Terlipressin compositions and methods of use thereof

Abstract

To provide terlipressin compositions and their methods of use.SOLUTION: Disclosed herein are methods for treating or preventing hypotension (e.g., neurogenic orthostatic hypotension or postprandial hypotension) or portal hypertension (e.g., bleeding esophageal varices associated with portal hypertension) or ascites (e.g., ascites associated with liver cirrhosis), by oral administration to affected subjects of compositions comprising a therapeutically effective amount of terlipressin or a pharmaceutically acceptable salt thereof. In some embodiments, terlipressin exhibits improved bioavailability (BA) in a composition or oral dosage form described herein relative to terlipressin configured in another formulation or dosage form.SELECTED DRAWING: None

Description

[Technical field]

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 410,971, filed October 21, 2016, and U.S. Provisional Patent Application No. 62 / 472,291, filed March 16, 2017, each of which is incorporated by reference in its entirety herein.

[0002] The present invention generally relates to compositions and methods 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 cirrhosis of the liver) comprising orally administering a pharmaceutical composition of terlipressin. [Background technology]

[0003] background Technologies that allow efficient transfer of target substances across biological barriers are of great interest in the fields of biotechnology and medicine. For example, such technologies can be used for transport of a variety of different substances across biological barriers controlled by tight junctions, i.e., mucosal epithelia (including intestinal and respiratory epithelia) and vascular endothelia (including the blood-brain barrier, nasal membranes, cornea and other ocular membranes, and urogenital membranes). In particular, there is great interest in oral delivery of therapeutic agents to avoid the use of more invasive means of administration, thus improving patient convenience and compliance.

[0004] Terlipressin is an analog of vasopressin and has been used intravenously, for example, for the treatment of esophageal varices, septic shock, hepatorenal syndrome, and in the management of hypotension. There is a need for efficient, specific, non-invasive, low-risk means of non-invasively delivering therapeutic agents such as terlipressin. Summary of the Invention

[0005] overview Described herein are certain oral compositions comprising terlipressin, oral dosage forms comprising terlipressin, and related methods of use, for example, to treat neurogenic orthostatic hypotension, portal hypertension (e.g., bleeding esophageal varices associated with portal hypertension), or ascites (e.g., ascites associated with cirrhosis of the liver).

[0006] In some embodiments, terlipressin in the compositions or oral dosage forms described herein has improved bioavailability (BA) compared to terlipressin comprised in another formulation or dosage form. In particular, terlipressin in the compositions or oral dosage forms described herein has improved oral bioavailability, for example, compared to compositions that are substantially free of the medium chain fatty acid salt component described herein or have a lower medium chain fatty acid salt component described herein. Such improvement in relative BA (e.g., oral BA) can be at least about 1.5-fold, 2-fold, 3-fold, 5-fold, 10-fold, or 20-fold. In some embodiments, oral terlipressin has a BA of at least 1% or 2% or more.

[0007] In some embodiments, the methods described herein provide a subject with a concentration of terlipressin of about 1 to about 1000 μg / mL. In some embodiments, the methods described herein provide a subject with a concentration of terlipressin (e.g., in the subject's plasma) of about 10 to about 600 μg / mL. In some embodiments, the methods described herein provide a subject with a concentration of terlipressin of about 20 to about 200 μg / mL. In some embodiments, the methods described herein provide a subject with a concentration of terlipressin of about 60 μg / mL.

[0008] In some embodiments, the methods described herein provide a subject with (lysine-)vasopressin at a concentration of about 1 to about 200 μg / mL. (Vasopressin is the active metabolite of terlipressin.) In some embodiments, the methods described herein provide a subject with vasopressin at a concentration of about 2 to about 100 μg / mL (e.g., in the subject's plasma). In some embodiments, the methods described herein provide a subject with vasopressin at a concentration of about 3 to about 30 μg / mL. In some embodiments, the methods described herein provide a subject with vasopressin at a concentration of about 10 μg / mL.

[0009] In one embodiment, a method of treating a subject suffering from hypotension (e.g., neurogenic orthostatic hypotension or postprandial hypotension) is provided, comprising orally administering a pharmaceutical composition (e.g., a solid dosage composition, oral dosage form) configured as a tablet or capsule containing a therapeutically effective amount (e.g., at least 5 mg (e.g., 5, 7, 10, 15, 17, 20, 25, 30 mg)) of terlipressin or a pharma- ceutically acceptable salt thereof one, two, three, or four times daily, thereby treating the subject.

[0010] In some embodiments, the tablet or capsule is administered once or twice daily. In some embodiments, the tablet or capsule is administered twice daily. In some embodiments, the tablet or capsule is administered four times daily. In some embodiments, the tablet or capsule is administered three times daily. In some embodiments, the tablet or capsule contains 5-30 mg of terlipressin. In some embodiments, the tablet or capsule contains about 10 to about 30 mg of terlipressin (e.g., about 15 to about 25 mg, about 18 to about 22 mg of terlipressin). In some embodiments, the tablet or capsule contains at least 5 mg (e.g., 5, 7, 10, 15, 17, 20, 25, 30 mg).

[0011] In some embodiments, the tablet or capsule contains 20 mg of terlipressin.

[0012] In some embodiments, the subject is administered 5-100 mg of terlipressin per day (e.g., 20-100 mg of terlipressin per day, 40-100 mg of terlipressin per day, 60-100 mg of terlipressin per day, e.g., 80 mg of terlipressin per day).

[0013] In some embodiments, multiple tablets or capsules are administered two times per day. In some embodiments, multiple tablets or capsules are administered three times per day.

[0014] In some embodiments, the subject is administered at least 10, 20, 30, 40, 50, 60 mg of terlipressin per day.

[0015] In some embodiments, the methods result in reduced side effects as compared to methods of administering terlipressin by other modes of administration (eg, intravenous administration).

[0016] In some embodiments, the methods provide better patient compliance (e.g., compliance by subjects as described herein) as compared to methods of administering terlipressin by other modes of administration (e.g., intravenous administration).

[0017] In one embodiment, a method of treating a subject suffering from portal hypertension (e.g., bleeding esophageal varices associated with portal hypertension) is provided comprising orally administering a pharmaceutical composition (e.g., a solid dosage composition, oral dosage form) configured as a tablet or capsule containing a therapeutically effective amount (e.g., at least 5 mg (e.g., 5, 7, 10, 15, 17, 20, 25, 30 mg)) of terlipressin or a pharma- ceutically acceptable salt thereof one, two, three, or four times daily, thereby treating the subject.

[0018] In some embodiments, the tablets or capsules are administered 1-4 times per day. In some embodiments, the tablets or capsules are administered 1 or 2 times per day. In some embodiments, the tablets or capsules are administered 2 times per day. In some embodiments, the tablets or capsules are administered 4 times per day. In some embodiments, the tablets or capsules are administered 3 times per day.

[0019] In some embodiments, the tablet or capsule contains 5-30 mg of terlipressin. In some embodiments, the tablet or capsule contains 10-30 mg of terlipressin. In some embodiments, the tablet or capsule contains 15-25 mg of terlipressin. In some embodiments, the tablet or capsule contains 18-22 mg of terlipressin. In some embodiments, the tablet or capsule contains 20 mg of terlipressin.

[0020] In some embodiments, the subject is administered 5-100 mg of terlipressin per day (e.g., 20-100 mg of terlipressin per day, 40-100 mg of terlipressin per day, 60-100 mg of terlipressin per day, e.g., 80 mg of terlipressin).

[0021] In some embodiments, multiple tablets or capsules are administered two times per day. In some embodiments, multiple tablets or capsules are administered three times per day.

[0022] In some embodiments, the subject is administered at least 10, 20, 30, 40, 50, 60 mg of terlipressin per day.

[0023] In some embodiments, the methods result in reduced side effects as compared to methods of administering terlipressin by other modes of administration (eg, intravenous administration).

[0024] In some embodiments, the methods provide better patient compliance (e.g., compliance by subjects as described herein) as compared to methods of administering terlipressin by other modes of administration (e.g., intravenous administration).

[0025] In one embodiment, a method of treating a subject suffering from ascites (e.g., associated with cirrhosis of the liver) is provided comprising orally administering a pharmaceutical composition (e.g., a solid dosage composition, oral dosage form) configured as a tablet or capsule containing a therapeutically effective amount (e.g., at least 5 mg (e.g., 5, 7, 10, 15, 17, 20, 25, 30 mg)) of terlipressin or a pharma- ceutically acceptable salt thereof one, two, three, or four times daily, thereby treating the subject.

[0026] In some embodiments, the tablets or capsules are administered 1-4 times per day. In some embodiments, the tablets or capsules are administered 1 or 2 times per day. In some embodiments, the tablets or capsules are administered 2 times per day. In some embodiments, the tablets or capsules are administered 4 times per day. In some embodiments, the tablets or capsules are administered 3 times per day.

[0027] In some embodiments, the tablet or capsule contains 5-30 mg of terlipressin. In some embodiments, the tablet or capsule contains 10-30 mg of terlipressin. In some embodiments, the tablet or capsule contains 15-25 mg of terlipressin. In some embodiments, the tablet or capsule contains 18-22 mg of terlipressin. In some embodiments, the tablet or capsule contains 20 mg of terlipressin.

[0028] In some embodiments, the subject is administered 5-100 mg of terlipressin per day (e.g., 20-100 mg of terlipressin per day, 40-100 mg of terlipressin per day, 60-100 mg of terlipressin per day, e.g., 80 mg of terlipressin).

[0029] In some embodiments, multiple tablets or capsules are administered once or twice daily, hi some embodiments, multiple tablets or capsules are administered three times daily.

[0030] In some embodiments, the subject is administered at least 10, 20, 30, 40, 50, 60 mg of terlipressin per day.

[0031] In some embodiments, the methods result in reduced side effects as compared to methods of administering terlipressin by other modes of administration (eg, intravenous administration).

[0032] In some embodiments, the methods provide better patient compliance (e.g., compliance by subjects as described herein) as compared to methods of administering terlipressin by other modes of administration (e.g., intravenous administration).

[0033] In one embodiment, a unit dosage formulation for oral administration (oral dosage form) is provided that comprises a therapeutically effective amount of terlipressin, or a pharma- ceutically acceptable salt of terlipressin (e.g., at least 5 mg (e.g., 5, 7, 10, 15, 17, 20, 25, 30 mg), or a pharma- ceutically acceptable salt thereof).

[0034] In some embodiments, the oral dosage formulation (ie, oral dosage form) comprises about 5, 10, 15, 20, 25, 30, or 50 mg of terlipressin.

[0035] In some embodiments, the oral dosage form contains 5-50 mg (e.g., 5-40 mg, 5-30 mg, 5-25 mg, 15-25 mg, 18-22 mg) of terlipressin. In some embodiments, the formulation contains at least 5 mg of terlipressin.

[0036] In some embodiments, the oral dosage form is enterically coated.

[0037] In some embodiments, the oral dosage formulations (i.e., oral dosage forms) described herein are used for the treatment of subjects suffering from hypotension (e.g., neurogenic orthostatic hypotension or postprandial hypotension) or portal hypertension or ascites.

[0038] In one embodiment, an oral dosage formulation (i.e., oral dosage form) is provided that includes a therapeutically effective amount of terlipressin, or a pharma- ceutically acceptable salt of terlipressin (e.g., at least 5 mg (e.g., 5, 7, 10, 15, 17, 20, 25, 30 mg)), or a pharma- ceutically acceptable salt thereof).

[0039] In some embodiments, the oral dosage formulation (ie, oral dosage form) comprises about 5, 10, 15, 20, 25, 30, or 50 mg of terlipressin.

[0040] In some embodiments, the oral dosage formulation (i.e., oral dosage form) contains 5-50 mg (e.g., 5-40 mg, 5-30 mg, 5-25 mg, 15-25 mg, 18-22 mg) of terlipressin. In some embodiments, the dosage form contains at least 5 mg of terlipressin.

[0041] In some embodiments, the oral dosage formulation (ie, oral dosage form) is further enterically coated.

[0042] In one embodiment, a capsule is provided containing a composition comprising a therapeutically effective amount of terlipressin, or a pharma- ceutically acceptable salt of terlipressin (e.g., at least 5 mg (e.g., 5, 7, 10, 15, 17, 20, 25, 30 mg)), or a pharma- ceutically acceptable salt thereof).

[0043] In some embodiments, the capsule is a hard gel capsule or a soft gel capsule.

[0044] In some embodiments, the oral dosage formulation (i.e., oral dosage form) contains about 5, 10, 15, 20, 25, 30, or 50 mg of terlipressin. In some embodiments, the capsule contains 5-50 mg (e.g., 5-40 mg, 5-30 mg, 5-25 mg, 15-25 mg, 18-22 mg) of terlipressin. In some embodiments, the capsule contains at least 5 mg of terlipressin. In some embodiments, the capsule is enteric coated.

[0045] In one embodiment, a tablet is provided that includes a therapeutically effective amount of terlipressin, or a pharma- ceutically acceptable salt of terlipressin (e.g., at least 5 mg (e.g., 5, 7, 10, 15, 17, 20, 25, 30 mg)), or a pharma- ceutically acceptable salt thereof).

[0046] In one embodiment, a kit is provided that includes instructions and a dosage form described herein.

