JP7294807B2 - L-ornithine phenylacetate formulation - Google Patents

Description

INCORPORATION BY REFERENCE OF PRIOR APPLICATIONS and U.S. Patent Application No. 15/133,087, filed April 19, 2016, all of which are expressly incorporated herein by reference in their entireties be

FIELD This application relates to pharmaceutical compositions comprising oral formulations of L-ornithine phenylacetate and various acute and chronic liver diseases and disorders such as acute liver failure, cirrhosis, liver decompensation, portal hypertension, liver Methods and uses of administration to treat hyperammonemia in patients with encephalopathy or urea cycle disorders.

Description Chronic liver disease is characterized by the progressive destruction of liver tissue over time, whereby healthy, regenerating liver tissue is slowly replaced by scar and necrotic tissue. This is known as cirrhosis. Normal liver function is impaired, and scar tissue progressively reduces blood flow through the liver. Due to the loss of normal, regenerating liver tissue, nutrients, hormones, drugs, and toxins are not processed effectively. These include accumulation of ammonia due to abnormal clearance of proteins absorbed through the intestinal tract, abnormal excretion that accumulates bilirubin in the blood and leads to the formation of jaundice, increased sinusoidal pressure that leads to accumulation of fluid in the abdomen (ascites), And scarred liver tissue can become a barrier to blood flow, leading to symptoms including portal hypertension (and portosystemic shunt) leading to increased portal blood pressure and esophageal varices.

Patients with chronic liver disease have a fairly stable clinical condition and may exhibit few or no symptoms. However, such patients are at risk of acute deterioration of their condition, which can lead to acute exacerbation of liver failure. The transition from a 'compensated' state in which the liver can function, albeit at a reduced level, to a 'decompensated' state in which liver function does not work involves the effects of the triggering event. Precipitating events associated with chronic liver disease include gastrointestinal bleeding, infection (sepsis), portal vein thrombosis, and dehydration.

Hepatic encephalopathy (HE) is a common complication of decompensated cirrhosis that has a significant adverse impact on survival even after liver transplantation and is associated with irreversible impairment of cognitive function. there is An estimated 60-70% of subjects with cirrhosis have at least subtle signs of neurocognitive impairment, and HE is the leading diagnosis in hospitalized subjects. Overt HE has a prevalence of approximately 30% in the cirrhotic population and is the leading cause of approximately 150,000 hospitalizations annually in the United States.

Hepatic encephalopathy (HE) is a complex neuropsychiatric disorder that occurs in diverse clinical settings such as acute or chronic liver disease and spontaneous portosystemic shunts. Early in hepatic encephalopathy, subtle mental changes such as poor concentration, confusion, and disorientation occur. In severe cases, hepatic encephalopathy can lead to stupor, coma, brain swelling (cerebral edema), and death. For patients who develop HE as a result of chronic liver disease, the onset of HE is often the result of clinical precipitating events such as gastrointestinal bleeding, sepsis (infection), portal vein thrombosis, or dehydration. .

Gastrointestinal hemorrhage and portosystemic shunts are the result of toxic substances that are normally metabolized by the liver bypassing the liver, entering the systemic circulation, crossing the blood-brain barrier, and causing direct or indirect neurotoxicity to the central nervous system. Allows you to act. Ammonia accumulation is thought to play an important role in the progression of hepatic encephalopathy and multiple organ failure (respiratory, circulatory and renal failure). In addition to ammonia, sepsis (or bacterial peritonitis), which develops shortly after gastrointestinal bleeding, is also a likely factor leading to hepatic encephalopathy.

Liver decompensation can in turn lead to multiple organ failure and hepatic encephalopathy. Early in hepatic encephalopathy, subtle mental changes occur, such as poor concentration or the ability to construct simple objects. In severe cases, hepatic encephalopathy can lead to stupor, coma, brain swelling, and death.

Urea cycle disorders or urea cycle deficiencies are genetic disorders caused by a deficiency in one of the enzymes in the urea cycle responsible for removing ammonia from the bloodstream. Urea is normally carried in the urine and eliminated from the body. In urea cycle disorders, nitrogen accumulates in the form of the toxic substance ammonia and is not removed from the body. It has been reported that sodium phenylbutyrate may be used for the management of this condition. See, for example, Batshaw, M. L. et al., "Alternative pathway therapy for urea cycle disorders: twenty years later," J. Pediatr. (2001) 138 (1 Suppl): S46-S55.

Common therapies for patients with hepatic encephalopathy include strategies to lower ammonia levels. This includes restriction of dietary protein intake, administration of lactulose, neomycin, L-ornithine L-aspartate (LOLA), or sodium benzoate, and cleansing enemas. Currently, commercial products containing phenylacetic acid (e.g., AMMONUL®) are used as ammonia scavengers (binding agents) for the treatment of hyperammonemia due to urea cycle disorder (UCD). , or prodrugs of phenylacetic acid, such as phenylbutyric acid (BUPHENYL®) or glycerol phenylbutyric acid (RAVICTI®). RAVICTI® has also been evaluated in clinical trials and has shown preliminary efficacy for the treatment of hepatic encephalopathy. See, for example, Rockey D. et al., "Randomized, Double-Blind, Controlled Study of Glycerol Phenylbutyrate in Hepatic Encephalopathy," Hepatology, 2014, 59(3):1073-1083. Additionally, L-ornithine phenylacetate has been reported to be an effective treatment for hyperammonemia and hepatic encephalopathy. Jalan et al. reported a clinical study in which data showed that L-ornithine phenylacetate was useful for ammonia lowering. See Jalan et al., "L-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy," Med Hypotheses 2007; 69(5):1064-69. See also U.S. Patent Application Publication Nos. 2008/0119554, 2010/0280119, and 2013/0211135. each of which is incorporated herein by reference in its entirety.

L-ornithine phenylacetate has been granted orphan drug status by the US Food and Drug Administration and given Fast Track designation for the treatment of hyperammonemia and consequent hepatic encephalopathy. L-ornithine phenylacetate is currently under clinical investigation for the treatment of overt HE in patients with decompensated cirrhosis. Patients receive a continuous intravenous infusion of L-ornithine phenylacetate at doses of 10, 15, or 20 g per day for 5 days depending on the baseline severity of liver dysfunction.

Typically, L-ornithine phenylacetate has excellent solubility in water or aqueous solutions. In all known clinical studies of L-ornithine phenylacetate to treat acute or chronic liver disease, L-ornithine phenylacetate has been administered by intravenous infusion for a period of time, e.g. being administered. A need exists to develop alternative routes of administration to improve patient convenience.

Some embodiments of the present disclosure comprise an oral dose of L-ornithine phenylacetate of about 0.1 g to about 10 g and one or more pharmaceutically acceptable excipients or carriers, It relates to oral pharmaceutical formulations. In some embodiments, the formulation provides an immediate release profile of L-ornithine phenylacetate upon oral administration. In some embodiments, the oral dose of L-ornithine phenylacetate is about 2g to about 8g. In one embodiment, the oral dose of L-ornithine phenylacetate is about 5 g. In another embodiment, the oral dose of L-ornithine phenylacetate is about 2.5 g. In some other embodiments, the oral pharmaceutical formulation provides controlled release of L-ornithine phenylacetate.

