Patent Description:
The present invention relates generally to compositions for treating a subject suffering from hypotension (e.g., neurogenic orthostatic hypotension or postprandial hypotension), portal hypertension (e.g., bleeding esophageal varices associated with portal hypertension) or ascites (e.g., ascites associated with liver cirrhosis), the treatment comprising orally administering pharmaceutical compositions of terlipressin.

Techniques enabling efficient transfer of a substance of interest across a biological barrier are of considerable interest in the fields of biotechnology and medicine. For example, such techniques may be used for the transport of a variety of different substances across a biological barrier regulated by tight junctions (i.e., the mucosal epithelia, which include the intestinal and respiratory epithelia, and the vascular endothelia, which include the blood-brain barrier, nasal membrane, cornea and other eye membranes, and genito-urinary membranes). In particular, there is great interest in oral delivery of therapeutic agents to avoid the use of more invasive means of administration and hence improve patient convenience and compliance.

Terlipressin is an analog of vasopressin and has been used, administered intravenously, for example for treatment of esophageal varices, septic shock, hepatorenal syndrome, and in the management of low blood pressure. A need exists for an efficient, specific, non-invasive, low-risk means for the non-invasive delivery of therapeutic agents such as terlipressin.

<CIT> discloses an improved protocol for paracentesis. <CIT> discloses a method of treating patients with hepatorenal syndrome type <NUM>. <CIT> discloses pharmaceutical compositions and related methods of delivery. <CIT> discloses improved pharmaceutical compositions and methods of delivery.

Described herein are certain orally available compositions comprising terlipressin, oral dosage forms comprising terlipressin, and related methods of use, for example for treating neurogenic orthostatic hypotension, portal hypertension (e.g., bleeding esophageal varices associated with portal hypertension) or ascites (e.g. ascites associated with liver cirrhosis). Terlipressin in a composition or oral dosage form described herein may exhibit improved bioavailability (BA) relative to terlipressin configured in another formulation or dosage form. In particular, terlipressin in a composition or oral dosage form described herein may exhibit improved oral bioavailability relative to composition substantially free of the medium chain fatty acid salt component described herein or having a lower amount of the medium chain fatty acid salt component described herein. Such improvement in relative BA (e.g., oral BA) may be on the order of at least about <NUM>-, <NUM>-, <NUM>-, <NUM>-, <NUM>- or <NUM>- fold. Oral terlipressin may have a BA of at least <NUM>% or <NUM>% or more.

The methods described herein may provide about <NUM> to about <NUM>µg/mL terlipressin concentration in a subject, for example about <NUM> to about <NUM>µg/mL terlipressin concentration in a subject, e.g., in the plasma of the subject. The methods described herein may provide about <NUM> to about <NUM>µg/mL terlipressin concentration in a subject, for example about <NUM>µg/mL terlipressin concentration in a subject.

The methods described herein may provide about <NUM> to about <NUM>µg/mL (lysine-) vasopressin concentration in a subject. (Vasopressin is the active metabolite of terlipressin. ) The methods described herein may provide about <NUM> to about <NUM>µg/mL vasopressin concentration in a subject (e.g. in the plasma of the subject), for example about <NUM> to about <NUM>µg/mL vasopressin concentration in a subject, e.g. about <NUM>µg/mL vasopressin concentration in a subject.

The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of terlipressin or a pharmaceutically acceptable salt thereof, for use in treating ascites in a subject, wherein the pharmaceutical composition is configured as a tablet or capsule comprising about <NUM> to about <NUM> of terlipressin or pharmaceutically acceptable salt thereof and is administered orally thereby treating the subject.

In some embodiments, the tablet or capsule is administered <NUM>, <NUM>, <NUM> or <NUM> times daily. For example, the tablet or capsule may be administered <NUM> or <NUM> times daily, or may be administered <NUM> times daily. Alternatively, the tablet or capsule may be administered <NUM> times daily, or may be administered <NUM> times daily.

In some embodiments, multiple tablets or capsules are administered <NUM> or <NUM> times daily. For example, multiple tablets or capsules may be administered <NUM> times daily. Alternatively, multiple tablets or capsules may be administered <NUM> or <NUM> times daily.

The tablet or capsule comprises <NUM> to <NUM> terlipressin. For example, the tablet or capsule may comprise <NUM> to <NUM> terlipressin, <NUM> to <NUM> terlipressin, or <NUM> terlipressin.

In some embodiments, the subject is administered <NUM> to <NUM> terlipressin daily, <NUM> to <NUM> terlipressin daily, <NUM> to <NUM> terlipressin daily, or <NUM> terlipressin daily. Alternatively, the subject may be administered at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> terlipressin daily.

In some embodiments, the terlipressin is administered for about one day to about <NUM> months.

In some embodiments, the ascites is associated with liver cirrhosis.

In some embodiments, the treatment of the subject suffering from ascites comprises.

In some embodiments, the terlipressin is administered in combination with a diuretic; albumin; a beta blocker; or a vasopressin V2-receptor antagonist for example vaptan.

In some embodiments, the pharmaceutical composition is administered at least one hour before a meal or at least two hours after a meal.

In some embodiments, the subject suffers from hepatorenal syndrome (HRS).

Administration of the pharmaceutical composition may result in reduced side effects relative to other forms of terlipressin administration (e.g., intravenous administration).

Provision of the pharmaceutical composition may provide greater patient compliance (e.g., compliance by a subject described herein) relative to other forms of terlipressin administration (e.g., intravenous administration).

Also disclosed herein is a method of treating a subject suffering from hypotension (e.g., neurogenic orthostatic hypotension or postprandial hypotension), the method comprising orally administering a pharmaceutical composition (e.g., solid dosage composition, oral dosage form) configured as a tablet or capsule comprising a therapeutically effective amount (e.g., at least <NUM> (e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>)) of terlipressin or a pharmaceutically acceptable salt thereof, <NUM>, <NUM>, <NUM>, or <NUM> times daily, thereby treating the subject.

Also disclosed herein is a method of treating a subject suffering from portal hypertension (e.g., bleeding esophageal varices associated with portal hypertension), the method comprising orally administering a pharmaceutical composition (e.g., solid dosage composition, oral dosage form) configured as a tablet or capsule comprising a therapeutically effective amount (e.g., at least <NUM> (e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>)) of terlipressin or a pharmaceutically acceptable salt thereof, <NUM>, <NUM>, <NUM>, or <NUM> times daily, thereby treating the subject.

In the above methods, the tablet or capsule may be administered <NUM> or <NUM> times daily, e.g. <NUM> times daily. Alternatively, the tablet or capsule may be administered <NUM> times daily or may be administered <NUM> times daily.

In the above methods, the tablet or capsule may comprise <NUM> to <NUM> terlipressin, <NUM> to <NUM> terlipressin, <NUM> to <NUM> terlipressin, <NUM> to <NUM> terlipressin, or <NUM> terlipressin.

In the above methods, the subject may be administered <NUM> to <NUM> terlipressin daily (e.g., <NUM> to <NUM> terlipressin daily, <NUM> to <NUM> terlipressin daily, <NUM> to <NUM> terlipressin daily, e.g., <NUM> terlipressin).

In the above methods, multiple tablets or capsules may be administered <NUM> times daily. Alternatively, multiple tablets or capsules may be administered <NUM> times daily.

Inthe above methods, the subject may be administered at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> terlipressin daily.

The above methods may result in reduced side effects relative to a method of administering terlipressin by other forms of administration (e.g., intravenous administration). the above methods may provide greater patient compliance (e.g., compliance by a subject described herein) relative to a method of administering terlipressin by other forms of administration (e.g., intravenous administration).

Also disclosed herein is a unit dosage formulation for oral administration (an oral dosage form) which comprises a therapeutically effective amount of terlipressin, or a pharmaceutically acceptable salt thereof (e.g., at least <NUM> e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>) of terlipressin, or a pharmaceutically acceptable salt thereof).

For example, the oral dosage form may comprise <NUM> to <NUM> (e.g., <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>) terlipressin. For example, the oral dosage formulation (i.e., oral dosage form) may comprise about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> terlipressin.

The oral dosage form may be enteric-coated.

The oral dosage formulation (i.e., oral dosage form) described herein may be used for treatment of a subject suffering from hypotension (e.g., neurogenic orthostatic hypotension or postprandial hypotension) or portal hypertension or ascites.

Also disclosed herein is an oral dosage formulation (i.e., oral dosage form) comprising a therapeutically effective amount of terlipressin, or a pharmaceutically acceptable salt thereof (e.g., at least <NUM> e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>) of terlipressin, or a pharmaceutically acceptable salt thereof).

For example, the oral dosage formulation (i.e., oral dosage form) may comprise <NUM> to <NUM> (e.g., <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>) terlipressin. For example, the oral dosage formulation (i.e., oral dosage form) may comprise about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> terlipressin.

The oral dosage formulation (i.e., oral dosage form) may be additionally enteric-coated.

Also disclosed herein is a capsule containing the composition comprising a therapeutically effective amount of terlipressin, or a pharmaceutically acceptable salt thereof (e.g., at least <NUM> (e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>)) of terlipressin, or a pharmaceutically acceptable salt thereof).