[0047] In one embodiment, a method of treating a subject suffering from neurogenic orthostatic or postprandial hypotension is provided, comprising administering to said subject a therapeutically effective amount of oral terlipressin in combination with a therapeutically effective amount of fludrocortisone.

[0048] In one embodiment, a method of treating a subject suffering from neurogenic orthostatic or postprandial hypotension is provided, comprising administering to said subject a therapeutically effective amount of oral terlipressin in combination with a therapeutically effective amount of fludrocortisone, optionally in combination with a large volume of water, which can be about 100, 200, 300, 400, or 500 ml or more of water.

[0049] In one embodiment, a unit dosage formulation for oral administration (oral dosage form) is provided that comprises a therapeutically effective amount of terlipressin in combination with a therapeutically effective amount of fludrocortisone.

[0050] In one embodiment, a method of treating a subject suffering from portal hypertension / bleeding esophageal varices is provided, comprising administering to said subject a therapeutically effective amount of oral terlipressin in combination with a therapeutically effective amount of a liver fibrosis agent.

[0051] In one embodiment, a unit dosage formulation for oral administration (oral dosage form) is provided that includes a therapeutically effective amount of terlipressin in combination with a therapeutically effective amount of a liver fibrosis agent.

[0052] In one embodiment, a method of treating a subject suffering from ascites is provided, comprising administering to said subject a therapeutically effective amount of oral terlipressin in combination with a therapeutically effective amount of a diuretic.

[0053] In one embodiment, a unit dosage formulation for oral administration (oral dosage form) is provided that includes a therapeutically effective amount of terlipressin in combination with a therapeutically effective amount of a diuretic.

[0054] In one embodiment, a method of treating a subject suffering from ascites is provided, comprising administering to said subject a therapeutically effective amount of oral terlipressin in combination with a therapeutically effective amount of albumin.

[0055] In one embodiment, a method of treating a subject suffering from ascites is provided, comprising administering to said subject a therapeutically effective amount of oral terlipressin in combination with a therapeutically effective amount of a beta-blocker.

[0056] In one embodiment, a unit dosage formulation for oral administration (oral dosage form) is provided that includes a therapeutically effective amount of terlipressin in combination with a therapeutically effective amount of a beta-blocker.

[0057] In some aspects, the compositions described herein improve the absorption of terlipressin into the gastrointestinal (GI) tract, where terlipressin is present in a composition or dosage form that is otherwise generally characterized by low or no oral bioavailability and / or absorption (e.g., low or no bioavailability in aqueous solutions and other oral formulations known in the art). In at least one aspect, the compositions described herein improve bioavailability by enhancing the permeability of terlipressin to the GI wall / barrier. For example, the compositions described herein can facilitate absorption primarily by penetrating the GI wall / barrier by breaking tight junctions between GI epithelial cells, although the compositions can also act by transcellular absorption. In some embodiments, the BA of terlipressin is at least 0.5%, at least 1%, at least 2%, or at least 3% or more.

[0058] Described herein is a process for producing a pharmaceutical composition (bulk drug product) that includes preparing an aqueous composition that includes a therapeutically effective amount of terlipressin and medium chain fatty acid salts (and other ingredients - see below), drying the aqueous composition (e.g., by lyophilization) to obtain a solid powder, and suspending the lyophilized material (solid powder) in a hydrophobic (oily) medium, preferably castor oil or glyceryl tricaprylate (including other ingredients (e.g., PVP polymer and surfactants and viscosity modifiers - see below)) to produce a suspension that includes terlipressin and medium chain fatty acid salts in solid form, thereby producing a bulk drug product that includes at least 10% by weight of medium chain fatty acid salts (e.g., at least 11%, at least 12%, or more). The solid form may include particles (e.g., consist essentially of particles or consist of particles). The particles may be produced by lyophilization, spray drying, or granulation. The bulk pharmaceutical agent can then be encapsulated in a capsule, which can be coated with a pH-sensitive coating (eg, an enteric coating) and used for oral delivery.

[0059] Thus, in one aspect, the invention features a composition. The composition includes terlipressin and a medium chain fatty acid salt in association with a substantially hydrophobic medium (e.g., castor oil), where the terlipressin and medium chain fatty acid salt are in a solid form (e.g., the same solid form (such as particles)) obtained by drying from an aqueous medium (e.g., lyophilization of the aqueous medium), where the medium chain fatty acid salt is present at 10% or more by weight, preferably 12-15% by weight (e.g., about 12%, about 13%, about 14%, or about 15% by weight or about 16%, or about 17% by weight). In some embodiments, the composition includes other ingredients (described herein).

[0060] The compositions of the present invention are not emulsions, hi embodiments, the compositions are oil suspensions and the amount of water in the composition is very low (e.g., less than 1%, less than 0.5%, less than 0.1%).

[0061] In the compositions of the present invention, the terlipressin and medium chain fatty acid salt are in intimate contact with a substantially hydrophobic medium, e.g., a powder containing terlipressin and a medium chain fatty acid salt is coated, immersed, or suspended in the substantially hydrophobic medium.

[0062] During the production process, the aqueous medium containing the terlipressin and medium chain fatty acid salt and other components is dried (e.g., by lyophilization) to obtain a hydrophobic fraction that is a powder (e.g., a solid form containing a plurality of particles), the particles in the powder containing all the components (i.e., both the terlipressin and the medium chain fatty acid salt are present in a single particle). The solid form can be, for example, a granulated particle or a lyophilized particle.

[0063] In some embodiments, the composition comprises a plurality of medium chain fatty acid salts and derivatives thereof. For example, the solid particles may further comprise a plurality of medium chain fatty acid salts and derivatives thereof.

[0064] In some embodiments, the medium chain fatty acid salt is 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 mixtures thereof. According to one or more embodiments, the composition is substantially free of sodium dodecanoate, sodium tridecanoate, and sodium tetradecanoate. In some embodiments, the medium chain fatty acid is sodium octanoate, and the sodium octanoate is present at a concentration of greater than 10% (e.g., about 11% to about 50% weight / weight (wt / wt)). In other embodiments, the medium chain fatty acid is sodium decanoate. In some embodiments, the sodium decanoate is present at a concentration of greater than 10% (e.g., about 11% to about 50% weight / weight (wt / wt)).

[0065] In some embodiments, the substantially hydrophobic medium comprises a triglyceride. For example, the triglyceride can be selected from the group consisting of glyceryl tributyrate, glyceryl monooleate, glyceryl monocaprylate, and glyceryl tricaprylate.

[0066] In some embodiments, the substantially hydrophobic medium comprises mineral oil, castor oil, olive oil, corn oil, coconut oil, peanut oil, soybean oil, cottonseed oil, sesame oil, or rapeseed oil, or a combination thereof.

[0067] In some embodiments, the water-soluble composition comprises a medium chain fatty acid salt and the hydrophobic medium comprises the corresponding medium chain fatty acid; in some particular embodiments, 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.

[0068] In some embodiments, the water soluble composition comprises a medium chain fatty acid salt and the hydrophobic medium comprises a corresponding medium chain monoglyceride or a corresponding medium chain triglyceride or a combination thereof; in some particular embodiments, the medium chain fatty acid salt is sodium octanoate, the monoglyceride is glyceryl monocaprylate, and the triglyceride is glyceryl tricaprylate.

[0069] In some embodiments, the composition further comprises one or more excipients. The excipient can be a salt (e.g., MgCl2) or an amine-containing compound or mannitol. In some embodiments, the excipient is the same solid form as terlipressin.

[0070] In some embodiments, the composition further comprises one or more surfactants. For example, the surfactant can be selected from the group consisting of sorbitan monopalmitate (Span-40®), polyoxyethylene sorbitan monooleate (Tween 80), lecithin, and glyceryl monooleate (GMO). In one or more embodiments, the surfactant comprises about 0.1% to about 6% by weight of the composition.

[0071] In a preferred embodiment, the composition is in an oral dosage form. For example, the composition can be filled into a hard or soft capsule.

[0072] The pharmaceutical compositions described herein incorporate terlipressin as a therapeutic agent in an enteric coated oral dosage form. The oral dosage form of the present invention includes additives or excipients suitable for preparing the oral dosage form of the present invention. The oral dosage form may preferably include a capsule or capsule that is enteric coated.

[0073] In some embodiments, the bioavailability of terlipressin, when administered to a subject, is at least 0.5% to 2% compared to parenteral (subcutaneous or intravenous) administration. In some embodiments, the composition, when administered to a subject, provides greater than 0.5%, greater than 1%, greater than 2%, greater than 3%, greater than 5%, greater than 10%, or greater than 20% or greater than 30% absorption of terlipressin across a biological barrier. The level of absorption achieved is the therapeutic level required for the applicable indication.

[0074] The formulation of the present invention allows terlipressin to be incorporated into the formulation without causing any chemical modification or degradation of terlipressin. Furthermore, the formulation of the present invention allows terlipressin to be loaded with high flexibility. Finally, the formulation of the present invention protects the cargo compound from inactivation in the GI environment due to, for example, protein degradation and oxidation.

[0075] In some embodiments, the method may include the step of encapsulating the suspension to form a capsule. The method may further include the step of coating the capsule, for example with an enteric coating.

[0076] In some embodiments, the method may include preparing instructions for administering the capsule to a subject. The instructions may relate to administering the capsule to a subject for any indication described herein. In one aspect, the invention features a capsule provided with instructions for administering the capsule to a subject for any indication described herein.

[0077] Further and other aspects, embodiments, and advantages of these exemplary aspects and embodiments are discussed in detail below. Moreover, it should be understood that both the preceding information and the following detailed description are merely exemplary of the various aspects and embodiments and are intended to provide an overview or framework for understanding the nature and characteristics of the claimed aspects and embodiments.

[0078] The accompanying drawings are included to illustrate and provide a further understanding of various aspects and embodiments, and are incorporated in and constitute a part of this specification, and together with the remainder of the specification, serve to explain the principles and operation of the described and claimed aspects and embodiments.