Some embodiments of the present disclosure include administering an oral pharmaceutical formulation comprising L-ornithine phenylacetate described herein to a subject in need of treatment or amelioration of hyperammonemia. It relates to a method of treating or ameliorating anemia. In some embodiments, the subject has acute liver failure or chronic liver disease. In some embodiments, the subject has cirrhosis or liver decompensation. In some embodiments, the subject has hepatic encephalopathy. Further, in some embodiments, the subject has portal hypertension. In some further embodiments, the chronic liver disease or cirrhosis is classified as Child-Pugh A, B, or C.

Some embodiments of the present disclosure comprise administering an oral pharmaceutical formulation comprising L-ornithine phenylacetate to a subject in need of treatment for hyperammonemia, wherein the pharmaceutical formulation comprises from about 10 μg/mL to about It relates to a method of treating hyperammonemia that results in a plasma Cmax of phenylacetic acid in the range of 150 μg/mL. In some embodiments, the pharmaceutical formulation also provides a plasma Cmax of phenylacetylglutamine ranging from about 5 μg/mL to about 100 μg/mL. In some embodiments, oral pharmaceutical formulations of L-ornithine phenylacetate provide controlled release of L-ornithine phenylacetate following administration. In some other embodiments, oral pharmaceutical formulations of L-ornithine phenylacetate provide immediate release of L-ornithine phenylacetate following administration. In some embodiments, the pharmaceutical formulation comprises an oral dose of L-ornithine phenylacetate from about 0.1 g to about 10 g.

Lines showing the in vivo plasma pharmacokinetic profile of phenylacetic acid (PAA) in humans following administration of controlled release formulations A, B, and C, RAVICTI®, and an immediate release oral formulation of L-ornithine phenylacetate. graph. In Vivo Plasma Alternatives to Phenylacetylglutamine (PAGN) in Humans After Administration of Controlled Release Formulations A, B, and C, RAVICTI®, and Immediate Release Oral Formulation of L-Ornithine Phenylacetate 4 is a line graph showing a dynamics profile; In vivo plasma pharmacokinetic profile of phenylacetic acid (PAA) in subjects with chronic liver disease classification Child Pugh class A after administration of a single dose of 5 g of L-ornithine phenylacetate in four different treatments. It is a line graph. In Vivo Plasma Replacement of Phenylacetylglutamine (PAGN) in Subjects with Child-Pugh Class A Chronic Liver Disease After Administration of a Single Dose of 5 g of L-Ornithine Phenylacetate in Four Different Treatments FIG. 10 is a line graph showing pharmacodynamic profiles. FIG.

Some embodiments of the present disclosure are directed to oral formulations of L-ornithine phenylacetate. Some embodiments of the present formulations provide low dose formulations using comparable phenylacetate at significantly lower doses compared to RAVICTI®. Some such embodiments are immediate release formulations. Other embodiments of the present formulations provide controlled or extended release systems.

DEFINITIONS The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Use of the term "including" and other forms such as "include," "includes," and "included" is not limiting. The use of the term "having" and other forms such as "have," "has," and "had" is not limiting. As used herein, whether in transitional phrases or in the body of the claims, the terms "comprise(s)" and "comprising" shall have an open-ended meaning. shall be interpreted. That is, the above terms are to be interpreted synonymously with the phrases "having at least" or "including at least." For example, the term "comprising" when used in the context of a process means that the process includes at least the recited steps, but may include additional steps. The term "comprising" when used in the context of a compound, composition, formulation, or device means that the compound, composition, formulation, or device includes at least the recited features or components. may include additional features or components.

As used herein, systematic general abbreviations are defined as follows.
AUC: area under the curve AUC _0-t : area under the concentration versus time curve from time=0 (zero) to the time of the last quantifiable concentration AUC _0-inf : plasma concentration time curve extrapolated to infinite time Area CL: total plasma clearance C ₁₂ : drug concentration at 12 hours after drug administration Cmax: maximum plasma concentration F: bioavailability absolute value (%)
hr: time IR: immediate release ORN: ornithine PAA: phenylacetic acid (or phenylacetate as conjugate base)
PAGN: phenylacetylglutamine PD: pharmacodynamic PK: pharmacokinetic

As used herein, the term "immediate release" has its ordinary meaning as understood by those skilled in the art, thus, as a non-limiting example, release from the dosage form in a relatively short period of time after administration. Including drug release.

As used herein, the terms "controlled release" and "long-term release" each have their ordinary meaning as understood by those skilled in the art, and thus, as a non-limiting example, Including the controlled release of drugs from the form. For example, in some embodiments, a controlled release or extended release formulation is one that has a substantially longer release rate than that of a comparable immediate release form. These two terms can be used interchangeably.

As used herein, the term "about" refers to a reference quantity, value, number, proportion, quantity or weight to that kind of quantity, value, number, proportion, amount or weight. Refers to quantities, values, numbers, proportions, amounts, or weights that differ only by the difference that a person skilled in the art would consider. In various embodiments, the term "about" means 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, relative to a reference quantity, value, number, proportion, amount, or weight. Refers to a difference of 2, or 1%.

The term "oral dosage form" as used herein has its ordinary meaning as understood by those skilled in the art, thus non-limiting examples are pills, tablets, cores, capsules, caplets. formulations of drugs in forms that are orally administrable to humans, including loose powders, liquid solutions, or suspensions.

The term "phenylacetic acid" as used herein is also known as benzeneacetic acid or 2-phenylacetic acid. It has the following chemical structure.

As used herein, the term "phenylacetate" refers to the anionic form of phenylacetic acid having the following chemical structure.

The term "L-ornithine phenylacetate" as used herein refers to a compound consisting of the L-ornithine cation and the phenylacetate anion. It has the following chemical structure.

As used herein, the term "phenylacetylglutamine" refers to the product formed by conjugation of phenylacetic acid and glutamine. It is a common metabolite found in human urine. It has the following chemical structure.

As used herein, the term "24-hour conversion rate of phenylacetate to phenylacetylglutamine" refers to the percentage of phenylacetate administered to a patient that is collected in the urine over a 24-hour period. refers to the mass percent converted to

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. include. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions or formulations is contemplated. Supplementary active ingredients can also be incorporated into the compositions or formulations. Additionally, various adjuvants, such as those commonly used in the art, may be included. These and other such compounds are described, for example, in the Merck Index, Merck & Company, Rahway, NJ. Considerations for including various ingredients in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press. .

The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds of the preferred embodiments, and which are not biologically or otherwise undesirable. In many cases, compounds of preferred embodiments are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandel acid. acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., and ammonium, potassium, sodium, calcium, and magnesium salts. is particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, especially isopropyl amines, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, and the like. Many such salts are described in International Publication No. WO 87/05297 to Johnston et al., published September 11, 1987, which is incorporated herein by reference in its entirety. Known in the technical field.

