CN105246472B - Composition containing ornithine and/or L-aminobutanedioic acid and its application - Google Patents

Abstract

Present specification describes composition and method comprising ornithine and/or L-aminobutanedioic acid, can be used for reducing one or more hyperlipidemia risk factors；More particularly, including the composition of ornithine and/or L-aminobutanedioic acid is suitable for reducing lipid and (or) lipoprotein levels individual blood, such as triglycerides, cholesterol and low-density lipoprotein；Present specification also describes composition and method comprising ornithine and/or L-aminobutanedioic acid simultaneously, can be used for mitigating and increases adverse reaction caused by a kind of (rhabdomyolysis or muscle disease) related condition by a kind of lipid-lowering medicine (such as statins) or with CPK.

Description

Composition containing ornithine and/or L-aminobutanedioic acid and its application

Background technology

Hyperlipidemia is a kind of heterologous disease, shows as cholesterol in body blood, cholesteryl ester, phosphatide and glycerine three The lipid levels such as ester are excessively high, which is transported in blood in a manner of large-scale lipoprotein.Hyperlipidemia be mostly derived from diabetes, The diseases such as thyroid disease, kidney trouble, liver diseases and Cushing's syndrome；In addition, it is fat, drink, using estrogen and its The drug of its changeable lipid metaboli can also cause hyperlipidemia；Hyperlipidemia be also atherosclerosis, angiocardiopathy for example Main, adjustable risk factors of coronary heart disease.Under normal condition, lipid is in blood with blood flow；If in blood Lipid level is too high, and excessive lipid can accumulate on arterial wall, and cholesterol therein and other materials further accumulate to be formed Patch causes lumen of artery narrow, and atherosclerosis or artery sclerosis, the artery of hardening is caused so that normal structure is become again in turn It obtains more fragile.

It is said from clinicing aspect, the drug for treating hyperlipidemia is numerous, such as HMG-CoA inhibitor (statins), Ni Ke Acid, fibrate, fenofibrate, fenofibrate powder, bile acid-binding resin, Colestipol, CETP antagonists and cholesterol Absorption inhibitor (such as ezetimibe).Statins especially Atorvastatin (Lipitor) is that conventional to be clinically used for treatment high The drug of pionemia, clinical study results show that statins can effectively reduce cholesterol and low density lipoprotein in blood samples of patients Protein level, however for being not obvious the effect of triglycerides in blood samples of patients, reduction amplitude is only 8~35%.In addition, to the greatest extent Managing most of clinical datas confirms that statins can reduce the lipid level in blood, but effect is not always so apparent, A small number of clinical effectiveness report statins even can increase triglyceride levels.Clinically 5 kinds of different types of hyperlipemia Disease, respectively I~V-type, the wherein serum triglyceride level of I, III, IV and V-type hyperlipidemia patient can increase, and II types Only there are cholesterol levels and increases in hyperlipidemia patient.Clinical evidence shows that increasing for triglyceride levels is that hyperlipidemia is suffered from The most universals of person, and lead to the strongest risk factors of the pathogenetic relevance of angiocardiopathy especially coronary disease.

Although statins are typically effectively and safely, also to there is clinical evidence prompt for treatment hyperlipidemia, Atorvastatin or other treatments are given for a long time, especially in the case of high dose, rhabdomyolysis can be caused And muscle changes, and apparent dosage correlation is presented in these side effects, and patient can be caused serious myalgia and void occur Weak symptom.

Show compared with low dosage statin in addition, having been reported that, the statin of high dose can dramatically increase the blood glucose of patient's body Level, and then further increase the onset risk of primary diabetes mellitus.Cholesterol-lowering drug is suggested in the drug warning of FDA publications (such as Lipitor) may increase the blood glucose level of medication patient and then lead to the disturbance of consciousness.This kind of side effect of statins may The termination in advance for leading to this therapeutic scheme, to limit its application in clinicing aspect.

Ornithine and L-aminobutanedioic acid can form compound in a salt form, and " ornithine-is named as in present specification L-aminobutanedioic acid " or " aspartic acid ornithine ", the symbol "-" among two kinds of ingredients represent ionic bond, and one of ingredient is The gegenion of another ingredient.Aspartic acid ornithine is initially used to treatment clinically such as hepatic encephalopathy, hepatitis, fat The diseases such as liver, jaundice, hepatic sclerosis.In the hepatic sclerosis stage, hepatic metabolism is disorderly and blood flow variation can lead to serum and central nervous system Ammonia density of uniting increases.Ornithine and L-aminobutanedioic acid are amino acid important in body biochemical pathway, have effects that solve ammonia poison.By Ammonia metabolism disorder causes the accumulation of toxicity ammonia to be one of pathogenesis of hepatic encephalopathy, and ornithine and L-aminobutanedioic acid are by ammonia respectively It is metabolized into the matrix of urea and glutamine.As urea, L-Orn is arginase catalysis L-arginine formation One product, supplement L-Orn can delay the feeling of fatigue of individual, improve the efficiency of energy loss, promote the excretion of ammonia, specifically It can be seen that report (Sugino et al. (2008) " the L-ornithine supplementation attenuates of Sugino etc. physical fatigue in healthy volunteers by modulating lipid and amino acid metabolism",Nutrition Research 28(11):738-43).The spirit that L-Orn can also alleviate individual is tight , refer to report (Kurata et al. (2011) " the Orally administered L-ornithine of Kurata etc. elevates brain L-ornithine levels and has an anxiolytic-like effect in mice", Nutritional Neuroscience 14(6):243-8)。

Invention content

As described above, there is an urgent need to research and develop that one or more hyperlipidemia risks in individual blood can be effectively reduced at present The drug ingedient and method of factor.Equally, it is also desirable to which research and development can effectively reduce the medicine of fat-reducing medicament such as statins side effect Object.For this purpose, the present invention implements the research of this respect and reports its dominance.

