CN108366983A

CN108366983A - L-ornithine phenyl acetate preparation

Info

Publication number: CN108366983A
Application number: CN201680066488.5A
Authority: CN
Inventors: L·王; L·S·格莱斯; S·布科夫策尔
Original assignee: Ocera Therapeutics Inc
Current assignee: Ocera Therapeutics Inc
Priority date: 2015-11-13
Filing date: 2016-11-11
Publication date: 2018-08-03
Also published as: EP3373923A4; MX2018005088A; AU2016353350B2; CA3004331A1; WO2017083758A1; RU2018113801A; AU2016353350A1; SG11201802987UA; EP3373923A1; MX2022001517A; IL258630B1; BR112018009349A2; JP2022058446A; JP7294807B2; KR20180086431A; IL258630B2; CN113768863A; AU2021290236A1; BR112018009349A8; IL258630A

Abstract

Some embodiments of the application are related to the oral preparation and its application method of L ornithine phenylacetates.These oral preparations provide the replacement administration route being administered in the standard IV of L ornithine phenylacetates, and various acute and chronic liver diseases and illness such as acute hepatic failure, hepatic sclerosis, liver decompensation, portal hypertension, the hyperammonemia of the patient of hepatic encephalopathy or urea cycle disorder patient are suffered from for treatment.

Description

L-ornithine phenyl acetate preparation

It is included in priority application by reference

This application claims 62/255,300, the 2016 year January 8 of U.S. Provisional Patent Application No. submitted on November 13rd, 2015 The U.S. Provisional Patent Application No. 62/276,754 that day submits and the U.S. Application No. 15/133 submitted on April 19th, 2016, The interests of 087 priority；The full content of all these applications is expressly incorporated into this specification by reference herein.

Background technology

Field

This application involves the pharmaceutical composition comprising L-ornithine phenyl acetate oral preparation and medication and it is used for Treatment suffers from various acute and chronic liver diseases and illness (such as acute hepatic failure, hepatic sclerosis, liver decompensation, the high blood of portal vein Pressure, hepatic encephalopathy) patient or urea cycle disorder patient hyperammonemia purposes.

Description

Chronic hepatic diseases are characterized in that hepatic tissue is gradually destroyed at any time, thus health and regenerated hepatic tissue slowly It is substituted by cicatricial tissue and slough.This phenomenon is known as hepatic sclerosis.Normal liver function is damaged, and cicatricial tissue Make to gradually decrease by the blood flow of liver.As normal regenerating hepatic tissue is lost, nutrients, hormone, drug and toxin are just No longer it is processed.This can lead to a variety of symptoms, including：Removing by the protein of intestinal absorption is abnormal, leads to ammonia Accumulation；Diacrisis leads to the accumulation of blood mesobilirubin, generates jaundice；Sinus pressure increases, and leads to abdomen hydrops (ascites)； And portal hypertension (and Door deformation), the wherein ulotic hepatic tissue of shape play the role of blood flow barrier, cause door quiet Arteries and veins blood pressure increases and varices of esophagus.

Chronic hepatic diseases patient can be at the clinical state of quite stable, and shows seldom symptom or do not show Go out symptom.However, this kind of patient has the risk that its illness deteriorates suddenly, this can lead to acute-on-chronic liver failure.It is this from liver Can work (although under level of reduction) " compensatory " state to not active " decompensation " state of liver turn Become related with the effect of accident.With the relevant accident of chronic hepatic diseases include gastrointestinal bleeding, infection (pyemia), Portal vein thrombosis and dehydration.

Hepatic encephalopathy (HE) is the common complication of Decompensational cirrhosis；Even if it still has survival rate after liver transfer operation There is significant negative effect, and it is related with the irreversible damage of cognitive function.Estimate the hepatic sclerosis subject of 60-70% extremely Slight sign with neurocognitive impairment less, and HE is the Main Diagnosis of subject in hospital.Dominant HE is in cirrhotic population In incidence be about 30%, and in the U.S. every year there are about 150,000 people since dominant HE is hospitalized.

Hepatic encephalopathy (HE) is that one kind betiding for example acute or chronic liver diseases of various clinical condition and spontaneous door body Complicated neuropsychiatric illness in venous shunt.Early stage hepatic encephalopathy, slight spirit variation such as attention occurs not Concentration, confusion of consciousness and disorientation.In severe cases, hepatic encephalopathy can lead to numb, stupor, Brain edema (brain edema) And death.For the patient of HE occurs because of chronic hepatic diseases, the morbidity of HE is it is usually because clinical accident such as stomach and intestine Bleeding, pyemia (infection), portal vein thrombosis or dehydration.

Gastrointestinal bleeding and door body venous shunt enable and are usually entered around liver by the toxicant of liver metabolism Body circulation, and across blood brain barrier and Central nervous system generates direct or indirect neurotoxic effect.Ammonia accumulation is recognized To play an important role in the progress of hepatic encephalopathy and multiple organ failure (respiratory failure, cardiovascular failure, kidney failure).Except ammonia it Outside, the septicemia (or bacterial peritonitis) occurred soon after gastrointestinal bleeding is also likely to be the precipitating factor of hepatic encephalopathy.

Thus liver decompensation can lead to multiple organ failure and hepatic encephalopathy.Early stage hepatic encephalopathy, slight essence occurs God's variation is such as absent minded or cannot build simple objects.In severe cases, hepatic encephalopathy can cause numb, confused Fan, Brain edema and death.

Urea cycle disorder or urea cycle defect are by lacking a kind of be responsible for from blood flow except deammoniation in urea cycle Enzyme caused by genetic block.In general, urea is transferred in urine and is removed from internal.In urea cycle disorder, nitrogen It is accumulated in the form of ammonia (noxious material), and will not be from internal discharge.It is reported that phenylbutyrate sodium can be used for handling this disease Disease.See, e.g. Batshaw, M.L. et al., " Alternative pathway therapy for urea cycle disorders:Twenty years later, " J.Pediatr. (2001) 138 (supplementary issue 1)：S46-S55.

Routine treatment to hepatic encephalopathy includes reducing the strategy of ammonia density.These strategies include restrict meal albumen The intake of matter；Give lactulose, neomycin, L-Orn L-Aspartic acid salt (LOLA) or sodium benzoate；And cleansing enema. Have currently on the market containing phenylacetic acid (such as) or phenylacetic acid prodrug (such as phenylbutyrateOr phenylbutyric acid glyceride) product as ammonia scavenger (in conjunction with Agent), for treating the hyperammonemia caused by urea cycle disorder (UCD).Also in clinical test It is assessed, and shows the primary efficacy for the treatment of hepatic encephalopathy.See, e.g., Rockey D. et al., “Randomized,Double-Blind,Controlled Study of Glycerol Phenylbutyrate in Hepatic Encephalopathy,”Hepatology,2014,59(3):1073-1083.In addition, it was reported that L-Orn benzene Acetate is effective therapeutic agent of hyperammonemia and hepatic encephalopathy.Jalan et al. reports a clinical research, and wherein data are aobvious Show that L-ornithine phenyl acetate is beneficial to reduce ammonia.Referring to Jalan et al., " L-Ornithine phenylacetate (OP):a novel treatment for hyperammonemia and hepatic encephalopathy,”Med Hypotheses 2007；69(5):1064-69.Referring further to US publication 2008/0119554,2010/0280119 and 2013/0211135, The full content of middle each single item is included in this specification by reference herein.