The capsule may be a hard gel or a soft gel capsule.

For example, the capsule may comprise <NUM> to <NUM> (e.g., <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>) terlipressin. For example, the capsule may comprise about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> terlipressin. The capsule may be is enteric-coated.

Also described herein is a tablet comprising a therapeutically effective amount of terlipressin, or a pharmaceutically acceptable salt thereof (e.g., at least <NUM> (e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>)) of terlipressin, or a pharmaceutically acceptable salt thereof).

Also described herein is a kit comprising instructions and the dosage form described herein.

Also disclosed herein is a unit dosage formulation for oral administration (oral dosage form) comprising a therapeutically effective amount of terlipressin in combination with a therapeutically effective amount of a diuretic.

Also disclosed herein is a unit dosage formulation for oral administration (oral dosage form) comprising a therapeutically effective amount of terlipressin in combination with a therapeutically effective amount of a beta-blocker.

A composition described herein may improve the absorption in the gastrointestinal (GI) tract of terlipressin, wherein terlipressin is otherwise in a composition or dosage form that is generally characterized by low or zero oral bioavailability and/or absorption, e.g., low or zero bioavailability, e.g., in aqueous solution, and in other oral formulations known in the art. A composition described herein may improve bioavailability by enhancing the GI wall/barrier permeability to terlipressin. For example, a composition described herein may facilitate absorption by permeating the GI wall/barrier primarily via unsealing of the tight junctions between GI epithelial cells, although it may also work by transcellular absorption. In some embodiments, the BA of terlipressin is at least <NUM>%, at least <NUM>%, at least <NUM>%, or at least <NUM>% or more.

Described herein is a process for producing a pharmaceutical composition (bulk drug product) which involves preparing a water soluble composition comprising a therapeutically effective amount of terlipressin and a medium chain fatty acid salt (and other ingredients - see below), drying (e.g., by lyophilization) the water soluble composition to obtain a solid powder, and suspending the lyophilized material (the solid powder) in a hydrophobic (oily) medium, preferably castor oil or glyceryl tricaprylate (including other ingredients, e.g. a PVP polymer and surfactants and viscosity modifiers - see below), to produce a suspension containing in solid form terlipressin and the medium chain fatty acid salt, thereby producing the bulk drug product, which contains at least <NUM>% by weight of medium chain fatty acid salt (e.g., at least <NUM>%, at least <NUM>%, or greater). The solid form may comprise a particle (e.g., consists essentially of particles, or consists of particles). The particle may be produced by lyophilization, by spray drying or by granulation. The bulk drug product may then be encapsulated in capsules which can be coated by a pH sensitive coating (e.g., an enteric coating) and may be used for oral delivery.

Also described herein is a composition including terlipressin and a medium chain fatty acid salt associated with a substantially hydrophobic medium, e.g., castor oil, wherein terlipressin and the medium chain fatty acid salt are in solid form, e.g. in the same solid form such as a particle, obtained by drying from an aqueous medium, e.g. by lyophilizing the aqueous medium, and wherein the medium chain fatty acid salt is present at <NUM> % by weight or more, preferably <NUM> -<NUM>%, e.g., about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>% or about <NUM>%, or about <NUM>%. The composition may also contain other ingredients (as described herein).

The present compositions of the invention are not emulsions. The compositions may be oily suspensions, and the amount of water in the compositions may be very low (e.g., less than <NUM>%, less than <NUM>%, less than <NUM>%).

The terlipressin and the medium chain fatty acid salt are in intimate contact with the substantially hydrophobic medium. For example, a powder comprising terlipressin and medium chain fatty acid salt is coated, immersed or suspended in the substantially hydrophobic medium.

During the production process, the aqueous medium which contains terlipressin and the medium chain fatty acid salt and the other ingredients is dried (e.g. by lyophilization) to obtain the hydrophilic fraction which is a powder (e.g., a solid form comprising a plurality of particles), and a particle in that powder contains all the ingredients i.e. terlipressin and medium chain fatty acid salt are together in a single particle. The solid form may be, for example, a granulated particle or a lyophilized particle.

The composition may include a plurality of medium chain fatty acid salts and derivatives thereof. For example, the solid particle may further include a plurality of medium chain fatty acid salts and derivatives thereof.

The medium chain fatty acid salt may be selected from the group consisting of sodium hexanoate, sodium heptanoate, sodium octanoate, sodium nonanoate, sodium decanoate, sodium undecanoate, sodium dodecanoate, sodium tridecanoate, and sodium tetradecanoate or a combination thereof. Alternatively, the composition may be substantially free of sodium dodecanoate, sodium tridecanoate, and sodium tetradecanoate. In one example, the medium chain fatty acid is sodium octanoate and the sodium octanoate is present at a concentration of above <NUM>% e.g. about <NUM>% to about <NUM>% weight/weight (wt/wt). In other examples, the medium chain fatty acid is sodium decanoate, for example present at a concentration of above <NUM>%, e.g., about <NUM>% to about <NUM>% weight/weight (wt/wt).

The substantially hydrophobic medium may comprise a triglyceride. For example, the triglyceride may be selected from the group consisting of glyceryl tributyrate, glyceryl monooleate, glyceryl monocaprylate and glyceryl tricaprylate.

The substantially hydrophobic medium may comprise mineral oil, castor oil, olive oil, corn oil, coconut oil, peanut oil, soybean oil, cotton seed oil, sesame oil or canola oil, or combinations thereof.

The water-soluble composition may contain a medium chain fatty acid salt and the hydrophobic medium contains the corresponding medium chain fatty acid; e.g. the medium chain fatty acid salt is a salt of octanoic acid such as sodium octanoate and the medium chain fatty acid is octanoic acid.

The water-soluble composition may contain a medium chain fatty acid salt and the hydrophobic medium may contain the corresponding medium chain monoglyceride or the corresponding medium chain triglyceride or a combination thereof; e.g. the medium chain fatty acid salt is sodium octanoate and the monoglyceride is glyceryl monocaprylate and the triglyceride is glyceryl tricaprylate.

The composition may further include one or more excipients. The excipients may be a salt e.g. MgCl<NUM> or an amine containing compound or mannitol. The excipient may be in the same solid form as terlipressin.

The composition may further include one or more surfactants. For example, the surfactant may be selected from the group consisting of sorbitan monopalmitate (Span-<NUM>®), polyoxyethylene sorbitan monooleate (Tween80), lecithin, and glyceryl monooleate (GMO). For example, the surfactant may comprise from about <NUM>% to about <NUM>% by weight of the composition.

The composition may be an oral dosage form. For example, the composition may be filled in a hard or soft capsule.

The pharmaceutical compositions described herein include incorporation of terlipressin as a therapeutic agent within an oral dosage form which may be enteric-coated. An oral dosage form as described herein may comprise additives or excipients that are suitable for the preparation of the oral dosage form. The oral dosage form may comprise tablets or capsules, preferably enteric coated.

The bioavailability of terlipressin, when administered to a subject in accordance with the present invention, may be at least <NUM>% - <NUM>% relative to parenteral (subcutaneous or intravenous) administration. The composition, when administered to a subject, may provide above <NUM>%, above <NUM>%, above <NUM>%, above <NUM>%, above <NUM>%, above <NUM>%, or above <NUM>% or above <NUM>% absorption of terlipressin across a biological barrier. The levels of absorption achieved produce the therapeutic levels needed for the indication concerned.

The formulations of the invention allow incorporation of terlipressin into the formulation without any chemical modification or degradation of terlipressin. Furthermore, the formulations of the invention allow for high flexibility in loading of terlipressin. Finally, the formulations of the invention protect the cargo compounds from inactivation in the GI environment due to for example proteolytic degradation and oxidation.

A suspension may be encapsulated to form a capsule. The capsule may further be coated, e.g., with an enteric coating.

Instructions to administer the capsule to a subject may also be provided. The instructions may relate to administering the capsule to a subject for any indication described herein. The capsules may be provided with instructions relating to administering the capsule to a subject for any indication described herein.

Still other aspects, embodiments, and advantages of these exemplary aspects and embodiments, are discussed in detail below. Moreover, it is to be understood that both the foregoing information and the following detailed description are merely illustrative examples of various aspects and embodiments, and are intended to provide an overview or framework for understanding the nature and character of the claimed aspects and embodiments.

The accompanying drawings are included to provide illustration and a further understanding of the various aspects and embodiments, and are incorporated in and constitute a part of this specification.

Throughout this application, various publications, including United States patents, are referenced by author and year and patents and applications by number.

Various aspects of at least one embodiment are discussed below with reference to the accompanying Figures. The Figures are provided for the purposes of illustration and explanation and are not intended as a definition of the limits of the invention. In the Figures:.

The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of terlipressin or a pharmaceutically acceptable salt thereof, for use in treating ascites in a subject, wherein the pharmaceutical composition is configured as a tablet or capsule comprising about <NUM> to about <NUM> of terlipressin or pharmaceutically acceptable salt thereof and is administered orally thereby treating the subject. Also disclosed are methods of treating a subject suffering from hypotension (e.g., neurogenic orthostatic hypotension or postprandial hypotension) or portal hypertension (e.g., bleeding esophageal varices associated with portal hypertension), the method comprising administering a therapeutically effective amount (e.g., at least <NUM> (e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>)) of terlipressin <NUM>, <NUM>, <NUM>, or <NUM> times daily, thereby treating the subject.