In one embodiment, the present invention provides a kind of methods to be intended to reduce the one or more of the individual to want help Hyperlipidemia risk factors, this method include to give the combination containing ornithine and/or L-aminobutanedioic acid of an individual effective dose Object,

Effectively to reduce one or more hyperlipidemia risk factors of individual.

In another embodiment, the present invention provides a kind of a kind of side of fat-reducing medicament is given for the individual that wants help Method, this method include by an effective dose of the lipid-lowering medicine and by one containing ornithine and/or the composition of L-aminobutanedioic acid A effective dose implements administration to individual simultaneously.If desired, this formula also can oral administration.This is matched can be before lipid-lowering medicine administration Or rear implementation administration, or be administered simultaneously with lipid-lowering medicine.

In another embodiment, the present invention provides a kind of method that can reduce medicine side effect, institute here The side effect of finger refers to that individual takes the CPK activity levels increase generated after above-mentioned medicine, also includes ornithine and/or door The side effect generated after winter propylhomoserin and above-mentioned medicine administering drug combinations (CPK activity increases).

In another embodiment, the present invention provides one kind can treating individual test subjects rhabdomyolysis and muscle changes Method, this method includes giving individual an a kind of effective agent of the compound component for including ornithine and/or L-aminobutanedioic acid Amount, the dosage are approximately less than 9g.

In the practice process of any method referred in present specification, the composition of individual administration may be wrapped at least Include the molecular structure to form aspartic acid ornithine salt；On the other hand, may include bird to the composition of individual administration The counter anion that propylhomoserin and present specification are shown；In contrast, may also include door to the composition of individual administration Cation coexists in show one of winter propylhomoserin and present specification；In some cases, the composition may also include ornithine And/or the free state molecule of L-aminobutanedioic acid；In some cases, the composition may also include ornithine and/or L-aminobutanedioic acid And its pharmaceutically acceptable salt.

On the one hand, the day dosage of ornithine and/or L-aminobutanedioic acid is 0.01g to 100g, on the other hand, ornithine And/or the day dosage of L-aminobutanedioic acid is 0.01g to 20g；Sometimes, the day dosage of ornithine and/or L-aminobutanedioic acid is low In 9g, however it is also possible to be less than 3g；In some cases, the dosage of ornithine and/or L-aminobutanedioic acid does not cause The blood glucose level for stating individual increases.

In some cases, the individual for the composition treatment announced using present specification may suffer from hyperlipidemia, by height Fatty Liver Disease, obesity, atherosclerosis, angiocardiopathy, rhabdomyolysis or the muscle disease of pionemia induction.At certain In the case of a little, compound as described above is given, the individual plasma C PK activity levels of lipid-lowering medicine treatment are less than 400U/L.

The method that present specification provides includes that composition disclosed by the invention is administered by following approach：It is oral, quiet Arteries and veins injection, sucking, nasal cavity be blown into, intra arterial injection, subcutaneous administration, mucosa delivery or drug administration at pharynx section.Snibject is held The continuous time may be at least 10 days, or at least 1,2,3,4,5,6 month or longer time.Composition can be added and eaten It is administered in object, can also add and be administered in pharmaceutical formulation.

In some embodiments, the method that present specification provides can reduce one or more hyperlipidemia risk factors and include Triglycerides, low-density lipoprotein and cholesterol.

In some embodiments, the method that present specification provides may mitigate the side effect generated by certain lipid-lowering medicine, The side effects such as the including but not limited to above-mentioned CPK activity referred to increases, blood glucose level increases, rhabdomyolysis and muscle changes.

The lipid-lowering medicine mentioned in the method for the present invention and composition includes but is not limited to HMG-CoA inhibitor, niacin, shellfish Special class drug, fenofibrate, cholic acid chelating agent, Ezetimibe, Lome Tapai, phytosterol, CETP antagonists, Ao Silita with And the combination medicine between them.The lipid-lowering medicine that the method for the present invention uses includes but is not limited to HMG-CoA inhibitor, such as atropic Cut down statin, Fluvastatin, Pravastatin, Lovastatin, Simvastatin or Rosuvastatin and their arbitrary joints therein Medication；Lipid-lowering medicine may be the combination of Atorvastatin/Ezetimibe.If desired, lipid-lowering medicine can be administered in a manner of single dose, Including but not limited to a kind of tablet, capsule, pill, granule, emulsion, colloid, using the glass powder of encapsulated, powder, outstanding Floating agent, liquid, semiliquid, semisolid, syrup, suspension, chewable tablets.

Present invention provides a kind of combination products, including：(a) a kind of fat-reducing medicament, and a kind of (b) component include Imitate the ornithine and/or L-aminobutanedioic acid of dosage.On the one hand, including L-aminobutanedioic acid and/or ornithine dosage can effectively reduce One or more hyperlipidemia risk factors are horizontal in body blood plasma；On the other hand, this combination product is prepared into a kind of dosage form.It is another Aspect, this combination product can be formulated into a kind of solid-state or liquid form.On the one hand, the composition of preparation is suitably adapted for mouth Clothes, intravenous injection, sucking, nasal cavity are blown into, intra arterial injection, subcutaneous administration, mucosa delivery or drug administration at pharynx section.On the other hand, should Combination product can be made into formula of oral.