L-ornithine phenyl acetate has been authorized the status of seldom used medicine by Food and Drug Adminstration of the US, and is approved for controlling Treat the fast track designation of hyperammonemia and combined hepatic encephalopathy.It is lost currently, L-ornithine phenyl acetate is in for treating In the clinical research of the dominant HE of Compensated cirrhosis patient.According to the baseline severity of hepar damnification, patient receives continuous Intravenous infusion L-ornithine phenyl acetate, dosage are daily 10,15 or 20g, continue 5 days.

In general, L-ornithine phenyl acetate has excellent dissolubility in water or aqueous solution.For treat it is acute or In all known clinical researches of the L-ornithine phenyl acetate of chronic hepatic diseases, L-ornithine phenyl acetate is ground in the mankind By intravenous infusion, (such as 1 day or for up to 5 days) is given for a period of time in studying carefully.Need exploitation substitute administration route with Improve the convenience of patient.

Invention content

Some embodiments of present disclosure are related to oral drug preparation, are about 0.1g to about it includes oral dose The L-ornithine phenyl acetate of 10g and one or more pharmaceutically acceptable excipient or carrier.In some embodiments In, the preparation provides the L-ornithine phenyl acetate of quick-release distribution in oral medication.In some embodiments, L- birds ammonia The oral dose of sour phenylacetate is about 2g to about 8g.In one embodiment, the oral dose of L-ornithine phenyl acetate It is about 5g.In another embodiment, the oral dose of L-ornithine phenyl acetate is about 2.5g.In some other implementation In scheme, the oral drug preparation provides the L-ornithine phenyl acetate of controlled release.

Some embodiments of present disclosure are related to the method for treating or improving hyperammonemia comprising to there is demand Subject gives the oral drug preparation as described herein for including L-ornithine phenyl acetate.In some embodiments, tested Person suffers from acute hepatic failure or chronic hepatic diseases.In some embodiments, subject suffers from hepatic sclerosis or liver decompensation. In some embodiments, subject suffers from hepatic encephalopathy.In other embodiment, subject suffers from portal hypertension. In some other embodiments, the type of chronic hepatic diseases or hepatic sclerosis has Child-Pugh A, B or C.

Some embodiments of present disclosure are related to treating the method for hyperammonemia comprising to the subject for having demand The oral drug preparation for including L-ornithine phenyl acetate is given, wherein the pharmaceutical preparation provides about 10 μ g/mL to about 150 μ The plasma C max of the phenylacetic acid of g/mL.In some embodiments, the pharmaceutical preparation also provides about 5 μ g/mL to about 100 μ g/ The plasma C max of the phenylacetylglutamine of mL.In some embodiments, the oral drug preparation of L-ornithine phenyl acetate The L-ornithine phenyl acetate of controlled release is provided upon administration.In some other embodiments, the mouth of L-ornithine phenyl acetate Take the L-ornithine phenyl acetate that pharmaceutical preparation provides quick-release upon administration.In some embodiments, the pharmaceutical preparation packet It is L-ornithine phenyl acetates of the about 0.1g to about 10g containing oral dose.

Description of the drawings

Fig. 1 is to be depicted in controlled release preparation A, B and C for giving L-ornithine phenyl acetate,And speed After releasing oral preparation, the Line Chart of internal plasma pharmacokinetics distribution of the phenylacetic acid (PAA) in human body.

Fig. 2 is to be depicted in controlled release preparation A, B and C for giving L-ornithine phenyl acetate,And speed After releasing oral preparation, the Line Chart of internal substitute blood plasma drug effect distribution of the phenylacetylglutamine (PAGN) in human body.

Fig. 3 is depicted under four kinds of different treatments, to the trouble with chronic hepatic diseases Type C hild-Pugh A classes After person gives the 5g L-ornithine phenyl acetates of single dose, the distribution of the internal plasma pharmacokinetics of phenylacetic acid (PAA) it is linear Figure.

Fig. 4 is depicted under four kinds of different treatments, to the trouble with chronic hepatic diseases Type C hild-Pugh A classes After person gives the 5g L-ornithine phenyl acetates of single dose, the internal substitute blood plasma drug effect of phenylacetylglutamine (PAGN) The Line Chart of distribution.

Specific implementation mode

Some embodiments of present disclosure are related to the oral preparation of L-ornithine phenyl acetate.Some of the preparation Embodiment use withLow dose formulation is provided compared to the equivalent phenylacetate of much lower dosage.One A little such embodiments are quick releasing formulations.Other embodiments of the preparation improve control delivery or slow-releasing system.

Definition

Chapter title used herein is only used for layout purpose, and should not be construed as limiting the theme.

Unless otherwise defined, all technical and scientific terms used herein have logical with those of ordinary skill in the art The identical meaning of meaning understood.Term " including (including) " and other forms (as " including (include) ", " including (includes) " and " including (included) ") use be not limiting.Term " have (having) " and The use of other forms (such as " with (have) ", " with (has) " and " with (had) ") is not limiting.Such as in this theory Used in bright book, either in transitional phrases or in the main body of claim, term " includes (comprise (s)) it " all should be interpreted that with open meaning with " including (comprising) ".That is, above-mentioned term should be interpreted that It is synonymous with phrase " at least having " or " including at least ".For example, working as in the context of method in use, term "comprising" means The method includes at least the step, it is also possible to including other step.When in compound, composition, preparation or dress In use, term "comprising" means that the compound, composition, preparation or device include at least the feature in the context set Or component, it is also possible to including other feature or component.

As it is used herein, common organic abbreviation is defined as follows：

AUC areas under a curve

AUC_0-tFrom time=0 (zero) to the end can quantitative concentrations time concentration time curve under area

AUC_0-infThe area being extrapolated under the plasma concentration versus time curve of Infinite Time

The total plasma clearances of CL

C₁₂Drug concentration after being administered 12 hours

Cmax maximal plasma concentrations

F absolute bioavailabilities value (%)

Hr hours

IR quick-releases

ORN ornithines

PAA phenylacetic acids (or conjugate base phenylacetic acid root)

PAGN phenylacetylglutamines

PD drug effects

PK pharmacokinetics

Term as used herein " quick-release " has ordinary meaning as understood by those skilled in the art, and therefore wraps It includes and discharges drug from dosage form within the period of relative brevity after administration --- by way of non-limiting example ---.

Term as used herein " controlled release " and term " sustained release (extended release) " respectively have such as this field The ordinary meaning that technical staff is understood, and therefore include --- by way of non-limiting example --- in the extended time The interior controlled release drug from dosage form of section.For example, in some embodiments, controlled or sustained release formulations are that the apparent ratio of those release rates can The longer preparation of the immediate release forms that compare.The two terms may be used interchangeably.

Term as used herein " about " be exponential quantity, numerical value, number, percentage, amount or weight deviate from reference to quantity, Numerical value, number, percentage, amount or weight difference be that those of ordinary skill in the art think the quantity for that type, number Value, number, percentage, amount or weight are acceptable.In each embodiment, term " about " refer to relative to reference to quantity, Numerical value, number, percentage, amount or weight difference be 20,15,10,9,8,7,6,5,4,3,2 or 1%.