As used herein, "subject" refers to a human or non-human mammal such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, such as a chicken, as well as any It also means other vertebrates or invertebrates.

"Treat," "treatment," or "treating," as used herein, refers to administering a pharmaceutical composition/formulation for prophylactic and/or therapeutic purposes. refers to doing The term "prophylactic treatment" is defined by treating patients who are not already suffering from the disease, but who are predisposed to or otherwise at risk for a particular liver disease, so that the treatment Refers to reducing the likelihood that a patient will develop liver disease. The term "therapeutic treatment" refers to administering treatment to a patient who already has liver disease.

The compositions or formulations described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" contains an amount of the compound suitable for administration to an animal, preferably mammalian, subject in a single dose according to sound medical practice. , compositions/formulations. However, the preparation of a single or unit dosage form contains all of the doses that the dosage form is to be administered once per day or once during the course of treatment, or that the unit dosage form is to be administered in a single dose. does not imply that Such dosage forms are envisioned to be administered once, twice, three times, or more times per day, and although single doses are not specifically excluded, they may be given more than once during the course of treatment. good. Additionally, multiple unit dosage forms may be administered substantially simultaneously to achieve the total intended dose (e.g., two or more tablets may be swallowed by the patient to achieve the full dose). may be used). Those skilled in the art will appreciate that the formulations do not specifically contemplate the entire course of therapy, and that such decisions are left to those skilled in the art of treatment rather than formulation.

As used herein, the act of "providing" includes supplying, obtaining, or administering (including self-administering) the compositions described herein.

As used herein, the term "administering" a drug includes self-obtaining and ingesting the drug by an individual. For example, in some embodiments, an individual obtains a drug from a pharmacy and self-administers the drug according to the methods provided herein.

In any of the embodiments described herein, the method of treatment may alternatively imply use claims, such as Swiss-type use claims. For example, a method of treating fibrosis with a composition may alternatively involve use of the composition in the manufacture of a medicament for treatment of fibrosis, or use of the composition for treatment of fibrosis.

Pharmacokinetic parameters can be determined by comparison to reference standards using clinical trial methods known and accepted by those skilled in the art, for example, as described in the Examples herein. , will be understood by those skilled in the art. Because the pharmacokinetics of a drug can vary from patient to patient, such clinical trials generally include multiple patients and appropriate statistical analysis of the resulting data (eg, ANOVA with 90% confidence level). Comparison of pharmacokinetic parameters can be the basis for dose adjustment, as understood by those skilled in the art.

Low-dose formulations Some embodiments of the present disclosure comprise L-ornithine phenylacetate at a dose of about 0.1 g to about 10 g and one or more pharmaceutically acceptable excipients or carriers. Oral pharmaceutical formulations, including: In some embodiments, the formulation provides an immediate release profile of L-ornithine phenylacetate upon administration (eg, an immediate release oral formulation in the form of a liquid solution or suspension). Other embodiments provide controlled release or extended release profiles. In preferred embodiments, the pharmaceutical formulation is an oral pharmaceutical formulation. In some embodiments, L-ornithine phenylacetate is about 0.5g, about 1g, about 1.5g, about 2g, about 2.5g, about 3g, about 3.5g, about 4g, about 4.5g , about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, or about 10 g, or before Dosage ranges defined by any two of the above values (e.g., about 1 g to about 9 g, about 2 g to about 8 g, about 3 g to about 7 g, about 4 g to about 6 g, about 1 g to about 6 g, about 1 g from about 5 g, from about 1 g to about 4 g, from about 1 g to about 3 g, from about 2 g to about 6 g, from about 2 g to about 5 g, or from about 2 g to about 4 g). In one embodiment, the oral dose is about 2.5g. In another embodiment, the oral dose is about 5g.

In some embodiments, the pharmaceutical formulation is a single unit dosage form. In some other embodiments, the pharmaceutical formulation is in two or more unit dosage forms (ie divided doses). For example, if the oral dose is about 5 g, it may be provided in the form of 4 or 5 tablets each containing about 1.25 g or 1 g of L-ornithine phenylacetate. In some embodiments, the unit dosage form is a tablet, capsule, pill, pellet, free-flowing powder, or liquid. In one embodiment, the unit dosage form is a liquid solution containing 5g of L-ornithine phenylacetate.

In some embodiments, the pharmaceutical formulation is greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, or greater than about 90% in 24 hours of phenylacetate to phenylacetylglutamine. In some further embodiments, the formulation provides greater than about 80% conversion of phenylacetate to phenylacetylglutamine in 24 hours. In some embodiments, conversion efficiency is determined based on excreted urinary phenylacetylglutamine.

In some embodiments, the pharmaceutical formulation is greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, or greater than about 90% in 12 hours of phenylacetate to phenylacetylglutamine. In some further embodiments, the formulation provides greater than about 60% conversion of phenylacetate to phenylacetylglutamine in 12 hours. In some embodiments, conversion efficiency is determined based on excreted urinary phenylacetylglutamine.

The low-dose pharmaceutical formulations described herein may be administered by any suitable route, for example, by oral, intravenous, intragastric, intraperitoneal, or intravascular routes. In one preferred embodiment, the pharmaceutical formulation of L-ornithine is an oral dosage form, such as an oral solution. In another embodiment, the pharmaceutical formulation is an intravenous dosage form.

Methods of Treatment Some embodiments of the present disclosure provide pharmaceutical formulations, particularly oral pharmaceuticals described herein, comprising an effective amount of L-ornithine phenylacetate in subjects in need of treatment or amelioration of hyperammonemia. It relates to a method of treating or ameliorating hyperammonemia comprising orally administering the formulation. In some embodiments, the subject has acute liver failure or chronic liver disease. In some embodiments, the subject has cirrhosis or liver decompensation. In some such embodiments, the chronic liver disease or cirrhosis has a Child-Pugh class A, B, or C classification. Some embodiments comprise identifying a subject with Child-Pugh A liver disease and then administering a composition described herein. Some embodiments comprise identifying a subject with Child-Pugh B liver disease and then administering a composition described herein. In some embodiments, the subject has hepatic encephalopathy. Some embodiments comprise identifying a subject with Child-Pugh C liver disease and then administering a composition described herein. Further, in some embodiments, the subject has portal hypertension. In some embodiments, the subject has a urea cycle disorder. In some other embodiments, the subject has recently discontinued lactulose treatment, e.g., the subject has been off lactulose treatment for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, discontinued for 1 week, 2 weeks, 3 weeks, 4 weeks, or longer.

In some embodiments of the methods described herein, the methods described herein provide a plasma Cmax for phenylacetic acid in the range of about 10 μg/mL to about 150 μg/mL. In some such embodiments, the plasma Cmax for phenylacetic acid is from about 20 μg/mL to about 140 μg/mL. In some such embodiments, the plasma Cmax for phenylacetic acid is from about 30 μg/mL to about 130 μg/mL. In some such embodiments, the plasma Cmax for phenylacetic acid is from about 40 μg/mL to about 120 μg/mL. In some further embodiments, the plasma Cmax for phenylacetic acid is from about 50 μg/mL to about 110 μg/mL.