On the one hand, the combination product can effectively reduce one or more hyperlipidemia risk factors include triglycerides, it is low close Spend lipoprotein and cholesterol；On the other hand, which does not increase the CPK activity levels in above-mentioned individual blood plasma；The group Product is closed because needing can be packaged into a kind of solid-state or liquid forms include but is not limited to a kind of tablet, capsule, pill, particle Agent, emulsion, colloid, using the glass powder of encapsulated, powder, suspending agent, liquid, semiliquid, semisolid, syrup, suspension, Chewable tablets.If desired, ingredient (a) and ingredient (b) can also be packed or hybrid packed respectively.In the component that present specification refers to Lipid-lowering medicine include HMG-CoA inhibitor, niacin, fibrate, bile acid sequestrant, Ezetimibe, Lome Tapai, plant Object sterol, CETP antagonists, orlistat or their arbitrary combination.The above-mentioned HMG-CoA inhibitor referred to is large number of, Including but not limited to Atorvastatin, Fluvastatin, Pravastatin, Lovastatin, Simvastatin, Rosuvastatin.

In some aspects, present specification is announced composition, which includes effective dose, can effectively reduce hyperlipidemia The lipid-lowering medicine of the triglyceride levels of patient.

In some aspects, ornithine of the composition disclosed in present specification containing about 0.01~100g and/or L-aminobutanedioic acid, Containing about the ornithine of 0.01~20g and/or L-aminobutanedioic acid or containing about less than 9g, 8g, 7g, 6g, 5g, 4g, 3g, even lower bird Propylhomoserin and/or L-aminobutanedioic acid.

Draw and sets clause

During above-mentioned all publication, Patent Case and patent application case are hereby incorporated by reference in their entirety, the reference Degree is just as specifically and individually by the entirety disclosure of each publication, Patent Case or patent application case to quote Mode be incorporated to generally.

Summary of drawings

The novel features of this patent are especially announced in appendix claim book.To more fully understand the present invention's Characteristic and advantage can refer to the following illustrative embodiment and attached drawing about the principle of the invention stated in detail：

Specific implementation mode

Terminology used in the present invention purpose is to describe specific embodiment, is not intended to limit the present invention.Except non-specifically Mark, singular forms used herein such as "one", " this " also include relevant plural form.In addition to this, in certain journey On degree, the terms "include", "comprise" mentioned in specification and (or) claims, " having ", " with or and " or such as Such other statements, are somewhat similarly to term " comprising ".

In this field, term " about ", the meaning of " close to " refer to being used the routine techniques of this field one to measure spy One rational acceptable error range when definite value, this depends on the numerical value is how to be measured or measure to a certain extent, The limitation etc. of measuring system.For example, " about " can be translated into one or more standard deviations that this field is put into practice every time, Or 20%, 10%, 5% or 1% upper limit of a certain given value；When being related to biology system or process, this term also refers to With a certain given value in an order of magnitude, as being within 5 times of given value, within more excellent 2 times for given value.Unless otherwise Illustrate, the rational error range for " about " referring to a certain given value in description of the invention and claims.

" therapy " that this patent occurs, " treatment ", " mitigation ", the terms such as " alleviation " are used interchangeably, these terms with adopt The benefit or desired value occurred with a kind of method is related, including but not limited to curative effect benefit and (or) preventative benefit.It treats Effect benefits to include that patient is cured or disease is alleviated, and also includes and the relevant one or more pathophysiological conditions of disease It disappears or alleviates, although patient is still tormented by disease.Prevent to benefit to refer to carrying to prevent a certain patient from suffering from certain disease Before take that this composition or patient main suit have the pathophysiological condition of a certain disease but the disease is not yet diagnosed by clinician When take this composition.

" medicament " that the present invention uses represents a kind of biology, pharmaceutics, chemical compound or its a part of structure. Including but not limited to single or compound organic or inorganic molecules, albumen, oligonucleotides, antibody, antibody derivatives, resist peptide fragment Body segment, vitamin derivative, carbohydrate, toxin, chemotherapy compound.Most compounds can be by synthesizing It arrives, such as small molecule and oligomer (oligomeric peptide fragment, oligonucleotide), the organic compound based on the synthesis of various mother nucleus structures Deng.In addition, many natural resources can be used for the screening of these compounds, such as the extract etc. of plant or animal.Ability Also these known acquisition patterns will not bring the property of these medicaments in the present invention influence of essence to field technique personnel.

Generally, term " being administered simultaneously ", " cooperativing medicine-feeding " or " with ... is administered simultaneously " indicate give two kinds or with In upper drug to individual body, such as compound, reagent, substance, material, synthetic, dosage, time with administration It is spaced and (is such as administered in individual body simultaneously), is related in the internal site of action of individual, acceptable overtime range.Time Interval can be the time ranges such as any suitable period, such as minute, hour, day or week.Drug can when individual is administered It is administered together with the part collectively as a medicament, or otherwise co-administered.Administration time can be with generally one Cause (such as dosing interval be less than or equal to 5min, about 3 minutes or about 1 minute) or in a short time administration (be, for example, less than or Equal to 1h, 30min, 10min or about 5min to 1h), it can be regarded as same time and be administered simultaneously.The common skill of this field Art personnel can determine that suitable dosage, time interval give drug in individual internal, guarantee medicine according to the common knowledge of grasp Object is more than the internal floor level of individual and (or) individual internal effective concentration.It is any when being administered simultaneously to individual implementation A kind of drug is all in the effective dose scope of administration, but this effective quantity is likely lower than the effective quantity used when being administered alone.