Term as used herein " peroral dosage form " have ordinary meaning as understood by those skilled in the art, and because This includes --- by way of non-limiting example --- by it is oral give the mankind in the form of drug or a variety of drugs preparation, Including pill, tablet, core agent (core), capsule, caplet agent (caplet), loose powder, aqueous agent or suspending agent.

Term as used herein " phenylacetic acid (phenylacetic acid) " is also referred to as phenylacetic acid (benzeneacetic ) or 2- phenylacetic acids acid.It has following chemical constitution：

Term as used herein " phenylacetic acid root " refers to the anionic form of the phenylacetic acid with following chemical constitution：

Term as used herein " L-ornithine phenyl acetate " refer to by L-Orn cation and phenylacetic acid root the moon from Molecular compound.It has following chemical constitution：

Term as used herein " phenylacetylglutamine " refers to the conjugated formation by phenylacetic acid and glutamine Product.It is visible general metabolic object in human urine.It has following chemical constitution：

As it is used herein, term " in 24 hours phenylacetate to phenylacetylglutamine percent conversion " Refer to giving the phenylacetate of patient to be converted into the mass percent of phenylacetylglutamine, the phenylacetylglutamine be It is collected in urine in 24 hours.

Term " pharmaceutically acceptable carrier " or " pharmaceutically acceptable excipient " include any and all solvent, Decentralized medium, coating, antibacterial agent and antifungal agent, isotonic agent and absorption delaying agent etc..This kind of medium and reagent are used for drug Active material is well known in the art.Unless to any conventional media or the reagent degree incompatible with active constituent, otherwise It is contemplated that using it in therapeutic combination or preparation.Supplement activity ingredient can also be mixed in composition or preparation.In addition, Can also include various adjuvants commonly used in the art.These and other such compounds are recorded in following documents：For example, Merck Index,Merck&Company,Rahway,NJ.To considering that the various components for including are recorded in pharmaceutical composition, Such as Gilman et al. (editor) (1990)；Goodman and Gilman:The Pharmacological Basis of Therapeutics, the 8th edition, Pergamon Press.

Term " pharmaceutically acceptable salt " refers to the biological effectiveness and characteristic for the compound for retaining preferred embodiment And it is not biologically or other undesirable salt of aspect.In many cases it is preferred to which the compound of embodiment is due to existing Amino and/or carboxyl or similar group and ackd salt and/or basic salt can be formed.Pharmaceutically acceptable acid addition Inorganic acid and organic acid can be used to be formed for salt.Can include by the inorganic acid of its salt derivative, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid etc..Can include by the organic acid of its salt derivative, for example, acetic acid, propionic acid, glycolic, pyruvic acid, oxalic acid, Malaysia Acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, to first Benzene sulfonic acid, salicylic acid etc..Inorganic base and organic base can be used to be formed for pharmaceutically acceptable base addition salts.It can be by its salt derivative Inorganic base include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminium etc.；Particularly preferably ammonium salt, sylvite, sodium Salt, calcium salt and magnesium salts.Can include by the organic base of its salt derivative, for example, primary amine, secondary amine and tertiary amine, substituted amine comprising day So existing amine replaced, cyclammonium, deacidite etc., specifically, such as isopropylamine, trimethylamine, diethylamine, three second Amine, tripropyl amine (TPA) and ethanol amine.Many such salt are well known in the art, such as Johnston et al., on September 11st, 1987 It is recorded in disclosed WO 87/05297 (entire contents are included in this specification by reference).

" subject " used herein means the mankind or non-human mammal, for example, dog, cat, mouse, rat, ox, Sheep, pig, goat, non-human primate or bird, such as chicken and any other vertebrate or invertebrate.

" treatment (treat) " used herein, " treatment (treatment) " or " treatment (treating) " refer in order to Prevent and/or therapeutic purposes give pharmaceutical composition/preparation.Term " prophylactic treatment " refer to treatment not yet suffer from disease but easily It is infected by specific liver diseases or the patient in the risk with specific liver diseases, the thus treatment reduces patient and will send out Transform into the possibility of liver diseases.Term " therapeutic treatment " refers to giving to treat to the patient for having suffered from liver diseases.

Composition or preparation as described herein are preferably provided with unit dosage forms.As used herein, " unit dosage forms " are to contain There is composition/preparation of a certain amount of compound, the amount is suitable for giving with single-dose dynamic according to good medical practice Object, preferably mammalian subject.However, the preparation of one-pack type or unit dosage forms is not meant to that the dosage form is administered once a day Or each all dosage that therapeutic process is administered once or unit dosage forms include single administration.Such dosage form can be considered It is administered once a day, twice, three times or more, and although indefinite exclusion single-dose, it can be over the course for the treatment of It gives more than once.In addition, multiple unit dosage forms can substantially simultaneously be administered to realize expected full dosage (for example, patient Two or more tablets can be swallowed to reach complete dosage).It would be recognized by those skilled in the art that the preparation is not Specifically consider entire therapeutic process, and such decision leave for therapy field technical staff rather than the technology people of formulation art Member.

As it is used herein, the action of " offer " is described herein including supplying, obtaining or give (including self giving) Composition.

As it is used herein, it includes individual voluntarily acquisition or drug administration that term, which " gives " drug,.For example, at some In embodiment, individual from pharmacy obtains drug and according to method automedication provided herein.

In any embodiment as described herein, therapy is alternatively related to purposes claim, such as Swiss-type purposes claims.For example, a kind of can be alternatively related to using composition come the method for treating cystic fibrosis Purposes or composition of the composition in preparing the drug for treating cystic fibrosis are used to treat the purposes of cystic fibrosis.

It will be understood by those skilled in the art that pharmacokinetic parameter can be by using known to those skilled in the art and connect The clinical testing procedure received compares to measure with reference standard, such as described in embodiment illustrated herein.Due to the medicine of drug For dynamics can due to patient it is different, therefore, this clinical test is usually directed to patient at double and is carried out to the data obtained proper When statistical analysis (for example, ANOVA is in 90% confidence interval).As understood by those skilled in the art, pharmacokinetic parameter Comparison can be based on dosage after the adjustment.

Low dose formulation

Some embodiments of present disclosure are related to oral drug preparation, are about 0.1g to about 10g it includes dosage L-ornithine phenyl acetate and one or more pharmaceutically acceptable excipient or carrier.In some embodiments, institute It states preparation and provides the L-ornithine phenyl acetate of quick-release distribution in administration (for example, with liquid solution or suspension form Immediate release oral preparation).Other embodiments provide controlled release or sustained release profile.In preferred embodiments, pharmaceutical preparation is Oral drug preparation.In some embodiments, the dosage of L-ornithine phenyl acetate be about 0.5g, about 1g, about 1.5g, about 2g, about 2.5g, about 3g, about 3.5g, about 4g, about 4.5g, about 5g, about 5.5g, about 6g, about 6.5g, about 7g, about 7.5g, about 8g, about 8.5g, about 9g, about 9.5g or about 10g or in the dosage range defined by any two aforementioned value (for example, about 1g is to about 9g, about 2g are to about 8g, about 3g to about 7g, about 4g to about 6g, about 1g to about 6g, about 1g to about 5g, about 1g to about 4g, about 1g to about 3g, about 2g are to about 6g, about 2g to about 5g or about 2g to about 4g).In one embodiment, the oral dose is about 2.5g. In another embodiment, the oral dose is about 5g.