Neurogenic Orthostatic Hypotension (nOH) is a subtype of orthostatic hypotension that occurs in people with an existing neurologic disease (e.g., neurological conditions that are chronic and irreversible). In some embodiments, the neurologic disease is Parkinson's Disease or Multi-System Atrophy (MSA) or pure autonomic failure. Orthostatic (postural) hypotension refers to a reduction in systolic blood pressure (e.g., of at least <NUM> Hg) or a reduction in diastolic blood pressure (e.g., of at least <NUM> Hg) during the first <NUM> minutes of standing. Neurogenic orthostatic hypotension can be caused by autonomic nervous system malfunction, which is the part of the nervous system controlling involuntary body activity (e.g., keeping blood pressure normal). Symptoms include dizziness, lightheadedness, syncope (fainting), fatigue, blurry vision, weakness, trouble concentrating, head and neck pain. Outcomes include injuries such as tooth damage, broken bones, even death as a result of falling. Current pharmacologic treatments include fludrocortisone and/or midodrine, and/or pyridostigmine and/ or droxidopa and/or erythropoietin; <NPL>; and <NPL>. Drugs in development include Northera - norepinephrine pro-drug - (<NUM> - Lundbeck/Chelsea) and TD-<NUM> - norepinephrine and serotonin reuptake inhibitor - (P1/<NUM> - Theravance).

Intravenous injection of terlipressin has been shown to be effective in nOH (<NPL>) at a level of <NUM>-<NUM>µg per kilogram of body weight; however, this method of administration is clearly not suitable for use as home therapy. Oral terlipressin dosage forms as disclosed herein can be administered as home therapy, and can be used, inter alia for the prophylaxis and treatment of orthostatic hypotension.

Postprandial hypotension is commonly defined as a decrease in systolic blood pressure of 20mmHg or more observed within two hours after meal ingestion. It is very common in older patients especially in those living in long-term healthcare homes. Patients with postprandial hypotension may develop symptomatic hypotension, syncope (fainting) and falls. See <NPL>; <NPL>; and <NPL>. Hormonal treatments with intravenous vasopressin (see <NPL> are known to be effective, but they are unsuitable for home use.

Oral terlipressin dosage forms as disclosed herein can be administered as home therapy, and can be used, inter alia for the prophylaxis and treatment of postprandial hypotension.

Portal hypertension, or bleeding esophageal varices (or other varices) associated with portal hypertension, can occur when blood flow to the liver is blocked (e.g., by severe liver scarring (cirrhosis) in the liver tissue resulting from liver disease); as a result, veins (varices), most commonly in the lower esophagus, rupture and bleed. Thus esophageal varices are a direct result of high blood pressure in the portal vein. Symptoms include vomiting and significant visible amounts of blood in vomit; stomach pain; black, tarry or bloody stools; lightheadedness; loss of consciousness; signs of liver disease (e.g., yellow coloration of the skin and eyes; easy bleeding or bruising; fluid buildup in the abdomen). Although esophageal varices are the most common varices produced as a result of portal hypertension, varices can also be produced in the stomach, rectum, or umbilical area.

In patients who survive the first episode of esophageal variceal hemorrhage, the risk of recurrent bleeding is as high as <NUM>% with a mortality rate of up to <NUM>%. Terlipressin is effective in control of variceal bleeding but is currently administered intravenously and therefore is not convenient for prophylaxis; see <NPL>). In some embodiments, the subject suffers from cirrhosis (i.e., the subject has severe scarring of the liver as a result, e.g., due to excessive alcohol consumption or serious infections, such as hepatitis). In some embodiments, the subject suffers from portal vein thrombosis (i.e., blood clotting inside the portal vein). In some embodiments, the subject suffers from hepatorenal syndrome and/or ascites which are frequent complication of liver cirrhosis. In some embodiments, the subject suffers from nonalcoholic fatty liver disease and /or nonalcoholic steatohepatitis (NASH) and /or primary biliary cirrhosis or a parasitic infection, schistosomiasis, which can damage the liver.

Intravenously administered vasoconstrictors such as terlipressin are used to treat acute variceal bleeding but there is a <NUM>% re-bleed rate and <NUM>% mortality. There are no approved therapies to prevent (or delay) re-bleeds of varices. There is off-label use of beta blockers. It is estimated that in the US there are <NUM> secondary prophylaxis patients ineligible for beta blockers. Off-label beta-blockers are also the only long-term medication for prevention (or delay) of variceal bleeds.

Beta-adrenergic blocking agents are a class of medicines that bind to beta-adrenoreceptors and prevent the binding of norepinephrine and epinephrine at these receptors. This prevents sympathetic stimulation of the heart and reduces heart rate, cardiac contractility, conduction velocity, and relaxation rate which decreases myocardial oxygen demand and increases exercise tolerance. Beta-adrenergic blocking agents are commonly referred to as beta-blockers.

Beta-blockers can be grouped into those that are non-selective (block both beta-<NUM> and beta-<NUM> receptors, such as nadolol, penbutolol, pindolol, propranolol, sotalol, and timolol), and those that are cardioselective (only block beta-<NUM> receptors, and include acebutolol, betaxolol, bisoprolol, esmolol, and metoprolol). Some, like atenolol, are only cardioselective at low dosages. Beta-blockers for treatment of variceal bleeding are normally non-selective beta blockers.

Currently there is no approved therapy for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH); see Filozof (<NUM>)<NUM>:<NUM>-<NUM> and <NPL>. See also <NPL> and de Vries et al (<NUM>) <NUM>(<NUM>),<NUM>-<NUM>.

Oral terlipressin therapy as disclosed herein is suitable as an in-home therapy and can be used for prophylaxis and long-term management of varices (e.g., esophageal varices) and variceal bleeding.

Ascites is a frequent and life-threatening complication of diseases such as advanced liver cirrhosis, heart failure, and cancer (malignant ascites), with an expected <NUM>% mortality rate within two years of diagnosis. To date the US FDA has not approved any therapies specifically to treat ascites, although a few drugs (e.g., diuretics) are being used off-label with limited and temporary efficacy. First-line diuretic therapy for cirrhotic ascites is the use of spironolactone (Aldactone) preferably the combined use of spironolactone and furosemide (Lasix). Studies have shown the efficacy of terlipressin administered as intravenous (IV) bolus injections every <NUM> hours or administered as an intravenous infusion in patients with type <NUM> hepatorenal syndrome (HRS), alone and/or in combination with albumin; <NPL>; <NPL>.

HRS is the beginning of renal failure and frequently occurs in patients with ascites that has become refractory to treatment with diuretics; <NPL>. Note that two forms of hepatorenal syndrome have been defined: Type <NUM> HRS entails a rapidly progressive decline in kidney function, while type <NUM> HRS is associated with ascites (fluid accumulation in the abdomen) that does not improve with standard diuretic medications. Refractory ascites is ascites that cannot be mobilized or for which early recurrence after therapeutic paracentesis cannot be satisfactorily prevented by medical therapy. This includes two different subgroups:.

Refractory ascites is sometimes treated by aquaretics (e.g., vasopressin V2-receptor antagonists also known as vaptans, e.g., lixivaptan, satavaptan, tolvaptan) which promote excretion of electrolyte-free water and thus might be beneficial in patients with ascites and hyponatremia. Intravenous treatment of terlipressin, optionally in combination with diuretics, may resolve refractory ascites in hospitalized patients.

However, these intermittent high-dose IV injections (typically <NUM> or <NUM> in a single dose) carry a high risk of side-effects. More recent studies with hospitalized HRS patients indicate that a continuous infusion of terlipressin can achieve similar efficacy to intermittent injections with a much better safety profile. Recently there have been reports of treating ascites by administering terlipressin by continuous infusion in non-hospitalized patients (see <CIT>). However, this is still an invasive procedure with the attendant risks (such as infection) and inconvenience involved. Additionally, these patients are at risk of systemic hypotension, and intravenous dosing of terlipressin may heighten this risk because of its short Tmax. The oral terlipressin therapy for ascites of the present invention is suitable for out-patient administration and can be better tolerated in terms of hypotension risk due to a longer terlipressin Tmax.

Described herein is a method of treating a subject suffering from a disease or disorder which comprises orally administering to the subject a therapeutically effective amount of terlipressin; the disease or disorder may be, for example, orthostatic hypotension, portal hypertension, bleeding varices (e.g. esophageal varices) and ascites (e.g., ascites associated with liver cirrhosis) and associated symptoms and side-effects thereof. Also described herein is a composition of terlipressin for use in treating orally a disease or disorder in a subject.

Described herein is a method of treating a subject suffering from hypotension (e.g., neurogenic orthostatic hypotension), the method comprising administering one or two doses (e.g., a dose comprising <NUM> to <NUM> (or more) tablets or capsules comprising terlipressin) <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> minutes before getting up (e.g., in the morning or afternoon; before <NUM> or <NUM> pm), for example daily. The tablet or capsule comprising terlipressin may be about <NUM> to about <NUM> (e.g., about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>) terlipressin.