" effective quantity " that the present invention uses includes smaller effective quantity and conventional effective quantity and can cause a kind of specified conditions (shadow Ring and/or reaction) arbitrary effective dose.For example, when a certain drug cooperativing medicine-feeding is in a certain individual, dosage may The dosage that should be used when being administered alone less than the medicine, and a certain drug also may be used to one or more effects of a certain individual or group Can be accumulation or superposition, in addition, individual or group are also possible to by multiple dosing.Rely on desired use (in vitro or in vivo Research), individual and disease incidence the condition such as age of individual and weight, the severity of disease, the mode of administration and in reality The other related factors for being easy to be measured in example by those of ordinary skill are applied, effective quantity is also likely to be diversified.This term is also fitted For causing a certain specifically react a dosage in target cell, such as it improves the hyperplasia of cell or promotes target egg White active downward.Whether the dosage that will implement in by the type of candidate compound, research and design is combined joint and is used The influence of the physics transmission system of medicine, administration time, target tissue, load medicine, specific dosage may be varied from.

Term " the acceptable salt of pharmacology " in the present invention refer to it is mentioned in the present invention a large amount of known organic and Salt caused by inorganic counterion.The acceptable acid of pharmacology, which adds salt, to be realized at salt by inorganic acid and organic acid, Salifiable inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc., salifiable organic acid include acetic acid, propionic acid, Hydroxyacetic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, propenyl benzene Acid, phenylglycolic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, salicylic acid etc..The acceptable alkali addition salt of pharmacology can lead to It crosses inorganic base and organic base is realized at salt, salifiable inorganic base includes sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminium Include primary amine, secondary amine, tertiary amine, substitution amine include the substitution amine of self-assembling formation, cycle amine, basic ion Deng, salifiable organic base Exchanger resin and the like, particularly including such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropyl amine (TPA) and ethanol amine.One In a little specific examples, the acceptable alkali addition salt of pharmacology can be selected from ammonium, potassium, sodium, calcium, magnesium salts.

" the acceptable carrier of pharmacology " or " the acceptable excipient of pharmacology " includes whole solvents, decentralized medium, painting Cover agent, antibacterium and epiphyte pharmaceutical, equipressure and absorption delaying agent and the like.These media and reagent are as pharmacological active substance Application method be well known in the art.The medium used in therapeutic component or reagent provided by the invention be it is anticipated that , but except person incompatible with active constituent.A part for additional active constituent also this patent combination product.

As already mentioned, antihyperlipidemic of the present invention such as statins are possibly can not be safely, effectively Ground reduces the blood serum designated object concentration that can indicate hyperlipidemia risk, such as triglycerides, cholesterol and LDL levels.The present invention relates to And blood serum designated object concentration also include the marker such as blood plasma, blood flow concentration of other body fluid.Therefore, it can safely, effectively drop Low triglyceride, the drug ingedient of cholesterol and (or) low-density lipoprotein white level or method need clinic to be confirmed.Meanwhile Clinic is also required to reduce the adverse reaction of lipidemia drug (such as Statins) and reduces the level of serum CPK.This patent provides To include the combination product of ornithine and/or L-aminobutanedioic acid can solve corresponding demand.The combination product and method that this patent provides It is horizontal to can be used for reducing hyperlipidemia risks and assumptions in blood flow.Sometimes, common a effective amount of medicine in medical domain Object such as lipid-lowering medicine can be used for reducing medicine with the individual components cooperativing medicine-feeding, the present composition and method The side effect of (such as Statins) and reduction serum CPK are horizontal.This patent in all its bearings, characteristic, specific features and embodiment Aspect has been described.

The combination product including ornithine and/or L-aminobutanedioic acid is disclosed in the present invention and uses this combination product Method.This product can effectively reduce one or more hyperlipidemia risks and assumptions (such as triglycerides, low-density lipoprotein in individual serum In vain, cholesterol) it is horizontal.In some cases, this product can also increase hdl level.In some cases, this production Product also can effectively reduce the side effect of certain medicine, such as reduce CPK activity levels.In some cases, this product pair The effective of relevant illness is increased with serum active CPK levels.This method and product may include ornithine but not include the door winter Propylhomoserin, this method and product are also possible to include L-aminobutanedioic acid without including ornithine, and this method and product may also include door Winter propylhomoserin and ornithine monomer rather than compound.

The product of this patent may include ornithine, and ornithine may form compound with a balance cation.Balance Cation can be any cation that the present invention enumerates.Cation include but not limited to L-aminobutanedioic acid, glutamic acid, chloride, Sulfate, phosphate, carbonate, acetate, lactate, citrate.L-aminobutanedioic acid is in mammals and non-essential amino Acid, can be turned by oxaloacetic acid amino generation, can also by urea cycle ornithine and citrulling synthesize.L-aminobutanedioic acid energy quilt It is disorderly for preventing fatigue and liver.L-aminobutanedioic acid is a kind of carboxylate anion, salt or aspartate.Invention Individual products may include L-aminobutanedioic acid, L-aminobutanedioic acid can be mutually compound with balance anion, and balance anion can be Invent any anion for pointing out, including but not limited to arginine, cysteine, glutamate, glycine, serine, sodium, Calcium, magnesium and potassium.Ornithine balance cation and (or) L-aminobutanedioic acid balance anion can be the forms of salt.