In some embodiments of the methods described herein, the plasma Cmax of the metabolite phenylacetylglutamine ranges from about 5 μg/mL to about 100 μg/mL. In some such embodiments, the plasma Cmax of the metabolite phenylacetylglutamine is from about 10 μg/mL to about 80 μg/mL. In some such embodiments, the plasma Cmax of the metabolite phenylacetylglutamine is from about 20 μg/mL to about 60 μg/mL. In some such embodiments, the plasma Cmax of the metabolite phenylacetylglutamine is from about 25 μg/mL to about 50 μg/mL. In some further embodiments, the plasma Cmax of the metabolite phenylacetylglutamine is from about 30 μg/mL to about 45 μg/mL.

Some embodiments of the present disclosure comprise administering an oral pharmaceutical formulation comprising L-ornithine phenylacetate to a subject in need of treatment for hyperammonemia, wherein the pharmaceutical formulation comprises from about 10 μg/mL to about It relates to a method of treating hyperammonemia that results in a plasma Cmax of phenylacetic acid in the range of 150 μg/mL. In particular, oral pharmaceutical compositions comprising L-ornithine phenylacetate are about 10 μg/mL, about 15 μg/mL, about 20 μg/mL, about 25 μg/mL, about 30 μg/mL, about 35 μg/mL, about 40 μg/mL, about 45 μg/mL, about 50 μg/mL, about 55 μg/mL, about 60 μg/mL, about 65 μg/mL, about 70 μg/mL, about 75 μg/mL, about 80 μg/mL, about 85 μg/mL, about 90 μg/mL, about 95 μg/mL, about 100 μg/mL, about 105 μg/mL, about 110 μg/mL, about 115 μg/mL, about 120 μg/mL, about 125 μg/mL, about 130 μg/mL, about 135 μg/mL, about 140 μg/mL, It provides a plasma Cmax for phenylacetic acid in the range defined by about 145 μg/mL, or about 150 μg/mL, or any two of the preceding values. In one embodiment, the plasma Cmax level of phenylacetic acid is from about 20 μg/mL to about 140 μg/mL. In another embodiment, the plasma Cmax level of phenylacetic acid is from about 30 μg/mL to about 130 μg/mL. In yet another embodiment, the plasma Cmax level of phenylacetic acid is from about 40 μg/mL to about 120 μg/mL. In a further embodiment, the plasma Cmax level of phenylacetic acid is from about 50 μg/mL to about 110 μg/mL. In some embodiments, the plasma AUC _0-t or AUC _0-inf of phenylacetic acid is from about 100 to about 1000 hr*μg/mL, from about 150 hr*μg/mL to about 900 hr*μg/mL, from about 200 hr*μg/mL /mL to about 800 hr*μg/mL, from about 250 hr*μg/mL to about 700 hr*μg/mL, from about 300 hr*μg/mL to about 650 hr*μg/mL, from about 350 hr*μg/mL to about 600 hr*μg/mL mL, or from about 400 hr*μg/mL to about 550 hr*μg/mL. In some embodiments, the pharmaceutical formulation also provides a plasma Cmax of phenylacetylglutamine ranging from about 5 μg/mL to about 100 μg/mL. In particular, oral pharmaceutical compositions comprising L-ornithine phenylacetate are about 5 μg/mL, about 10 μg/mL, about 15 μg/mL, about 20 μg/mL, about 25 μg/mL, about 30 μg/mL, about 35 μg/mL, about 40 μg/mL, about 45 μg/mL, about 50 μg/mL, about 55 μg/mL, about 60 μg/mL, about 65 μg/mL, about 70 μg/mL, about 75 μg/mL, about 80 μg/mL, about 85 μg/mL, Resulting in a plasma Cmax of phenylacetylglutamine in the range defined by about 90 μg/mL, about 95 μg/mL, or about 100 μg/mL, or any two of the preceding values. In one embodiment, the plasma Cmax for phenylacetylglutamine is from about 10 μg/mL to about 80 μg/mL. In another embodiment, the plasma Cmax for phenylacetylglutamine is from about 20 μg/mL to about 60 μg/mL. In yet another embodiment, the plasma Cmax for phenylacetylglutamine is from about 25 μg/mL to about 50 μg/mL. In some embodiments, the plasma AUC _0-t of phenylacetylglutamine is about 25 hr*μg/mL to about 500 hr*μg/mL, about 50 hr*μg/mL to about 300 hr*μg/mL, about 100 hr*μg/mL /mL to about 200 hr*μg/mL, or from about 120 hr*μg/mL to about 180 hr*μg/mL. In some embodiments, the plasma AUC _0-inf of phenylacetylglutamine is about 25 hr*μg/mL to about 500 hr*μg/mL, or about 50 hr*μg/mL to about 400 hr*μg/mL, about 75 hr* μg/mL to about 300 hr*μg/mL, from about 100 hr*μg/mL to about 250 hr*μg/mL, or from about 150 hr*μg/mL to about 200 hr*μg/mL.

In some embodiments of the methods described herein, the oral pharmaceutical composition is administered under fasting conditions. In some other embodiments, the oral pharmaceutical composition is administered under fed conditions, eg, at the same time as or within 60 minutes after a meal.

In some embodiments of the methods described herein, the oral pharmaceutical formulation of L-ornithine phenylacetate provides controlled release of L-ornithine phenylacetate following administration. In some other embodiments, oral pharmaceutical formulations of L-ornithine phenylacetate provide immediate release of L-ornithine phenylacetate following administration.

In some embodiments of the methods described herein, L-ornithine phenylacetate is about 0.1 g to about 50 g per day, about 0.5 g to about 45 g per day, about 1 g to about 40 g per day , about 1.5 g to about 35 g per day, about 2 g to about 30 g per day, about 2.5 g to about 25 g per day, about 3 g to about 20 g per day, or about 5 g to about 15 g per day. be. In some embodiments, the pharmaceutical formulation is for administration at least once daily. In some further embodiments, the pharmaceutical formulation is for administration more than once a day. In one embodiment, the pharmaceutical formulation is for oral administration three times daily.