Also described herein is a method of treating a subject suffering from hypotension (e.g., postprandial hypotension) the method comprising administering one or two doses (e.g., a dose comprising <NUM> to <NUM> (or more) tablets or capsules comprising terlipressin).

Also described herein is a method of treating a subject suffering from portal hypertension or bleeding esophageal varices associated with portal hypertension, the method comprising administering oral terlipressin in a therapeutically effective amount.

<NUM> to <NUM> doses (e.g., a dose comprising <NUM> to <NUM> tablets or capsules comprising terlipressin) may be administered daily. The tablet or capsule comprising terlipressin may be about <NUM> to about <NUM> (e.g., about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>) terlipressin. The terlipressin may be administered orally for prevention of recurrence after a treated episode of bleeding varices. The subject may be able to return home while maintaining treatment (which is not possible with current intravenous administration of terlipressin). Oral terlipressin formulations may be used for primary and secondary prophylaxis of variceal bleeding.

Also described herein is a method of treating a subject suffering from portal hypertension or bleeding esophageal varices associated with portal hypertension, the method comprising administering <NUM> to <NUM> doses (e.g., a dose comprising <NUM> to <NUM> tablets or capsules comprising terlipressin) daily. The tablet or capsule comprising terlipressin may contain about <NUM> to about <NUM> (e.g., about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>) terlipressin.

Also described herein are compositions described herein, e.g., a composition comprising terlipressin, for the treatment of hypotension, e.g., neurogenic orthostatic hypotension or postprandial hypotension; or hypertension, e.g., portal hypertension (e.g., bleeding esophageal varices associated with portal hypertension); or ascites (e.g., associated with liver cirrhosis). The composition comprising terlipressin may be administered in an oral dosage form (e.g., comprising <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> terlipressin).

Also described herein is a method of treating a subject suffering from neurogenic orthostatic hypotension, the method comprising administration to the subject of a therapeutically effective amount of terlipressin in combination with another drug used for treatment of neurogenic orthostatic hypotension. For example, the drugs to be used in combination with oral terlipressin include mineralocorticoids including but not limited to fludrocortisone and/or midodrine, and/or pyridostigmine and/ or droxidopa and/or erythropoietin and/or Northera and/or TD-<NUM>.

Also described herein is a method for treating a subject suffering from postprandial hypotension, the method comprising administration to the subject of a therapeutically effective amount of terlipressin in combination with another drug used for treatment of postprandial hypotension. For example, compounds to be used in combination with oral terlipressin include one or more of acarbose and guar gum and midodrine and/or Northera and/or TD-<NUM>.

Oral terlipressin may be administered in combination with a large volume (a bolus) of physiological liquid (e.g., <NUM>, <NUM>, <NUM> or greater volume of physiological liquid).

Also disclosed herein is a unit dosage formulation for oral administration (oral dosage form) comprising terlipressin and a second or third oral drug used in treatment of neurogenic orthostatic hypotension, including mineralocorticoids including but not limited to fludrocortisone and/or midodrine, and/or pyridostigmine and/ or droxidopa and/or erythropoietin and/or Northera and/or TD-<NUM>.

Also disclosed herein is a unit dosage formulation for oral administration (oral dosage form) comprising terlipressin and a second or third oral drug used in treatment of postprandial hypotension, including but not limited to acarbose, guar gum and midodrine and/or Northera and/or TD-<NUM>.

Also disclosed herein is a unit dosage formulation for oral administration (oral dosage form) comprising a therapeutically effective amount of terlipressin in combination with a therapeutically effective amount of fludrocortisone.

Oral terlipressin may be administered in combination with a large volume of physiological liquid (e.g., <NUM>, <NUM>, <NUM> or greater volume of physiological liquid).

Also disclosed herein is a method for treating a subject suffering from portal hypertension / bleeding esophageal varices, the method comprising administration to the subject of a therapeutically effective amount of terlipressin in combination with another drug used for treatment of portal hypertension / bleeding esophageal varices. Such drugs to be used in combination with oral terlipressin include beta blockers and isosorbide mononitrate. Non-drug therapies that may be used in combination with oral terlipressin include but are not limited to endoscopic ligation, sclerotherapy and surgical shunts.

Also disclosed herein is a method for treating a subject suffering from cirrhosis, portal hypertension/ bleeding esophageal varices, the method comprising administration to the subject of a therapeutically effective amount of terlipressin in combination with another drug used for treatment of hepatitis C. Such drugs to be used in combination with oral terlipressin include alfa-interferon such as Peg-IFN-2a or IFN-a-2b.

Also disclosed herein is a method for treating a subject suffering from cirrhosis, portal hypertension/ bleeding esophageal varices, the method comprising administration to the subject of a therapeutically effective amount of terlipressin in combination with another drug used for treatment of hepatitis B. Such drugs to be used in combination with oral terlipressin include Lamivudine, Telbivudine, Entecavir, Adefovir, and Tenofovir.

Also disclosed herein is a method for treating a subject suffering from cirrhosis, portal hypertension/ bleeding esophageal varices, the method comprising administration to the subject of a therapeutically effective amount of terlipressin in combination with another drug used for treatment of fibrosis and/ or nonalcoholic steatohepatitis (NASH) and /or primary biliary cirrhosis. Such drugs to be used in combination with oral terlipressin include pirfenidone, nintedanib, obeticholic acid, urodeoxycholic acid and emricasan all administered orally; also vitamin E and pioglitazone.

Also disclosed herein is a unit dosage formulation for oral administration (oral dosage form) comprising a therapeutically effective amount of terlipressin in combination with a therapeutically effective amount of a liver fibrosis agent.

In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of terlipressin or a pharmaceutically acceptable salt thereof, for use in treating a subject suffering from ascites associated with liver cirrhosis, wherein the pharmaceutical composition is configured as a tablet or capsule comprising about <NUM> to about <NUM> of terlipressin or pharmaceutically acceptable salt thereof and is orally administering thereby treating the subject. In one aspect <NUM> to <NUM> doses (e.g., a dose comprising <NUM> to <NUM> or more tablets or capsules comprising terlipressin) are administered daily. In some embodiments, the tablet or capsule comprising terlipressin contains about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>) terlipressin. In some embodiments of, the subject is administered <NUM> to <NUM> terlipressin daily, <NUM> to <NUM> terlipressin daily, <NUM> to <NUM> terlipressin daily, or <NUM> terlipressin daily. In some embodiments the terlipressin is administered for about one day to about <NUM> months. In some embodiments the condition of the subject has not progressed to hepatorenal syndrome (HRS). In some embodiments the administration of terlipressin is provided on an out-patient basis. In some embodiments the terlipressin dose escalates over the about one day to about <NUM> months. In some embodiments, the treatment of the subject comprises reducing the volume of ascitic fluid prior to, during or following a paracentesis procedure.

In some embodiments, the treatment of the subject comprises improving renal function in the subject, for example by reducing serum creatinine concentration and/or increasing plasma sodium concentration and/or increasing urinary sodium excretion and /or decreasing urea concentration in serum. In some embodiments, the treatment of the subject comprises correcting hyponatremia in the subject.

In some embodiments, the terlipressin is administered in combination with a diuretic and /or in combination with albumin and/or in combination with a beta blocker.

Also disclosed herein is a unit dosage formulation for oral administration (oral dosage form) comprising a therapeutically effective amount of terlipressin in combination with a therapeutically effective amount of at least one diuretic and /or at least one a beta-blocker, for treatment of a subject suffering from ascites.

The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

The present invention relates to a pharmaceutical composition for use in treating ascites in a subject. Also described herein are methods for treating hypotension (e.g., neurogenic orthostatic hypotension or postprandial hypotension) or portal hypertension (e.g., bleeding esophageal varices associated with portal hypertension) in a subject. In some embodiments, the subject suffers from a neurological condition. In some embodiments, the neurological condition is chronic or irreversible (e.g., the condition is chronic and irreversible). In some embodiments, the subject suffers from Parkinson Disease or Multi-System Atrophy (MSA). In some embodiments, the subject suffers from Non-Alcoholic Fatty Liver Disease (NAFLD) or Non-Alcoholic Steatohepatitis (NASH). In some embodiments, the subject suffers from Hepatorenal Syndrome (HRS) (e.g., HRS type <NUM> or HRS type <NUM>). In some embodiments the subject suffers from cancer. In some embodiments the subject suffers from heart failure.

Described herein are methods for treating hypotension (e.g., neurogenic orthostatic hypotension or postprandial hypotension), portal hypertension (e.g., bleeding esophageal varices associated with portal hypertension) or ascites in a subject, the method comprising oral administration of a composition comprising terlipressin. The composition comprising terlipressin may be an oral dosage form (e.g., comprising <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> terlipressin).

The methods described herein may provide about <NUM> to about <NUM>µg/mL terlipressin concentration in a subject. The methods described herein may provide about <NUM> to about <NUM>µg/mL terlipressin concentration in a subject, e.g., in the plasma of the subject. The methods described herein may provide about <NUM> to about <NUM>µg/mL terlipressin concentration in a subject, e/g/ about <NUM>µg/mL terlipressin concentration in a subject.