[0079] Throughout this application, various publications, including U.S. patents, are referenced by author and year, and patents and applications are referenced by number. The disclosures of these publications and patents and patent applications in their entireties are incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. In an embodiment of the present invention, for example, the following items are provided: (Item 1) 1. A method of treating a subject suffering from a condition selected from hypotension (e.g., orthostatic hypotension, postprandial hypotension), portal hypertension (e.g., bleeding esophageal varices associated with portal hypertension), and ascites (e.g., ascites associated with cirrhosis of the liver), comprising orally administering a pharmaceutical composition constituted as a tablet or capsule containing a therapeutically effective amount of terlipressin or a pharma- ceutical acceptable salt thereof, thereby treating the subject, wherein if the condition is portal hypertension (e.g., bleeding esophageal varices associated with portal hypertension), the tablet or capsule contains 5-30 mg of terlipressin and is administered 1-4 times daily. (Item 2) 2. The method of claim 1, wherein the tablet or capsule is administered 1, 2, 3 or 4 times daily. (Item 3) The method according to claim 1, wherein the tablet or capsule is administered 1, 2, or 3 times a day. 2. The method of claim 1, wherein the tablet or capsule is administered twice a day. (Item 5) 2. The method of claim 1, wherein multiple tablets or capsules are administered twice daily. (Item 6) 2. The method of claim 1, wherein the tablet or capsule is administered three times a day. (Item 7) 2. The method of claim 1, wherein multiple tablets or capsules are administered three times a day. (Item 8) 8. The method of any one of items 1 to 7, wherein the tablet or capsule contains 5 to 30 mg (e.g., at least 5 mg (e.g., 5, 7, 10, 15, 17, 20, 25, 30 mg)) of terlipressin or a pharma- ceutically acceptable salt thereof. (Item 9) 8. The method according to any one of items 1 to 7, wherein the tablet or capsule contains about 10 to about 30 mg of terlipressin (e.g., about 15 to about 25 mg, about 18 to about 22 mg of terlipressin) or a pharma- ceutically acceptable salt thereof. (Item 10) 8. The method according to any one of items 1 to 7, wherein the tablet or capsule contains 15 to 25 mg of terlipressin. (Item 11) 8. The method according to any one of items 1 to 7, wherein the tablet or capsule contains 18 to 22 mg of terlipressin. (Item 12) 8. The method according to any one of items 1 to 7, wherein the tablet or capsule contains 20 mg of terlipressin. (Item 13) 13. The method of any one of items 1 to 12, wherein the subject is administered 5 to 100 mg of terlipressin per day (e.g., 20 to 100 mg of terlipressin per day, 40 to 100 mg of terlipressin per day, 60 to 100 mg of terlipressin per day, e.g., 80 mg of terlipressin per day). (Item 14) 14. The method of any one of items 1 to 13, wherein the subject is administered at least 10, 20, 30, 40, 50, 60 mg of terlipressin per day. (Item 15) 15. The method according to any one of items 1 to 14, wherein the terlipressin is administered for about 1 day to about 12 months. (Item 16) 16. The method according to any one of items 1 to 15, wherein the dose of terlipressin is gradually increased over a period of about 1 day to about 12 months. (Item 17) 17. The method according to any one of items 1 to 16, which has reduced side effects as compared to a method of administering terlipressin by another administration form (e.g., intravenous administration). (Item 18) The method of any one of items 1 to 16, which provides better patient compliance (e.g., compliance by a subject as described herein) compared to methods of administering terlipressin by other modes of administration (e.g., intravenous administration). (Item 19) 19. The method according to any one of items 1 to 18, wherein the condition is hypotension. (Item 20) 20. The method of claim 19, wherein the hypotension is neurogenic orthostatic hypotension. (Item 21) 20. The method of claim 19, wherein the hypotension is postprandial hypotension. (Item 22) 19. The method according to any one of items 1 to 18, wherein the condition is portal hypertension (e.g., bleeding esophageal varices associated with portal hypertension). (Item 23) 19. The method according to any one of items 1 to 18, wherein the condition is ascites (eg, ascites associated with cirrhosis of the liver). (Item 24) 21. The method of claim 20, wherein oral terlipressin is administered in combination with a therapeutically effective amount of fludrocortisone. (Item 25) The method of item 20, wherein oral terlipressin is administered in combination with a therapeutically effective amount of fludrocortisone and / or midodrine, and / or pyridostigmine and / or droxidopa and / or erythropoietin and / or Northera and / or TD-9855, optionally in combination with large amounts of water. (Item 26) The method according to claim 21, wherein oral terlipressin is administered in combination with a therapeutically effective amount of at least one of guar gum, acavalose, or midodrine and / or northera and / or TD-9855, optionally in combination with large amounts of water. 23. The method of claim 22, wherein the terlipressin is administered in combination with a therapeutically effective amount of at least one liver fibrosis agent and / or at least one beta-blocker. (Item 28) 24. The method of claim 23, wherein treating the subject suffering from ascites comprises reducing the volume of ascites before, during, or after a paracentesis procedure. (Item 29) 24. The method of claim 23, wherein the treatment of the subject suffering from ascites comprises improving renal function in the subject. (Item 30) 30. The method of claim 29, wherein the improvement comprises a decrease in serum creatinine concentration. (Item 31) 30. The method of claim 29, wherein the improvement comprises an increase in plasma sodium concentration. (Item 32) 30. The method of claim 29, wherein the improvement comprises increased urinary sodium excretion. (Item 33) 30. The method of claim 29, wherein the improvement comprises a decrease in serum urea concentration. (Item 34) 24. The method of claim 23, wherein treating the subject suffering from ascites comprises correcting hyponatremia in the subject. (Item 35) 35. The method according to any one of items 23 and 28 to 34, wherein the subject's condition has not progressed to hepatorenal syndrome (HRS). (Item 36) 36. The method of any one of items 23 and 28-35, wherein the administration is performed on an outpatient basis. (Item 37) 37. The method of any one of items 23 and 28-36, wherein the terlipressin is administered in combination with a diuretic. (Item 38) 38. The method of any one of items 23 and 28-37, wherein the terlipressin is administered in combination with albumin. (Item 39) 39. The method of any one of items 23 and 28-38, wherein the terlipressin is administered in combination with a beta-blocker. (Item 40) 40. The method of any one of items 23 and 28-39, wherein the terlipressin is administered in combination with a vasopressin V2-receptor antagonist (vaptan). (Item 41) An oral dosage form comprising a therapeutically effective amount of terlipressin, or a pharma- ceutically acceptable salt of terlipressin (eg, at least 5 mg (eg, 5, 7, 10, 15, 17, 20, 25, 30 mg)), or a pharma- ceutically acceptable salt of terlipressin. (Item 42) 42. The oral dosage form of claim 41, wherein the form contains about 5, 10, 15, 20, 25, 30, or 50 mg of terlipressin. (Item 43) 42. The oral dosage form according to item 41, wherein the form contains 5-50 mg (e.g., 5-40 mg, 5-30 mg, 5-25 mg, 15-25 mg, 18-22 mg) of terlipressin. (Item 44) 42. The oral dosage form according to item 41, wherein the form contains at least 5 mg of terlipressin. (Item 45) The oral dosage form according to any one of items 41 to 44, which is enteric coated. (Item 46) 45. The oral dosage form according to any one of items 41 to 44, which is a capsule. (Item 47) 47. The capsule according to item 46, which is enteric coated. (Item 48) 48. The capsule according to item 46 or 47, which is a hard gel capsule or a soft gel capsule. (Item 49) 45. The oral dosage form according to any one of items 41 to 44, which is a tablet. (Item 50) 50. The tablet according to item 49, which is enteric coated. (Item 51) 51. The oral dosage form according to any one of items 41 to 50, further comprising a therapeutically effective amount of fludrocortisone and / or midodrine, and / or pyridostigmine and / or droxidopa and / or erythropoietin and / or Norsera and / or TD-9855. (Item 52) 51. The oral dosage form according to any one of items 41 to 50, further comprising a therapeutically effective amount of at least one of guar gum or acabarose or midodrine and / or norcera and / or TD-9855. (Item 53) 51. The oral dosage form according to any one of items 41 to 50, further comprising a therapeutically effective amount of at least one liver fibrosis agent and / or at least one beta-blocker. (Item 54) 51. The oral dosage form according to any one of items 41 to 50, further comprising a therapeutically effective amount of at least one diuretic. (Item 55) 51. The oral dosage form according to any one of items 41 to 50, further comprising a therapeutically effective amount of at least one beta-blocker. (Item 56) 51. The oral dosage form according to any one of items 41 to 50, further comprising a therapeutically effective amount of at least one vasopressin V2-receptor antagonist (vaptan). (Item 57) 53. The oral dosage form according to any one of items 41 to 52, for treating a subject suffering from hypotension (e.g., neurogenic orthostatic hypotension or postprandial hypotension). (Item 58) 54. The oral dosage form according to any one of items 41 to 50 and 53 for treating a subject suffering from portal hypertension and / or variceal bleeding. (Item 59) 57. The oral dosage form according to any one of items 41 to 50 and 54 to 56, for treating a subject suffering from ascites. (Item 60) A kit comprising instructions and a dosage form according to any one of items 41 to 59. [Brief description of the drawings]

[0080] Various aspects of at least one embodiment are discussed below with reference to the accompanying drawings, which are provided for purposes of illustration and description and are not intended to be a definition of the limits of the invention.

[0081] [Figure 1A] FIG. 1A shows the pharmacokinetics of terlipressin administered intravenously to dogs at a dose of 0.2 mg.

[0082] [Figure 1B] FIG. 1B shows the pharmacokinetics of terlipressin administered orally via capsule to dogs at a dosage of 20 mg. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0083] Detailed Description Provided herein is a method of 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, comprising administering a therapeutically effective amount (e.g., at least 5 mg (e.g., 5, 7, 10, 15, 17, 20, 25, 30 mg)) of terlipressin one, two, three, or four times daily, thereby treating the subject.

[0084] Hypotension: Neurogenic orthostatic hypotension Neurogenic orthostatic hypotension (nOH) is a subtype of orthostatic hypotension that occurs in humans with pre-existing neurological disorders (e.g., chronic or irreversible neurological conditions). In some embodiments, the neurological disorder is Parkinson's disease or multiple system atrophy (MSA) or pure autonomic failure. Orthostatic (postural) hypotension refers to a drop in systolic blood pressure (e.g., at least 20 mmHg) or a drop in diastolic blood pressure (e.g., at least 10 mmHg) during the first 3 minutes of standing up. Neurogenic orthostatic hypotension may be due to a malfunction of the autonomic nervous system, the part of the nervous system that regulates involuntary physical activity (e.g., maintaining normal blood pressure). Symptoms include dizziness, drowsiness, fainting (loss of consciousness), fatigue, blurred vision, weakness, difficulty concentrating, and pain in the head and neck. Outcomes include injury (dental damage, fractures, etc.) as a result of the fall, and even death. Current pharmacological treatments include fludrocortisone and / or midodrine, and / or pyridostigmine and / or droxidopa and / or erythropoietin; Lanier et al. (2011) American Family Physician, 84(5), 527-536; and Editorial (1998) J. Neurol. Neurosurg Psychiatry 65:285-289. Drugs in development include Northera - a norepinephrine prodrug - (2014 - Lundbeck / Chelsea) and TD-9855 - a norepinephrine and serotonin reuptake inhibitor - (P1 / 2 - Theravance).

[0085] Intravenous injection of terlipressin has been shown to be effective in nOH at levels of 5-10 μg / kilogram body weight (Rittig et al. (1991) Movement Disorders 6(1), p21-28); however, this method of administration is clearly not suitable for use as a home treatment. The oral terlipressin dosage forms of the present invention can be administered as a home treatment and can be used, inter alia, for the prevention and treatment of orthostatic hypotension.

[0086] Postprandial hypotension Postprandial hypotension is generally defined as a decrease in systolic blood pressure of 20 mmHg or more within 2 hours after ingestion of a meal. Postprandial hypotension is very common in elderly patients, especially those living in long-term residential care. Patients with postprandial hypotension may experience symptomatic hypotension, syncope (loss of consciousness), and falls. See Lisk, R. (April 2010) Postprandial hypotension in www.gerimed.co.uk, Cardiology 203-206; Lubart et al. (Sept 2006) Journal of the American Geriatrics Society, Vol. 54, Issue 9, pages 1377-1381, Postprandial Hypotension in Long-Term Care Elderly Patients on Enteral Feeding; and Trahair et al. (et el) (2014) JAMDA 15, 394-409, Postprandial Hypotension: A Systematic Review. Hormonal treatment using intravenous vasopressin (see Hakusui et al. (1991) Neurology 41(5), 712-715) is known to be effective, but this treatment is unsuitable for home use.

[0087] The oral terlipressin dosage forms of the present invention can be administered as a home therapy and can be used, inter alia, for the prevention and treatment of postprandial hypotension.

[0088] Portal hypertension / bleeding esophageal varices 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 liver tissue due to liver disease); as a result, veins (varices) in the lower esophagus most commonly rupture and bleed. Esophageal varices are thus a direct result of high blood pressure in the portal vein. Symptoms include vomiting and significant visible hematemesis; stomach pain; black, tarry, or bloody stools; drowsiness; loss of consciousness; signs of liver disease (e.g., yellow discoloration of the skin and eyes; easy bleeding or purpura; fluid accumulation in the abdomen). Esophageal varices are the most common varices resulting from portal hypertension, but varices can also occur in the stomach, rectum, or umbilical region.

[0089] In patients who survive a first episode of esophageal variceal bleeding, the risk of recurrent bleeding is as high as 60%, with a mortality rate of up to 33%. Terlipressin is effective in controlling variceal bleeding, but is currently administered intravenously and is therefore not convenient for prophylaxis; see Biecker (2013) Hindawi Publishing Corp, ISRN Hepatology (2013), Article ID 541836 (20 pp). In some embodiments, the subject suffers from cirrhosis (i.e., the subject has severe scarring of the liver as a result of, for example, excessive alcohol consumption or severe infection (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 (a frequent complication of cirrhosis). In some embodiments, the subject has non-alcoholic fatty liver disease and / or non-alcoholic steatohepatitis (NASH) and / or primary biliary cirrhosis, or a parasitic infection that can damage the liver (schistosomiasis).

[0090] Intravenous vasoconstrictors (e.g., terlipressin) are used to treat acute variceal bleeding, but 60% of patients will rebleed and 20% will die. No medications are approved to prevent (or delay) variceal rebleeding. Beta-blockers are used off-label. An estimated 40,000 secondary prevention patients in the United States are not eligible for beta-blockers. Off-label beta-blockers are also the only long-term drug treatment to prevent (or delay) variceal bleeding.

[0091] β-adrenergic blockers are a class of drugs that bind to β-adrenergic receptors and prevent the binding of norepinephrine and epinephrine at these receptors. This prevents sympathetic stimulation of the heart and reduces heart rate, myocardial contractility, conduction velocity, and relaxation rate, thereby reducing myocardial oxygen demand and increasing exercise tolerance. β-adrenergic blockers are commonly referred to as β-blockers.

[0092] Beta-blockers can be classified into non-selective beta-blockers (which block both beta-1 and beta-2 receptors, such as nadolol, penbutolol, pindolol, propranolol, sotalol, and timolol) and cardioselective beta-blockers (which block only beta-1 receptors, including acebutolol, betaxolol, bisoprolol, esmolol, and metoprolol). Some beta-blockers, such as atenolol, only show cardioselectivity at low dosages. Beta-blockers for variceal bleeding treatment are usually non-selective beta-blockers.

[0093] Currently, there are no approved treatments for nonalcoholic fatty liver disease / nonalcoholic steatohepatitis (NASH); see Filozof (2015) 75:1373-1392 and Cassidy et al. (2016 Nature reviews) 15, 745-746. See also Nusrat et al. (2014) World J Gastroenterol 20(18) 5442-5460 and de Vries et al. (2017) 37(1), 123-129.

[0094] Oral terlipressin therapy of the present invention is suitable as a home therapy and can be used for the prevention and long-term management of varices (eg, esophageal varices) and variceal bleeding.

