about 14% by weight.

According to some embodiments, the drug load of CVC is about 14.5% by weight.

According to some embodiments, the drug load of CVC is about 15% by weight.

According to some embodiments, the drug load of CVC is about 15.5% by weight.

According to some embodiments, the drug load of CVC is about 16% by weight.

According to some embodiments, the drug load of CVC is about 16.5% by weight.

According to some embodiments, the drug load of CVC is about 17% by weight.

According to some embodiments, the drug load of CVC is about 17.5% by weight.

According to some embodiments, the drug load of CVC is about 18% by weight.

According to some embodiments, the drug load of CVC is about 18.5% by weight.

According to some embodiments, the drug load of CVC is about 19% by weight.

According to some embodiments, the drug load of CVC is about 19.5% by weight.

According to some embodiments, the drug load of CVC is about 20% by weight.

According to some embodiments, the drug load of CVC is about 25% by weight.

According to some embodiments, the drug load of CVC is about 30% by weight.

According to some embodiments, the drug load of CVC is about 35% by weight.

According to some embodiments, the drug load of CVC is about 40% by weight.

According to some embodiments, the drug load of CVC is about 45% by weight.

According to some embodiments, the drug load of CVC is about 50% by weight. According to some embodiments, the drug load of CVC is about 55% by weight.

According to some embodiments, the drug load of CVC is about 60% by weight.

According to some embodiments, the drug load of CVC is about 65% by weight.

According to some embodiments, the drug load of CVC is about 70% by weight.

According to some embodiments, the drug load of CVC is about 75% by weight.

According to some embodiments, the drug load of CVC is about 80% by weight.

According to some embodiments, the drug load of CVC is about 85% by weight.

According to some embodiments, the drug load of CVC is about 90% by weight.

According to some embodiments, the drug load of CVC is about 95% by weight.

According to some embodiments, the drug load of CVC is about 100% by weight.

[00181] According to some embodiments, the pharmaceutical formulations of the described invention comprising a therapeutic agent further comprise one or more additional therapeutic agents.

[00182] According to some embodiments, the pharmaceutical formulations of the described invention are loaded with one or more additional therapeutic agents.

According to some embodiments, the pharmaceutical formulations are loaded with less than (<) 1 % by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with greater than (>) 1 % by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with from about 0.1 % by weight to about 100% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with from about 0.5% by weight to about 50% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with from about 1 % by weight to about 10% by weight of one or more additional therapeutic agents.

According to some embodiments, the pharmaceutical formulations are loaded with about 0.1 % by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 0.5% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 1 % by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 2% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 3% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 4% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 5% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 6% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 7% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 8% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 9% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 10% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 15% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 20% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 25% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 30% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 35% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 40% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 45% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 50% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 55% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 60% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 65% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 70% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 75% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 80% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 85% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 90% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 95% by weight of one or more additional therapeutic agents. According to some embodiments, the pharmaceutical formulations are loaded with about 100% by weight of one or more additional therapeutic agents.

[00183] According to some embodiments, the pharmaceutical formulations of the described invention comprising a therapeutic agent are co-administered with one or more additional therapeutic agents. The term“co-administration” refers to

administration of (a) an additional therapeutic agent; and (b) CVC, together in a coordinated fashion. For example, the co-administration can be simultaneous administration, sequential administration, overlapping administration, interval administration, continuous administration, or a combination thereof.

[00184] According to some embodiments, the co-administration is carried out for one or more treatment cycles. The phrase“treatment cycle”, refers to a pre-determ ined period of time for co-administering the additional therapeutic agent and CVC. Typically, a patient is examined at the end of each treatment cycle to evaluate the effect of the combination therapy. In one embodiment, the co-administration is carried out for 1 to 50 treatment cycles. In another embodiment, the co-administration is carried out for 1 to 36 treatment cycles. In another embodiment, the co-administration is carried out for

1 to 25 treatment cycles.

[00185] According to some embodiments, each of the treatment cycles has about

2 or more days. According to some embodiments, each of the treatment cycles has from about 2 days to about 60 days. According to some embodiments, each of the treatment cycles has from about 5 days to about 50 days. According to some embodiments, each of the treatment cycles has from about 7 days to about 28 days. According to some embodiments, each of the treatment cycle has 28 days. According to some embodiments, the treatment cycle has about 29 days. According to some embodiments, the treatment cycle has about 30 days. According to some

embodiments, the treatment cycle has about 31 days. According to some embodiments, the treatment cycle has about a month-long treatment cycle. According to some embodiments, the treatment cycle is any length of time from 3 weeks to 6 weeks.

According to some embodiments, the treatment cycle is any length of time from 4 weeks to 6 weeks. According to some embodiments, the treatment cycle is 4 weeks. According to some embodiments, the treatment cycle is one month. According to some embodiments, the treatment cycle is 5 weeks. In another embodiment, the treatment cycle is 6 weeks.

[00186] Depending on the patient’s condition and the intended therapeutic effect, the dosing frequency for each of the additional therapeutic agent(s) and CVC may vary from once per day to six times per day. According to some embodiments, the dosing frequency may be once per day, twice per day, three times per day, four times per day, five times per day, or six times per day.

[00187] According to some embodiments, there may be one or more void days in a treatment cycle. The phrase“void day”, refers to a day when neither the additional therapeutic agent(s) nor CVC is administered. In other words, none of the additional therapeutic agent(s) and the CVC is administered on a void day. According to some embodiments, a treatment cycle comprises at least one non-void day. The phrase“non void day” refers to a day when at least one of the additional therapeutic agent(s) and CVC is administered.

[00188] According to some embodiments, the pharmaceutical formulations of the described invention comprising a therapeutic agent and one or more additional therapeutic agents are co-administered as separate formulations. According to some embodiments, the co-administration of the separate formulations is performed simultaneously. The phrase“simultaneous administration” means that the additional therapeutic agent(s) are administered on the same day. According to some embodiments, the additional therapeutic agent and the CVC, or a salt, solvate, ester and/or prodrug thereof, can be administered at the same time or one at a time.

[00189] According to some embodiments, the co-administration of the separate formulations is performed sequentially. According to some embodiments, the

sequential co-administration is performed by first administering the pharmaceutical formulations of the described invention comprising a therapeutic agent and

subsequently administering the formulation of one or more additional therapeutic agents. According to some embodiments, the sequential co-administration is performed by first administering the formulation of one or more additional therapeutic agents and subsequently administering the pharmaceutical formulations of the described invention comprising a therapeutic agent. According to some embodiments, the phrase “sequential administration” means that during a period of two or more days of continuous co-administration without any void day, only one of the additional

therapeutic agents and the CVC is administered on any given day.

[00190] According to some embodiments, the co-administration of the separate formulations is performed by overlapping administration. The phrase“overlapping administration” means that during a period of two or more days of continuous co administration without any void day, there is at least one day of simultaneous

administration and at least one day when only one of the additional therapeutic agent(s) and the CVC is administered.

[00191] According to some embodiments, the co-administration of the separate formulations is performed by interval administration. The phrase“interval

administration” refers to a period of co-administration with at least one void day.

[00192] According to some embodiments, the co-administration of the separate formulations is performed continuously. The phrase“continuous administration” refers to a period of co-administration without any void day. Continuous administration may include, for example, simultaneous, sequential, or overlapping administration.