The methods described herein may provide about <NUM> to about <NUM>µg/mL (lysine -) vasopressin concentration in a subject. (Vasopressin is the active metabolite of terlipressin. ) The methods described herein provide about <NUM> to about <NUM>µg/mL vasopressin concentration in a subject, e.g., in the plasma of the subject. The methods described herein provide about <NUM> to about <NUM>µg/mL vasopressin concentration in a subject, e.g. about <NUM>µg/mL vasopressin concentration in a subject.

The composition may be configured in a solid dosage form such as a capsule, e.g., with an enteric coating. Alternatively, the solid dosage form may be a tablet e.g., with an enteric coating.

The capsule may contain <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> terlipressin. For example, the capsule may contain about <NUM> to about <NUM> terlipressin, about <NUM> to about <NUM> terlipressin, or <NUM> terlipressin.

The tablet may contain <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> terlipressin.

The method may comprise administration up to <NUM> times per day.

The method may comprise administration up to <NUM> or <NUM> times per day.

The dosage regimen utilizing the compounds may be selected in accordance with a variety of factors including age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Oral dosages of the present invention, when used for the treatment of ascites, may be provided in the form of capsules comprising <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> terlipressin.

In some embodiments, the oral dosage comprises about <NUM> to about <NUM> of terlipressin, about <NUM> to about <NUM> of terlipressin, about <NUM> to about <NUM> of terlipressin, or about <NUM> terlipressin.

Compositions described herein may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. In some embodiments, the method comprises administration up to <NUM> times per day. In some embodiments, the composition is administered up to <NUM> or <NUM> times per day.

In some embodiments, the composition is administered once or twice a day. For treating hypotension (e.g., neurogenic orthostatic hypotension), the composition may be administered <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> minutes prior to getting up (e.g., getting up in the morning, getting up after a nap e.g. an afternoon nap). In some examples, the composition is not administered in the late afternoon or evening (e.g., the composition is not administered after <NUM> or <NUM> pm); without being bound by theory, to prevent supine hypertension. For example, the composition comprising terlipressin (e.g., a coated capsule or tablet comprising terlipressin), is administered to a subject suffering from hypotension (e.g., neurogenic orthostatic hypotension), once in the morning and once in the afternoon. In another example, the composition comprising terlipressin (e.g., a coated capsule or tablet) comprising terlipressin), is administered to a subject suffering from portal hypertension or bleeding esophageal varices as <NUM>-<NUM> tablets up to <NUM> times a day.

In some embodiments, the administration occurs on an empty stomach. In some embodiments, the administration occurs prior to food intake (e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or more hours prior to food intake). In some embodiments, the administration occurs after food intake (e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or more hours after food intake). In some embodiments, the administration occurs during food intake. In some embodiments, the oral administration of terlipressin occurs at least <NUM> hour before a meal or least <NUM> hours after a meal, to thereby treat the subject. In some embodiments, the oral administration of terlipressin occurs at least <NUM> hour before a meal or least <NUM> hour after a meal, to thereby treat the subject.

A representative product of the invention is a formulation orally administered as enteric coated-capsules: each capsule contains terlipressin co-lyophilized with a PVP polymer and sodium octanoate, and suspended in a hydrophobic (lipophilic) medium containing: glyceryl tricaprylate, glyceryl monocaprylate, and Tween <NUM>; in another representative product of the invention castor oil is additionally present. The compositions described herein can be administered to a subject i.e. a human or an animal, in order to treat the subject with a pharmacologically or therapeutically effective amount of terlipressin described herein. The animal may be a mammal e.g. a mouse, rat, pig, dog, horse, cow or sheep.

Compositions of the present invention (e.g., compositions comprising terlipressin) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, four, five or six times daily. In some embodiments, the method comprises administration up to <NUM> times per day. In some embodiments, the composition is administered up to <NUM> or <NUM> times per day.

In some embodiments, orally administering terlipressin results in reduced side effects relative a method of administering terlipressin by other forms of administration (e.g., intravenous administration). In some embodiments, orally administering terlipressin provides greater patient compliance (e.g., compliance by a subject described herein) relative a method of administering terlipressin by other forms of administration (e.g., intravenous administration which is not convenient for domiciliary treatment).

As described herein, the active pharmaceutical ingredient described herein (e.g., compound described herein, therapeutic agent described herein) is terlipressin, or a pharmaceutically acceptable salt of terlipressin. Terlipressin (also known as triglycyl lysine vasopressin) is a synthetic analogue of the human neuropeptide hormone vasopressin. Terlipressin is a prohormone of lysine-vasopressin (triglycyl lysine vasopressin TGLVP), for example as described in <NPL>). Following administration and absorption to the circulation, the glycyl residues are cleaved from the prohormone by endothelial peptidases, allowing prolonged release of lysine-vasopressin. Thus terlipressin itself has weak intrinsic vasopressive activity but is transformed to the fully active lysine vasopressin (LVP) by endothelial endopeptidases. Terlipressin is also known by its tradenames Teripress and Glypressin. Terlipressin has a molecular weight of <NUM>/mol and is represented by the formula:
<CHM>
Terlipressin administered intravenously has been used, for example as a vasoactive drug in the management of hypotension (low blood pressure) and for example for treatment of esophageal varices, septic shock, hepatorenal syndrome and ascites.

The pharmaceutical compositions described herein include terlipressin and may include a medium chain fatty acid salt in intimate contact or association with a substantially hydrophobic medium. For example, terlipressin and the medium chain fatty acid or derivative thereof may be coated, suspended, sprayed by or immersed in a substantially hydrophobic medium forming a suspension. The compositions of the invention are not emulsions. The compositions are oily suspensions and the amount of water in the compositions is very low, usually <NUM>% or less or <NUM>% or less.

The suspension may be a liquid suspension incorporating solid material, or a semi-solid suspension incorporating solid material (an ointment). Many of the compositions described herein comprise a suspension which comprises an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of terlipressin and at least one salt of a medium chain fatty acid, and wherein the medium chain fatty acid salt is present in the composition at an amount of <NUM>% or more by weight. The solid form may comprise a particle (e.g., consist essentially of particles, or consist of particles). The particle may be produced by lyophilization, by spray drying or by granulation.

The medium chain fatty acid salt may generally facilitate or enhance permeability and/or absorption of terlipressin. The medium chain fatty acid salts may include derivatives of medium chain fatty acid salts. Terlipressin and the medium chain fatty acid salt are in solid form, for example, a solid particle such as a lyophilized particle, granulated particle, pellet or microsphere. Terlipressin and the medium chain fatty acid salt may both be in the same solid form, e.g., both in the same particle. Alternatively, terlipressin and the medium chain fatty acid salt may each be in a different solid form, e.g. each in a distinct particle.

Unlike emulsions, where water is an essential constituent of the formulation, the compositions described herein provide a solid form such as a particle containing terlipressin, which is then associated with the hydrophobic (oily) medium. The amount of water in the compositions is generally less than <NUM>% by weight, usually less than about <NUM>% or less than <NUM>% by weight or about <NUM> % by weight or less.

The compositions described herein are suspensions which comprise an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of terlipressin and at least one salt of a medium chain fatty acid. The solid form may be a particle (e.g., consist essentially of particles, or consist of particles). The particle may be produced by lyophilization or by spray drying or by granulation. The medium chain fatty acid salt is generally present in the compositions described herein at an amount of <NUM>% or more by weight. For example, the medium chain fatty acid salt may be present in the composition at an amount of <NUM>%-<NUM>%, preferably <NUM>%-<NUM>% or about <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or most preferably <NUM>% or <NUM>% by weight, and the medium chain fatty acid has a chain length from about <NUM> to about <NUM> carbon atoms preferably <NUM>, <NUM> or <NUM> carbon atoms.

The solid form including terlipressin may also include a stabilizer (e.g., a stabilizer of protein structure). Stabilizers of protein structure are compounds that stabilize protein structure under aqueous or non-aqueous conditions or can reduce or prevent aggregation of terlipressin, for example during a drying process such as lyophilization or other processing step. Stabilizers of structure can be polyanionic molecules, such as phytic acid, polyvalent ions such as Ca, Zn or Mg, saccharides such as a disaccharide (e.g., trehalose, maltose) or an oligo or polysaccharide such as dextrin or dextran, or a sugar alcohol such as mannitol, or an amino acid such as glycine, or polycationic molecules, such as spermine, or surfactants such as polyoxyethylene sorbitan monooleate (Tween <NUM>) or pluronic acid. Uncharged polymers, such as mannitol, methyl cellulose and polyvinyl alcohol, are also suitable stabilizers.

Although polyvinylpyrrolidone (PVP) is known in the art as a stabilizer, in the compositions of the invention described herein, a PVP polymer, for example PVP-<NUM>, can serve to increase the effect of the permeability enhancer, e.g., in a synergistic manner. Dextran and other matrix forming polymers may have a similar effect as PVP does.

A bulking agent may be added, for example, mannitol or glycin.

For example, the salt of the fatty acid may be sodium octanoate and the hydrophobic medium may be castor oil; the composition may further comprise glyceryl monooleate and sorbitan monopalmitate or glyceryl monocaprylate and glyceryl tricaprylate and polyoxyethylene sorbitan monooleate. The composition may further comprise glyceryl tributyrate, lecithin, ethylisovalerate and at least one stabilizer.