In some embodiments, pharmaceutical preparation is single unit dosage forms.In some other embodiments, drug system Agent is two or more unit dosage forms (i.e. divided dose).For example, when oral dose is about 5g, it can be with four or five Form provides, and every contains about 1.25g or 1g L-ornithine phenyl acetates.In some embodiments, unit dosage forms are piece Agent, capsule, pill, granula, the pulvis of free-flowing or liquid agent.In one embodiment, unit dosage forms are to include 5g The liquid solution of L-ornithine phenyl acetate.

In some embodiments, the phenylacetate that the pharmaceutical preparation provides in 24 hours is to phenylacetylglutamine Conversion ratio be 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 some other embodiments, phenylacetate that the preparation provides in 24 hours to phenylacetyl paddy The conversion ratio of glutamine is greater than about 80%.In some embodiments, transformation efficiency is the phenylacetyl paddy in the urine based on excretion What glutamine measured.

In some embodiments, the phenylacetate that the pharmaceutical preparation provides in 12 hours is to phenylacetylglutamine Conversion ratio be 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 some other embodiments, phenylacetate that the preparation provides in 12 hours to phenylacetyl paddy The conversion ratio of glutamine is greater than about 60%.In some embodiments, transformation efficiency is the phenylacetyl paddy in the urine based on excretion What glutamine measured.

Low-dose drugs preparation as described herein can be administered by any suitable approach, for example, it can be by oral, quiet In arteries and veins, stomach is interior, peritonaeum is interior or endovascular approach administration.In preferred embodiments, the pharmaceutical preparation of L-Orn is mouth Oral dosage form, such as oral administration solution.In another embodiment, pharmaceutical preparation is intravenous dosage form.

Therapy

Some embodiments of present disclosure are related to the method for treating or improving hyperammonemia comprising to there is demand Subject is oral to give a kind of pharmaceutical preparation including a effective amount of L-ornithine phenyl acetate, especially as described herein oral Pharmaceutical preparation.In some embodiments, subject suffers from acute hepatic failure or chronic hepatic diseases.In some embodiments In, subject suffers from hepatic sclerosis or liver decompensation.In some such embodiments, the class of chronic hepatic diseases or hepatic sclerosis Type has Child-PughA, B or C class.Some embodiments include that diagnosis subject suffers from Child-Pugh A class liver diseases, Then composition as described herein is given.Some embodiments include that diagnosis subject suffers from Child-Pugh B class liver diseases Then disease gives composition as described herein.In some embodiments, subject suffers from hepatic encephalopathy.Some embodiments Child-Pugh C class liver diseases are suffered from including diagnosis subject, then give composition as described herein.In other reality It applies in scheme, subject suffers from portal hypertension.In some embodiments, subject suffers from urea cycle disorder.One In a little others embodiments, subject has stopped the treatment of lactulose recently, such as subject has stopped the treatment 1 of lactulose It, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks or more long.

In some embodiments of method described herein, the plasma C max for the phenylacetic acid that method described herein provides It is about 10 μ g/mL to about 150 μ g/mL.In some such embodiments, the plasma C max of phenylacetic acid be about 20 μ g/mL extremely About 140 μ g/mL.In some such embodiments, the plasma C max of phenylacetic acid is about 30 μ g/mL to about 130 μ g/mL. In some such embodiments, the plasma C max of phenylacetic acid is about 40 μ g/mL to about 120 μ g/mL.In some other implementation In scheme, the plasma C max of phenylacetic acid is about 50 μ g/mL to about 110 μ g/mL.

In some embodiments of method described herein, the plasma C max of metabolin phenylacetylglutamine is about 5 μ G/mL to about 100 μ g/mL.In some such embodiments, the plasma C max of metabolin phenylacetylglutamine is about 10 μ G/mL to about 80 μ g/mL.In some such embodiments, the plasma C max of metabolin phenylacetylglutamine is about 20 μ G/mL to about 60 μ g/mL.In some such embodiments, the plasma C max of metabolin phenylacetylglutamine is about 25 μ G/mL to about 50 μ g/mL.In some other embodiments, the plasma C max of metabolin phenylacetylglutamine is about 30 μ G/mL to about 45 μ g/mL.

Some embodiments of present disclosure are related to treating the method for hyperammonemia comprising to the subject for having demand A kind of oral drug preparation including L-ornithine phenyl acetate is given, wherein it is about 10 that the pharmaceutical preparation, which provides plasma C max, The phenylacetic acid of μ g/mL to about 150 μ g/mL.Particularly, including the benzene that the combination of oral medication of L-ornithine phenyl acetate provides The plasma C max of acetic acid is about 10 μ g/mL, about 15 μ g/mL, about 20 μ g/mL, about 25 μ g/mL, about 30 μ g/mL, about 35 μ g/mL, About 40 μ g/mL, about 45 μ g/mL, about 50 μ g/mL, about 55 μ g/mL, about 60 μ g/mL, about 65 μ g/mL, about 70 μ g/mL, about 75 μ g/ ML, about 80 μ g/mL, about 85 μ g/mL, about 90 μ g/mL, about 95 μ g/mL, about 100 μ g/mL, about 105 μ g/mL, about 110 μ g/mL, About 115 μ g/mL, about 120 μ g/mL, about 125 μ g/mL, about 130 μ g/mL, about 135 μ g/mL, about 140 μ g/mL, about 145 μ g/mL Or about 150 μ g/mL, or by any two aforementioned value limited range.In one embodiment, the plasma C max of phenylacetic acid Level is about 20 μ g/mL to about 140 μ g/mL.In another embodiment, the plasma C max levels of phenylacetic acid are about 30 μ g/ ML to about 130 μ g/mL.In yet another embodiment, the plasma C max levels of phenylacetic acid are about 40 μ g/mL to about 120 μ g/ mL.In other embodiments, the plasma C max levels of phenylacetic acid are about 50 μ g/mL to about 110 μ g/mL.In some implementations In scheme, the plasma A UC of phenylacetic acid_0-tOr AUC_0-infIt is about 100 to about 1000hr* μ g/mL, about 150hr* μ g/mL to about 900hr* μ g/mL, about 200hr* μ g/mL to about 800hr* μ g/mL, about 250hr* μ g/mL to about 700hr* μ g/mL, about 300hr* μ g/mL are to about 650hr* μ g/mL, about 350hr* μ g/mL to about 600hr* μ g/mL or about 400hr* μ g/mL to about 550hr*μg/mL.In some embodiments, the plasma C max for the phenylacetylglutamine that pharmaceutical preparation also provides is about 5 μ g/ ML to about 100 μ g/mL.Particularly, the phenylacetyl paddy that the combination of oral medication comprising L-ornithine phenyl acetate provides The plasma C max of glutamine is about 5 μ g/mL, about 10 μ g/mL, about 15 μ g/mL, about 20 μ g/mL, about 25 μ g/mL, about 30 μ g/mL, About 35 μ g/mL, about 40 μ g/mL, about 45 μ g/mL, about 50 μ g/mL, about 55 μ g/mL, about 60 μ g/mL, about 65 μ g/mL, about 70 μ g/ ML, about 75 μ g/mL, about 80 μ g/mL, about 85 μ g/mL, about 90 μ g/mL, about 95 μ g/mL or about 100 μ g/mL or by any two Aforementioned value limited range.In one embodiment, the plasma C max of phenylacetylglutamine is about 10 μ g/mL to about 80 μg/mL.In another embodiment, the plasma C max of phenylacetylglutamine is about 20 μ g/mL to about 60 μ g/mL.Another In one embodiment, the plasma C max of phenylacetylglutamine is about 25 μ g/mL to about 50 μ g/mL.In some embodiments In, the plasma A UC of phenylacetylglutamine_0-tIt is about 25hr* μ g/mL to about 500hr* μ g/mL, about 50hr* μ g/mL to about 300hr* μ g/mL, about 100hr* μ the g/mL g/mL to about 200hr* μ g/mL or about 120hr* μ g/mL to about 180hr* μ.At some In embodiment, the plasma A UC of phenylacetylglutamine_0-infIt is about 25hr* μ g/mL to about 500hr* μ g/mL, or about 50hr* μ G/mL to about 400hr* μ g/mL, about 75hr* μ g/mL to about 300hr* μ g/mL, about 100hr* μ g/mL to about 250hr* μ g/mL, Or about 150hr* μ g/mL to about 200hr* μ g/mL.