[00193] According to some embodiments, the pharmaceutical formulations of the described invention comprising a therapeutic agent and one or more additional therapeutic agents are co-administered as a single combination formulation. [00194] According to some embodiments, the additional therapeutic agent is an anti-inflammatory agent.

[00195] According to some embodiments, the anti-inflammatory agent is a steroidal anti-inflammatory agent. The term "steroidal anti-inflammatory agent", as used herein, refer to any one of numerous compounds containing a 17-carbon 4-ring system and includes the sterols, various hormones (as anabolic steroids), and glycosides.

Representative examples of steroidal anti-inflammatory drugs include, without limitation, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl

dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone,

difluorosone diacetate, fluradrenolone, fludrocortisone, diflorosone diacetate,

fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, diflurprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone

cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures thereof.

[00196] According to some embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent. The term "non-steroidal anti-inflammatory agent" as used herein refers to a large group of agents that are aspirin-like in their action, including, but not limited to, ibuprofen (Advil^®), naproxen sodium (Aleve^®), and acetaminophen (Tylenol^®). Additional examples of non-steroidal anti-inflammatory agents that are usable in the context of the described invention include, without limitation, oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, and CP- 14,304; disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac; fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; propionic acid derivatives, such as benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone. Mixtures of these non-steroidal anti inflammatory agents also may be employed, as well as the dermatologically acceptable salts and esters of these agents. For example, etofenamate, a flufenamic acid derivative, is particularly useful for topical application.

[00197] According to another embodiment, the anti-inflammatory agent includes, without limitation, Transforming Growth Factor-beta3 (TGF-P3), an anti-Tumor Necrosis Factor-alpha (TNF-a) agent, or a combination thereof.

[00198] According to some embodiments, the additional therapeutic agent is an analgesic agent. According to some embodiments, the analgesic agent relieves pain by elevating the pain threshold without disturbing consciousness or altering other sensory modalities. According to some such embodiments, the analgesic agent is a non-opioid analgesic. "Non-opioid analgesics" are natural or synthetic substances that reduce pain but are not opioid analgesics. Examples of non-opioid analgesics include, but are not limited to, etodolac, indomethacin, sulindac, tolmetin, nabumetone, piroxicam, acetaminophen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozin, aspirin, choline magnesium trisalicylate, diflunisal, meclofenamic acid, mefenamic acid, and phenylbutazone. According to some other embodiments, the analgesic is an opioid analgesic. "Opioid analgesics", "opioid", or "narcotic analgesics" are natural or synthetic substances that bind to opioid receptors in the central nervous system, producing an agonist action. Examples of opioid analgesics include, but are not limited to, codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine.

[00199] According to some embodiments, the additional therapeutic agent is an anti-infective agent. According to another embodiment, the anti-infective agent is an antibiotic agent. The term "antibiotic agent" as used herein means any of a group of chemical substances having the capacity to inhibit the growth of, or to destroy bacteria, and other microorganisms, used chiefly in the treatment of infectious diseases.

Examples of antibiotic agents include, but are not limited to, Penicillin G; Methicillin; Nafcillin; Oxacillin; Cloxacillin; Dicloxacillin; Ampicillin; Amoxicillin; Ticarcillin;

Carbenicillin; Mezlocillin; Azlocillin; Piperacillin; Imipenem; Aztreonam; Cephalothin; Cefaclor; Cefoxitin; Cefuroxime; Cefonicid; Cefmetazole; Cefotetan; Cefprozil;

Loracarbef; Cefetamet; Cefoperazone; Cefotaxime; Ceftizoxime; Ceftriaxone;

Ceftazidime; Cefepime; Cefixime; Cefpodoxime; Cefsulodin; Fleroxacin; Nalidixic acid; Norfloxacin; Ciprofloxacin; Ofloxacin; Enoxacin; Lomefloxacin; Cinoxacin; Doxycycline; Minocycline; Tetracycline; Amikacin; Gentamicin; Kanamycin; Netilmicin; Tobramycin; Streptomycin; Azithromycin; Clarithromycin; Erythromycin; Erythromycin estolate;

Erythromycin ethyl succinate; Erythromycin glucoheptonate; Erythromycin lactobionate; Erythromycin stearate; Vancomycin; Teicoplanin; Chloramphenicol; Clindamycin;

Trimethoprim; Sulfamethoxazole; Nitrofurantoin; Rifampin; Mupirocin; Metronidazole; Cephalexin; Roxithromycin; Co-amoxiclavuanate; combinations of Piperacillin and Tazobactam; and their various salts, acids, bases, and other derivatives. Anti-bacterial antibiotic agents include, but are not limited to, penicillins, cephalosporins,

carbacephems, cephamycins, carbapenems, monobactams, aminoglycosides, glycopeptides, quinolones, tetracyclines, macrolides, and fluoroquinolones.

[00200] According to some embodiments, the additional therapeutic agent is a chemokine receptor antagonist. According to some embodiments, the chemokine receptor antagonist inhibits the binding of a chemokine to a chemokine receptor.

According to some embodiments, the chemokine receptor antagonist inhibits the binding of ligand to CCR1. According to some embodiments, the chemokine antagonist inhibits the binding of a CCR5 ligand to CCR1.

[00201] According to some embodiments, the additional therapeutic agent is a farnesoid X receptor (FXR) agonist. FXR agonists include, but are not limited to, tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266. According to some embodiments, the additional therapeutic agent is an Apoptosis signal regulating kinase 1 (ASK1 ) inhibitor. A non-limiting example of an ASKI inhibitor includes selosertib. According to some embodiments, the additional therapeutic agent is a thyroid receptor beta (TFIR-b) agonist. TFIR-b agonists include, but are not limited to, 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo- 2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-

2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]- dioxaphosphonane (MB07811/VK2809), (3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methylphosphonic acid (MB07344) and a thyroid hormone. Thyroid hormones include, but are not limited to, triiodothyronine (T3), thyroxine (T4) and a combination of T3 and T4 (e.g., Armour^® Thyroid). According to some

embodiments, the additional therapeutic agent is a peroxisome proliferator-activated receptor alpha (PPAR-a) agonist. According to some embodiments, the additional therapeutic agent is a PPAR-g agonist. According to some embodiments, the additional therapeutic agent is a PPAR-d agonist. According to some embodiments, the additional therapeutic agent is a high dose vitamin E (> 400 iU/d). According to some

embodiments, the additional therapeutic agent is a Glucagon-like peptide-1 (GLP-1 ) receptor agonist. According to some embodiments, the additional therapeutic agent is a sodium-glucose cotransporter-2 (SGLT2) inhibitor. According to some embodiments, the additional therapeutic agent is a dipeptidyl peptidase 4 (DPP-4) inhibitor. According to some embodiments, the additional therapeutic agent is an inhibitor of Toll-Like Receptor 4 signaling. According to some embodiments, the additional therapeutic agent is an anti-transforming growth factor beta (TGFP) antibody. According to some embodiments, the additional therapeutic agent is a thiazolidinedione. According to some embodiments, the additional therapeutic agent is a PPAR subtype a and g agonist. According to some embodiments, the additional therapeutic agent is an oral insulin sensitizer. According to some embodiments, the additional therapeutic agent is a obeticholic acid. According to some embodiments, the additional therapeutic agent is