An exemplary formulation of terlipressin is as follows:.

The compositions described herein may include the salt of a medium chain fatty acid or a derivative thereof in a solid form. For example, the salt of the medium chain fatty acid is in the form of a particle such as a solid particle. The particle may be characterized as a granulated particle. The solid form may generally result from a spray drying or evaporation process. The salt of the medium chain fatty acid may be in the same particle as terlipressin. For example, terlipressin and the salt of the medium chain fatty acid can be prepared together by first preparing a solution such as an aqueous solution comprising both terlipressin and the salt of the medium chain fatty acid and co-lyophilizing the solution to provide a solid form or particle that comprises both terlipressin and the salt of the medium chain fatty acid (and other ingredients). As described above, the resulting solid particles are associated with a hydrophobic medium. For example, the solid particles may be suspended or immersed in a hydrophobic medium.

Alternatively, the medium chain fatty acid salt may be in the same particle or in a different particle than that of the API. It is believed that if the medium chain fatty acid salt and terlipressin are dried after solubilization together in the hydrophilic fraction then they are in the same particle in the final powder.

Medium chain fatty acid salts include those having a carbon chain length of from about <NUM> to about <NUM> carbon atoms. Examples of fatty acid salts are sodium hexanoate, sodium heptanoate, sodium octanoate (also termed sodium caprylate), sodium nonanoate, sodium decanoate, sodium undecanoate, sodium dodecanoate, sodium tridecanoate, and sodium tetradecanoate. The medium chain fatty acid salt may contains a cation selected from the group consisting of potassium, lithium, ammonium and other monovalent cations e.g. the medium chain fatty acid salt is selected from lithium octanoate or potassium octanoate or arginine octanoate or other monovalent salts of the medium chain fatty acids.

In general, the amount of medium chain fatty acid salt in the compositions described herein may be from <NUM>% up to about <NUM>% by weight of the bulk pharmaceutical composition. For example, the medium chain fatty acid salt may be present at an amount of about <NUM>% -<NUM>%, preferably about <NUM>%-<NUM>% most preferably about <NUM>%-<NUM>% by weight for example at about <NUM>%-<NUM>%, <NUM>%-<NUM>%, <NUM>%-<NUM>% , <NUM>%-<NUM>%, <NUM>%-<NUM>%, <NUM>%-<NUM>%, <NUM>%-<NUM>%, <NUM>%-<NUM>%, <NUM>%-<NUM>%, <NUM>%-<NUM>%,<NUM><NUM>%-<NUM>%, <NUM>%-<NUM>%,<NUM><NUM>%-<NUM>%, <NUM>%-<NUM>%, <NUM>%-<NUM>%, or <NUM>%-<NUM>% by weight of the bulk pharmaceutical composition. For example, the medium chain fatty acid salt may be present at an amount of at least about <NUM>%, at least about12%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>% at least about <NUM>%,at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>% or at least about <NUM>% by weight of the bulk pharmaceutical composition. In particular, the medium chain fatty acid salt (sodium, potassium, lithium or ammonium salt or a mixture thereof) may be present at about <NUM>% -<NUM>% by weight of the bulk pharmaceutical composition preferably <NUM>%-<NUM>% or about <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or most preferably <NUM>% or <NUM>%. The medium chain fatty acid salt (having a carbon chain length of from about <NUM> to about <NUM> carbon atoms particularly <NUM>, <NUM> or <NUM> carbon atoms) may be present at about <NUM>% -<NUM>% by weight of the bulk pharmaceutical composition preferably <NUM>%-<NUM>% about <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or most preferably <NUM>% or <NUM>%. The medium chain fatty acid salt (for example salts of octanoic acid, salts of suberic acid, salts of geranic acid) may be present at about <NUM>% -<NUM>% by weight of the bulk pharmaceutical composition preferably <NUM>%-<NUM>% about <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or <NUM>%-<NUM>% or most preferably <NUM>% or <NUM>%. In The medium chain fatty acid salt may be present in the solid powder at an amount of <NUM>% to <NUM>%, preferably at an amount of <NUM>% to <NUM>%.

One example composition comprises a suspension which consists essentially of an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount terlipressin and at least one salt of a medium chain fatty acid, and wherein the medium chain fatty acid salt is not a sodium salt. The salt may be the salt of another cation e.g. lithium, potassium or ammonium; an ammonium salt is preferred.

The composition of the invention may comprise a suspension which comprises an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of terlipressin, at least one salt of a medium chain fatty acid and a matrix forming polymer, and wherein the matrix forming polymer is present in the composition at an amount of <NUM>% or more by weight. The composition may comprise a suspension which consists essentially of an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of terlipressin, at least one salt of a medium chain fatty acid and a matrix forming polymer, and wherein the matrix forming polymer is present in the composition at an amount of <NUM>% or more by weight. In particular, the matrix forming polymer may be dextran or a polyvinylpyrrolidone polymer (PVP), obtainable in various molecular weights from BASF. For example, the polyvinylpyrrolidone may be present in the composition at an amount of about <NUM>% to about <NUM>% by weight, preferably at an amount of about <NUM>% to about <NUM> % by weight, more preferably at an amount of about <NUM>% to about <NUM> % by weight, most preferably at an amount of about <NUM> % by weight. In particular, the polyvinylpyrrolidone may be PVP- <NUM> and/or may have a molecular weight of about <NUM>. Other matrix forming polymers have a similar effect in the compositions of the invention; such matrix forming polymers include ionic polysaccharides (for example alginic acid and alginates) or neutral polysaccharides (for example dextran and HPMC), polyacrylic acid and poly methacrylic acid derivatives and high molecular weight organic alcohols (for example polyvinyl alcohol).

The above compounds, including terlipressin and the medium chain fatty acid salt may be solubilized in an aqueous medium and then dried to produce a powder. The drying process may be achieved for example by lyophilization or spray drying or granulation. The powder obtained is termed the "hydrophilic fraction". In the hydrophilic fraction water is normally present at an amount of less than <NUM>% or less than <NUM>% or about <NUM>% or less.

Lyophilization may be carried out by methods known in the art e.g. as described in <NPL>) The lyophilizate may optionally be milled ( e.g. below <NUM> micron) or ground in a mortar. During industrial production the lyophilizate is preferably milled before mixing of the hydrophilic fraction and the hydrophobic medium in order to produce batch-to-batch reproducibility.

Spray drying may be carried out by methods known in the art e.g. as described by <NPL>.

Granulation may be carried out as shown by methods known in the art e.g. as described in <NPL>) and in <NPL>. Various binders may be used in the granulation process such as celluloses (including microcrystalline celluloses), lactoses (e.g., lactose monohydrate), dextroses, starch and mannitol and other binders as described in the previous two references.

Oil: As described above, in the compositions of the invention described herein terlipressin and the medium chain fatty acid salt may be in intimate contact or association with a hydrophobic medium. For example, one or both may be coated, suspended, immersed or otherwise in association with a hydrophobic medium. Suitable hydrophobic mediums can contain, for example, aliphatic, cyclic or aromatic molecules. Examples of a suitable aliphatic hydrophobic medium include, but are not limited to, mineral oil, fatty acid monoglycerides, diglycerides, triglycerides, ethers, esters, and combinations thereof. Examples of a suitable fatty acid are octanoic acid, decanoic acid and dodecanoic acid, also C7 and C9 fatty acids and di-acidic acids such as sebacic acid and suberic acid, and derivatives thereof. Examples of triglycerides include, but are not limited to, long chain triglycerides, medium chain triglycerides, and short chain triglycerides. For example, the long chain triglyceride can be castor oil or coconut oil or olive oil, and the short chain triglyceride can be glyceryl tributyrate and the medium chain triglyceride can be glyceryl tricaprylate. Monoglycerides are considered to be surfactants and are described below. Exemplary esters include ethyl isovalerate and butyl acetate. Examples of a suitable cyclic hydrophobic medium include, but are not limited to, terpenoids, cholesterol, cholesterol derivatives (e.g., cholesterol sulfate), and cholesterol esters of fatty acids. A non-limiting example of an aromatic hydrophobic medium includes benzyl benzoate.

It may be desirable that the hydrophobic medium include a plurality of hydrophobic molecules. The hydrophobic medium may also include one or more surfactants (see below).

The hydrophobic medium may also include one or more adhesive polymers such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose (HPMC), or poly(acrylate) derivative Carbopol®934P (C934P). Such adhesive polymers may assist in the consolidation of the formulation and/or help its adherence to mucosal surfaces.

The compositions of this invention described herein can further include a surface-active agent. For example, the surface-active agent can be a component of the hydrophobic medium as described above, and/or the surface-active agent can be a component of a solid form as described above, for example in the solid form or particle that includes terlipressin.