One component of the suitable individual administration that this patent is announced may include the ingredient being at least made of an ornithine And (or) the ingredient being made of L-aminobutanedioic acid, this ingredient may be that any suitable ornithine and/or L-aminobutanedioic acid form Ingredient, such as a kind of suitable ornithine and/or L-aminobutanedioic acid constituent with biological effect；This ingredient can also be The ingredient of biologically acceptable ornithine and/or the L-aminobutanedioic acid composition of any suitable；This ingredient can also be suitable Acylate；This ingredient can also be the ornithine and/or aspartate of an amino acid.

In one embodiment, compound disclosed in this patent includes at least an ornithine and/or L-aminobutanedioic acid balances Ion complex.In further embodiments, compound disclosed by the invention include 2,3,4,5 or more ornithines and/or L-aminobutanedioic acid ion balance compound.In further embodiments, ion balance with organic form to may exist.At some In embodiment, there may be 1,2,3,4,5,6,7,8,9,10 or more carbon atoms for the ion balance of organic.

Method or combination product disclosed in this patent may include ornithine with L-aminobutanedioic acid be compounded to form each other with salt Form existing for aspartic acid ornithine compound.Symbol "-" represents the ionic bond that two entities are combined with each other into salt.One The method that item patent of invention (Marumo, US3360549) is announced can make ornithine and L-aminobutanedioic acid form compound.One report Confirm that aspartic acid ornithine salt has been used for treating hepatic sclerosis (Sikorska et al. (2010) " Physiological functions of L-ornithine and L-aspartate in the body and the efficacy of administration of L-ornithine-L-aspartate in conditions of relative deficiency",PolskiMerkuriuszLekarski 28(168):490-5).Urea cycle is a metabolic pathway, can Have the function that eliminate ammonia by the way that ammonia is converted to neutral substance-urea, and aspartic acid ornithine compound can pass through urine Element cycle increases the generation of urea.If it is invalid that independent role controls symptom, aspartic acid ornithine can also be with lactulose, profit Good fortune former times bright drug combination.As of the present invention, the compound and preparation method of aspartic acid ornithine can be used for reducing by one Or multiple serum hyperlipidemia risk factors such as lipoprotein and (or) lipid (such as triglycerides), reduce the bad anti-of medicine It answers (such as lipidemia drug, Statins) or reduces serum CPK level.

Suitable for treat hyperlipidemia or a kind of composition of disease conditions related with hyperlipidemia may include ornithine and/ Or L-aminobutanedioic acid.In certain embodiments, aspartic acid ornithine may also be in the form of compound as the one of the composition Part.Aspartic acid ornithine may be with 1:1 ratio is compound.In certain embodiments, compound disclosed by the invention also may be used Can include the compound that ornithine and a balance anion are formed, it is also possible to including L-aminobutanedioic acid and a balance cation shape At compound.In some cases, which may also include a certain proportion of ornithine balance anion and Men Dong ammonia Acid balance cation, this ratio can be 1:1,1:1.5,1:2,1:2.5,1:3,1:3.5,1:4,1:4.5,1:5,1:5.5, 1:6,1:6.5,1:7,1:7.5,1:8,1:8.5,1:9,1:9.5,1:10,1:10.5,1:11,1:11.5,1:12,1:12.5, 1:13,1:13.5,1:14,1:14.5,1:15,1:15.5,1:16,1:16.5,1:17,1:17.5,1:18,1:18.5,1:19, 1:19.5or 1:20.Composition disclosed by the invention may also include ornithine and/or L-aminobutanedioic acid and other types of amino The compound that acid is jointly formed, the composition further include at least one other class other than including ornithine and/or L-aminobutanedioic acid Type amino acid；The amino acid can be the nonessential or essential amino acid of one kind, a kind of natural or non-natural amino acids, it is also possible to Its salt；In the composition, ornithine and/or aspartate may exist in a salt form, it is also possible to ionic dissociation shape Formula exists；Amino acid can be leucine, isoleucine, histidine, valine, lysine, methionine, phenylalanine, Soviet Union's ammonia Acid, tryptophan, arginine, cysteine, tyrosine, alanine, aspartic acid, glutamic acid, cystine, glutamine, sweet ammonia Acid, ornithine, serine, proline, taurine；In addition to glycine, other amino acid can exist with L or D types, wherein L-type It is enantiomter with D types.Ornithine can be L-Orn and L-aminobutanedioic acid can be L-ASPARTIC ACID.

Each ingredient disclosed by the invention can be adapted for preventative and (or) therapeutic benefit, and the ingredient is perhaps Ornithine and/or L-aminobutanedioic acid can be made rapidly to be absorbed, be supplied and (or) supplement, be likely to be suited for or benefit from multiple adaptations Disease, such as nutrition or prevention and treatment.The ingredient perhaps can be used as ornithine and/or L-aminobutanedioic acid intake, supply and (or) the suitable or advantageous medium of supplement application aspect, such as it is real by diet medium, consumption medium (such as food/beverage) Existing application.