In some embodiments of method described herein, combination of oral medication is given in the fasted state.One In a little others embodiments, combination of oral medication is given under fasting state, such as at table or 60 points after a meal In clock.

In some embodiments of method described herein, the oral drug preparation of L-ornithine phenyl acetate is being administered The L-ornithine phenyl acetate of controlled release is provided afterwards.In some other embodiments, the oral medicine of L-ornithine phenyl acetate Object preparation provides the L-ornithine phenyl acetate of quick-release upon administration.

In some embodiments of method described herein, the dosage of L-ornithine phenyl acetate is daily about 0.1g To about 50g, daily about 0.5g to about 45g, daily about 1g to about 40g, daily about 1.5g to about 35g, daily about 2g to about 30g, Daily about 2.5g to about 25g, daily about 3g to about 20g or daily about 5g to about 15g.In some embodiments, it is given once daily Pharmaceutical preparation at least once.In some other embodiments, 2 times or more pharmaceutical preparations are given once daily.In a reality It applies in scheme, daily Oral drug administration preparation is three times.

In some embodiments of method described herein, the dosage as single dose of L-ornithine phenyl acetate It is about 1.0g to about 10.0g.In some other embodiments, the dosage as single dose of L-ornithine phenyl acetate It is about 2g to about 8g.In multiple other embodiments, the dosage as single dose of L-ornithine phenyl acetate is about 1g to about 9g, about 2g to about 8g, about 3g to about 7g, about 4g to about 6g, about 1g to about 6g, about 1g to about 5g, about 1g to about 4g, about 1g to about 3g, about 2g are to about 6g, about 2g to about 5g or about 2g to about 4g.In one embodiment, L-ornithine phenyl acetate The dosage as single dose be about 2.5g.In another embodiment, the conduct single dose of L-ornithine phenyl acetate Dosage be about 5g.In some such embodiments, the pharmaceutical preparation of the L-ornithine phenyl acetate containing the amount For single peroral dosage form.In some other such embodiments, the drug of the L-ornithine phenyl acetate containing the amount Preparation is two or more unit dosage forms.For example, some embodiments include giving 1 to 5 unit dosage forms, each unit dose Type includes about 0.1g to about 2g L-ornithine phenyl acetates, or gives about 2 to 4 unit dosage forms, each unit dosage forms include about 0.5g is to about 1.25g L-ornithine phenyl acetates.Some embodiments include giving 4 unit dosage forms, each unit dosage forms packet Containing about 1.25g L-ornithine phenyl acetates.Some embodiments include giving 5 unit dosage forms, and each unit dosage forms include about 1g L-ornithine phenyl acetates.Some other embodiments includes giving 1 unit dosage forms, and each unit dosage forms include about 5g L-ornithine phenyl acetates.In one embodiment, pharmaceutical preparation three times is given once daily.For example, multiple once giving In the case of unit dosage forms, multiple unit dosage forms are repeated daily three times.In another embodiment, it is administered once per day for the treatment of Pharmaceutical preparation.

In some embodiments of method described herein, phenylacetate that pharmaceutical preparation provides in 24 hours to benzene The conversion ratio of acetyl-glutamine is greater than about 30%, is greater than about 40%, is greater than about 50%, is greater than about 60%, is greater than about 70%, is big In about 80% or greater than about 90%.In some other embodiments, phenylacetate that pharmaceutical preparation provides in 24 hours Conversion ratio to phenylacetylglutamine is greater than about 80%.In some embodiments, transformation efficiency is in the urine based on excretion Phenylacetylglutamine measure.

In some embodiments of method described herein, phenylacetate that pharmaceutical preparation provides in 12 hours to benzene The conversion ratio of acetyl-glutamine is greater than about 30%, is greater than about 40%, is greater than about 50%, is greater than about 60%, is greater than about 70%, is big In about 80% or greater than about 90%.In some other embodiments, phenylacetic acid that the preparation provides in 12 hours The conversion ratio of salt to phenylacetylglutamine is greater than about 60%.In some embodiments, transformation efficiency is the urine based on excretion In phenylacetylglutamine measure.

In any embodiment of plasma C max as described herein or AUC value, described value can be selected from plasma C max or AUC The average value or intermediate value of value.In some embodiments, in the oral drugs system for the L-ornithine phenyl acetate for giving single dose Plasma C max and AUC as described herein is obtained after agent.In some other embodiments, plasma C max as described herein and AUC be the stable state obtained after the oral drug preparation for the L-ornithine phenyl acetate for giving multi-dose plasma C max and AUC.In some embodiments, plasma C max and AUC as described herein is measured in the fasted state.In some other implementation In scheme, measured under these PK parameter fasting states.

Some examples that may be used as the substance of its pharmaceutically acceptable carrier or excipient are sugar, such as lactose, grape Sugar and sucrose；Starch, such as cornstarch and potato starch；Cellulose and its derivates, as sodium carboxymethylcellulose, ethyl are fine Dimension element and methylcellulose；Powdered tragacanth；Malt；Gelatin；Talcum；Kollag, such as stearic acid and magnesium stearate；Sulfuric acid Calcium；Vegetable oil, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cupu oil；Polyalcohol such as propylene glycol, glycerine, mountain Pears alcohol, mannitol and polyethylene glycol；Alginic acid；Emulsifier, such as TWEENS；Wetting agent, such as lauryl sodium sulfate；Colorant； Flavoring agent；Tablet agent, stabilizer；Antioxidant；Preservative；Apirogen water；Isotonic saline solution；And phosphate buffer solution.

In some embodiments, the peroral dosage form of L-ornithine phenyl acetate can be the form of liquid, especially liquid Solution.Peroral dosage form also may include the adjuvant, excipient or carrier of conventional pharmaceutically compatible, including as described herein oral molten Those of commonly used in liquid formulation.