3-[2-[2-Chloro-4-[[3-(2,6-dichlorophenyl)-5-(1 -methylethyl)-4- isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064). According to some embodiments, the additional therapeutic agent is 2-methyl-2-[[4-[2- [[(cyclohexylamino)carbonyl](4-cyclohexylbutyl)amino]ethyl]phenyl]thio]-propanoic acid (GW7647). According to some embodiments, the additional therapeutic agent is 2-[2,6 dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1 (E)-propenyl]phenoxyl]-2-methylpropanoic acid (GFT505). According to some embodiments, the additional therapeutic agent is 3- (3,4-Difluorobenzoyl)-1 ,2,3,6-tetrahydro-1 , 1 -dimethylazepino[4,5-b]indole-5-carboxylic acid 1-methylethyl ester (WAY-36245). According to some embodiments, the additional therapeutic agent is a bile Acid Derivative (e.g. INT-767, INT-777). According to some embodiments, the additional therapeutic agent is a azepino[4,5-b]indoles, 1 -[(4- Chlorophenyl)methyl]-3-[(1 , 1 -dimethylethyl)thio]-a,a-dimethyl-5-(1 -methylethyl)-1 H- lndole-2-propanoic acid (MK886). According to some embodiments, the additional therapeutic agent is N-((2S)-2-(((1Z)-1 -Methyl-3-oxo-3-(4-(trifluoromethyl)phenyl)prop- 1 -enyl)amino)-3-(4-(2-(5-methyl-2-phenyl-1 ,3-oxazol-4- yl)ethoxy)phenyl)propyl)propanamide (GW6471 ). According to some embodiments, the additional therapeutic agent is 2-[2,6 dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-1 (E)- propenyl]phenoxyl]-2-methylpropanoic acid (GFT505). According to some

embodiments, the additional therapeutic agent is liraglutide. According to some embodiments, the additional therapeutic agent is canagliflozin. According to some embodiments, the additional therapeutic agent is anagliptin. According to some embodiments, the additional therapeutic agent is TAK-242. According to some embodiments, the additional therapeutic agent is 1 D11. According to some

embodiments, the additional therapeutic agent is MSDC-0602. According to some embodiments, the additional therapeutic agent is pioglitazone. According to some embodiments, the additional therapeutic agent is rosiglitazone.

[00202] The pharmaceutical formulations of the described invention may be presented in unit dosage form and may be prepared by methods known in the art. Such methods include the step of bringing into association a therapeutic agent(s), or a pharmaceutically acceptable salt or solvate thereof ("active compound") with a carrier which constitutes one or more accessory agents. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[00203] According to some embodiments, the carrier is a controlled release carrier. The term "controlled release" is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This includes immediate as well as non-immediate release formulations, with non-immediate release formulations including, but not limited to, sustained release and delayed release formulations. According to some embodiments, the controlled release of the pharmaceutical formulation is mediated by changes in temperature. According to some other embodiments, the controlled release of the pharmaceutical formulation is mediated by changes in pH. [00204] According to some embodiments, the carrier is a delayed release carrier. According to another embodiment, the delayed release carrier comprises a

biodegradable polymer. According to another embodiment, the biodegradable polymer is a synthetic polymer. According to another embodiment, the biodegradable polymer is a naturally occurring polymer.

[00205] According to some embodiments, the carrier is a sustained release carrier. According to another embodiment, the sustained-release carrier comprises a biodegradable polymer. According to another embodiment, the biodegradable polymer is a synthetic polymer. According to another embodiment, the biodegradable polymer is a naturally occurring polymer.

[00206] According to some embodiments, the carrier is a short-term release carrier. The term "short-term" release, as used herein, means that the carrier is constructed and arranged to deliver therapeutic levels of the active ingredient for about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, or 23 hours. According to some other embodiments, the short-term release carrier delivers

therapeutic levels of the active ingredient for about 1 , 2, 3, or 4 days.

[00207] According to some embodiments, the carrier is a long-term release carrier. The term "long-term" release, as used herein, means that the carrier is constructed and arranged to deliver therapeutic levels of the active ingredient for at least about 5, 6, 7,

8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 29, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 48, 50, 51 , 52, 53, 54,

55, 56, 57, 58, 59, or 60 days. According to another embodiment, the long-term-release carrier comprises a biodegradable polymer. According to another embodiment, the biodegradable polymer is a synthetic polymer.

[00208] The therapeutic agent(s), including but not limited to CVC, may be provided in particles. According to some embodiments, the particles may be the size of nanoparticles or microparticles (or in some instances larger particles) that may contain in whole or in part CVC and/or the additional therapeutic agent(s) as described herein. The particles may contain the therapeutic agent(s) in a core surrounded by a coating. The therapeutic agent(s) also may be dispersed throughout the particles. The

therapeutic agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, etc., and any combination thereof. The particles may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, non-erodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules that contain CVC and/or the additional therapeutic agent(s) in a solution or in a semi-solid state. The particles may be of virtually any shape. The particles may be enteric-coated particles.

[00209] According to some embodiments, the particles are less than (<) 200nm in size. According to some embodiments, the particles are greater than (>) 200nm in size. According to some embodiments, the particles range in size from about 10nm to about 2000pm. According to some embodiments, the particles range in size from about 10nm to about 1000nm. According to some embodiments, the particles range in size from about 10nm to about 500nm. According to some embodiments, the particles range in size from about 10nm to about 300nm. According to some embodiments, the particles range in size from about 10nm to about 200nm. According to some embodiments, the particles are about 10nm in size. According to some embodiments, the particles are about 20nm in size. According to some embodiments, the particles are about 30nm in size. According to some embodiments, the particles are about 40nm in size. According to some embodiments, the particles are about 50nm in size. According to some embodiments, the particles are about 60nm in size. According to some embodiments, the particles are about 70nm in size. According to some embodiments, the particles are about 80nm in size. According to some embodiments, the particles are about 90nm in size. According to some embodiments, the particles are about 100nm in size.

According to some embodiments, the particles are about 110nm in size. According to some embodiments, the particles are about 120nm in size. According to some embodiments, the particles are about 130nm in size. According to some embodiments, the particles are about 140nm in size. According to some embodiments, the particles are about 150nm in size. According to some embodiments, the particles are about 160nm in size. According to some embodiments, the particles are about 170nm in size. According to some embodiments, the particles are about 180nm in size. According to some embodiments, the particles are about 190nm in size. According to some embodiments, the particles are about 200nm in size. According to some embodiments, the particles are about 210nm in size. According to some embodiments, the particles are about 220nm in size. According to some embodiments, the particles are about 230nm in size. According to some embodiments, the particles are about 240nm in size. According to some embodiments, the particles are about 250nm in size. According to some embodiments, the particles are about 260nm in size. According to some embodiments, the particles are about 270nm in size. According to some embodiments, the particles are about 280nm in size. According to some embodiments, the particles are about 290nm in size. According to some embodiments, the particles are about 300nm in size.

[00210] The pharmaceutical formulations comprising a therapeutic agent may be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[00211] According to some embodiments, the pharmaceutical formulations of the described invention are used for in vivo administration. According to some

embodiments, the pharmaceutical formulations are aseptic or sterile. Processes for making a formulation aseptic or sterile are known in the art, for example, by filtration through sterile filtration membranes.