[0095] ascites Ascites is a frequent and life-threatening complication of diseases such as progressive cirrhosis, heart failure, and cancer (malignant ascites), with an expected mortality rate of 40% within 2 years of diagnosis. To date, the US FDA has not approved any therapeutics to specifically treat ascites, but several drugs (e.g., diuretics) have been used off-label with limited and transient efficacy. The first-line diuretic treatment for cirrhotic ascites is the use of spironolactone (Aldactone), preferably in combination with spironolactone and furosemide (Lasix). Studies have shown efficacy of terlipressin alone and / or in combination with albumin in patients with type 1 hepatorenal syndrome (HRS) when administered as an intravenous (IV) bolus injection every 4 hours or as an intravenous infusion; Angeli (2011) in Gerbes (ed) Ascites, Hyponatremia and Hepatorenal Syndrome: Progress in treatment Front Gastrointest Res.Basel,Karger vol 28,187-189;Annamalai et al. (2016)World J Hepatol 2016 October 8;8(28):1182-1193;ISSN 1948-5182.

[0096] HRS occurs early in renal failure and frequently occurs in patients with ascites that become refractory to diuretic treatment; Krag Hepatology-46(6)1863-1871 DOI:10.1002 / hep.21901. Note that two forms of hepatorenal syndrome are defined: type 1 HRS is associated with a rapid progressive decline in renal function, while type 2 HRS is associated with ascites (abdominal fluid accumulation) that does not improve with standard diuretic drug therapy. Refractory ascites is ascites that cannot be mobilized or whose early recurrence after therapeutic paracentesis cannot be sufficiently prevented by medical treatment. This form of ascites includes two distinct subgroups:

[0097] Diuretic-resistant ascites - ascites in which a sodium-restricted diet and intensive diuretic treatment (spironolactone 400 mg / day and furosemide 160 mg / day for at least 1 week, and a salt-restricted diet of less than 90 mmol / day (5.2 g salt) / day) is ineffective. Diuretic-refractory ascites - Ascites in which treatment is ineffective due to the development of diuretic-induced complications that prevent the use of effective doses of diuretics.

[0098] Refractory ascites is sometimes treated with aquaretics (e.g., vasopressin V2-receptor antagonists, also known as vaptans (e.g., lixivaptan, satavaptan, tolvaptan)), which promote the excretion of electrolyte-free water and thereby may be beneficial in patients with ascites and hyponatremia. See Habib and Boyer (2012) Ther Adv Gastroenterol, 5(3) 189-197. Intravenous treatment of terlipressin, optionally in combination with a diuretic, can reverse refractory ascites in hospitalized patients.

[0099] However, these high-dose IV intermittent injections (typically 1 or 2 mg in a single dose) carry a high risk of side effects. More recent studies with hospitalized HRS patients have shown that continuous infusion of terlipressin can achieve similar efficacy to intermittent injections with a much higher safety profile. Recently, treatment of ascites with continuous infusion of terlipressin in non-hospitalized patients has been reported (see U.S. Patent No. 9,655,945 to Angeli et al.). However, this treatment is still an invasive procedure with risks (such as infection) and is inconvenient. In addition, these patients are at risk for systemic hypotension, and intravenous administration of terlipressin may increase this risk because of its short Tmax. The oral terlipressin treatment for ascites described herein is suitable for outpatient administration and may be better tolerated with respect to hypotension risk because of the longer terlipressin Tmax.

[0100] Treatment One embodiment of the present invention relates to a method of treating a subject suffering from a disease or disorder, comprising orally administering a therapeutically effective amount of terlipressin to said subject; said disease or disorder can be, for example, orthostatic hypotension, portal hypertension, bleeding varices (e.g., esophageal varices), and ascites (e.g., ascites associated with cirrhosis of the liver), and associated symptoms and side effects thereof. Another embodiment of the present invention relates to a terlipressin composition for use in the oral treatment of a disease or disorder in a subject.

[0101] Another embodiment of the present invention relates to the use of terlipressin in the manufacture of a medicament by the process of the present invention for the treatment of a disorder.

[0102] In some embodiments, the methods described herein treat a subject suffering from hypotension (e.g., neurogenic orthostatic hypotension), the methods comprising administering one or two doses (e.g., one dose comprises one to two (or more) tablets or capsules comprising terlipressin) 15, 20, 30, 40, 45, or 60 minutes prior to rising (e.g., in the morning or afternoon; before 4 or 5 pm), e.g., daily. In some embodiments, the tablet or capsule comprising terlipressin is about 2 to about 30 mg (e.g., about 5 to about 30 mg, about 10 to about 30 mg, about 15 to about 25 mg, about 18 to about 22 mg, about 20 mg, about 22 mg) of terlipressin.

[0103] In some embodiments, the methods described herein treat a subject suffering from hypotension (e.g., postprandial hypotension), the methods comprising administering one or two doses (e.g., one dose comprising one to two (or more) tablets or capsules comprising terlipressin).

[0104] In some embodiments, the methods described herein treat a subject suffering from portal hypertension or bleeding esophageal varices associated with portal hypertension, the methods comprising administering oral terlipressin in a therapeutically effective amount.

[0105] In one aspect, one to four doses (e.g., one to two tablets or capsules each containing terlipressin) are administered daily. In some embodiments, the tablet or capsule containing terlipressin is about 2 to about 30 mg (e.g., about 5 to about 30 mg, about 10 to about 30 mg, about 15 to about 25 mg, about 18 to about 22 mg, about 20 mg, about 22 mg) of terlipressin. In some embodiments, terlipressin is administered orally to prevent recurrence after treatment of bleeding variceal episodes. In some embodiments, subjects are able to return home while maintaining treatment (not possible with current intravenous terlipressin administration). In some embodiments, oral terlipressin formulations can be used for primary and secondary prevention of variceal bleeding.

[0106] In some embodiments, the methods described herein treat a subject suffering from portal hypertension or bleeding esophageal varices associated with portal hypertension, the methods comprising administering 1 to 4 doses (e.g., one dose comprising 1 to 2 tablets or capsules comprising terlipressin) daily. In some embodiments, the tablet or capsule comprising terlipressin comprises about 2 to about 30 mg (e.g., about 5 to about 30 mg, about 10 to about 30 mg, about 15 to about 25 mg, about 18 to about 22 mg, about 20 mg, about 22 mg) of terlipressin.

[0107] In some embodiments, the methods described herein relate to administration of a composition 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., ascites associated with cirrhosis of the liver). In some embodiments, the methods described herein involve administration of a composition comprising terlipressin in an oral dosage form (e.g., comprising 1, 2, 3, 4, 5, 7, 10, 15, 17, 20, 25, 30, 40, 50 mg of terlipressin).

[0108] Another aspect of the present invention is a method for treating a subject suffering from neurogenic orthostatic hypotension, comprising administering a therapeutically effective amount of terlipressin to said subject in combination with another drug used for treating neurogenic orthostatic hypotension.For example, 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-9855.

[0109] Another aspect of the present invention is a method for treating a subject suffering from postprandial hypotension, comprising administering a therapeutically effective amount of terlipressin to said subject in combination with another drug used for the treatment of postprandial hypotension.For example, the compound used in combination with oral terlipressin includes one or more of acarbose and guar gum and midodrine and / or northera and / or TD-9855.

[0110] In some embodiments, oral terlipressin is administered in combination with a large volume (bolus) of physiological fluid (eg, 100 mL, 200 mL, 500 mL, or more volumes of physiological fluid).

[0111] Another aspect of the invention is a unit dosage formulation for oral administration (oral dosage form) comprising terlipressin and a second and third oral agent used in the treatment of neurogenic orthostatic hypotension, including a mineralocorticoid (including but not limited to fludrocortisone) and / or midodrine, and / or pyridostigmine and / or droxidopa and / or erythropoietin and / or Northera and / or TD-9855.

[0112] Another aspect of the invention is a unit dosage formulation for oral administration (oral dosage form) comprising terlipressin and second and third oral agents used in the treatment of postprandial hypotension, including, but not limited to, acarbose, guar gum and midodrine and / or Northera and / or TD-9855.

[0113] Another aspect of the invention 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.

[0114] In some embodiments, oral terlipressin is administered in combination with a large volume of physiological fluid (eg, 100 mL, 200 mL, 500 mL, or more volumes of physiological fluid).

[0115] Another aspect of the present invention is a method for treating a subject suffering from portal hypertension / bleeding esophageal varices, comprising administering a therapeutically effective amount of terlipressin to said subject in combination with another drug used for the treatment of portal hypertension / bleeding esophageal varices.The drugs to be used in combination with such oral terlipressin include beta-blockers and isosorbide mononitrate.Non-drug treatments that can be used in combination with oral terlipressin include, but are not limited to, endoscopic ligation, sclerotherapy, and surgical shunts.

[0116] Another aspect of the invention is a method of treating a subject suffering from cirrhosis, portal hypertension / bleeding esophageal varices, comprising administering to said subject a therapeutically effective amount of terlipressin in combination with another drug used for the treatment of Hepatitis C. Such drugs to be used in combination with oral terlipressin include alpha-interferons (such as Peg-IFN-2a or IFN-a-2b).

[0117] Another aspect of the invention is a method of treating a subject suffering from cirrhosis, portal hypertension / bleeding esophageal varices, comprising administering to said subject a therapeutically effective amount of terlipressin in combination with another drug used for the treatment of Hepatitis B. Such drugs to be used in combination with oral terlipressin include lamivudine, telbivudine, entecavir, adefovir, and tenofovir.

[0118] Another aspect of the present invention is a method for treating a subject suffering from cirrhosis, portal hypertension / bleeding esophageal varices, comprising administering to said subject a therapeutically effective amount of terlipressin in combination with another drug used for the treatment of fibrosis and / or nonalcoholic steatohepatitis (NASH) and / or primary biliary cirrhosis.Drugs to be used in combination with such oral terlipressin include pirfenidone, nintedanib, obeticholic acid, urodeoxycholic acid, and emricasan (all for oral administration); also includes vitamin E and pioglitazone.

[0119] Another aspect of the invention 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.

[0120] One embodiment of the present invention relates to a method of treating a subject suffering from ascites associated with liver cirrhosis, comprising orally administering a therapeutically effective amount of terlipressin or a pharma- ceutically acceptable salt thereof, thereby treating said subject. In one aspect, one to four doses (e.g., one dose containing one to two or more tablets or capsules containing terlipressin) are administered daily. In some embodiments, the tablets or capsules containing terlipressin contain about 2 to about 30 mg (e.g., about 5 to about 30 mg, about 10 to about 30 mg, about 15 to about 25 mg, about 18 to about 22 mg, about 20 mg, about 22 mg) of terlipressin. In some embodiments of the methods of the invention, the subject is administered 5-100 mg of terlipressin per day (e.g., 20-100 mg of terlipressin per day, 40-100 mg of terlipressin per day, 60-100 mg of terlipressin per day, e.g., 80 mg of terlipressin per day). In some embodiments, the terlipressin is administered for about 1 day to about 12 months. In some embodiments, the subject's condition has not progressed to hepatorenal syndrome (HRS). In some embodiments, the administration of terlipressin is outpatient. In some embodiments, the dose of terlipressin is gradually increased over a period of about 1 day to about 12 months. One aspect of the invention is a method of reducing ascites volume before, during, or after a paracentesis procedure in a subject suffering from ascites, comprising orally administering a therapeutically effective amount of terlipressin or a pharmacologic acceptable salt thereof. In one aspect, one to four doses are administered per day (e.g., one dose includes one to two or more tablets or capsules containing terlipressin). In some embodiments, the tablet or capsule containing terlipressin includes about 2 to about 30 mg (e.g., about 5 to about 30 mg, about 10 to about 30 mg, about 15 to about 25 mg, about 18 to about 22 mg, about 20 mg, about 22 mg) of terlipressin. In one embodiment, the subject is administered 5 to 200 mg of terlipressin per day (e.g., 20 to 100 mg of terlipressin per day, 40 to 100 mg of terlipressin per day, 60 to 100 mg of terlipressin per day, e.g., 80 mg of terlipressin per day).In another embodiment, terlipressin is administered for about 1 day to about 12 months. In another embodiment, the subject's condition has not progressed to hepatorenal syndrome (HRS). In another embodiment, it is administered on an outpatient basis.

[0121] Another embodiment of the invention is a method of improving renal function in a subject suffering from ascites, comprising orally administering a therapeutically effective amount of terlipressin or a pharma- ceutically acceptable salt thereof. In one aspect, the improvement comprises a decrease in serum creatinine concentration and / or an increase in plasma sodium concentration and / or an increase in urinary sodium excretion and / or a decrease in serum urea concentration. In one aspect, 1 to 4 doses (e.g., one dose comprises 1 to 2 or more tablets or capsules comprising terlipressin) are administered daily. In some embodiments, the tablets or capsules comprising terlipressin are about 2 to about 30 mg (e.g., about 5 to about 30 mg, about 10 to about 30 mg, about 15 to about 25 mg, about 18 to about 22 mg, about 20 mg, about 22 mg) of terlipressin. In one aspect, the subject is administered 5-200 mg of terlipressin per day (e.g., 20-100 mg of terlipressin per day, 40-100 mg of terlipressin per day, 60-100 mg of terlipressin per day, e.g., 80 mg of terlipressin per day). In another aspect, the terlipressin is administered for about 1 day to about 12 months. In another aspect, the subject's condition has not progressed to hepatorenal syndrome (HRS). In another aspect, the administration is on an outpatient basis. In another aspect, the dose of terlipressin is gradually increased over a period of about 1 day to about 12 months. Another embodiment of the invention is a method of correcting hyponatremia in a subject suffering from ascites, comprising orally administering to said subject a therapeutically effective amount of terlipressin or a pharma- ceutically acceptable salt thereof. In one aspect, one to four doses are administered per day (e.g., one dose includes one to two or more tablets or capsules containing terlipressin). In some embodiments, the tablet or capsule containing terlipressin is about 2 to about 30 mg (e.g., about 5 to about 30 mg, about 10 to about 30 mg, about 15 to about 25 mg, about 18 to about 22 mg, about 20 mg, about 22 mg) of terlipressin. In one aspect, the subject is administered 5 to 200 mg of terlipressin per day (e.g., 20 to 100 mg of terlipressin per day, 40 to 100 mg of terlipressin per day, 60 to 100 mg of terlipressin per day, e.g., 80 mg of terlipressin per day).In another embodiment, terlipressin is administered for about 1 day to about 12 months. In one embodiment, the subject's condition has not progressed to hepatorenal syndrome (HRS). In another embodiment, it is administered on an outpatient basis.