Suitable surface-active agents include ionic and non-ionic surfactants. Examples of ionic surfactants are lecithin (phosphatidyl choline), bile salts and detergents. Examples of non-ionic surfactants include monoglycerides, cremophore, a polyethylene glycol fatty alcohol ether, a sorbitan fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, Solutol HS <NUM>, or a poloxamer or a combination thereof. Examples of monoglycerides are glyceryl monocaprylate (also termed glyceryl monooctanoate), glyceryl monodecanoate, glyceryl monolaurate, glyceryl monomyristate, glyceryl monostearate, glyceryl monopalmitate, and glyceryl monooleate. Examples of sorbitan fatty acid esters include sorbitan monolaurate, sorbitan monooleate, and sorbitan monopalmitate (Span <NUM>), or a combination thereof. Examples of polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan monooleate (Tween <NUM>), polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate or a combination thereof. The commercial preparations of monoglycerides that were used also contain various amounts of diglycerides and triglycerides.

Compositions described herein including a surface-active agent generally include less than about <NUM>% by weight of total surface active agent (e.g., less than about <NUM>%, less than about <NUM>%, less than about <NUM>%, less than about <NUM>%, less than about <NUM>%, or less than about <NUM>%). In particular embodiments of the invention the total sum of all the surfactants is about <NUM>%.

Also described herein are methods of producing the compositions described herein, e.g. a process for producing a pharmaceutical composition which comprises preparing a water-soluble composition comprising a therapeutically effective amount of terlipressin and a medium chain fatty acid salt (as described above), drying the water soluble composition to obtain a solid powder, and suspending the solid powder in a hydrophobic medium, to produce a suspension containing in solid form terlipressin and the medium chain fatty acid salt, thereby producing the pharmaceutical composition, wherein the pharmaceutical composition contains <NUM>% or more by weight of medium chain fatty acid salt.

For example, a process for producing a pharmaceutical composition may comprise providing a solid powder of a therapeutically effective amount terlipressin and a solid powder comprising a medium chain fatty acid salt, and suspending the solid powders in a hydrophobic medium, to produce a suspension containing in solid form terlipressin and the medium chain fatty acid salt, thereby producing the pharmaceutical composition, wherein the pharmaceutical composition contains <NUM>% or more by weight of medium chain fatty acid salt.

The water-soluble composition may be an aqueous solution. Drying of the water-soluble composition may be achieved by lyophilization (freeze-drying), spray-drying or by granulation. The drying step may remove sufficient water so that the water content in the bulk pharmaceutical composition is lower than about <NUM>% by weight, about <NUM>% by weight, about <NUM>% by weight, about <NUM>% or about <NUM> % or about <NUM>% or about <NUM> % or less by weight. The drying step may remove an amount of water so that the water content in the solid powder is lower than <NUM>% or <NUM>% or <NUM>% or <NUM>% or preferably lower than <NUM>% by weight. The water content is normally low and the water may be adsorbed to the solid phase during lyophilization i.e. the water may be retained by intermolecular bonds, the water-soluble composition may additionally comprise a stabilizer for example methyl cellulose. The hydrophobic medium may be castor oil or glyceryl tricaprylate or glyceryl tributyrate or a combination thereof and may additionally contain octanoic acid; e.g. the hydrophobic medium may comprise an aliphatic, olefinic, cyclic or aromatic compound, a mineral oil, a paraffin, a fatty acid such as octanoic acid, a monoglyceride, a diglyceride, a triglyceride, an ether or an ester, or a combination thereof. The triglyceride may be a long chain triglyceride, a medium chain triglyceride preferably glyceryl tricaprylate or a short chain triglyceride preferably glyceryl tributyrate, and the long chain triglyceride may be castor oil or coconut oil or a combination thereof. The hydrophobic medium may comprise castor oil or glyceryl tricaprylate or glyceryl tributyrate or a combination or mixture thereof, and may additionally comprise octanoic acid. For example, the hydrophobic medium may comprise glyceryl tricaprylate or a low molecular weight ester for example ethyl isovalerate or butyl acetate. The main component by weight of the hydrophobic medium may be castor oil and may additionally comprise glyceryl tricaprylate. IAlternatively, the main component by weight of the hydrophobic medium may be glyceryl tricaprylate and may additionally comprise castor oil.

The composition may comprise a suspension which consists essentially of an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of terlipressin and at least one salt of a medium chain fatty acid, and wherein the medium chain fatty acid salt is present in the composition at an amount of <NUM>% or more by weight. For example, the hydrophobic medium may consist essentially of castor oil, glyceryl monooleate and glyceryl tributyrate; or the hydrophobic medium may consist essentially of glyceryl tricaprylate and glyceryl monocaprylate; or the hydrophobic medium consists essentially of castor oil, glyceryl tricaprylate and glyceryl monocaprylate. The hydrophobic medium may comprise a triglyceride and a monoglyceride, e.g. wherein the monoglyceride has the same fatty acid radical as the triglyceride (e.g. the triglyceride is glyceryl tricaprylate and the monoglyceride is glyceryl monocaprylate). The medium chain fatty acid salt in the water-soluble composition may have the same fatty acid radical as the medium chain monoglyceride or as the medium chain triglyceride or a combination thereof. For example, the medium chain fatty acid salt may be sodium caprylate (sodium octanoate), the monoglyceride may be glyceryl monocaprylate and the triglyceride may be glyceryl tricaprylate.

Many of the compositions described herein comprise a suspension which comprises an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of terlipressin and at least one salt of a medium chain fatty acid, and wherein the medium chain fatty acid salt is present in the composition preferably at an amount of <NUM>% or more by weight. The solid form may be a particle (e.g., consist essentially of particles, or consists of particles). The particle may be produced by lyophilization or by granulation or by spray drying. The formulation may consist essentially of or comprise a suspension which comprises an admixture of a hydrophobic medium and a solid form wherein the solid form comprises a therapeutically effective amount of terlipressin and about <NUM>-<NUM>% preferably <NUM>% medium chain fatty acid salt preferably sodium octanoate and a polyvinylpyrrolidone polymer ; and wherein the hydrophobic medium comprises about <NUM>-<NUM>% , preferably <NUM>-<NUM>% medium or short chain triglyceride preferably glyceryl tricaprylate or glyceryl tributyrate, about <NUM>- <NUM>% preferably <NUM>-<NUM>% castor oil, about <NUM>-<NUM>% surfactants, preferably about <NUM>%, preferably glyceryl monocaprylate and Tween <NUM> ; in particular embodiments terlipressin is present at an amount of less than <NUM>%, or less than <NUM>%, or less than <NUM>%, or less than <NUM>% or less than <NUM>%.

In the above formulations, the percentages are weight/weight.

Under normal storage conditions, terlipressin, within the formulations of the invention, is stable over an extended period of time. The chemical and physical state of the formulation is stable. Once administered to the intestine, terlipressin is protected from damage by the GI environment since the formulations are oil-based and therefore a separate local environment is created in the intestine where terlipressin is contained in particles suspended in oil which confers stability in vivo.

The process may produce a composition which consists essentially of terlipressin and a medium chain fatty acid salt and a hydrophobic medium. The solid powder (solid form) may consist essentially of terlipressin and a medium chain fatty acid salt. Also described are pharmaceutical compositions produced by the process described herein. For example, an oral dosage form comprising the pharmaceutical composition, in particular an oral dosage form which is enteric coated. Also disclosed herein ia a capsule containing the compositions of the invention, e.g. wherein the capsule is a hard gel or a soft gel capsule. Generally the capsule is enteric-coated. Also provided is a rectal dosage form comprising the pharmaceutical composition, in particular a suppository, or a buccal dosage form. A kit comprising instructions and the dosage form is also envisaged.

Terlipressin and/or medium chain fatty acid salt, or any combination of terlipressin and other components, such as protein stabilizers, can be prepared in a solution of a mixture (e.g., forming an aqueous solution or mixture) which can be lyophilized together and then suspended in a hydrophobic medium. Other components of the composition can also be optionally lyophilized or added during reconstitution of the solid materials.

Terlipressin may be solubilized in a mixture, for example, including one or more additional components such as a medium chain fatty acid salt, a stabilizer and/or a surface-active agent, and the solvent is removed to provide a resulting solid powder (solid form), which is suspended in a hydrophobic medium. Terlipressin and/or the medium chain fatty acid salt may be formed into a granulated particle that is then associated with the hydrophobic medium (for example suspended in the hydrophobic medium or coated with the hydrophobic medium). If desired, the pharmaceutical composition may also contain minor amounts of non-toxic auxiliary substances such pH buffering agents, and other substances such as for example, sodium acetate and triethanolamine oleate.

The solid form may be a particle (e.g., consist essentially of particles, or consists of particles). The particle may be produced by lyophilization, by spray drying or by granulation. The fatty acid salt may be sodium octanoate; the medium chain fatty acid salt may be present in the composition at an amount of about <NUM>% to about <NUM>% by weight or at an amount of about <NUM>% to about <NUM>% by weight or at an amount of about <NUM>% by weight. The composition may additionally comprise a matrix forming polymer, e.g. wherein the matrix forming polymer is dextran or a polyvinylpyrrolidone polymer (PVP); for example wherein the polyvinylpyrrolidone is present in the composition at an amount of about <NUM>% to about <NUM>% by weight or at an amount of about <NUM>% to about <NUM> % by weight, or at an amount of about <NUM> % by weight. The polyvinylpyrrolidone polymer may be PVP- <NUM> and /or may have a molecular weight of about <NUM>. The composition may in addition include surfactants as described above. The solid form may also contain a binder. There also may be small quantities of other hydrophobic constituents as described above.