[00212] According to some embodiments, the pharmaceutical formulation is used to treat inflammation, fibrosis, liver disease or a combination thereof. According to some embodiments, the fibrosis is liver fibrosis. According to some embodiments, the liver fibrosis is associated with emerging cirrhosis. According to some embodiments, the cirrhosis is associated with alcohol damage. According to some embodiments, the cirrhosis is associated with a hepatitis infection. Hepatitis infections include, but are not limited to, hepatitis B, hepatitis C, primary biliary cirrhosis (PBC), primary sclerosing cholangitis and the like. According to some embodiments, the fibrosis comprises non cirrhotic hepatic fibrosis. According to some embodiments, the liver disease is nonalcoholic fatty liver disease (NAFLD). According to some embodiments, the NAFLD is nonalcoholic fatty liver (NAFL). According to some embodiments, the NAFLD is nonalcoholic steatohepatitis (NASH). [00213] According to some embodiments, the pharmaceutical formulation of the described invention reduces inflammation. According to some embodiments, the pharmaceutical formulation of the described invention reduces the incidence of inflammation. According to some embodiments, the pharmaceutical formulation of the described invention prevents inflammation. According to some embodiments, the pharmaceutical formulation of the described invention prevents the incidence of inflammation.

[00214] According to some embodiments, the pharmaceutical formulation of the described invention reduces fibrosis. According to some embodiments, the

pharmaceutical formulation of the described invention reduces the incidence of fibrosis. According to some embodiments, the pharmaceutical formulation of the described invention prevents fibrosis. According to some embodiments, the pharmaceutical formulation of the described invention prevents the incidence of fibrosis.

[00215] According to some embodiments, the pharmaceutical formulation of the described invention reduces nonalcoholic fatty liver disease (NAFLD). According to some embodiments, the pharmaceutical formulation of the described invention reduces the incidence of NAFLD. According to some embodiments, the pharmaceutical formulation of the described invention prevents NAFLD. According to some

embodiments, the pharmaceutical formulation of the described invention prevents the incidence of NAFLD.

[00216] According to some embodiments, the pharmaceutical formulation of the described invention reduces nonalcoholic fatty liver (NAFL). According to some embodiments, the pharmaceutical formulation of the described invention reduces the incidence of NAFL. According to some embodiments, the pharmaceutical formulation of the described invention prevents NAFL. According to some embodiments, the pharmaceutical formulation of the described invention prevents the incidence of NAFL.

[00217] According to some embodiments, the pharmaceutical formulation of the described invention reduces nonalcoholic steatohepatitis (NASH). According to some embodiments, the pharmaceutical formulation of the described invention reduces the incidence of NASH. According to some embodiments, the pharmaceutical formulation of the described invention prevents NASH. According to some embodiments, the pharmaceutical formulation of the described invention prevents the incidence of NASH.

[00218] According to some embodiments, the additional therapeutic agent can suppress hepatic apolipoprotein Clll expression. According to some embodiments, the additional therapeutic agent can suppress cholesterol 7 alpha-hydroxylase (CYP7A1 ) expression. According to some embodiments, the additional therapeutic agent can induce high-density lipoprotein-mediated transhepatic cholesterol efflux. According to some embodiments, the additional therapeutic agent can protect against cholestatic liver damage. According to some embodiments, the additional therapeutic agent can attenuate liver inflammation, fibrosis or both. According to some embodiments, the additional therapeutic agent can decrease hepatic lipid accumulation. According to some embodiments, the additional therapeutic agent can inhibit proinflam matory gene expression, profibrotic gene expression or both.

[00219] According to some embodiments, the described invention provides methods for monitoring and/or predicting efficacy of treatment with the pharmaceutical formulations. Such methods include, without limitation, detecting the level of one or more biological molecules, for example, biomarkers, in a subject or in a biological sample obtained from a subject treated for fibrosis or a fibrotic disease or condition. An increase or decrease in the level of one or more biological molecules compared to a predetermined standard level indicates or is predictive of the treatment efficacy

[00220] According to some embodiments, the described invention provides a method of treatment comprising detecting the level of one or more biological molecules in a subject treated for fibrosis or a fibrotic disease or condition and determining a treatment regimen based on an increase or a decrease in the level of one or more biological molecules. Biological molecules include, but are not limited to, zonulin-1 , collagen 1 a1 and 3a1 , TGF-b, fibronectin-1 , hs-CRP, IL-1 b, IL-6, IL-33, fibrinogen, MCP-1 , MIP-1 a and -1 b, RANTES, sCD163k, TNF-a, a biomarker of hepatocyte apoptosis such as CK-18 (caspase-cleaved and total), biomarkers of bacterial translocation such as lipopolysaccharide (LPS), LPS-binding protein (LBP), 16S rDNA, sCD14, intestinal fatty acid binding protein (l-FABP) or a combination thereof. [00221] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein also can be used in the practice or testing of the described invention, the preferred methods and materials are now described.

[00222] All publications mentioned herein are incorporated by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the described invention is not entitled to antedate such publication. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[00223] Where a range of values is provided, it is understood that each

intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges which may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.

[00224] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise.

[00225] The described invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention. EXAMPLES

[00226] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

[00227] Example ! Preparation of Cenicriviroc (CVC) Free Base

[00228] This example describes the synthesis of the free base of CVC.

[00229] Alkylation of piperidin-2-one with 4-methoxybenzyl chloride was alkylated to give 1 -(4-methoxybenzyl)piperidin-2-one, which was then converted to 5-[(4-bromo- 2-formylphenyl)(4-methoxybenzyl) amino]pentanoic acid via hydrolysis followed by reaction with 5-bromo-2fluorobenzaldehyde in a one-pot reaction. The resulting carboxylic acid was then esterified using iodomethane and potassium carbonate, to provide the cyclization precursor methyl 5-[(4-bromo-2-formylphenyl) (4- methoxybenzyl)amino]pentanoate. Next, an intramolecular Claisen-Schmidt-type cyclization of the tertiary amine precursor with sodium methoxide in dimethyl carbonate resulted in [6,8]-fused 1-benzazocine compound. The 4-methoxybenzyl group was removed and subsequent reductive amination with isobutyraldehyde resulted in 1 - isobutyl-1 -benzazocine. Suzuki coupling followed by alkaline hydrolysis provided 1 - isobutyl 1 -benzazocine-5-carboxylic acid. Finally, the 1 -isobutyl 1 -benzazocine-5- carboxylic acid intermediate was reacted with thionyl chloride to give the acid chloride. Subsequent condensing with 4-[[(1 -propyl-1 /-/-imidazol-5-yl)methyl]sulfinyl]aniline (converted to the free base from the di-4-toluoyl-D-tartic acid salt monohydrate) yielded the target free base of CVC.

[00230] Example 2: Solubility of CVC Free Base in Lipid, Surfactant and Co solvent Excipients [00231] In this example, the solubility of CVC free base in lipid, surfactant and co solvent excipients was determined.

[00232] CVC free base was mixed with various lipid, surfactant and co-solvent excipients and the mixtures were screened for solubility of CVC free base. Briefly, 20- 40 mg of CVC free base was added to 1 gram of excipient and mixed by stirring, rotating, heating by heat gun or a combination of these techniques. If the initial amount of CVC free based dissolved in excipient after the solution was equilibrated at room temperature (20-25°C), then an additional 20-40 mg of CVC were added until no more CVC was able to dissolve in excipient. Excipients were categorized by their ability to solubilize CVC free base as shown in Table 1.