In certain embodiments, including the composition of ornithine and/or L-aminobutanedioic acid may be to exist with single dose form, But in some cases, the composition may be to exist with multiple dose form.The compound can single dose or multi-dose use, Dosage can be 1 time a day, 2 times, 3 times, 4 times, 5 times, 6 times or be more than 6 times, can also be monthly 1 time, 1 time every 2 weeks, one Week 1 time or 1 time every other day.Ornithine and/or L-aminobutanedioic acid can be with one or more medicines (such as lipid-lowering medicine) with 1 day 1 time Be administered together to 1 day 6 times modes, this administering mode continuously can not be more than 1 week, can also successive administration be equal to or more than 6 days, 10 days, 14 days, 20 days, 28 days, 30 days, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 Year, 15 years, 16 years, 17 years, 18 years, 19 years, 20 years, 21 years, 22 years, 23 years, 24 years, 25 years, 26 years, 27 years, 28 years, 29 Year, 30 years.In some cases, holding time for successive administration can be with long enough.In some cases, including ornithine and/ Or the compound of L-aminobutanedioic acid is one month at least to be administered, in yet some other cases, administration at least continues 10 days.Administration includes The duration of the composition of ornithine and/or L-aminobutanedioic acid perhaps answers long enough, in some embodiments, of the invention change Closing object administration may be no more than 28,14,7,6,5,4,3,2 or 1 days, and in further embodiments, an of the invention chemical combination Object can be administered in a manner of slow, lasting, for example, chronic effect treatment.

The compound that the present invention announces can be administered in a manner of various dose.People in the art is aware that, due to tested There is individual heterogeneity in person, the human oriented design of dose prescription is that optimal treatment institute is required to the Pharmacokinetic Characteristics of compound , therefore the dosage of a compound of this patent can be disclosed according to the instant messages of routine experiment and be determined.

Determine that the optimal dose comprising ornithine and/or L-aminobutanedioic acid compound is perhaps limited by Multiple factors, such as on State the intention such as condition treatment that the factor that those of refers to, any possible or actual side effect and (or) drug are implemented Purpose, a reduction side effect purpose etc..It is any one in these factors to determine that an optimal dose may be also required to consider A factor, an other suitable factors, any side effect, animal research models, human research's model, clinical research model, Any factor of drug research model and centre.

The ornithine and/or L-aminobutanedioic acid content that can be absorbed by subject or its absorption rate have individual difference, Restricted by factors, may include metabolic rate, renal function, total health status and (or) it is related with subject it is other because Element, it is also possible to include the inherent characteristic or natural attribute of compound containing ornithine and/or L-aminobutanedioic acid itself, such as balance Ion, sensitizer, administration medium or method and (or) other factors related with the compound itself.

Composition object disclosed by the invention comprising ornithine and/or L-aminobutanedioic acid has wider validity window.Example Such as, adult be administered daily dosage range include but be not limited to from 0.005 to 100g, from 0.01 to 100g, from 0.001 to 50g, from 0.005 to 30g and from 0.01 to 20g, accurate dosage is dependent on administration route, compound form, tested Person, subject's weight, the preference of doctor and experience.

The dosage of ornithine and/or L-aminobutanedioic acid perhaps can combine shape by ornithine, L-aminobutanedioic acid or the two It is estimated at the molecular weight of compound (if compound includes), perhaps 1.5mg can also be administered by daily per kilogram of body weight arrives 1g is administered to estimate in daily per kilogram of body weight, for example, for treatment disease and (or) certain pathological conditions, such as treatment hyperlipidemia, The side effect etc. of disease conditions related with hyperlipidemia, the raised condition of CPK concentration, certain medicines, dosage can To be estimated as ornithine and/or L-aminobutanedioic acid less than about per kilogram of body weight 0.9g, can also be estimated as about daily per public Jin weight 300mg to 1g, can also be estimated as daily per kilogram of body weight 150mg to 300mg.Above-mentioned dosage range may be suitable for Human body.The dosage of ornithine and/or L-aminobutanedioic acid is likely lower than per kilogram 150mg.

As described above, one perhaps determines, influences, adjusting a dosage suitable for factor, such as it is related to individual such as people The clinical test results of body subject.In some embodiments, for example, based on experimental study or test (as being based on conversion appropriate The factor, animal dosage appropriate are transformed into human dose appropriate), the dosage appropriate of an animal model appropriate is determined Determine, influence and (or) have adjusted human administration's dosage appropriate.Again for example, any human body be suitble to dosage by Human clinical trial determines, influences and (or) adjusts.

From clinical practice angle, there are many polymorphic type lipid-loweringings for treating hyperlipidemia and (or) illness associated therewith Drug can be with prescription, these fat-reducing medicaments perhaps can be effectively reduced one or more hyperlipidemia risks and assumptions.Some Fat-reducing medicament can also reduce subject's triglycerides, low-density lipoprotein or cholesterol levels, some can also increase highly dense Spend lipoprotein levels.Such fat-reducing medicament includes but is not limited to HMG-CoA inhibitor (or Statins), cigarette known to this field Alkali acid, fibrates, cholic acid chelating agent (resin), cholesterol absorption inhibitor (Ezetimibe), Lome Tapai, phytosterol, Austria Li Sita and other medicines.Statins include but not limited to Atorvastatin, Fluvastatin, Pravastatin, Lovastatin, Simvastatin, Pitavastatin, simvastatin, Rosuvastatin, Lovastatin/niacin sustained release agent；Cholesterol absorption inhibitor Including but not limited to Ezetimibe, combine with Simvastatin according to folding；Fibrate lipid-lowering drugs include but not limited to Gemfibrozil Capsules, non- Nobert, fenofibrate, Clofibrate, micronizing fenofibrate；Niacin class includes but not limited to niacin, niacin Sustained release agent；Bile acid chelate includes but not limited to Colestipol, Cholestyramine or examines and carry out polyvinyl.Other lipid-lowering medicines may include Dextrothyroxine sodium or eicosapentaenoic acid.

When composition includes that ornithine and/or L-aminobutanedioic acid and one or more of the other medicine are same, and these are treated The half-life short of drug is when ornithine and/or L-aminobutanedioic acid, the list of these medicines and ornithine and/or L-aminobutanedioic acid Position dosage can targetedly make adjustment.