[0122] Another aspect of the present invention relates to a method of treating a subject suffering from a disease or disorder, such as cirrhosis, portal hypertension, and bleeding varices, ascites, including symptoms and side effects thereof, comprising orally administering to said subject a therapeutically effective amount of terlipressin in combination with a diuretic, and / or in combination with albumin, and / or in combination with a beta-blocker.

[0123] One embodiment of the present invention relates to a unit dosage formulation (oral dosage form) for oral administration comprising a therapeutically effective amount of terlipressin in combination with a therapeutically effective amount of at least one diuretic and / or at least one beta-blocker. One aspect of this embodiment is a unit dosage formulation (oral dosage form) for treating a subject suffering from ascites.

[0124] The dosing regimen utilizing the compound is selected according to a variety of factors, including the type, species, age, weight, sex, and condition of the patient; the severity of the condition being treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof being used. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, reverse or halt the progression of the condition.

[0125] In some embodiments, the methods described herein treat a subject suffering from hypotension (e.g., neurogenic orthostatic hypotension or postprandial hypotension), the methods comprising administering one or two doses (e.g., one dose comprising one to two (or more) tablets or capsules comprising terlipressin) 15, 20, 30, 40, 45, or 60 minutes prior to rising (e.g., in the morning or afternoon; before 4 or 5 pm), e.g., daily. In some embodiments, the tablet or capsule comprising terlipressin is about 10 to about 30 mg (e.g., about 15 to about 25 mg, about 18 to about 22 mg, about 22 mg) of terlipressin.

[0126] Subject Described herein are methods of 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. In some embodiments, the subject is suffering 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 is suffering from Parkinson's disease or multiple system atrophy (MSA). In some embodiments, the subject is suffering from nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). In some embodiments, the subject is suffering from hepatorenal syndrome (HRS) (e.g., HRS type 1 or HRS type 2). In some embodiments, the subject is suffering from cancer. In some embodiments, the subject is suffering from heart failure.

[0127] Medication and Administration Described herein are methods of 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, comprising administering a composition comprising terlipressin. In some embodiments, the methods described herein comprise oral administration of a composition comprising terlipressin. In some embodiments, the methods described herein comprise administration of a composition comprising terlipressin in an oral dosage form (e.g., comprising 1, 2, 3, 4, 5, 7, 10, 15, 17, 20, 25, 30, 40, 50 mg of terlipressin).

[0128] In some embodiments, the methods described herein provide a subject with a concentration of terlipressin of about 1 to about 1000 μg / mL. In some embodiments, the methods described herein provide a subject with a concentration of terlipressin (e.g., in the subject's plasma) of about 10 to about 600 μg / mL. In some embodiments, the methods described herein provide a subject with a concentration of terlipressin of about 20 to about 200 μg / mL. In some embodiments, the methods described herein provide a subject with a concentration of terlipressin of about 60 μg / mL.

[0129] In some embodiments, the methods described herein provide a subject with (lysine-)vasopressin at a concentration of about 1 to about 200 μg / mL. (Vasopressin is the active metabolite of terlipressin.) In some embodiments, the methods described herein provide a subject with vasopressin at a concentration of about 2 to about 100 μg / mL (e.g., in the subject's plasma). In some embodiments, the methods described herein provide a subject with vasopressin at a concentration of about 3 to about 30 μg / mL. In some embodiments, the methods described herein provide a subject with vasopressin at a concentration of about 10 μg / mL.

[0130] In some embodiments, the composition is configured into a solid dosage form. In some embodiments, the solid dosage form is, for example, a capsule with an enteric coating. In some embodiments, the solid dosage form is, for example, a tablet with an enteric coating.

[0131] In some embodiments, the capsule contains 5, 10, 15, 20, 25, 30, 50 mg of terlipressin. In some embodiments, the capsule contains about 15 to about 25 mg of terlipressin. In some embodiments, the capsule contains about 18 to about 22 mg of terlipressin. In some embodiments, the capsule contains 20 mg of terlipressin.

[0132] In some embodiments, the tablets contain 5, 10, 15, 20, 25, 30, 50, or 100 mg of terlipressin.

[0133] In some embodiments, the method comprises administration up to two times per day.

[0134] In some embodiments, the method comprises administration up to three or four times per day.

[0135] The dosing regimen utilizing the compound is selected according to various factors, including the 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 used. A physician of ordinary skill can easily determine and prescribe the effective amount of drug required to prevent, reverse, or stop the progression of the condition. The oral dosage of the present invention, when used to obtain the indicated effect, can be provided in the form of a capsule containing 0.3, 0.5, 1, 1.5, 2, 4, 5, 10, 15, 17, 19, 20, 21, 23, 25, 30, 35, 40, 45, 50 mg or more of a therapeutic agent (e.g., terlipressin). In some embodiments, an oral dosage comprising a therapeutic agent (e.g., terlipressin) is 1, 1.5, 2, 4, 5, 10, 15, 17, 19, 20, 21, 23, 25, 30, 35, 40, 45, 50 mg, or more in a solid dosage form (e.g., a capsule (e.g., a capsule with an enteric coating), a tablet). In some embodiments, the capsule is a 5, 10, 15, 20, 25, 30, 50, or 100 mg capsule. In some embodiments, the capsule is about 15 to about 25 mg. In some embodiments, the capsule is about 18 to about 22 mg. In some embodiments, the capsule is a 20 mg capsule.

[0136] In some embodiments, the oral dosage comprises about 0.3 to about 50 mg of terlipressin (e.g., about 1 to about 50 mg of terlipressin, about 5 to about 50 mg of terlipressin, about 10 to about 40 mg of terlipressin, about 10 to about 30 mg of terlipressin, about 15 to about 25 mg of terlipressin, about 18 to about 22 mg of terlipressin, about 20 mg of terlipressin).

[0137] In some embodiments, the oral dosage comprises at least 0.1, 0.3, 0.5, 1, 1.5, 2, 4, 5, 10, 15, 17, 19, or 20 mg of terlipressin.

[0138] The compositions described herein can be administered in a single daily dose, or the total daily dose can be administered in divided doses, two, three, or four times a day. In some embodiments, the method includes administering up to two doses per day. In some embodiments, the compositions are administered up to three or four times a day.

[0139] In some embodiments, the composition is administered at a daily dose of about 1 to about 200 mg / day (e.g., about 1 to about 100 mg / day, about 5 to about 100 mg / day, about 5 to about 50 mg / day) (e.g., administered at least 1, 2, 3, or 4 times per day (e.g., in the morning, in the afternoon)). In some embodiments, the composition is administered once or twice per day. In some embodiments for the treatment of hypotension (e.g., neurogenic orthostatic hypotension), the composition is administered 15, 20, 30, 45, or 60 minutes before rising (e.g., rising in the morning, rising after a nap (e.g., afternoon nap)). In some embodiments, without being bound by theory, to prevent supine hypertension, the composition is not administered before or in the evening (e.g., the composition is not administered after 4 pm or 5 pm). For example, a composition comprising terlipressin (e.g., a coated capsule or tablet comprising terlipressin) is administered once in the morning and once in the afternoon to a subject suffering from hypotension (e.g., neurogenic orthostatic hypotension). In another example, a composition comprising terlipressin (e.g., a coated capsule or tablet comprising terlipressin) is administered as two to four tablets up to four times daily to a subject suffering from portal hypertension or bleeding esophageal varices.

[0140] In some embodiments, it is administered on an empty stomach. In some embodiments, it is administered before food intake (e.g., 1, 2, 3, 4, 6, 8 hours before or earlier than food intake). In some embodiments, it is administered after food intake (e.g., 1, 2, 3, 4, 6, 8 hours after food intake or later). In some embodiments, it is administered during food intake. In some embodiments, terlipressin is orally administered at least 1 hour before or at least 2 hours after a meal, thereby treating the subject. In some embodiments, terlipressin is orally administered at least 1 hour before or at least 1 hour after a meal, thereby treating the subject.

[0141] In one embodiment, the compositions described herein are provided as oral dosage forms.The oral dosage of the present invention can be provided in the form of capsules containing 0.3, 0.5, 1, 1.5, 2, 4, 5, 10, 15, 17, 19, 20, 21, 23, 25, 30, 35, 40, 45, 50mg or more of therapeutic agent (e.g., terlipressin) when used to obtain the indicated effect.In some embodiments, the oral dosage containing therapeutic agent (e.g., terlipressin) is 1, 1.5, 2, 4, 5, 10, 15, 17, 19, 20, 21, 23, 25, 30, 35, 40, 45, 50mg or more of solid dosage form (e.g., capsule or tablet with enteric coating).In some embodiments, the capsule is a 5, 10, 15, 20, 25, 30, 50, or 100mg capsule. In some embodiments, the capsule is about 15 to about 25 mg. In some embodiments, the capsule is about 18 to about 22 mg. In some embodiments, the capsule is a 20 mg capsule.

[0142] A representative product of the present invention is a formulation administered orally as an enteric capsule: each capsule contains terlipressin co-lyophilized with PVP polymer and sodium octanoate and suspended in a hydrophobic (lipophilic) medium containing glyceryl tricaprylate, glyceryl monocaprylate, and Tween 80; in another representative product of the present invention, castor oil is additionally present. The compositions described herein can be administered to a subject (i.e., a human or an animal) to treat the subject with a pharmacologically or therapeutically effective amount of the terlipressin described herein. The animal can be a mammal (e.g., a mouse, a rat, a pig, a dog, a horse, a cow, or a sheep).

[0143] The compositions of the invention (e.g., compositions comprising terlipressin) can be administered in a single daily dose, or the total daily dose can be administered in divided doses, 2, 3, 4, 5, or 6 times per day. In some embodiments, the method includes administration up to 2 times per day. In some embodiments, the compositions are administered up to 3 or 4 times per day.

[0144] In some embodiments, the composition is administered at a daily dose of about 1 to about 200 mg / day (e.g., about 1 to about 100 mg / day, about 5 to about 100 mg / day, about 5 to about 50 mg / day) (e.g., administered at least 1, 2, 3, or 4 times per day (e.g., in the morning, afternoon)). In some embodiments, the composition is administered twice per day. In some embodiments, the composition is administered four times per day. In some embodiments, the composition is administered three times per day.

[0145] In another example, a composition comprising terlipressin (e.g., a capsule or tablet (e.g., a coated capsule or tablet) comprising terlipressin) is administered 1, 2, 3, or 4 times per day to a subject suffering from portal hypertension (e.g., bleeding esophageal varices associated with portal hypertension). In some embodiments, the subject is administered 1 or 2 tablets or capsules comprising terlipressin 1, 2, 3, or 4 times per day. For example, the subject is administered 1 to 2 tablets of a composition comprising terlipressin up to 4 times per day. In some embodiments, the tablet or capsule comprising terlipressin is about 10 to about 30 mg (e.g., about 15 to about 25 mg, about 18 to about 22 mg, about 22 mg) of terlipressin. One embodiment of the present invention is a method of treating a subject suffering from hypotension (e.g., neurogenic orthostatic hypotension or postprandial hypotension), comprising administering a therapeutically effective amount of oral terlipressin to the subject. Another embodiment of the present invention is a method of treating a subject suffering from portal hypertension / bleeding esophageal varices, comprising administering a therapeutically effective amount of oral terlipressin in combination with a therapeutically effective amount of at least one liver fibrosis agent to the subject. Another embodiment of the present invention is a unit dose 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 liver fibrosis agent.

[0146] Another aspect of the present invention is a method for treating a subject suffering from hypotension (e.g., neurogenic orthostatic hypotension or postprandial hypotension), comprising administering to said subject a therapeutically effective amount of oral terlipressin in combination with another drug used for the treatment of neurogenic orthostatic hypotension or postprandial hypotension. For example, drugs to be used in combination with oral terlipressin include mineralocorticoids, including but not limited to fludrocortisone. In some embodiments, oral terlipressin is administered in combination with a large volume of physiological fluid (e.g., 100mL, 200mL, 500mL or more of physiological fluid). Accordingly, one embodiment of the present invention is a method of treating a subject suffering from neurogenic orthostatic hypotension comprising administering to said subject a therapeutically effective amount of oral terlipressin in combination with a large amount of water and a therapeutically effective amount of at least one therapeutic agent selected from fludrocortisone, midodrine, pyridostigmine, droxidopa and erythropoietin and / or Northera and / or TD-9855.