[00233] Table 1 : Solubility (% weight/weight (w/w)) of CVC Free Base in Various Excipients

[00234] Example 3: Particle Size Distribution (PSD) of CVC Lipid-based

Formulations

[00235] In this example, in vitro dispersion tests were performed to determine the particle size distribution (PSD) of lipid-based formulations comprising CVC/oleic acid/Cremophor^® EL/ethanol. [00236] To achieve 5% by weight CVC concentration in the excipient blend, CVC free base was dissolved in either 20% v/v oleic acid/70% v/v Cremophor^® EL/10% v/v ethanol or 60% v/v oleic acid/30% v/v Cremophor^® EL/10% v/v ethanol by stirring at room temperature for approximately 1 hour. If solid was observed, the solution was heated (temperature not monitored) using a heat gun for 10-20 seconds and vortex- mixed to aid in dissolution of the solid. Heating and vortex-mixing were repeated until solid was no longer observed in solution. Next, the CVC free base/oleic

acid/Cremophor^® EL/ethanol mixtures were emulsified by dispersing 300 pL of the mixtures in 10 mL of simulated gastric fluid without pepsin (0.2% w/v sodium chloride in 0.7% v/v hydrochloric acid). Particle size was measured by laser diffraction (Malvern Mastersizer 3000 with Hydro MV) of emulsions in the dispersion media with a stirring speed of 2,000 RPM.

[00237] As shown in Figure 1 , the formulation comprising 5% w/w of CVC and 95% w/w of a mixture of 20% v/v oleic acid/70% v/v Cremophor^® EL/10% v/v ethanol had a PSD with a D90 of approximately 200 nm. The formulation comprising 5% w/w of CVC and 95% w/w of a mixture of 60% v/v oleic acid/30% v/v Cremophor^® EL/10% v/v ethanol had a PSD with a D90 between 2 and 15 pm (Figure 1 ).

[00238] Example 4: Parameter Sensitivity Analysis of Particle Size on the absorption of CVC

[00239] In this example, GastroPlus^™ (SimulationsPlus) was used to predict the effect of particle size changes on the absorption of CVC. GastroPlus^™

(SimulationsPlus) is a mechanistically-based simulation software package that predicts absorption, pharmacokinetics and pharmacodynamics in humans and animals.

[00240] Simulations were run in GastroPlus^™ 9.0 Physiologically-based

Pharmacokinetic (PBPK) modeling software using Advanced Compartmental Absorption and Transit (ACAT) model with the parameters shown in Table 2.

[00241] Table 2: GastroPlus^™ 9.0 Software Parameters

[00242] Based on the results of the parameter sensitivity analysis, the

GastroPlus™ simulation predicted that a reduction in particle size to <200nm could improve the percent absorption of CVC by roughly 20% (Figure 2). Without being bound by theory, it is believed that an increase in surfactant content (e.g., Cremophor^® EL) could reduce particle size of the formulations and thus increase the absorption of CVC.

[00243] Example 5: Dissolution Study of CVC Lipid-Based Formulations

[00244] In this example, dissolution of a formulation containing 5% w/w CVC free base and 95% w/w of a mixture of 80% glycerol/glyceryl monooleate (Peceol™)/20% v/v polysorbate 80 (Tween^®-80) was compared to dissolution of solid CVC mesylate powder in fasted and fed state simulated gastric and intestinal fluids in vitro.

[00245] The formulation containing 5% w/w CVC free base and 95% w/w mixture of 80% v/v glycerol/glyceryl monooleate (Peceol™)/20% v/v polysorbate 80 (Tween^®-80) was prepared according to the methods described in Example 2 and Example 3. CVC mesylate was prepared as described in U.S. Pat. No. 8, 183,273. Briefly, 100mg of (-)- 8-[4-(2-butoxyethoxy)phenyl]-1 -isobutyl-N-[4-[[[1 -propyl-1 H-imidazol-5- yl]methyl]sulfinyl]phenyl]-1 ,2,3,4-tetrahydro-1 -benzoazocine-5-carboxamide dissolved in ethyl acetate (4mL) was added to a solution of methanesulfonic acid (9.31 uL) in ethyl acetate (2mL) in a dropwise fashion and rigorous stirring, after which the mixture was stirred under light shielding overnight to precipitate crystals. The precipitated crystals were filtered and further washed with ethyl acetate (5mL), followed by drying under reduced pressure. The resulting crystals were recrystallized from 2-butanone (4 ml) to give (-)-8-[4-(2-butoxyethoxy)phenyl]-1 -isobutyl-N-[4-[[[1 -propyl-1 H-imidazol-5- yl]methyl]sulfinyl]phenyl]-1 ,2,3,4-tetrahydro-1 -benzoazocine-5-carboxamide methanesulfonate (mesylate powder) (88.4 mg).

[00246] 300 pL of the CVC lipid-based formulation and 17 mg of the CVC mesylate powder were dispersed in 10 mL of fasted state simulated gastric fluid, pH 1.6 (FaSSIF/FeSSIF/FaSSGF powder prepared according to biorelevant.com protocol) for 30 minutes, or 10ml_ of fed state simulated gastric fluid, pH 5 (aqueous buffer containing 237 nM of sodium chloride; 17.12 mM acetic acid; 29.75 mM sodium acetate) for 60 minutes. Next, 4 mL of the dispersed mixture in fasted state simulated gastric fluid was transferred to 20 mL of fasted state simulated intestinal fluid

(FaSSIF/FeSSIF/FaSSGF powder, prepared according to biorelevant.com protocol), and 4 mL of the dispersed mixture in fed state simulated gastric fluid was transferred to 20 mL of fasted state simulated intestinal fluid (FaSSIF/FeSSIF/FaSSGF powder, prepared according to biorelevant.com protocol). The resultant solutions were then filtered through a syringe filter (0.2 pm), diluted with 0.1 % trifluoroacetic acid in 50% v/v acetonitrile/50% v/v water and assayed for CVC concentration by HPLC using the parameters shown in Table 3.

[00247] Table 3: HPLC Parameters Used to Determine CVC Concentration

[00248] As shown in Figure 3, the CVC lipid-based formulation (i.e. , 80% glycerol/glyceryl monooleate) resulted in higher solubilization in both fasted and fed state SIFs compared to the solid powder of CVC. Without being bound by theory, it is believed that an increase in solubilization can induce an increase in absorption and, in turn, increase bioavailability of CVC. Moreover, dissolution of the CVC lipid-based formulation resulted in closer dissolution profiles between fasted and fed states as compared to the dissolution profiles between fasted and fed states of the solid CVC powder (Figure 3). This result suggests that CVC lipid-based formulations could reduce or potentially eliminate the effect that food has on the absorption and bioavailability of CVC in its mesylate salt form.

[00249] Example 6: Dissolution Study to Determine the Effect of Proton Pump Inhibitors (PPIs) on CVC Lipid-Based Formulations

[00250] In this example, dissolution of a formulation containing 12.5% w/w CVC free base and 87.5% w/w of a mixture of 49% w/w propylene glycol monolaurate type I (Lauroglycol™ FCC)/40% w/w polysorbate 80 (Tween^®-80)/10% w/w propylene glycol/1 % w/w vitamin E was compared to dissolution of solid CVC mesylate powder in fasted and fed state simulated gastric and intestinal fluids in vitro. Because proton pump inhibitors (PPIs) have been shown to increase pH in the gastrointestinal tract, fasted state simulated gastric fluid with pH 4 was used to simulate the effect of PPIs on CVC mesylate powder and CVC lipid-based formulations.