The compositions of the invention may be formulated using microparticulate technology for example as described in <NPL>) and in <NPL>.

Oral dosage forms may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U. Food and Drug Administration for prescription drugs or of an approved product insert.

As used herein the term "pharmacologically or therapeutically effective amount" means that amount of a drug or pharmaceutical agent (e.g. terlipressin) that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician and /or halts or reduces the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition described herein or prevents development of the condition described herein (e.g., hypotension for example neurogenic orthostatic hypotension or postprandial hypotension; portal hypertension for example bleeding esophageal varices associated with portal hypertension) or ascites for example associated with liver cirrhosis.

Administered "in combination", as used herein, means that two (or more) different therapeutic agents are delivered to the subject during the course of the subject's affliction with the disorder, e.g., the two or more therapeutic agents are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one therapeutic agent is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as "simultaneous" or "concurrent delivery". In other embodiments, the delivery of one therapeutic agent ends before the delivery of the other treatment begins. In some embodiments of either case, the therapeutic agents are more effective because of combined administration. For example, the second therapeutic agent is more effective, e.g., an equivalent effect is seen with less of the second therapeutic agent, or the second therapeutic agent reduces symptoms and side-effects to a greater extent, than would be seen if the second therapeutic agent were administered in the absence of the first therapeutic agent, or the analogous situation is seen with the first therapeutic agent. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one therapeutic agent delivered in the absence of the other. The effect of the two therapeutic agents can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first therapeutic agent delivered is still detectable when the second is delivered.

As used herein, the term "treatment" as for example in "method of treatment" or "treat" or "treating" refers to therapeutic treatment, wherein the object is to reduce or reverse or prevent the symptoms or side-effects of a disease or disorder. In some embodiments, the compounds or compositions disclosed herein are administered prior to onset of the disease or disorder. In some embodiments, the compounds or compositions disclosed herein are during or subsequent to the onset of the disease or disorder.

As used herein the term "therapy reducing liver fibrosis agent" and the term "liver fibrosis agent" are used interchangeably. A liver fibrosis agent is a drug used for treatment of liver fibrosis and/ or non-alcoholic steatohepatitis (NASH) and/ or primary biliary cirrhosis. Such liver fibrosis agents (drugs) to be used in combination with oral terlipressin include pirfenidone, nintedanib, obeticholic acid, urodeoxycholic acid, emricasan, vitamin E, pioglitazone, liraglutide, pentoxifylline and metformin. The agents pioglitazone, liraglutide, pentoxifylline and metformin are particularly used for treatment of NASH.

The function and advantages of these and other embodiments will be more fully understood from the following examples. These examples are intended to be illustrative in nature and are not to be considered as limiting the scope of the systems and methods discussed herein.

Terlipressin (tradename Glypressin, Ferring) was administered to one group of six dogs via intravenous (IV) administration and terlipressin (BCN Peptides) in the proprietary formulation below (Table <NUM>) was administered to another group of six dogs via oral administration as enteric-coated capsules. The IV dosage was <NUM> per dog which is similar to the therapeutic dosage in humans. The oral dosage was <NUM>, and was selected by assuming a BA of about <NUM>%. The concentration of both terlipressin and the active metabolite lysine vasopressin are shown as a function of time. The pharmacokinetic parameters of the active metabolite lysine-vasopressin were determined as well as terlipressin. Each Glypressin ampule contains <NUM> terlipressin acetate, which is equivalent to <NUM> terlipressin base. All doses in this study are expressed on the basis of terlipressin base.

All animals were fasted for at least <NUM> hours prior to dosing and through the first <NUM> hours of blood sample collection.

In the oral terlipressin capsule treatments, in order to acidify the stomach of the dog, approximately <NUM> minutes prior to dosing each animal received a single subcutaneous (SC) injection of pentagastrin (<NUM>/mL) at a dose level of <NUM>/kg and a dose volume of <NUM>/kg. The same dogs can be used for more than one treatment, with a wash-out period of at least 1week.

Blood was withdrawn at pre-determined times as follows:
IV: pre-dose, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> hours post-dose. Oral capsule: pre-dose, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> hours post-dose.

Results are shown for the intravenous administration group in <FIG> and for the oral administration group in <FIG> and also are shown in Table <NUM> below.

TABLE <NUM> below provides the composition comprising terlipressin as used in this dog study. The formulation comprises <NUM>% PVP and <NUM>% sodium octanoate in the hydrophilic fraction, and contains glyceryl tricaprylate as the main constituent of the hydrophobic medium.

TABLE <NUM> below shows the Cmax, AUC, and half time for terlipressin administered IV ("IV terlipressin") and orally ("Oral terlipressin") in this study.

These results demonstrate that orally administered terlipressin produces blood (plasma) levels which are similar to the therapeutic dose.

Patients with neurogenic orthostatic hypotension are randomly assigned to be treated with oral terlipressin (for example up to <NUM> daily administered twice daily) or placebo, in addition to standard of care. The patient has to be fasting for at least two hours prior to start of the study. Blood pressure and heart rate are measured in the supine position before and after oral administration of terlipressin or placebo. After <NUM> mins in the supine position the patients are tilted head up to <NUM>° for <NUM> minutes, at which point the blood pressure and heart rate are measured again.

Measurement of dizziness, lightheadedness, syncope (fainting), fatigue, blurry vision, weakness in the tilt position.

Patients that are confirmed to have ascites, for example ascites associated with liver disease such as liver cirrhosis (e.g., liver cirrhosis without type <NUM> or type <NUM> HRS), hepatorenal syndrome (HRS) (e.g., type <NUM> or type <NUM> HRS), heart disease (e.g. heart failure) or malignant ascites are orally administered terlipressin for example up to <NUM> daily administered twice daily over the course of treatment ranging from <NUM> day to <NUM> days. The patient must take the drug at least one hour before a meal or at least two hours after a meal.

A decrease in the severity of ascites and the accumulation of ascites fluid compared to the <NUM>-day period prior to treatment. This method is also expected to reduce the number of paracentesis procedures required to remove ascitic fluid over a <NUM>-day period, compared to the <NUM>-day period prior to treatment inception, and some patients may avoid paracentesis altogether. Additionally, the average amount of fluid withdrawn after beginning oral terlipressin therapy is expected to be significantly less than prior to the start of treatment.

Improvement in patient health status (achieved safely with no serious side effects) compared to the <NUM>-day period prior to treatment inception.

The purpose of this clinical trial is to study the efficacy of beta blocker (e.g., propranolol) versus oral terlipressin in the prevention of esophageal variceal re-bleeding and improvement in survival.

Patients that have had an episode of esophageal bleeding are randomized to receive beta blocker (e.g., propranolol) or oral terlipressin.

The beta blocker propanol is administered as known in the art e.g., propranolol is started at a dose of <NUM> twice daily. The principle of incremental dosing is used to achieve the target heart rate for propranolol. The dose is increased every alternate day to achieve a target heart rate of <NUM>/min or to the maximal dose to <NUM>/day if the medication was well tolerated and the systolic blood pressure was ><NUM> Hg. On the occurrence of intolerable adverse effects, systolic blood pressure <<NUM> Hg or pulse rate <<NUM>/min, the dose of the medication is decreased step-wise, and eventually stopped if these adverse events persist.

The terlipressin is administered orally at the dosage of one to four capsules (<NUM> each) per day, preferably one hour before a meal or two hours after a meal.

Re-bleeding from esophageal varices or death [Time Frame: One year].

Increase or decrease in the size of esophageal varices, appearance of new esophageal varices and appearance or worsening of portal hypertensive gastropathy and complications.

Patients with post-prandial hypotension are randomly assigned to two groups - one to be treated with oral terlipressin (for example up to <NUM>, administered to a fasting patient one hour prior to a Meal Test) and the other to be treated with placebo; a third group can comprise patients receiving standard of care.

Tests administered before and after a standard meal in all groups:.

Heart rate is measured continuously one hour prior to and during the Meal Tests. Each Meal Test takes approximately <NUM> hours.

Blood pressure is measured continuously during each of the Meal Tests (approximately <NUM> hours).

Middle cerebral artery velocity is measured continuously e.g., by transcranial doppler one hour prior to and during the Meal Tests (approximately <NUM> hours).

Serum glucose is measured one hour prior to and every <NUM> minutes during Meal Tests.

Serum insulin levels are collected every <NUM> minutes during the Meal Tests (approximately <NUM> hours).

Serum peptides are collected every <NUM> minutes for the duration of the Meal Tests (approximately <NUM> hours).

Catecholamine levels are collected continuously during the Meal Tests (approximately <NUM> hours).

Blood pressure changes between the pre- and post- prandial measurements and difference (improvement) in those changes between terlipressin and the two other groups.

Claim 1:
Pharmaceutical composition comprising a therapeutically effective amount of terlipressin or a pharmaceutically acceptable salt thereof, for use in treating ascites in a subject, wherein the pharmaceutical composition is configured as a tablet or capsule comprising about <NUM> to about <NUM> of terlipressin or pharmaceutically acceptable salt thereof and is administered orally thereby treating the subject.