In some embodiments of the methods described herein, L-ornithine phenylacetate is administered as a single dose in an amount of about 1.0 g to about 10.0 g. In some further embodiments, L-ornithine phenylacetate is administered as a single dose in an amount of about 2g to about 8g. In various other embodiments, L-ornithine phenylacetate is about 1 g to about 9 g, about 2 g to about 8 g, about 3 g to about 7 g, about 4 g to about 6 g, about 1 g to about 6 g, about 1 g to about 5 g. , about 1 g to about 4 g, about 1 g to about 3 g, about 2 g to about 6 g, about 2 g to about 5 g, or about 2 g to about 4 g. In one embodiment, L-ornithine phenylacetate is administered as a single dose in an amount of about 2.5g. In another embodiment, L-ornithine phenylacetate is administered as a single dose in an amount of about 5g. In some such embodiments, the pharmaceutical formulation containing such amount of L-ornithine phenylacetate is a single oral dosage form. In some other such embodiments, pharmaceutical formulations containing such amounts of L-ornithine phenylacetate are in two or more unit dosage forms. For example, some embodiments include 1 to 5 unit dosage forms each comprising from about 0.1 g to about 2 g of L-ornithine phenylacetate, or from about 0.5 g to about 1.25 g of L-ornithine each. Including administering about 2 to 4 unit dosage forms containing phenylacetate. Some embodiments comprise administering four unit dosage forms each containing about 1.25 g of L-ornithine phenylacetate. Some embodiments comprise administering 5 unit dosage forms each containing about 1 g of L-ornithine phenylacetate. Some other embodiments comprise administering one unit dosage form comprising about 5g of L-ornithine phenylacetate. In one embodiment, the pharmaceutical formulation is administered three times daily. For example, where multiple unit dosage forms are administered at one time, the multiple unit dosage forms are repeated three times daily. In another embodiment, the pharmaceutical formulation is administered once daily.

In some embodiments of the methods described herein, the pharmaceutical formulation is greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, about It provides greater than 80%, or greater than about 90% conversion of phenylacetate to phenylacetylglutamine. In some further embodiments, the pharmaceutical formulation provides greater than about 80% conversion of phenylacetate to phenylacetylglutamine in 24 hours. In some embodiments, conversion efficiency is determined based on excreted urinary phenylacetylglutamine.

In some embodiments of the methods described herein, the pharmaceutical formulation is greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, about It provides greater than 80%, or greater than about 90% conversion of phenylacetate to phenylacetylglutamine. In some further embodiments, the formulation provides greater than about 60% conversion of phenylacetate to phenylacetylglutamine in 12 hours. In some embodiments, conversion efficiency is determined based on excreted urinary phenylacetylglutamine.

In any of the embodiments of plasma Cmax or AUC values described herein, such value may be selected from mean or median plasma Cmax or AUC values. In some embodiments, the plasma Cmax and AUC described herein are achieved following single dose administration of an oral pharmaceutical formulation of L-ornithine phenylacetate. In some other embodiments, the plasma Cmax and AUC described herein are the steady-state plasma Cmax and AUC achieved after multiple dose administration of an oral pharmaceutical formulation of L-ornithine phenylacetate. In some embodiments, plasma Cmax and AUC described herein are measured in the fasting state. In some other embodiments, these PK parameters are measured in the fed state.

Some examples of substances that can serve as pharmaceutically acceptable carriers or excipients thereof are sugars such as lactose, glucose, and sucrose; starches such as corn and potato starch; cellulose and its derivatives such as carboxylate; Malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEENS; humectants such as sodium lauryl sulfate; pyrogen-free water; isotonic saline; and phosphate buffered saline.

In some embodiments, oral dosage forms of L-ornithine phenylacetate may be in the form of liquids, particularly liquid solutions. Oral dosage formulations may also contain conventional pharmaceutically compatible adjuvants, excipients, or carriers, including those commonly used in oral solution formulations detailed herein.

In some embodiments, the oral formulations described herein provide lower doses than heretofore expected. For example, RAVICTI® (glycerol phenylbutyric acid, a preprodrug of phenylacetate) reduces the incidence of hepatic encephalopathy events at a dose of 6 mL twice daily (delivering approximately 1.02 g/mL phenylbutyric acid). Clinical studies have shown that Both the immediate-release and controlled-release oral pharmaceutical formulations of L-ornithine phenylacetate described herein provide similar urinary excretion rates of PAGN and are therefore comparable to RAVICTI® or other phenylacetate formulations. allows the use of substantially lower API doses.
(Example)

The following examples, including experiments and results achieved, are provided for illustrative purposes only and should not be construed as limiting the present application.

Phase I Pharmacokinetic Study in Healthy Humans An open-label, five-drug, five-period, single-dose, cross-over Phase I human clinical study was conducted to investigate three extended-release oral dosage forms of L-ornithine phenylacetate. The pharmacokinetics of phenylacetic acid and phenylacetylglutamine after single dose administration were evaluated in comparison to RAVICTI® (glycerol phenylbutyric acid), a prodrug of phenylacetic acid. The study also compared the pharmacokinetics and safety of three single-dose extended-release oral dosage forms of L-ornithine phenylacetate compared to a single-dose immediate-release oral solution of L-ornithine phenylacetate.

The five treatments are as listed below: Treatments A, B, and C each refer to a single 10 g oral dose of Formulations A, B, and C (each equivalent to about 5 g PAA), which are summarized in Table 1 below, where Treatment D refers to a single 6 mL oral dose of RAVICTI® (equivalent to approximately 5 g PAA) and Treatment E refers to a single 5 g oral dose of Refers to an immediate release formulation of L-ornithine phenylacetate (equivalent to approximately 2.5 g of PAA).

The primary objective was to evaluate the efficacy of phenylacetic acid (a potent ammonia scavenger), ornithine, and phenylacetylglutamine (ammonia elimination) after a single oral dose of three long-release formulations of L-ornithine phenylacetate in healthy human subjects. To assess the plasma profile and pharmacokinetics of L-ornithine phenylacetate in oral solution and a prodrug of phenylacetic acid (glycerol phenylbutyric acid, RAVICTI®) in comparison. A secondary objective is to determine the safety, tolerability, and palatability of the three extended-release formulations in healthy subjects.

Eligible male or female healthy adult subjects were enrolled initially in a crossover fashion using a balanced 4x4 Latin square design with at least a 7-day washout period between each treatment. , four treatments (Treatments AD) over four dosing periods, followed by treatment E in the fifth (final) dosing period after a minimum of 7-day washout period. rice field. After dosing in each dosing period, subjects underwent serial blood and urine sampling up to 24 hours post-dose for PK assessment.

PK Assessment Venous blood samples (5 mL each) were taken at : Immediately before dosing (within 15 minutes), then 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours after dosing, Samples were taken at 8, 10, 12, 16, 20 and 24 hours. In the dosing period in which the immediate release formulation of L-ornithine phenylacetate was administered (Period 5), venous blood samples (5 mL each) were taken at the following time points: immediately before dosing (within 15 minutes), then 0.25 hours after dosing, 0 .5 hours, 0.75 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, Samples were taken at 8, 10, and 12 hours.

In addition, urine samples were collected at the following time intervals: within 1 hour prior to dosing (spot samples), then cumulatively over intervals of 0-4 hours, 4-8 hours, 8-12 hours, and 12-24 hours after dosing. Taken. Plasma samples were separated by centrifugation within 1 hour of blood collection and stored at approximately −80° C. until analysis. Total urine volume was measured and recorded at each collection interval and urine aliquots were stored at approximately −80° C. until analysis.