[00251] The formulation of 12.5% w/w CVC free base dissolved in the mixture of 49% w/w propylene glycol monolaurate type I (Lauroglycol™ FCC)/40% w/w polysorbate 80 (Tween^®-80)/10% w/w propylene glycol/1 % v/v vitamin E was prepared according to the method described in Example 2 and Example 3. 120 pL of the CVC formulation and 17 mg of the CVC mesylate powder were dispersed in one of three media: 1 ) 10 mL of fasted state simulated gastric fluid, pH 1 .6 (FaSSIF/FeSSIF/FaSSGF powder, prepared according to biorelevant.com protocol) for 30 minutes; 2) 10mL of fasted state simulated gastric fluid, pH 4 (FaSSIF/FeSSIF/FaSSGF powder, prepared according to

biorelevant.com protocol and titrated to pH 4) for 30 minutes; or 3) fed state simulated gastric fluid (pH 5 aqueous buffer containing 237 mM of sodium chloride, 17.12 mM of acetic acid and 29.75 mM of sodium acetate) for 60 minutes. Next, 4 mL of the dispersed mixture in fasted state simulated gastric fluid (pH 1 .6 or pH 4) was transferred to 20 mL of fasted state simulated intestinal fluid (FaSSIF/FeSSIF/FaSSGF powder, prepared according to biorelevant.com protocol), and 4 mL of the dispersed mixture in fed state simulated gastric fluid was transferred to 20 mL of fasted state simulated intestinal fluid (FaSSIF/FeSSIF/FaSSGF powder, prepared according to biorelevant.com protocol). The resultant solutions were filtered through a syringe filter (0.2 pm), diluted with 0.1 % trifluoroacetic acid in 50% v/v acetonitrile/50% v/v water, and assayed for CVC concentration by HPLC using the parameters shown in Table 3.

[00252] As shown in Figure 4, the CVC lipid-based formulation (i.e. , 49% propylene glycol monolaurate and 40% polysorbate 80) resulted in higher solubilization in all three conditions (fasted state, fasted state at pH 4 (“Fasted-PPI”), fed state), compared to the solid powder of CVC mesylate. The CVC lipid-based formulation also resulted in closer dissolution profiles in all three conditions as compared to the dissolution profiles of solid powder of CVC mesylate in all three conditions. This result suggests that CVC lipid-based formulations are less dependent on the pH of the gastrointestinal tract and could potentially eliminate the effect that PPIs have on the absorption and bioavailability of CVC in its mesylate salt form.

[00253] Example 7: Pharmacokinetic (PK) Study to Evaluate the Effect of Food on CVC Lipid-Based Formulations

[00254] Food can change the rate of absorption, pharmacodynamics and pharmacokinetics of orally-administered drugs. Cenicriviroc (CVC) tablet formulation (DP7A) has shown a significant positive food effect in humans (3-5 fold). In this example, the effect of food (i.e., food effect) on CVC tablet formulation (DP7A) and CVC lipid-based formulations was evaluated in a dog PK model.

[00255] Food Effect of CVC Tablet Formulation (DP7A)

[00256] CVC tablet formulation (DP7A) was administered as a single 25 mg dose (CVC free-base equivalent) to five (5) Beagle dogs in a fasted state. The same five (5) dogs were administered a single 25 mg dose in a fed state after a 6-day washout period. A 1 mL blood sample was collected at 0, 0.5, 1 , 2, 3, 4, 6, 8 and 24 hours after dosing. Fasted dogs had food withheld in the morning and returned after the 4-hour blood collection. Fed dogs were provided adequate time to eat (e.g., >1 hour) prior to dosing. [00257] A comparison of pharmacokinetic (PK) parameters for fed and fasted dogs is shown in Table 4. Pharmacokinetic profiles for CVC tablet formulation (DP7A) in fed and fasted dogs are shown in Figure 5. Dogs with unusually low concentrations (e.g. unsuccessful dosing, outliers, etc.) were excluded. The data shows a roughly 3-fold positive food effect for CVC tablet formulation (DP7A).

[00258] Table 4: PK Parameters for DP7A in Fed vs. Fasted dogs

Cmax: maximum serum concentration

AUCIast: area under the curve up to the last measurable concentration

Tmax: time maximum plasma concentration is reached

GM-AUC: geometric mean of area under the curve

[00259] PK Profile of CVC Lipid-Based Formulations in Fasted Dogs

[00260] The composition of each CVC lipid-based formulation used in this example is shown in Table 5. CVC lipid-based formulations were filled in size 1 hard gelatin capsules with each capsule receiving approximately 200 mg of CVC lipid-based formulation to achieve 25 mg of CVC per capsule.

[00261] Table 5: Composition of CVC Lipid-Based Formulations

[00262] A CVC lipid-based formulation (i.e. Variant #1 ) was administered as a single 25 mg dose (CVC free-base equivalent) to 5 fasted Beagle dogs. A 1 ml_ blood sample was collected at 0, 0.5, 1 , 2, 3, 4, 6, 8 and 24 hours after dosing. Dogs had food withheld in the morning and returned after the 4-hour blood collection. After a 7- day washout period, the same beagle dogs were dosed with a different CVC lipid-based formulation variant (i.e. Variant #2). The same procedure was repeated until all four lipid-based formulation variants were tested. CVC lipid-based formulations with similar or higher PK values compared to DP7A in fed dogs were selected to be dosed in fed dogs to evaluate the effect that food has on these lipid-based formulations (i.e., food effect).

[00263] A summary of the PK parameters for the CVC lipid-based formulations tested in fasted dogs is shown in Table 6. Pharmacokinetic profiles for these CVC lipid- based formulations are shown in Figure 6. Dogs with unusually low concentrations (e.g. unsuccessful dosing, outliers, etc.) were excluded. The PK profiles of lipid-based formulation Variant #1 and Variant #2 in fasted dogs were similar to the PK profile of DP7A in fasted dogs but were significantly lower than the PK profile of DP7A in fed dogs. This data suggests that Variant #1 and Variant #2 will not reduce the positive food effect observed for DP7A. Lipid-based formulation Variant #3 in fasted dogs had a similar PK profile as DP7A in fed dogs, whereas lipid-based formulation Variant #4 in fasted dogs resulted in higher PK exposure (approximately 2-fold) compared to DP7A in fed dogs. Based on these results, Variant #3 and Variant #4 were selected for dosing in fed dogs. [00264] Table 6: PK Parameters for CVC Lipid-Based Formulations in Fasted Dogs

GMR (AUC): geometric mean ratio of area under the curve calculated using the formula:

GM(AUC) of Variant#X fasted

GMR (AUC)

GM(AUC)of DP7A fed

[00265] PK Profile of CVC Lipid-Based Formulations Variant #3 and Variant #4 in Fed Dogs

[00266] CVC lipid-based formulation Variant #3 was administered as a single 25 mg dose (CVC free-base equivalent) to the same 5 Beagle dogs in the fasted study, but under fed state condition. Dogs were provided adequate time to eat (e.g., >1 hour) prior to dosing. A 1 ml_ blood sample was collected at 0, 0.5, 1 , 2, 3, 4, 6, 8 and 24 hours after dosing. After 7-day washout period, the same beagle dogs were dosed with Variant #4, followed by the same procedure performed for Variant #3.