In some embodiments, oral preparation as described herein is provided than previous expected lower dosage.For example, It is found in clinical research, dosage is 6mL (delivering about 1.02g/mL phenylbutyric acids ester) twice daily(phenyl Glycerol monobutyralte, pre--prodrug (pre-prodrug) of phenylacetic acid root) reduce hepatic encephalopathy event incidence.It is as described herein The immediate release oral pharmaceutical preparation and controlled release oral pharmaceutical preparation of L-ornithine phenyl acetate are provided which the PAGN urine of percent similarity Liquid excreta, be enable to use withOr other phenylacetate preparations compare significantly lower API agent Amount.

Embodiment

The purpose that following embodiment (including the result tested and obtained) is merely to illustrate is provided, should not be construed as limitation originally Application.

Embodiment 1 --- the I phase pharmacokinetics in healthy human body

Carry out opening, five kinds of therapeutic agents, five period single doses intersect I phase Human clinicals research to assess and(phenylbutyric acid glyceride) --- the prodrug of phenylacetic acid is compared, and takes the L-Orn phenylacetic acid of single dose The pharmacokinetics of phenylacetic acid and phenylacetylglutamine after three kinds of sustained-release oral dosage forms of salt.The research also compares and list The immediate release oral solution of the L-ornithine phenyl acetate of dosage is compared, three kinds of sustained release mouths of the L-ornithine phenyl acetate of single dose The pharmacokinetics of oral dosage form and safety.

Five kinds of therapeutic agents are listed below：Therapeutic agent A, B and C each refer to 10g preparations A, B and C of single oral dose (respectively Equivalent to about 5g PAA), the component of these preparations is summarized in the following table 1；Therapeutic agent D refers to the 6mL of single oral dose(equivalent to about 5g PAA)；Therapeutic agent E refers to the quick-release of the 5g L-ornithine phenyl acetates of single oral dose Preparation (equivalent to about 2.5g PAA).

Main target is assessment and the oral administration solution of L-ornithine phenyl acetate and prodrug (the phenylbutyric acid glycerine of phenylacetic acid Ester,) compare, after taking three kinds of sustained release preparations of the L-ornithine phenyl acetate of single oral dose, benzene second Sour (effective ammonia scavenger), ornithine and phenylacetylglutamine (being responsible for removing the final product of ammonia) are tested in healthy human Blood plasma distribution in person and pharmacokinetics.By-end be to determine safety of three kinds of sustained release preparations in health volunteer, Tolerance and palatability.

Qualified sex adult health volunteer is recruited, first to use the friendship of 4 × 4 Latin―Square designs of balance Fork mode receives four kinds of therapeutic agents (therapeutic agent A-D) in 4 dosage periods, wherein there is at least 7 days clear between therapeutic agent Except interval, then behind minimum 7 days removing intervals in the 5th (the last one) dosage period, all subjects receive treatment Agent E.After the administration of each dosage period, subject carry out continuous blood and urine sampling after administration 24 hours with into Row PK assessments.

PK is assessed

Give therapeutic agent A, B, C or D (L-ornithine phenyl acetate orER preparations) administration week Interim, point acquires venous blood sample (each 5mL) at the following time：Before it will be administered (in 15 minutes), then it is being administered 0.5,1,1.5,2,2.5,3,3.5,4,5,6,8,10,12,16,20 and 24 hour afterwards.Giving L-ornithine phenyl acetate In the dosage period (the 5th period) of quick releasing formulation, point acquires venous blood sample (each 5mL) at the following time：It will be administered Before (in 15 minutes), then 0.25,0.5,0.75,1,1.5,2,2.5,3,3.5,4,4.5,5,6,7,8,10 and upon administration 12 hours.

In addition, acquiring urine sample in the following period：Administration first 1 hour in (spot sample), then upon administration 0-4, It is accumulated in 4-8,8-12 and 12-24 hours sections.It by centrifugal separation plasma sample and is stored in blood collection 1 hour Until being analyzed at about -80 DEG C.The total volume of urine in each acquisition section is measured and recorded, and the aliquot of urine is stored in Until being analyzed at about -80 DEG C.

Bioanalytical method

The phenylacetic acid (PAA) of plasma sample, the concentration use experience of phenylacetylglutamine (PAGN) and ornithine (ORN) The LC-MS/MS methods of card are analyzed.The LC-MS/MS methods of the PAGN concentration use experiences card of all urine samples are divided Analysis.

Terminal

Pharmacokinetics：Take phenylacetic acid root, ornithine and phenylacetyl paddy ammonia after each research drug of single oral dose The distribution of the plasma concentration relative time of amide is analyzed by non-chamber PK methods.The pharmacokinetic parameter of measurement includes C_max、t_max、AUC_0-t、AUC_0-∞、C₁₂And t_1/2.It also measured were and is arranged in urine in each acquisition section and entire 24 hours sections The amount of the PAGN let out and percentage as the PAGN PAA dosage drained in urine.

Fig. 1 and Fig. 2 respectively illustrates the average blood plasma distribution of the PAA and PAGN of 1 phase research.Fig. 1 is shown and quick-release Solution is compared with phenylbutyric acid glyceride, gives average blood plasma PAA concentration relative times after the controlled release preparation of single oral dose Curve.Fig. 2 shows compared with quick-release solution and phenylbutyric acid glyceride, give average blood after the controlled release preparation of single oral dose Starch the curve of PAGN concentration relative times.

The Mean maximum concentrations (Cmax) of the blood plasma PAA of three kinds of sustained release preparations are about 50 to 90 μ g/mL, appear in administration Each point in time in 4 to 9 hours afterwards.As a comparison,

4 to 6 hours average blood plasma PAACmax for generating about 10 μ g/mL upon administration.Take single port clothes The 6mL of dosageBlood plasma PAA data later are consistent with the data in the health volunteer of announcement.In addition, L- The PAA exposures of the sustained release preparation of ornithine phenylacetate show ratioDifference between lower subject.

The blood plasma distribution of PAGN (final product that ammonia is removed) also shows that and pattern as PAA distributional class.L-Orn The average Cmax of the blood plasma PAGN of three kinds of sustained release preparations of phenylacetate is about 30 to 45 μ g/mL, occurs upon administration 4 to 10 Each point in time in hour.As a comparison,The average blood of about 20 to 25 μ g/mL is generated at about 5 hours Starch PAGN Cmax.These data are also consistent with the data in the health volunteer of announcement.

Total homaluria data summarization of PAGN in 24 hours is in the following table 2.The average PAGN excretions of therapeutic agent A to C It is comparable, has about 80% PAA to be converted into PAGN excretas in each comfortable 24 hours.In contrast, it rubs about the same Under your PAA dosage (In the case of, PAA is provided by the prodrug of phenylbutyric acid glyceride), with therapeutic agent A to C is compared,Therapeutic agent D only shows about 40% transformation efficiency.It has surprisingly been observed that quick-release system Agent therapeutic agent E also shows about 80% transformation efficiency, thisAbout half mole of the PAA given in scheme Similar average PAGN excretions are provided under dosage.