[0147] Accordingly, one embodiment of the present invention is a method of treating a subject suffering from postprandial hypotension comprising administering to said subject a therapeutically effective amount of oral terlipressin in combination with a therapeutically effective amount of at least one therapeutic agent selected from guar gum, acacia rose, and midodrine, optionally in combination with a large amount of water.

[0148] Another aspect of the present invention is a method for treating a subject suffering from ascites (e.g., due to cirrhosis of the liver), comprising administering to said subject a therapeutically effective amount of oral terlipressin in combination with another drug used for treating ascites. For example, drugs to be used in combination with oral terlipressin include albumin, diuretics, and / or beta-blockers. One aspect of the present invention is a method for treating a subject suffering from ascites, comprising administering to said subject a therapeutically effective amount of oral terlipressin in combination with at least one therapeutic drug selected from a therapeutically effective amount of a diuretic, a beta-blocker, or albumin.

[0149] In some embodiments, the methods described herein treat a subject suffering from hypotension (e.g., neurogenic orthostatic hypotension), the methods comprising administering one or two doses (e.g., one dose comprising one to two (or more) tablets or capsules comprising terlipressin) 15, 20, 30, 40, 45, or 60 minutes prior to arising (e.g., in the morning or afternoon; before 4 or 5 pm), e.g., daily.

[0150] In some embodiments, the methods described herein treat a subject suffering from postprandial hypotension, the methods comprising administering one or two doses (e.g., one dose comprising one to two tablets or capsules comprising terlipressin) 15, 20, 30, 40, 45, or 60 minutes before a meal.

[0151] In some embodiments, the tablet or capsule containing terlipressin is about 10 to about 30 mg (eg, about 15 to about 25 mg, about 18 to about 22 mg, about 20 mg) of terlipressin.

[0152] In some embodiments, the methods described herein (e.g., methods of administering terlipressin orally) result in reduced side effects compared to methods of administering terlipressin by other modes of administration (e.g., intravenous administration). In some embodiments, the methods described herein (e.g., methods of administering terlipressin orally) result in better patient compliance (e.g., compliance by subjects as described herein) compared to methods of administering terlipressin by other modes of administration (e.g., intravenous administration, which is not convenient for home treatment).

[0153] Terlipressin As described herein, the pharmacoactive agent described herein (e.g., the compound described herein, the therapeutic agent described herein) is terlipressin or a pharmacologic acceptable salt of terlipressin. Terlipressin (also known as triglycyl lysine vasopressin) is a synthetic analog of the human neuropeptide hormone vasopressin. Terlipressin is a prohormone of lysine-vasopressin (triglycyl lysine vasopressin, TGLVP), and is described, for example, in Rittig et al., Movement Disorders, 1991, Vol. 6(1), p21-28. After administration and absorption into the circulation, the glycyl residue is cleaved from the prohormone by endothelial peptidases, thereby allowing the extended release of lysine-vasopressin. Thus, terlipressin itself has weak intrinsic vasoconstrictor activity, but is converted to fully active lysine vasopressin (LVP) by endothelial endopeptidases. Terlipressin is also known by its trade names Teripress and Glypressin. Terlipressin has a molecular weight of 1227.37 g / mol and has the following formula: [ka]

[0154] Intravenously administered terlipressin is used, for example, as a vasoactive agent in the management of hypotension (low blood pressure) and for the treatment of, for example, esophageal varices, septic shock, hepatorenal syndrome, and ascites.

[0155] Pharmaceutical Compositions The pharmaceutical composition described herein comprises terlipressin and medium chain fatty acid salt in intimate contact with or associated with a substantially hydrophobic medium. For example, terlipressin and medium chain fatty acid or its derivative can be coated, suspended, sprayed, or immersed in a substantially hydrophobic medium to form a suspension. The composition of the present invention is not an emulsion. The composition is an oil suspension, and the amount of water in the composition is very low (usually 1% or less, or 0.5% or less).

[0156] The suspension may be a liquid suspension incorporating a solid material, or a semi-solid suspension (ointment) incorporating a solid material. Many of the compositions described herein include a suspension comprising a mixture of a hydrophobic medium and a solid form, where the solid form comprises a therapeutically effective amount of terlipressin and at least one salt of a medium chain fatty acid, and the medium chain fatty acid salt is present in the composition in an amount of 10% by weight or more. The solid form may comprise particles (e.g., consist essentially of particles or consist of particles). The particles may be produced by freeze-drying, spray-drying, or granulation.

[0157] Medium chain fatty acid salts can generally facilitate or enhance the permeability and / or absorption of terlipressin. In some embodiments, medium chain fatty acid salts include derivatives of medium chain fatty acid salts. Terlipressin and medium chain fatty acid salts are in a solid form (e.g., solid particles, such as freeze-dried particles, granulated particles, pellets, or microspheres). In preferred embodiments, terlipressin and medium chain fatty acid salts are both present in the same solid form (e.g., in the same particle). In other embodiments, terlipressin and medium chain fatty acid salts may be present in different solid forms (e.g., in different particles).

[0158] Unlike emulsions, where water is an essential component of the formulation, the compositions described herein provide a solid form, such as particles, containing terlipressin, which is then associated with a hydrophobic (oily) medium. The amount of water in the composition is generally less than 3% by weight, usually less than about 2% by weight, or less than 1% by weight, or about 0.5% by weight or less.

[0159] The compositions described herein are suspensions comprising a mixture 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 can be particulate (e.g., essentially or consisting of particles). The particles can be produced by freeze-drying or spray-drying or granulation. The medium chain fatty acid salt is generally present in the compositions described herein in an amount of 10% by weight or more. In certain embodiments, the medium chain fatty acid salt is present in the composition in an amount of 10% to 50% by weight, preferably 11% to 18% by weight or about 11% to 17% by weight or 12% to 16% by weight or 12% to 15% by weight or 13% to 16% by weight or 13% to 15% by weight or 14% to 16% by weight or 14% to 15% by weight or 15% to 16% by weight or most preferably 15% or 16% by weight, and the chain length of the medium chain fatty acid is from about 6 to about 14 carbon atoms, preferably 8, 9, or 10 carbon atoms.

[0160] In some embodiments of the above compositions, the solid form containing terlipressin also contains a stabilizer (e.g., a protein structure stabilizer). A protein structure stabilizer is a compound that can stabilize the protein structure under aqueous or non-aqueous conditions or reduce or prevent aggregation of terlipressin during, for example, a drying process such as lyophilization or other processing steps. The structure stabilizer can be a polyanionic molecule (such as phytic acid), a multivalent ion (such as Ca, Zn, or Mg), a saccharide (such as a disaccharide (e.g., trehalose, maltose) or an oligosaccharide or polysaccharide (such as dextrin or dextran)), or a sugar alcohol (such as mannitol), or an amino acid (such as glycine), or a polycationic molecule (such as spermine), or a surfactant (such as polyoxyethylene sorbitan monooleate (Tween 80) or pluronic acid). Non-charged polymers (such as mannitol, methylcellulose, and polyvinyl alcohol) are also suitable stabilizers.

[0161] Polyvinylpyrrolidone (PVP) is known in the art as a stabilizer, but in the compositions of the invention described herein, PVP polymers (e.g., PVP-12) may serve to increase the effect of permeability enhancers, for example, in a synergistic manner. Dextran and other matrix-forming polymers may have a similar effect as PVP.

[0162] In some embodiments, bulking agents (eg, mannitol or glycin) can be added.

[0163] In certain embodiments of the compositions described herein, the salt of the fatty acid is sodium octanoate and the hydrophobic medium is castor oil; in another particular embodiment, the composition further comprises glyceryl monooleate and sorbitan monopalmitate or glyceryl monocaprylate and glyceryl tricaprylate and polyoxyethylene sorbitan monooleate; in another particular embodiment, the composition further comprises glyceryl tributyrate, lecithin, ethyl isovalerate, and at least one stabilizer.

[0164] An exemplary formulation of terlipressin is shown below: [Table A]

[0165] Medium chain fatty acid salts: The compositions described herein include a salt of a medium chain fatty acid or a derivative thereof in a solid form. For example, the salt of a medium chain fatty acid is in the form of particles (such as solid particles). In some embodiments, the particles can be characterized as granulated particles. In at least some embodiments, the solid form can generally be obtained from a spray drying or evaporation process. In a preferred embodiment, the salt of a medium chain fatty acid is present in the same particle as terlipressin. For example, terlipressin and a salt of a medium chain fatty acid can be prepared together by first preparing a solution, such as an aqueous solution, containing both terlipressin and a salt of a medium chain fatty acid, and freeze-drying the aforementioned solution simultaneously to obtain a solid form or particle containing both terlipressin and a salt of a medium chain fatty acid (and other components). As described above, the resulting solid particles are associated with a hydrophobic medium. For example, the solid particles can be suspended or immersed in the hydrophobic medium.

[0166] In different embodiments of the compositions described herein, the medium chain fatty acid salt may be present in the same particles as the particles of the API or in different particles. When the medium chain fatty acid salt and terlipressin are co-solubilized in the hydrophilic fraction prior to drying, they will be present in the same particles in the final powder.

[0167] Medium chain fatty acid salts include those having a carbon chain length of about 6 to about 14 carbon atoms. Examples of fatty acid salts are sodium hexanoate, sodium heptanoate, sodium octanoate (also called sodium caprylate), sodium nonanoate, sodium decanoate, sodium undecanoate, sodium dodecanoate, sodium tridecanoate, and sodium tetradecanoate. In some embodiments, the medium chain fatty acid salt comprises 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 medium chain fatty acids).

[0168] Generally, the amount of medium chain fatty acid salt in the compositions described herein can be from 10% to about 50% by weight of the bulk pharmaceutical composition. For example, the medium chain fatty acid salt may be present in an amount of about 10% to 50% by weight of the bulk pharmaceutical composition, preferably about 11% to 40% by weight, and most preferably about 11% to 28% by weight, such as about 12% to 13%, 13% to 14%, 14% to 15%, 15% to 16%, 16% to 17%, 17% to 18%, 18% to 19%, 19% to 20%, 20% to 21%, 21% to 22%, 22% to 23%, 23% to 24%, 24% to 25%, 25% to 26%, 26% to 27%, or 27% to 28% by weight. In other embodiments, the medium chain fatty acid salt may be present in an amount of at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, or at least about 28% by weight of the bulk pharmaceutical composition. In certain embodiments, the medium chain fatty acid salt (sodium, potassium, lithium, or ammonium salt, or mixtures thereof) is present at about 12% to 21% by weight of the bulk pharmaceutical composition, preferably 11% to 18% or about 11% to 17% or 12% to 16% or 12% to 15% or 13% to 16% or 13% to 15% or 14% to 16% or 14% to 15% or 15% to 16% or most preferably 15% or 16%.In certain embodiments, the medium chain fatty acid salts (having a carbon length of about 6 to about 14 carbon atoms, particularly 8, 9, or 10 carbon atoms) are present at about 12% to 21% by weight of the bulk pharmaceutical composition, preferably 11% to 18%, about 11% to 17% or 12% to 16% or 12% to 15% or 13% to 16% or 13% to 15% or 14% to 16% or 14% to 15% or 15% to 16% or most preferably 15% or 16%. In certain embodiments, the medium chain fatty acid salt (e.g., salt of octanoic acid, salt of suberic acid, salt of geranic acid) is present in about 12% to 21% by weight of the bulk pharmaceutical composition, preferably 11% to 18%, about 11% to 17% or 12% to 16% or 12% to 15% or 13% to 16% or 13% to 15% or 14% to 16% or 14% to 15% or 15% to 16% or most preferably 15% or 16% by weight. In certain embodiments, the medium chain fatty acid salt is present in the solid powder in an amount of 50% to 90%, preferably 70% to 80%.

[0169] One embodiment of the invention includes a composition comprising a suspension consisting essentially of a mixture 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, wherein the medium chain fatty acid salt is not a sodium salt. The salt may be a salt of other cations, such as lithium, potassium, or ammonium; the ammonium salt is preferred.

[0170] Matrix forming polymer: In certain embodiments, the compositions of the present invention include suspensions comprising a mixture 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, wherein the matrix-forming polymer is present in an amount of 3% or more by weight in the composition. In certain embodiments, the compositions include suspensions consisting essentially of a mixture 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, wherein the matrix-forming polymer is present in an amount of 3% or more by weight in the composition. In certain embodiments, the matrix-forming polymer is dextran or polyvinylpyrrolidone polymer (PVP), which can be obtained from BASF in various molecular weights. In certain embodiments, polyvinylpyrrolidone is present in the composition in an amount of about 2% to about 20% by weight, preferably about 3% to about 18% by weight, more preferably about 5% to about 15% by weight, and most preferably about 10% by weight. In certain particular embodiments, the polyvinylpyrrolidone is PVP-12 and / or has a molecular weight of about 3000. Other matrix-forming polymers have similar effects to the compositions of the present invention; such matrix-forming polymers include ionic (e.g., alginic acid and alginates) or neutral polysaccharides (e.g., dextran and HPMC), polyacrylic and polymethacrylic acid derivatives, and high molecular weight organic alcohols (e.g., polyvinyl alcohol).