[00267] A summary of the PK parameters for CVC lipid-based formulation Variant #3 and CVC lipid-based formulation Variant #4 as compared to PK parameters for DP7A is shown in Table 7. Pharmacokinetic profiles for these CVC lipid-based formulations as compared to DP7A are shown in Figure 7. Dogs with unusually low concentrations (e.g. unsuccessful dosing, outliers, etc.) were excluded. PK values showed that there was a lower food effect for both Variant #3 and Variant #4 (1.03 and 1.12, respectively) when compared to DP7A (2.94). In addition, lower variability was achieved by the two lipid-based formulations as compared to DP7A. For example, the percent coefficient of variation (CV%) for AUCIast of Variant #3 and Variant #4 in fasted dogs was 17.9% and 26.5%, respectively, as compared to 44.6% for AUCIast of DP7A in fasted dogs (Table 7).

[00268] Table 7: PK Parameters for Variant #3, Variant #4 and DP7A

[00269] These data show that CVC lipid-based formulations, such as Variant #3 and Variant #4, have low to marginal food effects as well as lower variability than CVC tablet formulation (DP7A). Moreover, Variant #4 had a PK exposure that was 2-fold higher than the PK exposure of DP7A, indicating that the dose of CVC may be reduced in a lipid-based formulation. Without being bound by theory, these data suggest that the PK exposure of CVC can be modified by adjusting the composition of CVC formulation (e.g., lipid-based vs. solid tablet).

[00270] While the present invention has been described with reference to the specific embodiments thereof it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adopt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

CLAIMS What is claimed is:

1 . A pharmaceutical formulation comprising Cenicriviroc and a pharmaceutically acceptable excipient selected from the group consisting of a lipid, a surfactant, a co solvent and a combination thereof.

2. The pharmaceutical formulation according to claim 1 , wherein the Cenicriviroc is amorphous free base.

3. The pharmaceutical formulation according to claim 1 , wherein the lipid is selected from the group consisting of propylene glycol monolaurate type I (Lauroglycol™ FCC), propylene glycol monolaurate type II (Lauroglycol™ 90), propylene glycol monocaprylate (Capryol™ 90), glycerol caprylate/caprate (Capmul^® MCM), castor oil, glycerol/glyceryl monooleate (Peceol™), glyceryl monolinoleate (Maisine^® CC), glycerol/glyceryl monolinoleate (Maisine™ 35-1 ), propylene glycol dicaprylocaprate (Labrafac™ PG), medium chain triglycerides (Labrafac™ lipophile WL1349), olive oil, flaxseed oil, a mixture of phosphatidyl choline and propylene glycol (Phosal^® 50PG), a mixture of phosphatidyl choline and medium chain triglycerides (Phosal^® 53) and a combination thereof.

4. The pharmaceutical formulation according to claim 1 , wherein the surfactant is selected from the group consisting of caprylocaproyl macrogol-8 / polyoxyl-8 glycerides (Labrasol^®), linoleoyl polyoxyl-6 glycerides (Labrafil^® M 2125 CS), ethoxylated castor oil (Cremophor^® EL), ethoxylated hydrogenated castor oil (Cremophor^® RH40),

polysorbate 80 (Tween^®-80), vitamin E TPGS and a combination thereof.

5. The pharmaceutical formulation according to claim 1 , wherein the

pharmaceutical formulation comprises more than one surfactant.

6. The pharmaceutical formulation according to claim 5, wherein the more than one surfactant is a combination of a lipophilic surfactant and a hydrophilic surfactant.

7. The pharmaceutical formulation according to claim 1 , wherein the co-solvent is selected from the group consisting of ethanol, propylene glycol, PEG-400, glycerol and a combination thereof.

8. The pharmaceutical formulation according to claim 1 , wherein the

pharmaceutical formulation further comprises one or more additional therapeutic agents.

9. The pharmaceutical formulation according to claim 8, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

10. The pharmaceutical formulation according to claim 9, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

11. The pharmaceutical formulation according to claim 8, wherein the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist.

12. The pharmaceutical formulation according to claim 11 , wherein the TFIR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo- 1 ,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6- carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

(MB07811L/K2809), (3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methylphosphonic acid (MB07344) and a combination of T3 and T4 (Armour^® Thyroid).

13. A pharmaceutical formulation comprising

(a) Cenicriviroc;

(b) 20% v/v oleic acid;

(c) 70% v/v ethoxylated castor oil (Cremophor^® EL); and

(d) 10% v/v ethanol.

14. The pharmaceutical formulation according to claim 13, wherein the pharmaceutical formulation further comprises one or more additional therapeutic agents.

15. The pharmaceutical formulation according to claim 14, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

16. The pharmaceutical formulation according to claim 15, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

17. The pharmaceutical formulation according to claim 14, wherein the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist.

18. The pharmaceutical formulation according to claim 16, wherein the TFIR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo- 1 ,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6- carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

19. A pharmaceutical formulation comprising

(a) Cenicriviroc;

(b) 60% v/v oleic acid;

(c) 30% v/v ethoxylated castor oil (Cremophor^® EL); and

(d)10% v/v ethanol.

20. The pharmaceutical formulation according to claim 18, wherein the

21. The pharmaceutical formulation according to claim 20, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

22. The pharmaceutical formulation according to claim 21 , wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

23. The pharmaceutical formulation according to claim 20, wherein the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist.

24. The pharmaceutical formulation according to claim 23, wherein the TFIR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo- 1 ,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6- carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

25. A pharmaceutical formulation comprising

(a) Cenicriviroc;

(b) 80% v/v glycerol/glyceryl monooleate (Peceol^™); and

(c) 20% v/v polysorbate-80 (Tween^®-80).

26. The pharmaceutical formulation according to claim 25, wherein the

27. The pharmaceutical formulation according to claim 26, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

28. The pharmaceutical formulation according to claim 27, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

29. The pharmaceutical formulation according to claim 26, wherein the one or more additional therapeutic agents are a thyroid receptor beta (THR-b) agonist.

30. The pharmaceutical formulation according to claim 29, wherein the THR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo- 1 ,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6- carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

31. A method of treating fibrosis in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising

a. a therapeutically effective amount of Cenicriviroc; b. oleic acid;

c. ethoxylated castor oil (Cremophor^® EL); and d. ethanol.

32. The method according to claim 31 , wherein the method further comprises administering to the subject one or more additional therapeutic agents.

33. The method according to claim 32, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

34. The method according to claim 33, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

35. The method according to claim 32, wherein the one or more additional therapeutic agents are a thyroid receptor beta (THR-b) agonist.

36. The method according to claim 35, wherein the THR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

(MB07811/VK2809), (3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methylphosphonic acid (MB07344) and a combination of T3 and T4 (Armour^® Thyroid).

37. The method according to claim 31 , wherein the pharmaceutical formulation further comprises one or more additional therapeutic agents.

38. The method according to claim 37, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

39. The method according to claim 38, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

40. The method according to claim 37, wherein the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist.

41. The method according to claim 40, wherein the TFIR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

42. A method of treating non-alcoholic steatohepatitis (NASH) in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising

e. a therapeutically effective amount of Cenicriviroc; f. oleic acid;

g. ethoxylated castor oil (Cremophor^® EL); and h. ethanol.

43. The method according to claim 42, wherein the method further comprises administering to the subject one or more additional therapeutic agents.

44. The method according to claim 43, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

45. The method according to claim 44, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

46. The method according to claim 43, wherein the one or more additional therapeutic agents are a thyroid receptor beta (THR-b) agonist.

47. The method according to claim 46, wherein the THR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

48. The method according to claim 42, wherein the pharmaceutical formulation further comprises one or more additional therapeutic agents.