Composition disclosed by the invention comprising ornithine and/or L-aminobutanedioic acid can provide a bird by preparation method The effective dose of propylhomoserin and/or L-aminobutanedioic acid, this effective dose can be used as active constituent, or as pharmaceutically acceptable salt, Ester, prodrug, solvent, hydrate or derivative therein.The compound may be the synthetic in pharmaceutics, it is also possible to contain The medicine that one or more selects to treat some condition of disease according to particular utility.This medicine may be A kind of lipid-lowering medicine, and a dosage of this lipid-lowering medicine may effectively treat a symptom of hyperlipidemia.The compound it is expected Including pharmaceutically acceptable salt and (or) collaboration compound therein, one or more pharmaceutically acceptable excipient, carrier Include aseptic aqueous solution and various organic solvents, penetration enhancers, solubilising including inert solid diluent and filler material, diluent Agent and adjuvant.

Composition containing ornithine and/or L-aminobutanedioic acid can be administered in any suitable manner, and administration can be oral And (or) other any medications appropriate are for example percutaneous, vein, spraying, intramuscular injection, vagina, rectum, subcutaneous, non-gastrointestinal Road, eye, lung, mucous membrane, ear, nose and local administration.The composition component that the present invention describes such as L-aminobutanedioic acid bird ammonia Acid tries to increase one or more reagents, ornithine or a kind of and more than one other treatments that bioavilability uses Agent can cooperativing medicine-feeding, cooperativing medicine-feeding mode can be found in the present invention and (or) U.S. Patent Application Publication No. US2006/ 0089335A1.For example, parenteral administration includes muscle, subcutaneous, vein, intramedullary injection, also include cavum subarachnoidale, direct Ventricle, abdominal cavity, lymphatic and nasal injection.

Composition disclosed by the invention containing ornithine and/or L-aminobutanedioic acid can be administered alone can also with one or A number of other administered in combination, administering mode can be identical as the administering mode of individual compound.In the preparation, ornithine And/or L-aminobutanedioic acid and other medicines can mix and are formulated, and whole components can also be divided into independent preparation Prescription is separately or concurrently used in combination.In certain embodiments, these synthetics can be made into a kind of dosage form；In other realities Applying example, ornithine and/or L-aminobutanedioic acid and one or more of the other medicine can be packed individually or pack together；Ornithine And/or L-aminobutanedioic acid can also be packed but be administered simultaneously respectively with other treatment drug, ornithine and/or L-aminobutanedioic acid can also It is not administered simultaneously with other medicines.

In certain embodiments, the content of ornithine and/or L-aminobutanedioic acid may be about low in composition disclosed by the invention In 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (mass ratio or mass/volume)；In certain embodiments, bird ammonia in composition disclosed by the invention The content of acid and/or L-aminobutanedioic acid may be approximately higher than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (mass ratio or mass/volume ratio).In certain embodiments, bird ammonia in compound The content of acid and/or L-aminobutanedioic acid is about 49%.

In certain embodiments, include ornithine and/or L-aminobutanedioic acid in composition disclosed by the invention with salt or trip From content existing for form be equal to or less than 100,95,90,85,80,75,70,65,60,55,50,45,40,35,30,20, 19、18、17、16、15、14、13、12、11、10、9.5、9、8.5、8、7.5、7、6.5、6、5.5、5、4.5、4、3.5、3、2.5、 2、1.5、1、0.9、0.8、0.7、0.6、0.5、0.4、0.3、0.2、0.1、0.09、0.08、0.07、0.06、0.05、0.04、 0.03、0.02、0.01、0.009、0.008、0.007、0.006、0.005、0.004、0.003、0.002、0.001、0.0009、 0.0008,0.0007,0.0006,0.0005,0.0004,0.0003,0.0002 or 0.0001g.In some embodiments, compound In include ornithine and/or L-aminobutanedioic acid with content existing for salt or free form more than 0.0001,0.0002,0.0003, 0.0004、0.0005、0.0006、0.0007、0.0008、0.0009、0.001、0.002、0.003、0.004、0.005、 0.006、0.007、0.008、0.009、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.2、 0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、1.5、2、2.5、3、3.5、4、4.5、5、5.5、6、6.5、7、7.5、8、8.5、 9,9.5,10,11,12,13,14,15,16,17,18,19 or 20g.In certain embodiments, ornithine and/or L-aminobutanedioic acid with Content existing for salt or free form is more than 25,30,35,40,45,50,55,60,65,70,75,80,85,90,95 or 100g. In certain embodiments, ornithine and/or L-aminobutanedioic acid are less than 9g with content existing for salt or free form.In some embodiments In, ornithine and/or L-aminobutanedioic acid are less than 3g in compound with content existing for salt or free form.In some embodiments In, ornithine and/or L-aminobutanedioic acid are 0.95g with content existing for salt or free form in compound.In some embodiments In, ornithine and/or L-aminobutanedioic acid are in compound with content existing for salt or free form between 0.0001~1,0.0001 ~3,0.0001~2.5,0.001~2.5,0.1~2.5,0.001~3,0.01~3,0.1~3,0.01~20,0.01~ 15,0.01~10,0.01~5,0.01~100g.

Composition disclosed by the invention can include typically an active constituent (such as ornithine and/or L-aminobutanedioic acid) Or its pharmaceutically acceptable salt and (or) its complex, one or more pharmaceutically acceptable excipient, carrier, packet Include but be not limited to inert solid filler, filler, diluent, aseptic aqueous solution, various organic solvents, penetration enhancers, solubilising Agent and auxiliary agent.In addition, this synthetic may also include one or more replenishers or other active ingredients, one or more draft Extract, one or more colorants.