[0171] Hydrophilic fraction: In the embodiment of the present invention, the above-mentioned compound (including terlipressin and medium-chain fatty acid salt) is solubilized in aqueous medium, and then dried to produce powder. The drying process can be carried out by, for example, freeze-drying or spray-drying or granulation. The obtained powder is named "hydrophilic fraction". In the hydrophilic fraction, water is usually present in an amount of less than 6% or less than 3% or about 2% or less.

[0172] Lyophilization can be carried out by methods known in the art, for example as described in Lyophilization: Introduction and Basic Principles, Thomas Jennings, published by Interpharm / CRC Press Ltd (1999, 2002). The lyophilisate can be optionally milled (e.g., less than 150 microns) or ground in a mortar. In large-scale production, it is preferred to mill the lyophilisate before mixing the hydrophilic fraction with the hydrophobic medium to obtain batch-to-batch reproducibility.

[0173] Spray drying can be performed, for example, as described by Walters et al. (2014) Next Generation This can be done by methods known in the art, as described in Drying Technologies for Pharmaceutical Applications, J. of Pharm Sci 103; 2673-2695.

[0174] Granulation can be carried out as described by methods known in the art, for example, in Granulation, Salman et al., eds, Elsevier (2006) and in Handbook of Pharmaceutical Granulation Technology, 2nd edition, (2005) Dilip M. Parikh, ed. Various binders can be used in the granulation process, such as cellulose (including microcrystalline cellulose), lactose (e.g., lactose monohydrate), dextrose, starch, and mannitol, as well as other binders described in the previous two references.

[0175] Hydrophobic medium: Oil: As mentioned above, in the compositions of the invention described herein, terlipressin and medium chain fatty acid salts are in intimate contact with or associated with a hydrophobic medium. For example, one or both can be coated, suspended, immersed, or otherwise associated with the hydrophobic medium. Suitable hydrophobic mediums can include, for example, aliphatic, dry, or aromatic molecules. Examples of suitable aliphatic hydrophobic mediums include, but are not limited to, mineral oil, fatty acid monoglycerides, diglycerides, triglycerides, ethers, esters, and combinations thereof. Examples of suitable fatty acids are octanoic acid, decanoic acid, and dodecanoic acid, as well as C7 and C9 fatty acids, acidic diacids (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, the short-chain triglyceride can be glyceryl tributyrate, and the medium-chain triglyceride can be glyceryl tricaprylate. Monoglycerides are considered surfactants and are described below. Exemplary esters include ethyl isovalerate and butyl acetate. Examples of suitable cyclic hydrophobic media include, but are not limited to, terpenoids, cholesterol, cholesterol derivatives (e.g., cholesterol sulfate), and cholesterol esters of fatty acids. Non-limiting examples of aromatic hydrophobic media include benzyl benzoate.

[0176] In some embodiments of the compositions described herein, it is desirable for the hydrophobic medium to comprise a plurality of hydrophobic molecules. In some embodiments of the compositions described herein, the hydrophobic medium also comprises one or more surfactants (see below).

[0177] In some embodiments of the compositions described herein, the hydrophobic medium also includes one or more adhesive polymers, such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose (HPMC), or the poly(acrylate) derivative Carbopol® 934P (C934P). Such adhesive polymers may help strengthen the formulation and / or aid in adhesion to mucosal surfaces.

[0178] Surface active agents (surfactants): The compositions of the invention described herein can further include a surfactant. For example, the surfactant can be a component of the hydrophobic medium described above and / or the surfactant can be a component of the solid form described above (e.g., a solid form or particle comprising terlipressin).

[0179] Suitable surfactants include ionic surfactants and non-ionic surfactants. Examples of ionic surfactants are lecithin (phosphatidylcholine), bile salts, and detergents. Examples of non-ionic surfactants include monoglycerides, cremophor, polyethylene glycol fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, Solutol HS15, or poloxamers, or combinations thereof. Examples of monoglycerides are glyceryl monocaprylate (also called 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 40), or combinations thereof. Examples of polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan monooleate (Tween 80), polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, or combinations thereof. The commercial preparations of monoglycerides used also contain varying amounts of diglycerides and triglycerides.

[0180] Compositions described herein that include a surfactant generally have a total surfactant content of less than about 12% by weight (e.g., less than about 10% by weight, less than about 8% by weight, less than about 6% by weight, less than about 4% by weight, less than about 2% by weight, or less than about 1% by weight). In certain embodiments of the present invention, the cumulative total of all surfactants is about 6%.

[0181] Methods for making pharmaceutical compositions and resulting compositions Methods for producing the compositions described herein are also included in the present invention. Accordingly, one embodiment of the present invention is a process for producing a pharmaceutical composition, comprising the steps of 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, drying, and suspending the solid powder in a hydrophobic medium to obtain a suspension comprising terlipressin and a medium chain fatty acid salt in a solid form, thereby producing a pharmaceutical composition, suspending, wherein said pharmaceutical composition comprises 10% by weight or more of the medium chain fatty acid salt.

[0182] One embodiment is a process for producing a pharmaceutical composition comprising the steps of providing a solid powder comprising a therapeutically effective amount of a solid powder of terlipressin and a medium chain fatty acid salt, and suspending the solid powder in a hydrophobic medium to obtain a suspension comprising terlipressin in solid form and a medium chain fatty acid salt, thereby producing a pharmaceutical composition, wherein said pharmaceutical composition comprises 10% or more by weight of a medium chain fatty acid salt.

[0183] In one embodiment of the process and composition described herein, the water-soluble composition is an aqueous solution. In certain embodiments, the water-soluble composition is dried by lyophilization (freeze-drying), spray-drying, or granulation. In certain embodiments, the drying step removes a sufficient amount of water so that the water content in the bulk pharmaceutical composition is less than about 6% by weight, less than about 5% by weight, less than about 4% by weight, less than about 3% by weight, or less than about 2% by weight or about 1% by weight or about 0.5% by weight or less. In certain embodiments of the process and composition described herein, the drying step removes an amount of water so that the water content in the solid powder is less than 6% by weight or less than 5% by weight or less than 4% by weight or less than 3% by weight, or preferably less than 2% by weight. The water content is usually low, and water can be adsorbed to the solid phase during lyophilization (i.e., water can be held by intermolecular bonds). In certain embodiments, the water-soluble composition further comprises a stabilizer (e.g., methylcellulose). In a preferred embodiment of the process and composition described herein, the hydrophobic medium is castor oil or glyceryl tricaprylate or glyceryl tributyrate or a combination thereof, and may further include octanoic acid; in certain embodiments, the hydrophobic medium comprises an aliphatic, olefinic, cyclic, or aromatic compound, mineral oil, paraffin, fatty acid (such as octanoic acid), monoglyceride, diglyceride, triglyceride, ether or ester, or a combination thereof. In certain embodiments of the process and composition described herein, the triglyceride is a long-chain triglyceride, a medium-chain triglyceride, preferably glyceryl tricaprylate, or a short-chain triglyceride, preferably glyceryl tributyrate, and the long-chain triglyceride is castor oil or coconut oil or a combination thereof. In certain embodiments of the processes and compositions described herein, the hydrophobic medium comprises castor oil or glyceryl tricaprylate or glyceryl tributyrate or a combination or mixture thereof, and may further comprise octanoic acid. In certain embodiments of the processes and compositions described herein, the hydrophobic medium comprises glyceryl tricaprylate or a low molecular weight ester (e.g., ethyl isovalerate or butyl acetate).In certain embodiments of the processes and compositions described herein, the main component of the hydrophobic medium by weight is castor oil and may further include glyceryl tricaprylate.In certain embodiments of the processes and compositions described herein, the main component of the hydrophobic medium by weight is glyceryl tricaprylate and may further include castor oil.

[0184] In certain embodiments, the composition comprises a suspension consisting essentially of a mixture 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, wherein the medium chain fatty acid salt is present in the composition in an amount of 10% by weight or more.In certain embodiments, the hydrophobic medium consists essentially of castor oil, glyceryl monooleate, and glyceryl tributyrate; or the hydrophobic medium consists essentially of glyceryl tricaprylate and glyceryl monocaprylate; or the hydrophobic medium consists essentially of castor oil, glyceryl tricaprylate, and glyceryl monocaprylate.In certain embodiments, the hydrophobic medium comprises a triglyceride and a monoglyceride, and in certain particular embodiments, the monoglyceride has the same fatty acid radical as the triglyceride. In certain of these embodiments, the triglyceride is glyceryl tricaprylate and the monoglyceride is glyceryl monocaprylate. In certain of these embodiments, the medium chain fatty acid salt in the water-soluble composition has the same fatty acid radical as the medium chain monoglyceride or the medium chain triglyceride or a combination thereof. In certain of these embodiments, the medium chain fatty acid salt is sodium caprylate (sodium octanoate), the monoglyceride is glyceryl monocaprylate and the triglyceride is glyceryl tricaprylate.

[0185] Many of the compositions described herein include suspensions that include a mixture of a hydrophobic medium and a solid form, wherein the solid form includes a therapeutically effective amount of terlipressin and at least one salt of a medium chain fatty acid, wherein the medium chain fatty acid salt is preferably present in the composition in an amount of 10% by weight or more.The solid form can be particulate (e.g., essentially consisting of or consisting of particulate).The particulate can be produced by freeze-drying or granulation or spray-drying. In one embodiment, the formulation consists essentially of or comprises a suspension comprising a mixture of a hydrophobic medium and a solid form, wherein the solid form comprises a therapeutically effective amount of terlipressin and about 10-20%, preferably 15%, of a medium chain fatty acid salt, preferably sodium octanoate, and a polyvinylpyrrolidone polymer; wherein the hydrophobic medium comprises about 20-80%, preferably 30-70%, of a medium or short chain triglyceride, preferably glyceryl tricaprylate or glyceryl tributyrate, about 0-50%, preferably 0-30%, of castor oil, about 3-10% of a surfactant, preferably about 6%, preferably glyceryl monocaprylate, and Tween 80; in certain embodiments, terlipressin is present in an amount less than 33%, or less than 25%, or less than 10%, or less than 3%, or less than 2%.

[0186] In the above formulations the percentages are weight / weight.

[0187] Under normal storage conditions, terlipressin is stable in the formulation of the present invention for extended periods of time. The chemical and physical state of the formulation is stable. Upon administration to the intestine, the formulation is oil-based, thus creating a separate local environment in the intestine where terlipressin is contained in particles suspended in oil, thus providing stability in vivo, thus protecting terlipressin from damage by the GI environment.

[0188] In certain embodiments, the process produces a composition consisting essentially of terlipressin and a medium chain fatty acid salt and a hydrophobic medium. In an embodiment of the invention, the solid powder (solid form) consists essentially of terlipressin and a medium chain fatty acid salt. A further embodiment of the invention is a pharmaceutical composition produced by the process described herein. Certain embodiments of the invention include oral dosage forms comprising the pharmaceutical composition, particularly oral dosage forms that are enteric coated. Further embodiments of the invention include capsules comprising the composition of the invention, in various embodiments the capsules are hard gel capsules or soft gel capsules, and generally the capsules are enteric coated. Other embodiments of the invention include rectal dosage forms (particularly suppositories) or buccal dosage forms comprising the pharmaceutical composition. Kits comprising instructions and dosage forms are also envisioned.

[0189] Terlipressin and / or medium chain fatty acid salts, or any combination of terlipressin and other ingredients (such as protein stabilizers), can be prepared in a mixture solution (e.g., forming an aqueous solution or mixture), 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 material.

[0190] In some embodiments, terlipressin is solubilized in a mixture containing, for example, one or more additional components (such as medium chain fatty acid salts, stabilizers, and / or surfactants), and the solvent is removed to obtain a solid powder (solid form), which is suspended in a hydrophobic medium. In some embodiments, terlipressin and / or medium chain fatty acid salts can be formed into granulated particles, which are then associated with a hydrophobic medium (e.g., suspended in or coated with a hydrophobic medium). If desired, the pharmaceutical composition can also contain trace amounts of non-toxic auxiliary agents (such as pH buffers) and other substances (such as, for example, sodium acetate and triethanolamine oleate).

[0191] In some embodiments, the solid form can be particulate (e.g., consists essentially of or consists of particles). In some embodiments, the particles can be produced by freeze-drying, spray-drying, or granulation. In some embodiments of this process, the fatty acid salt is sodium octanoate; in further embodiments of this process, the medium chain fatty acid salt is present in the composition in an amount of about 11% to about 40% by weight, or in an amount of about 11% to about 28% by weight, or in an amount of about 15% by weight. In some embodiments of this process, the composition further comprises a matrix-forming polymer, and in certain embodiments of this process, the matrix-forming polymer is dextran or polyvinylpyrrolidone polymer (PVP); in further embodiments of this process, the polyvinylpyrrolidone is present in the composition in an amount of about 2% to about 20% by weight, or in an amount of about 4% to about 15% by weight, or in an amount of about 10% by weight. In certain embodiments of this process, the polyvinylpyrrolidone polymer is PVP-12 and / or has a molecular weight of about 3000. The composition can further comprise a surfactant as described above. The solid form may also include a binder. Small amounts of other hydrophobic components as described above may also be present. Pharmaceutical products of these processes are further embodiments of the present invention.