Table 2

Conclusion：Controlled release preparation and sustained release preparation have good tolerance in entire research, be not observed toxicity or Serious adverse events.As a result show that all three sustained release preparations have stable time release pattern, wherein upon administration at least 24 At all time points in hour, average blood plasma PAA concentration is more than(phenylbutyric acid glyceride) reaches dense Degree.In addition, under roughly the same mole of PAA dosage, the average blood plasma PAGN concentration and urine PAGN of all three sustained-release dosage types Excretion is all higher thanThe urine PAGN excretion efficiency for having also demonstrated the sustained release preparation of L-ornithine phenyl acetate is aboutTwice.

I phase pharmacokinetic of the embodiment 2-in Child-Pugh A class subjects

In this embodiment, single dose is carried out, the clinical research of incomplete randomization suffers from hepatic sclerosis (Child- to assess Pugh A classes) 5 subject's fasting states under, under fasting state or stop lactulose after fasting state under give 5g L-ornithine phenyl acetate oral administration solutions.Purpose is to measure and give the mono- intravenous injection dosage of 5g in the fasted state L-ornithine phenyl acetate is compared, and is suffered under subject's fasting state of hepatic sclerosis (Child-Pugh A classes), fasting state Under or stop giving under fasting state after lactulose after the L-ornithine phenyl acetate oral administration solutions of 5g single doses PAA and The pharmacokinetics of PAGN.

Therapeutic agent is summarized as follows：Therapeutic agent A is the L-Orn benzene second for the 5g single oral doses given in the fasted state Hydrochlorate oral administration solution；It is molten that therapeutic agent B is that the L-ornithine phenyl acetate for the 5g single oral doses given under fasting state takes orally Liquid；Therapeutic agent C is the L-ornithine phenyl acetate solution for the mono- intravenous dosages of 5g being transfused in 1 hour in the fasted state； And therapeutic agent D is the L-ornithine phenyl acetate for the 5g single oral doses given under the fasting state after stopping lactulose Oral administration solution.

Qualified subject received single dose quantifier elimination drug at first day.Subject is just limited in for first day from what is be admitted to hospital 1 phase unit is until obtaining the final blood sample for pharmcokinetic evaluation.In dosage period 1, all subjects receive Be injected intravenously L-ornithine phenyl acetate (therapeutic agent C), and in treatment cycle 4, all subjects stop lactulose it It is followed by the L-ornithine phenyl acetate oral administration solution (therapeutic agent D) by single dose.Therapeutic agent A and B is during dosage period 2 and 3 It gives in a random way.At the end of dosage period 1,2 and 3, subject returns to clinic and enters next dosage period.To At the end of the medicine period 3, all subjects stop lactulose.With at least 4 days removing phases between during continuous administration (washout interval)。

Pharmcokinetic evaluation

After each oral dose (therapeutic agent A, B and D), point acquires venous blood sample (each 5mL) at the following time： Before it will be administered (in 15 minutes), then upon administration 0.25,0.5,0.75,1,1.5,2,2.5,3,3.5,4,5,6,7, 8,10 and 12 hours.For therapeutic agent D (dosage period 4), other blood sample is obtained within 24 hours upon administration.It is noted in vein After penetrating dosage (therapeutic agent C), point acquires venous blood sample (each 5mL) at the following time：(at 15 points before it will start injection In clock), then start injection after 0.5 hour, before the injection that closes to an end, then terminate inject after 10,20,30,45 and 60 minutes, later 1.5,2,2.5,3,4,6,8,10,12 and 24 hours after terminating to inject.

In addition, for each therapeutic agent, urine sample is acquired under section at the following time：Administration (takes individually in first 1 hour Sample), then accumulated in 0-4,4-8 and 8-12 hours sections upon administration.For therapeutic agent C and D (dosage period 1 and 4), also Acquire the urine in 12-24 hours sections upon administration.

Fig. 3 and Fig. 4 respectively illustrates the average blood plasma distribution of the PAA and PAGN of 1 phase research.Fig. 3, which is shown, to be given The curve of above-mentioned four kinds of therapeutic agents (therapeutic agent A, B, C and D) average blood plasma PAA concentration relative time afterwards.Fig. 4, which is shown, to be given The curve of above-mentioned four kinds of therapeutic agents (therapeutic agent A, B, C and D) average blood plasma PAGN concentration relative time afterwards.The medicine of PAA and PAGN It is summarized in table 3 and table 4 for kinetic parameter.

The pharmacokinetic parameter estimation of table 3.PAA summarizes

The pharmacokinetic parameter estimation of table 4.PAGN summarizes

After taking single oral dose 5gL- ornithine phenylacetates, the blood plasma of the PAA of Child-Pugh A subjects is sudden and violent Reveal consistent desired by the prediction of data and PK estimates of parameters with the past data based on health volunteer.

Based on a small amount of subject, research shows that Child-Pugh A subjects are taking single oral dose 5gL- ornithines After phenylacetate, mean maximum plasma PAA concentration (Cmax) is slightly less than (20%) health volunteer, and to the whole blood plasma of PAA Exposure (AUC_0-inf) higher than health volunteer by about 30%.The AUC value of Child-Pugh A subjects is slightly higher be most likely to be due to The metabolism of the PAA of Child-Pugh A subjects relatively slow and PAA elimination half-life period is longer, from the pact of health volunteer Rise within 0.9 hour 1.4 hours of Child-Pugh A subjects.L-ornithine phenyl acetate is given being injected intravenously or taking orally Afterwards, blood plasma PAA exposures have larger individual difference.

It is oral give L-ornithine phenyl acetate after, PAA is almost completely bioavailable, as follows：With it is quiet Arteries and veins administration is compared, pair that Child-Pugh A subjects measure after taking single oral dose 5gL- ornithine phenylacetates The absolute bioavailability value (F) of PAA is 96%.

Before or after lactulose is eliminated, the subject for taking lactulose seems to have and gives single oral dose L-ornithine phenyl acetate similar PAA and PAGN blood plasma distributions and pharmacokinetics.

The plasma exposure and pharmacokinetic profiles of the PAGN of four kinds of therapeutic agents is comparable, i.e. Child-Pugh A are tested Person is being intravenously injected with or is taking orally together or not single oral dose 5gL- ornithine benzene together with lactulose with or without food After acetate.The average AUC of the PAGN of Child-Pugh A subjects_0-infSlightly less than (~10%) health volunteer.Child- The mean plasma half-life (2.6 hours) of the PAGN of Pugh subject is longer than health volunteer (1.4 hours).

The urine excretion data of table 5.PAGN summarizes

Urine excretion data shows after the L-ornithine phenyl acetate of single IV dosage, as PAGN recycling in urine Average PAA dosage percents are 78.3%, are 84.7% afterwards in the L-ornithine phenyl acetate (therapeutic agent D) of single oral dose. Lower as the PAA dosage of PAGN recycling in urine in therapeutic agent A and B may be the urine capture interval because shorter, I.e. 12 hours.

Claims

1. a kind of oral drug preparation is L-ornithine phenyl acetates of the about 0.1g to about 10g, Yi Jiyi it includes oral dose Kind or more pharmaceutically acceptable excipient or carrier.

2. the oral drug preparation of claim 1, wherein the preparation provides the L-Orn of quick-release distribution in oral medication Phenylacetate.

3. the oral dose of the oral drug preparation of claim 1, wherein L-ornithine phenyl acetate is about 2.5g.