49. The method according to claim 48, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

50. The method according to claim 49, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

51. The method according to claim 48, wherein the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist.

52. The method according to claim 51 , wherein the TFIR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

53. A method of treating fibrosis in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising

i. a therapeutically effective amount of Cenicriviroc; j. 80% v/v glycerol/glyceryl monooleate (Peceol™); and k. 20% v/v polysorbate-80 (Tween^®-80).

54. The method according to claim 53, wherein the method further comprises administering to the subject one or more additional therapeutic agents.

55. The method according to claim 54, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

56. The method according to claim 55, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

57. The method according to claim 54, wherein the one or more additional therapeutic agents are a thyroid receptor beta (THR-b) agonist.

58. The method according to claim 57, wherein the THR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

59. The method according to claim 53, wherein the pharmaceutical formulation further comprises one or more additional therapeutic agents.

60. The method according to claim 59, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

61. The method according to claim 60, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

62. The method according to claim 59, wherein the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist.

63. The method according to claim 62, wherein the TFIR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

64. A method of treating non-alcoholic steatohepatitis (NASH) in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising

L. a therapeutically effective amount of Cenicriviroc; m. 80% v/v glycerol/glyceryl monooleate (Peceol™); n. 20% v/v polysorbate-80 (Tween^®-80).

65. The method according to claim 64, wherein the method further comprises administering to the subject one or more additional therapeutic agents.

66. The method according to claim 65, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

67. The method according to claim 66, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

68. The method according to claim 65, wherein the one or more additional therapeutic agents are a thyroid receptor beta (THR-b) agonist.

69. The method according to claim 68, wherein the THR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

70. The method according to claim 64, wherein the pharmaceutical formulation further comprises one or more additional therapeutic agents.

71. The method according to claim 70, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

72. The method according to claim 71 , wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

73. The method according to claim 70, wherein the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist.

74. The method according to claim 73, wherein the TFIR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

75. A pharmaceutical formulation comprising 12.5% w/w Cenicriviroc dissolved in 87.5% of a mixture comprising

(a) 49% w/w propylene glycol monolaurate type II (Lauroglycol^™ 90);

(b) 40% w/w polysorbate-80 (Tween^®-80);

(c) 10% w/w propylene glycol; and

(d) 1 % w/w vitamin E.

76. The pharmaceutical formulation according to claim 75, wherein the

77. The pharmaceutical formulation according to claim 76, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

78. The pharmaceutical formulation according to claim 77, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

79. The pharmaceutical formulation according to claim 76, wherein the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist.

80. The pharmaceutical formulation according to claim 79, wherein the TFIR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo- 1 ,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6- carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

81. A method of treating fibrosis in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising

o. a therapeutically effective amount of Cenicriviroc; p. 49% w/w propylene glycol monolaurate type II

(Lauroglycol^™ 90);

q. 40% w/w polysorbate-80 (Tween^®-80);

r. 10% w/w propylene glycol; and

s. 1 % w/w vitamin E.

82. The method according to claim 81 , wherein the method further comprises administering to the subject one or more additional therapeutic agents.

83. The method according to claim 82, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

84. The method according to claim 83, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

85. The method according to claim 82, wherein the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist.

86. The method according to claim 85, wherein the TFIR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

87. The method according to claim 81 , wherein the pharmaceutical formulation further comprises one or more additional therapeutic agents.

88. The method according to claim 87, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

89. The method according to claim 88, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

90. The method according to claim 87, wherein the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist.

91. The method according to claim 90, wherein the THR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

92. A method of treating non-alcoholic steatohepatitis (NASH) in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising

t. a therapeutically effective amount of Cenicriviroc; u. 49% w/w propylene glycol monolaurate type II

(Lauroglycol^™ 90);

v. 40% w/w polysorbate-80 (Tween^®-80);

w. 10% w/w propylene glycol; and

x. 1 % w/w vitamin E.

93. The method according to claim 92, wherein the method further comprises administering to the subject one or more additional therapeutic agents.

94. The method according to claim 93, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

95. The method according to claim 94, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

96. The method according to claim 93, wherein the one or more additional therapeutic agents are a thyroid receptor beta (THR-b) agonist.

97. The method according to claim 96, wherein the THR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

98. The method according to claim 92, wherein the pharmaceutical formulation further comprises one or more additional therapeutic agents.

99. The method according to claim 98, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

100. The method according to claim 99, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

101. The method according to claim 98, wherein the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist.

102. The method according to claim 101 , wherein the TFIR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

103. A pharmaceutical formulation comprising 12.5% w/w Cenicriviroc dissolved in 87.5% of a mixture comprising (a) 45.5% w/w vitamin E TPGS;

(b) 45.5% w/w polysorbate-80 (Tween^®-80); and

(c) 9% propylene glycol.

104. The pharmaceutical formulation according to claim 103, wherein the

105. The pharmaceutical formulation according to claim 104, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

106. The pharmaceutical formulation according to claim 105, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

107. The pharmaceutical formulation according to claim 104, wherein the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist.

108. The pharmaceutical formulation according to claim 107, wherein the TFIR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo- 1 ,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6- carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

109. A method of treating fibrosis in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising

a. a therapeutically effective amount of Cenicriviroc; b. 45.5% w/w vitamin E TPGS;

c. 45.5% w/w polysorbate-80 (Tween^®-80); and d. 9% w/w propylene glycol.

110. The method according to claim 109, wherein the method further comprises administering to the subject one or more additional therapeutic agents.

111. The method according to claim 110, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

112. The method according to claim 111 , wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

113. The method according to claim 110, wherein the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist.

114. The method according to claim 113, wherein the TFIR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

115. The method according to claim 109, wherein the pharmaceutical formulation further comprises one or more additional therapeutic agents.

116. The method according to claim 115, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

117. The method according to claim 116, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

118. The method according to claim 115, wherein the one or more additional therapeutic agents are a thyroid receptor beta (THR-b) agonist.

119. The method according to claim 118, wherein the THR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

120. A method of treating non-alcoholic steatohepatitis (NASH) in a subject in need of such treatment, comprising administering to the subject a pharmaceutical formulation comprising

e. a therapeutically effective amount of Cenicriviroc; f. 45.5% w/w vitamin E TPGS;

g. 45.55 w/w polysorbate-80 (Tween^®-80); and h. 9% w/w propylene glycol.

121. The method according to claim 120, wherein the method further comprises administering to the subject one or more additional therapeutic agents.

122. The method according to claim 121 , wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

123. The method according to claim 122, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

124. The method according to claim 121 , wherein the one or more additional therapeutic agents are a thyroid receptor beta (THR-b) agonist.

125. The method according to claim 124, wherein the THR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane

126. The method according to claim 120, wherein the pharmaceutical formulation further comprises one or more additional therapeutic agents.

127. The method according to claim 126, wherein the one or more additional therapeutic agents are a farnesoid X receptor (FXR) agonist.

128. The method according to claim 127, wherein the farnesoid X receptor (FXR) agonist is selected from the group consisting of tropifexor, cilofexor, turofexorate isopropyl, AGN-242256 and AGN-242266.

129. The method according to claim 126, wherein the one or more additional therapeutic agents are a thyroid receptor beta (TFIR-b) agonist.

130. The method according to claim 129, wherein the TFIR-b agonist is selected from the group consisting of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1 ,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1 ,2,4]triazine-6-carbonitrile (MGL-3196), (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'- isopropylbenzyl)phenoxy)methyl]-2-oxido-[1 ,3,2]-dioxaphosphonane