[0192] Capsules: The preferred pharmaceutical composition is an oral dosage form or suppository. Exemplary dosage forms include gelatin capsules or vegetable capsules (such as starch hydroxypropyl methylcellulose ("HPMC") capsules) that are enterically coated and contain the bulk pharmaceutical agent. Capsules that can be used to encapsulate the compositions of the present invention are known in the art and are described in, for example, Pharmaceutical Capsules, 19 ... edited by Podczech and Jones, Pharmaceutical Press (2004) and Hard gelatin capsules This is found in today-and tomorrow, 2nd edition, edited by Steggeman and published by Capsugel Library (2002).

[0193] Tablet: The pharmaceutical composition described herein can also be configured as a tablet. Tablets can be made by tableting or molding, optionally with one or more ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0194] Additional Formulations: The compositions of the present invention can be formulated using additional methods known in the art, for example, as described in the following publications: Pharmaceutical Dosage Forms Vols 1-3 ed. Lieberman, Lachman and Schwartz, published by Marcel Dekker Inc, New York (1989); Water-insoluble Drug Formulation 2nd edition, Liu, editor, published by CRC Press, Taylor and Francis Group (2008); Therapeutic Peptides and Proteins: Formulation, Processing and Delivery Systems, 2nd edition by Ajay K. Banga (author) published by CRC Press, Taylor and Francis Group (2006); Protein Formulation and Delivery,2nd edition,McNally and Hasted eds, published by Informa Healthcare USA Inc(2008); and Advanced Drug Formulation to Optimize Therapeutic Outcomes, Williams et al. eds, published by Informa Healthcare USA(2008).

[0195] The composition of the present invention can be used, for example, in a Microparticulate Oral Drug Drug Delivery, Gerbre-Selassie ed., published by Marcel Dekker Inc (1994) and Dey et al., Multiparticulate Drug Delivery Systems for Controlled Release, Tropical Journal of Pharmaceutical Research, September 2008;7(3):1067-1075.

[0196] kit The oral dosage form can be provided in a pack or dispenser device, such as an FDA approved kit, which can contain one or more unit dosage forms containing the active ingredient, if necessary. The pack can, for example, contain metal or plastic foil (such as a blister pack). The pack or dispenser device can be accompanied by instructions for administration. The pack or dispenser can also be accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which reflects the approval by the agency of the form of composition or administration to humans or animals. Such notice can be, for example, a notice by a label approved by the US Food and Drug Administration for prescription drugs or an approved package insert.

[0197] definition As used herein, the term "pharmacologically or therapeutically effective amount" refers to an 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 being sought by a researcher or clinician and / or halt or reduce the progression of the condition being treated, or otherwise completely or partially cure, transiently affect, or prevent the onset of a condition described herein (e.g., 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 cirrhosis of the liver)).

[0198] "Combined" administration, as used herein, means that two (or more) different therapeutic agents are delivered to a subject during the period in which the subject suffers from a disease (e.g., two or more therapeutic agents are delivered after the subject is diagnosed with a disorder and before the disorder is cured or eliminated or treatment is discontinued for other reasons). In some embodiments, one therapeutic agent is still being delivered at the time delivery of the second therapeutic agent begins, resulting in overlapping administration. This is sometimes referred to herein as "simultaneous" or "concurrent delivery." In other embodiments, delivery of one therapeutic agent ends before delivery of the other treatment agent begins. In some embodiments in either case, the therapeutic agents become more effective due to combined administration. For example, the second therapeutic agent is more effective than would be observed if the second therapeutic agent were administered in the absence of the first therapeutic agent (e.g., an equivalent effect is observed using a smaller amount of the second therapeutic agent, or the second therapeutic agent relieves symptoms and side effects to a greater extent, or a similar situation is observed with the first therapeutic agent). In some embodiments, the therapeutic agents are delivered such that the reduction in symptoms or other parameters associated with the disorder is greater than that observed when one therapeutic agent is delivered in the absence of the other therapeutic agent. The effect of the two therapeutic agents can be partially additive, totally additive, or greater than additive. The effect of the first therapeutic agent delivered can be delivered such that the effect of the second therapeutic agent is still detectable when the second therapeutic agent is delivered.

[0199] As used herein, the term "treatment" (e.g., "method of treatment"), or "treat" or "treating" refers to a therapeutic procedure aimed at reducing, reversing, or preventing the symptoms or side effects of a disease or disorder. In some embodiments, a compound or composition disclosed herein is administered prior to the onset of a disease or disorder. In some embodiments, a compound or composition disclosed herein is administered during or after the onset of a disease or disorder.

[0200] As used herein, the term "treatment that reduces liver fibrosis agent" and the term "liver fibrosis agent" are used interchangeably.Liver fibrosis agent is a drug that is used for the treatment of liver fibrosis and / or nonalcoholic steatohepatitis (NASH) and / or primary biliary cirrhosis.Liver fibrosis agent (drug) that should be used in combination with such oral terlipressin includes pirfenidone, nintedanib, obeticholic acid, urodeoxycholic acid, emricasan, vitamin E, pioglitazone, liraglutide, pentoxifylline, and metformin.Drugs such as pioglitazone, liraglutide, pentoxifylline, and metformin are particularly used for the treatment of NASH.

[0201] The functionality and advantages of these and other embodiments will be better understood from the following examples, which are intended to be illustrative in nature and are not to be considered as limiting the scope of the systems and methods discussed herein. EXAMPLES

[0202] Working Example Example 1. Bioavailability of Terlipressin in Dogs Terlipressin (brand name Glypressin, Ferring) was administered via intravenous (IV) administration to a group of six dogs, and the following proprietary formulation of terlipressin (BCN Peptides) (Table 1) was administered via oral administration as enteric-coated capsules to another group of six dogs. The IV dosage was 0.2 mg / dog, which is similar to the therapeutic dosage in humans. The oral dosage was 20 mg, chosen to assume a BA of approximately 1%. The concentrations 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 in the same manner as for terlipressin. Each Glypressin ampoule contains 1 mg of terlipressin acetate, which is equivalent to 0.85 mg of terlipressin base. All doses in this study are shown based on terlipressin base.

[0203] All animals were fasted for at least 12 hours prior to dosing and until 4 hours prior to the first blood draw.

[0204] For oral terlipressin capsule treatment, each animal received a single subcutaneous (SC) injection of pentagastrin (0.12 mg / mL) at a dose level of 0.006 mg / kg and a dose volume of 0.05 mL / kg approximately 30 minutes prior to dosing to acidify the dog's stomach. The same dog can be used for more than one treatment with a washout period of at least 1 week. Blood was collected at the designated time points as follows:

[0205] IV: pre-dose, 0.083, 0.166, 0.33, 0.66, 1, 1.5, 2, 3, 4, 5, 6, and 9 hours after dosing. Oral capsules: Before dosing, and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5.5, 6.5, 7.5, 9, and 12 hours after dosing.

[0206] The results are shown in FIG. 1A for the intravenous administration group and in FIG. 1B for the oral administration group, and are also shown in Table 2 below.

[0207] Table 1 below provides the compositions containing terlipressin used in this dog study. The formulation contains 10% PVP and 15% sodium octanoate in the hydrophilic fraction, with glyceryl tricaprylate as the major component of the hydrophobic medium. [Table 1]

[0208] Table 2 below shows the Cmax, AUC, and half-life for IV administered terlipressin ("IV terlipressin") and orally administered terlipressin ("oral terlipressin") in this study. [Table 2]

[0209] Note: In the above table, AUC 0-t (hxpg / mL) was calculated by standard methods; AUC=area under the curve, h=time and t(hours)=9 hours for IV and t=12 hours for oral. AUC (inf) (hxpg / mL) where inf = infinity calculated by standard extrapolation.

[0210] These results demonstrate that oral administration of terlipressin produces blood (plasma) levels similar to therapeutic doses.

[0211] Example 2. Oral Terlipressin for the Treatment of Neurogenic Orthostatic Hypotension Patients with neurogenic orthostatic hypotension are randomly assigned to treatment with oral terlipressin (e.g., up to 100 mg twice daily) or placebo in addition to standard care. Patients must fast for at least 2 hours prior to the 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 40 minutes in the supine position, the patient's head is tilted to 45° for 20 minutes, at which point blood pressure and heart rate are measured again.

[0212] Primary endpoint: Change in blood pressure over baseline.

[0213] Secondary endpoints: Measurement of dizziness, dizziness, fainting (loss of consciousness), fatigue, blurred vision, and weakness in an inclined position.

[0214] Example 3. Oral Terlipressin for the Treatment of Ascites Patients confirmed to have ascites (e.g., ascites associated with liver disease (such as cirrhosis (e.g., cirrhosis with or without HRS type 1 or 2), hepatorenal syndrome (HRS) (e.g., HRS type 1 or 2), cardiac disease (e.g., heart failure), or malignant ascites) are given, for example, up to 100 mg of terlipressin per day orally twice daily for treatment ranging from 1 to 28 days. Patients should take the drug at least 1 hour before or at least 2 hours after a meal.

[0215] Primary endpoint: A reduction in the severity of ascites and accumulation of ascites fluid compared to the 28 days prior to treatment. The method is also expected to reduce the number of paracentesis procedures required for removal of ascites fluid over a 28 day period compared to the 28 days prior to treatment initiation, and in some patients paracentesis may be avoided altogether. Additionally, the average amount of ascites fluid removed after initiation of oral terlipressin therapy is expected to be significantly reduced from that prior to treatment initiation.

[0216] Secondary endpoints: An improvement in the patient's health status (achieved safely and without serious side effects) compared to the 28 days before treatment began.

[0217] Example 4. Oral Terlipressin for Secondary Prevention of Esophageal Variceal Bleeding The purpose of this clinical trial is to study the efficacy of beta-blockers (e.g., propranolol) versus oral terlipressin in preventing rebleeding of esophageal varices and improving survival.

[0218] Patients who experience an episode of esophageal bleeding are randomized to receive a beta-blocker (eg, propranolol) or oral terlipressin.

[0219] The beta-blocker propanolol is administered as known in the art (e.g., propranolol is initiated at a dose of 20 mg twice daily). The principle of titration is used to achieve the target heart rate of propranolol. If the medication is well tolerated and the systolic blood pressure is greater than 90 mmHg, the dose is increased every other day until a target heart rate of 55 beats / min is achieved or a maximum dose of 360 mg / day is reached. If intolerable adverse effects occur (systolic blood pressure less than 90 mmHg or heart rate less than 55 beats / min), the dose of the medication is gradually reduced and, if these adverse events persist, finally the medication is discontinued.

[0220] Terlipressin is administered orally at a dosage of 1 to 4 capsules (20 mg each) per day, preferably 1 hour before or 2 hours after a meal.

[0221] Primary endpoint: rebleeding or death from esophageal varices (time frame: 1 year).

[0222] Secondary endpoints: Increase or decrease in size of esophageal varices, appearance of new esophageal varices, and appearance or worsening of portal hypertensive gastropathy and complications (time frame: 1 year).

[0223] Example 5. Oral Terlipressin for the Treatment of Postprandial Hypotension Patients with postprandial hypotension can be randomized into two groups, one treated with oral terlipressin (e.g., up to 100 mg administered to fasting patients 1 hour before the meal test) and the other treated with placebo, with the third group including patients receiving standard care.

[0224] The following tests were performed in all groups before and after the standard meal: ●Heart rate (Time frame: measured continuously throughout the meal test; approximately 4 hours).

[0225] Heart rate is measured 1 hour before and continuously during the meal test, each meal test lasting approximately 4 hours. ●Blood pressure (time frame: measured 1 hour before and continuously during the meal test (approximately 4 hours)).

[0226] Blood pressure is measured continuously during each meal test (approximately 4 hours). • Middle cerebral artery blood flow velocity (Time frame: measured continuously during the meal test (approximately 4 hours)).

[0227] Middle cerebral artery blood flow velocity is measured, for example, by transcranial Doppler, 1 hour before and continuously throughout the meal test (approximately 4 hours). • Serum glucose (time frame: 1 hour before and every 15 minutes during the meal test).

[0228] Serum glucose is measured 1 hour before and every 15 minutes during the meal test. • Serum insulin (time frame: every 15 minutes during the meal test (approximately 4 hours)).

[0229] Serum insulin levels are collected every 15 minutes during the meal trial (approximately 4 hours). • Serum peptides: GIP (gastric inhibitory polypeptide) and GLP-1 (glucagon-like peptide) (time frame: every 15 minutes during the meal test (approximately 4 hours)).

[0230] Serum peptides are collected every 15 minutes during the meal test (approximately 4 hours). • Catecholamines (Time Frame: Measure continuously throughout the meal test (approximately 4 hours)).

[0231] Catecholamine levels are collected continuously during the meal test (approximately 4 hours).

[0232] Primary endpoint: Change in blood pressure between pre- and post-prandial measurements and the difference in change (improvement) between terlipressin and the other two groups.

[0233] Secondary endpoints: Measures postprandial dizziness, drowsiness, fainting (loss of consciousness), fatigue, blurred vision, and weakness.

Claims

[Claim 1] The invention described in this specification.

Images