Biochemical Analytical Methods A validated LC-MS/MS method was used to analyze the concentrations of phenylacetic acid (PAA), phenylacetylglutamine (PAGN), and ornithine (ORN) in plasma samples. A validated LC-MS/MS method was used to analyze the concentration of PAGN in all urine samples.

Endpoints Pharmacokinetics: Plasma concentration versus time profiles of phenylacetate, ornithine, and phenylacetylglutamine after a single oral dose of each of the study drugs were analyzed by non-compartmental PK methods. Pharmacokinetic parameters determined include C _max , t _max , AUC _0-t , AUC _0-∞ , C ₁₂ , and t _1/2 . The amount of PAGN excreted in urine and the percentage of PAA dose excreted as PAGN in urine for each collection interval and over the 24-hour interval were also determined.

Figures 1 and 2 illustrate the mean plasma profiles of PAA and PAGN, respectively, in this Phase 1 study. FIG. 1 shows mean plasma PAA concentration versus time curves following administration of a single oral dose controlled release formulation compared to immediate release solution and glycerol phenylbutyrate. FIG. 2 shows mean plasma PAGN concentration versus time curves following administration of a single oral dose controlled release formulation compared to immediate release solution and glycerol phenylbutyrate.

Mean maximum concentrations (Cmax) of plasma PAA from the three extended-release formulations ranged from approximately 50-90 μg/mL at various time points over 4-9 hours after dosing. For comparison, RAVICTI® produced a mean plasma PAA Cmax of approximately 10 μg/mL at 4-6 hours after dosing. Plasma PAA data following a single oral dose of RAVICTI® 6 mL are consistent with published data in healthy subjects. In addition, PAA exposure using an extended release formulation of L-ornithine phenylacetate showed less inter-subject variability than RAVICTI®.

The plasma profile of PAGN, the end product of ammonia scavenging, also showed a similar pattern to the PAA profile. Mean Cmax of plasma PAGN with the three extended-release formulations of L-ornithine phenylacetate ranged from approximately 30-45 μg/mL at various time points over 4-10 hours after dosing. For comparison, RAVICTI® produced a mean plasma PAGN Cmax of approximately 20-25 μg/mL at approximately 5 hours. These data are also consistent with published data in healthy subjects.

The total urinary excretion data for PAGN over 24 hours are summarized in Table 2 below. Mean PAGN excretion was comparable for treatments A through C, each of which converted about 80% of PAA to PAGN excretion over 24 hours. In contrast, treatment D with RAVICTI® showed only about 40% conversion efficiency compared to treatments A to C at approximately the same PAA molar dose (for RAVICTI®, PAA is provided from a glycerol phenylbutyric acid prodrug). Surprisingly, treatment E, an immediate release formulation, also showed a conversion efficiency of approximately 80%, resulting in similar mean PAGN excretion at roughly half the molar dose of PAA administered in the RAVICTI® arm. was observed.

Conclusions: Controlled-release and immediate-release formulations were well tolerated throughout the study, with no observed toxicity or serious adverse events. These results demonstrate robust long-term results for all three extended-release formulations, with mean plasma PAA concentrations exceeding those achieved with RAVICTI® (glycerol phenylbutyric acid) at all time points for at least 24 hours after dosing. showed the release pattern. In addition, mean plasma PAGN concentrations and urinary PAGN excretion rates were higher for all three extended release dosage forms than for RAVICTI® at approximately the same PAA molar doses. It was also shown that the immediate release formulation of L-ornithine phenylacetate was approximately twice as efficient in urinary PAGN excretion as RAVICTI®.

Phase I Pharmacokinetic Study in Child-Pugh Class A Subjects In this example, a single-dose, partially randomized clinical study was conducted in five subjects with liver cirrhosis (Child-Pugh class A), taking A 5 g L-ornithine phenylacetate oral solution administered under fed, fasted, or fasted conditions after lactulose discontinuation was evaluated. The objective was to administer a single dose of 5 g of L-ornithine phenylacetate oral solution under fed, fasted, or fasted after lactulose discontinuation in subjects with liver cirrhosis (Child-Pug class A). to determine the pharmacokinetics of PAA and PAGN after administration in comparison to a single intravenous dose of 5 g of L-ornithine phenylacetate under fasting conditions.

These treatments are summarized as follows: Treatment A was a single oral dose of 5 g of L-ornithine phenylacetate oral solution administered under fasting conditions and Treatment B was administered under fed conditions. Treatment C was a single intravenous dose of 5 g of L-ornithine phenylacetate oral solution infused over 1 hour under fasting conditions; Treatment D is a single oral dose of 5 g of L-ornithine phenylacetate oral solution administered under fasting conditions after lactulose withdrawal.

Eligible subjects received a single dose of study drug on Day 1. Subjects were restricted to Phase 1 units from Day 1 enrollment until the final blood sample for pharmacokinetic assessment was obtained. In Dosing Period 1, all subjects received L-ornithine phenylacetate intravenously (Treatment C), and in Dosing Period 4, all subjects received a single dose of L-ornithine phenylacetate oral solution after lactulose discontinuation. (Treatment D). Treatments A and B were administered in a randomized fashion during dosing periods 2 and 3. At the end of dosing periods 1, 2, and 3, subjects returned to the clinic for the next dosing period. At the end of dosing period 3, all subjects discontinued lactulose. There was a minimum 4-day washout period between consecutive dosing periods.

Pharmacokinetic Assessment After each oral dose (Treatments A, B, and D), venous blood samples (5 mL each) were taken at the following time points: immediately before dosing (within 15 minutes), then 0.25 hours, 0.5 hours after dosing. , 0.75 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, and 12 hours taken in time. For Treatment D (dosing period 4), an additional blood sample was obtained 24 hours after dosing. After intravenous dosing (Treatment C), venous blood samples (5 mL each) were taken at the following time points: just before the start of the infusion (within 15 minutes), then 0.5 hours after the start of the infusion, and just before the end of the infusion, then the infusion. 10 minutes, 20 minutes, 30 minutes, 45 minutes, and 60 minutes after the end of the infusion, then 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours after the end of the infusion, Harvested at 12 hours and 24 hours.

In addition, urine samples were collected for each treatment at the following time intervals: within 1 hour pre-dose (spot samples), then cumulatively over intervals of 0-4 hours, 4-8 hours, and 8-12 hours post-dose. Taken. For treatments C and D (dosing periods 1 and 4), urine was also collected at intervals of 12-24 hours after dosing.

Figures 3 and 4 illustrate the mean plasma profiles of PAA and PAGN, respectively, in this Phase 1 study. FIG. 3 shows mean plasma PAA concentration versus time curves following administration of the four treatments described above (Treatments A, B, C, and D). FIG. 4 shows mean plasma PAGN concentration versus time curves after administration of the four treatments described above (Treatments A, B, C, and D). Pharmacokinetic parameters of PAA and PAGN are summarized in Tables 3 and 4.

Plasma exposure data and PK parameter estimates for PAA in Child-Pugh A subjects after a single oral dose of L-ornithine phenylacetate 5 g were as expected based on predictions from historical data in healthy subjects. .