4. the oral dose of the oral drug preparation of claim 1, wherein L-ornithine phenyl acetate is about 5g.

5. the oral drug preparation of any one of claims 1 to 4, wherein the preparation is single unit dosage forms.

6. the oral drug preparation of any one of claim 1 to 5, wherein the preparation is two or more unit dosage forms.

7. the oral drug preparation of claim 6, wherein the unit dosage forms are tablet, capsule, pill, granula, free flow Dynamic pulvis or liquid agent.

8. the oral drug preparation of claim 7, wherein the unit dosage forms are liquid solution.

9. the oral drug preparation of any one of claim 1 to 8, wherein the phenylacetate that the preparation provides in 24 hours Conversion ratio to phenylacetylglutamine is greater than about 30%.

10. the oral drug preparation of claim 9, wherein the phenylacetate that is provided in 24 hours of the preparation is to phenylacetyl paddy The conversion ratio of glutamine is greater than about 50%.

11. the oral drug preparation of claim 10, wherein the phenylacetate that is provided in 24 hours of the preparation is to phenylacetyl The conversion ratio of glutamine is greater than about 80%.

12. a kind of method for the treatment of or improvement hyperammonemia comprising to the subject for having demand it is oral give claim 1 to Oral drug preparation described in any one of 11.

13. the method for claim 12, wherein the oral drug preparation provides the phenylacetic acid of about 10 μ g/mL to about 120 μ g/mL Plasma C max.

14. the plasma C max of the method for claim 13, wherein phenylacetic acid is about 20 μ g/mL to about 110 μ g/mL.

15. the method for any one of claim 12 to 14, wherein the oral drug preparation provides about 10 μ g/mL to about 80 μ The plasma C max of the phenylacetylglutamine of g/mL.

16. the plasma C max of the method for claim 15, wherein phenylacetylglutamine is about 20 μ g/mL to about 45 μ g/mL.

17. a kind of method for the treatment of or improvement hyperammonemia comprising include L- to the oral one kind of giving of the subject for having demand The pharmaceutical preparation of ornithine phenylacetate, wherein described give provides about 10 μ g/mL to the blood plasma of the phenylacetic acid of about 150 μ g/mL Cmax。

18. the plasma C max levels of the method for claim 17, wherein phenylacetic acid are about 20 μ g/mL to about 140 μ g/mL.

19. the plasma C max levels of the method for claim 18, wherein phenylacetic acid are about 30 μ g/mL to about 130 μ g/mL.

20. the plasma C max levels of the method for claim 19, wherein phenylacetic acid are about 40 μ g/mL to about 120 μ g/mL.

21. the method for any one of claim 17 to 20, wherein described give provides about 5 μ g/mL to the benzene of about 100 μ g/mL The plasma C max of acetyl-glutamine.

22. the plasma C max of the method for claim 21, wherein phenylacetylglutamine is about 10 μ g/mL to about 80 μ g/mL.

23. the plasma C max of the method for claim 22, wherein phenylacetylglutamine is about 20 μ g/mL to about 60 μ g/mL.

24. the plasma C max of the method for claim 23, wherein phenylacetylglutamine is about 25 μ g/mL to about 50 μ g/mL.

25. a kind of method for the treatment of or improvement hyperammonemia comprising include L- to the oral one kind of giving of the subject for having demand The pharmaceutical preparation of ornithine phenylacetate, wherein the plasma A UC of the phenylacetic acid for giving offer_0-tOr AUC_0-infBe about 100 to About 1000hr* μ g/mL.

26. the method for claim 25, wherein the plasma A UC of phenylacetic acid_0-tOr AUC_0-infIt is about 200hr* μ g/mL to about 800hr*μg/mL。

27. the method for claim 26, wherein the plasma A UC of phenylacetic acid_0-tOr AUC_0-infIt is about 350hr* μ g/mL to about 600hr*μg/mL。

28. the method for claim 26, wherein the plasma A UC of phenylacetic acid_0-tOr AUC_0-infIt is about 400hr* μ g/mL to about 550hr*μg/mL。

29. the method for any one of claim 25 to 28, wherein the plasma A UC of phenylacetylglutamine_0-tOr AUC_0-infIt is about 25hr* μ g/mL to about 500hr* μ g/mL.

30. the method for claim 29, wherein the plasma A UC of phenylacetylglutamine_0-tIt is about 50hr* μ g/mL to about 300hr* μg/mL。

31. the method for claim 30, wherein the plasma A UC of phenylacetylglutamine_0-tIt is about 100hr* μ g/mL to about 200hr*μg/mL。

32. the method for claim 31, wherein the plasma A UC of phenylacetylglutamine_0-tIt is about 120hr* μ g/mL to about 180hr*μg/mL。

33. the method for claim 29, wherein the plasma A UC of phenylacetylglutamine_0-infIt is about 50hr* μ g/mL to about 400hr*μg/mL。

34. the method for claim 33, wherein the plasma A UC of phenylacetylglutamine_0-infIt is about 75hr* μ g/mL to about 300hr*μg/mL。

35. the method for claim 34, wherein the plasma A UC of phenylacetylglutamine_0-infIt is about 100hr* μ g/mL to about 250hr*μg/mL。

36. the method for claim 35, wherein the plasma A UC of phenylacetylglutamine_0-infIt is about 150hr* μ g/mL to about 200hr*μg/mL。

37. the method for any one of claim 25 to 36, wherein the pharmaceutical preparation is any in claim 1 to 11 .

38. the method for any one of claim 12 to 37, wherein the subject suffers from acute hepatic failure or chronic liver disease Disease.

39. the method for claim 38, wherein the subject suffers from hepatic sclerosis or liver decompensation.

40. the type of the method for claim 38 or 39, wherein chronic hepatic diseases or hepatic sclerosis has Child-Pugh A, B or C Class.

41. the method for any one of claim 12 to 37, wherein the subject suffers from hepatic encephalopathy.

42. the method for any one of claim 12 to 37, wherein the subject suffers from portal hypertension.

43. the method for any one of claim 12 to 37, wherein the subject suffers from urea cycle disorder.

44. the method for any one of claim 12 to 43, wherein the oral drug preparation provides the L-Orn benzene of quick-release Acetate.

45. the method for any one of claim 12 to 44, wherein the oral drug preparation is at least given once daily.

46. the method for any one of claim 12 to 45, wherein the oral drug preparation is given once daily two or more times.

47. the method for any one of claim 12 to 46, wherein the phenylacetate that is provided in 24 hours given is to benzene The conversion ratio of acetyl-glutamine is greater than about 30%.

48. the method for claim 47, wherein the phenylacetate that is provided in 24 hours given is to phenylacetylglutamine Conversion ratio be greater than about 50%.

49. the method for claim 48, wherein the phenylacetate that is provided in 24 hours given is to phenylacetylglutamine Conversion ratio be greater than about 80%.

50. the method for any one of claim 12 to 49 comprising oral to give 1 to 5 unit dosage forms, each unit dosage forms Including about 0.1g is to about 2g L-ornithine phenyl acetates.

51. the method for any one of claim 12 to 50 comprising oral to give 2 to 4 unit dosage forms, each unit dosage forms Including about 0.5g is to about 1.25g L-ornithine phenyl acetates.