Based on a small number of subjects, in this study, after a single oral dose of L-ornithine phenylacetate 5 g in Child-Pugh A subjects, mean peak plasma PAA concentrations (Cmax) were slightly (20 %), indicating that the overall plasma exposure to PAA (AUC _0-inf ) was approximately 30% higher. The slightly higher AUC values in the Child-Pug A subjects are most likely due to the slow metabolism of PAA and the long elimination half-life of PAA in the Child-Pug A subjects, which is similar to that of healthy subjects. It increased from approximately 0.9 hours in subjects to 1.4 hours in Child-Pugh A subjects. There was great inter-subject variability in plasma PAA exposure following either intravenous or oral administration of L-ornithine phenylacetate.

L-ornithine phenylacetate, as demonstrated by an absolute PAA bioavailability value (F) of 96% determined compared to intravenous dosing in Child-Pugh A subjects after a single oral dose of L-ornithine phenylacetate 5 g PAA was almost completely bioavailable after oral dosing of acetate.

In subjects receiving lactulose, the plasma profile and pharmacokinetics of PAA and PAGN from administration of a single oral dose of L-ornithine phenylacetate appeared similar before and after lactulose was washed out.

Plasma exposure and pharmacokinetic profiles of PAGN were evaluated across four treatments in Child-Pugh A subjects: a single oral dose of L-ornithine phenylacetate 5 g, with or without food, or without lactulose. After dose they were comparable. The mean AUC _0-inf of PAGN in Child-Pugh A subjects was slightly (approximately 10%) lower than in healthy subjects. The mean plasma half-life of PAGN in Child-Pugh subjects was 2.6 hours, longer than 1.4 hours in healthy subjects.

Urinary excretion data show that the mean PAA dose rate recovered in the urine as PAGN was 78.3% after a single IV dose of L-ornithine phenylacetate, and 78.3% after a single oral dose of L-ornithine phenylacetate. (Treatment D) showed later that it was 84.7%. The lower PAA dose % recovered in urine as PAGN in treatments A and B may be due to the short urine collection interval, ie, 12 hours.
The present invention also includes the following aspects.
<1> An oral pharmaceutical preparation comprising an oral dosage of about 0.1 g to about 10 g of L-ornithine phenylacetate and one or more pharmaceutically acceptable excipients or carriers.
<2> The oral pharmaceutical formulation according to 1 above, which provides an immediate release profile of L-ornithine phenylacetate upon oral administration.
<3> The oral pharmaceutical formulation according to 1 above, wherein the oral dose of L-ornithine phenylacetate is about 2.5 g.
<4> The oral pharmaceutical preparation according to 1 above, wherein the oral dose of L-ornithine phenylacetate is about 5 g.
<5> The oral pharmaceutical preparation according to any one of 1 to 4 above, which is a single unit dosage form.
<6> The oral pharmaceutical preparation according to any one of 1 to 5 above, which is in two or more unit dosage forms.
<7> The oral pharmaceutical formulation of 6 above, wherein the unit dosage form is a tablet, capsule, pill, pellet, free-flowing powder, or liquid.
<8> The oral pharmaceutical formulation of 7 above, wherein the unit dosage form is a liquid solution.
<9> The oral pharmaceutical formulation according to any one of 1 to 8 above, which provides more than about 30% conversion of phenylacetate to phenylacetylglutamine in 24 hours.
<10> The oral pharmaceutical formulation of 9 above, which provides greater than about 50% conversion of phenylacetate to phenylacetylglutamine in 24 hours.
<11> The oral pharmaceutical formulation of 10 above, which provides greater than about 80% conversion of phenylacetate to phenylacetylglutamine in 24 hours.
<12> A method for treating or relieving hyperammonemia, comprising orally administering the oral pharmaceutical preparation according to any one of 1 to 11 above to a subject in need of treatment or remission of hyperammonemia Method.
<13> The method of Claim 12, wherein said oral pharmaceutical formulation provides a plasma Cmax of phenylacetic acid of about 10 μg/mL to about 120 μg/mL.
<14> The method according to 13 above, wherein the plasma Cmax of phenylacetic acid is from about 20 μg/mL to about 110 μg/mL.
<15> The method of any one of 12 to 14 above, wherein the oral pharmaceutical formulation provides a plasma Cmax of phenylacetylglutamine of about 10 μg/mL to about 80 μg/mL.
<16> The method according to 15 above, wherein the plasma Cmax of phenylacetylglutamine is about 20 μg/mL to about 45 μg/mL.
<17> comprising orally administering a pharmaceutical formulation comprising L-ornithine phenylacetate to a subject in need of treatment or amelioration of hyperammonemia, wherein said administration ranges from about 10 μg/mL to about 150 μg/mL A method for treating or ameliorating hyperammonemia that results in a plasma Cmax of phenylacetic acid of
<18> The method of 17 above, wherein the plasma Cmax level of phenylacetic acid is from about 20 μg/mL to about 140 μg/mL.
<19> The method of 18 above, wherein the plasma Cmax level of phenylacetic acid is from about 30 μg/mL to about 130 μg/mL.
<20> The method of 19 above, wherein the plasma Cmax level of phenylacetic acid is from about 40 μg/mL to about 120 μg/mL.
<21> The method of any of above 17-20, wherein said administering results in a plasma Cmax of phenylacetylglutamine ranging from about 5 μg/mL to about 100 μg/mL.
<22> The method according to 21 above, wherein the plasma Cmax of phenylacetylglutamine is about 10 μg/mL to about 80 μg/mL.
<23> The method of 22 above, wherein the plasma Cmax of phenylacetylglutamine is from about 20 μg/mL to about 60 μg/mL.
<24> The method of 23 above, wherein the plasma Cmax of phenylacetylglutamine is about 25 μg/mL to about 50 μg/mL.
<25> comprising orally administering a pharmaceutical formulation comprising L-ornithine phenylacetate to a subject in need of treatment or amelioration of hyperammonemia, wherein said administering is from about 100 hr*μg/mL to about 1000 hr*μg/mL A method for treating or ameliorating hyperammonemia that results in a plasma AUC _0-t or AUC _0-inf of phenylacetic acid in the range/mL .
<26> The method of 25 above, wherein the plasma AUC _0-t or AUC _0-inf of phenylacetic acid is from about 200 hr*μg/mL to about 800 hr*μg/mL.
<27> The method of 26 above, wherein the plasma AUC _0-t or AUC _0-inf of phenylacetic acid is from about 350 hr*μg/mL to about 600 hr*μg/mL.
<28> The method of 26 above, wherein the plasma AUC _0-t or AUC _0-inf of phenylacetic acid is from about 400 hr*μg/mL to about 550 hr*μg/mL.
<29> The method according to any one of 25 to 28 above, wherein the plasma AUC 0-t or _AUC 0 _-inf of phenylacetylglutamine is from about 25 hr*μg/mL to about 500 hr*μg/mL.
<30> The method of 29 above, wherein the plasma AUC _0-t of phenylacetylglutamine is from about 50 hr*μg/mL to about 300 hr*μg/mL.
<31> The method of 30 above, wherein the plasma AUC _0-t of phenylacetylglutamine is from about 100 hr*μg/mL to about 200 hr*μg/mL.
<32> The method of 31 above, wherein the plasma AUC _0-t of phenylacetylglutamine is from about 120 hr*μg/mL to about 180 hr*μg/mL.
<33> The method of 29 above, wherein the plasma AUC _0-inf of phenylacetylglutamine is from about 50 hr*μg/mL to about 400 hr*μg/mL.
<34> The method of 33 above, wherein the plasma AUC _0-inf of phenylacetylglutamine is from about 75 hr*μg/mL to about 300 hr*μg/mL.
<35> The method of 34 above, wherein the plasma AUC _0-inf of phenylacetylglutamine is from about 100 hr*μg/mL to about 250 hr*μg/mL.
<36> The method of 35 above, wherein the plasma AUC _0-inf of phenylacetylglutamine is from about 150 hr*μg/mL to about 200 hr*μg/mL.
<37> The method according to any one of 25 to 36 above, wherein the pharmaceutical preparation is selected from any one of 1 to 11 above.
<38> The method of any one of 12 to 37 above, wherein the subject has acute liver failure or chronic liver disease.
<39> The method of 38 above, wherein the subject has cirrhosis or liver decompensation.
<40> The method of 38 or 39 above, wherein the chronic liver disease or cirrhosis has a Child-Pugh class A, B, or C classification.
<41> The method of any one of 12 to 37 above, wherein the subject has hepatic encephalopathy.
<42> The method of any one of 12 to 37 above, wherein the subject has portal hypertension.
<43> The method of any one of 12 to 37 above, wherein the subject has a urea cycle disorder.
<44> The method of any one of 12 to 43 above, wherein the oral pharmaceutical formulation provides immediate release of L-ornithine phenylacetate.
<45> The method of any one of 12 to 44 above, wherein the oral pharmaceutical formulation is administered at least once a day.
<46> The method of any one of 12 to 45 above, wherein the oral pharmaceutical formulation is administered two or more times a day.
<47> The method of any of above 12-46, wherein said administering results in greater than about 30% conversion of phenylacetate to phenylacetylglutamine in 24 hours.
<48> The method of Claim 47, wherein said administering results in greater than about 50% conversion of phenylacetate to phenylacetylglutamine in 24 hours.
<49> The method of Claim 48, wherein said administering results in greater than about 80% conversion of phenylacetate to phenylacetylglutamine in 24 hours.
<50> The method of any of 12-49 above, comprising orally administering 1 to 5 unit dosage forms, each containing from about 0.1 g to about 2 g of L-ornithine phenylacetate.
<51> The method of any of 12-50 above, comprising orally administering 2 to 4 unit dosage forms, each containing from about 0.5 g to about 1.25 g of L-ornithine phenylacetate.

Claims (16)

An immediate release oral pharmaceutical formulation for treating or ameliorating hyperammonemia comprising L-ornithine phenylacetate, comprising:
The formulation comprises L-ornithine phenylacetate in an amount of 8 g to 12 g per day, and when administered orally, 10 μg/mL to 150 μg/mL, 20 μg/mL to 140 μg/mL, 30 μg/mL to 130 μg/mL. , or resulting in a plasma Cmax of phenylacetic acid ranging from 40 μg/mL to 120 μg/mL;
Said immediate release oral pharmaceutical formulation, wherein said formulation is administered once a day or more than once a day . plasma of phenylacetylglutamine in the range of 5 μg/mL to 100 μg/mL, 10 μg/mL to 80 μg/mL, 20 μg/mL to 60 μg/mL, or 25 μg/mL to 50 μg/mL upon oral administration; 2. The immediate release oral pharmaceutical formulation of claim 1, which provides Cmax. 100 hr*μg/mL to 1000 hr*μg/mL, 200 hr*μg/mL to 800 hr*μg/mL, 350 hr*μg/mL to 600 hr*μg/mL, or 400 hr*μg/mL when the formulation is administered orally 3. The immediate release oral pharmaceutical formulation of claim 1 or 2, which provides a plasma AUC _0-t or AUC _0-inf of phenylacetic acid in the range of /mL to 550 hr*μg/mL. Plasma AUC _0-t or AUC _0-inf of phenylacetylglutamine between 25 hr*μg/mL and 500 hr*μg/mL, 50 hr*μg/mL and 300 hr*μg/mL, 100 hr*μg/mL and 200 hr*μg/mL mL, or from 120 hr*μg/mL to 180 hr*μg/mL. Plasma AUC _0-inf of phenylacetylglutamine between 50 hr*μg/mL and 400 hr*μg/mL, 75 hr*μg/mL and 300 hr*μg/mL, 100 hr*μg/mL and 250 hr*μg/mL, or 150 hr*μg/mL 4. The immediate release oral pharmaceutical formulation of claim 3, wherein the μg/mL-200hr*μg/mL. 6. Any of claims 1-5, wherein the subject has one or more selected from the group consisting of acute liver failure, chronic liver disease, liver decompensation, and liver cirrhosis having a Child-Pugh Class A, B, or C classification. The immediate release oral pharmaceutical formulation according to any one of claims 1 to 3. 7. The immediate release oral pharmaceutical formulation of any one of claims 1-6, wherein the subject has hepatic encephalopathy or portal hypertension. 6. The immediate release oral pharmaceutical formulation of any one of claims 1-5, wherein the subject has a urea cycle disorder. 9. The immediate release oral pharmaceutical formulation of any one of claims 1 to 8 , wherein said immediate release oral pharmaceutical formulation is administered twice daily and each dose comprises 4g to 6g of L-ornithine phenylacetate. 10. The immediate release oral pharmaceutical formulation of Claim 9 , wherein said 4g to 6g of L-ornithine phenylacetate is in a single unit dosage form. 10. The immediate release oral pharmaceutical formulation of Claim 9 , wherein said 4g to 6g of L-ornithine phenylacetate is in two or more unit dosage forms. 12. The immediate release oral pharmaceutical formulation of claim 11 , wherein said 4g to 6g of L-ornithine phenylacetate is in 4 to 6 unit dosage forms, each containing 1g of L-ornithine phenylacetate. 13. The immediate release oral pharmaceutical formulation of any one of claims 10-12 , wherein said unit dosage form is a tablet, capsule, pill, pellet, free-flowing powder, or liquid. 14. The immediate release oral pharmaceutical formulation of any one of claims 1-13 , wherein the formulation provides greater than 50% conversion of phenylacetate to phenylacetylglutamine in 24 hours. 15. The immediate release oral pharmaceutical formulation of Claim 14 , wherein said formulation provides greater than 80% conversion of phenylacetate to phenylacetylglutamine in 24 hours. 16. The immediate release oral pharmaceutical formulation of any one of claims 1-15 , wherein the formulation is administered with a meal.

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