Following methods for being infinite exemplary composition and prepare the composition.In certain embodiments, The present invention provides a kind of oral pharmaceutical compositions, including ornithine and/or L-aminobutanedioic acid and the excipient suitable for taking orally. In certain embodiments, the present invention provides a kind of orally available solid pharmaceutical compositions, including：(a) ornithine and/or door winter ammonia One effective dose of acid；(b) dosage (such as a kind of lipid-lowering medicine or depressor) for a kind of medicine；Or (c) one The effective dose of a or a number of other drugs；(d) pharmaceutical excipient used for oral absorption.In certain embodiments, Use the triglyceride levels of the effective dose functions for the treatment of hyperlipidemia patient of this fat-reducing medicament.

Composition disclosed by the invention comprising ornithine and/or L-aminobutanedioic acid can be given by any suitable form Medicine, such as liquid form, colloidal form, semi-liquid form (such as a kind of viscous liquid includes fraction solids), semi-liquid form (such as a kind of solid includes partially liq) and (or) solid form.For simple example, a kind of tablet, capsule, food agent, Masticatory, non-masticatory, sustained release agent, non-time-release dose etc. can be selected.This patent includes the tablet gradually discharged, the agent Type can be found from United States Patent (USP) NO.3,456,049.This compound can also include other ingredients, whether is it with living Property.Such as it is a kind of any type of food additives, flavoring agent, colorant, filler, binder, lubricant, excipient, anti- Rotten agent, other be manufactured into are graded.Sustained release agent perhaps can delay compound and/or one or more components of itself in a timing The decomposition and/or absorption of (or in relative long term) in phase.Food agent can be the processed food for being such as pressed into block, cereal Product, baked goods, dairy products etc..Baked goods can be the food of loaf shape, such as bagel or bread itself, example It is only simple herein to introduce such as baked donut, muffin and (or) such other food.Group containing ornithine and/or L-aminobutanedioic acid The form that a kind of form of component in object can pass through different from another ingredient in the composition is closed to provide.For example, ornithine And/or L-aminobutanedioic acid can provide in solid form, such as food or cereal, and with the liquid of lipidemia drug Dosage form is administered simultaneously.The compound of ornithine existing in a variety of forms and/or L-aminobutanedioic acid can be administered simultaneously and can also divide Open medicine, being administered simultaneously can be exemplified as, and while taking a piece of lipid-lowering medicine, take one bottle of Asp-Orn and strengthen Breast.

In certain embodiments, including the composition of ornithine and/or L-aminobutanedioic acid may be it is a kind of be suitable for it is oral Solid or Liquid pharmaceutical component, it can be a kind of dispersion or unit dose that this patent was announced, which is suitable for oral Pharmaceutical Compositions, Type, each includes the active medicine for the certain effective dose being determined in advance.This certain effective dose being determined in advance Active medicine can be a kind of powdered either graininess, glass powder, a kind of solution or one kind in water, non-aqueous solution, water Suspended matter present in packet oil emulsion or water-in-oil emulsion.Individual dosage form can be prepared by any method of pharmacy. In some cases, this method includes mixing active constituent and one or more required carriers, which can also It is prepared by way of equably and promptly mixing active constituent with liquid carrier, it can also be by being carried with uniform solid Prepared by the method that body or solid and liquid-carrier mix simultaneously, then can be processed into desired compound.For example, a kind of tablet can By selectively with together with one or more auxiliary agents by compression or modeling in a manner of prepare.Tablet can be by a kind of appropriate Instrument compresses, and active constituent can exist in a manner of nonfluid form such as powder or particle, also may be selected and a kind of excipient Mixing, excipient include but not limited to a kind of binder, lubricant, inert diluent and/or a kind of surfactant or dispersion Agent.Tablet can pass through a kind of a kind of mixing of machine, powdered compounds and a kind of formation of inert liquid diluent appropriate It is prepared by the method for object.

The present invention also includes dehydrated pharmaceutical component and comprising a kind of dosage form of active constituent, because water can make certainization Object is closed to degrade.For example, to measure the characteristic such as shelf-life of compound or being formulated long-term stability, the medicine that this patent is announced Learn the means that can increase water (such as 5%) in technique as simulation long term storage.Dehydrated pharmaceutical component by the invention and agent Type can also be prepared by using anhydrous sodium sulfate or low moisture material preparation under low moisture or low-moisture conditions. If the lactinated drug component of packet and dosage form that the present invention announces may continue during production, packaging and/or storage It can then be prepared by the method for dehydration with moisture and/or moist be in contact.A kind of preparation of anhydrous drug component and store it Purpose is the natural anhydrous character to maintain it, therefore anhydrous compound can be packed using water proof material, can be placed on suitable When medicine box in, packaging appropriate includes but not limited to foil, plastics or the like, the container of unit dose, cover plate packet of sealing Dress and band-like packaging.

A kind of active constituent can require to be used in mixed way with a kind of pharmaceutical carrier according to pharmaceutical technology, and the selection of carrier is main It is determined by desired means of administration.When preparing a kind of composition of peroral dosage form, in the pharmaceutics of any type routine Medium can be used as carrier.In oral solution (such as suspension, solution and elixir) or the preparation of aerosol, these Carrier includes but not limited to water, ethylene glycol, oil, ethyl alcohol, flavoring agent, preservative, colorant and the like；In oral administration solid In preparation, these carriers include but not limited to starch, sugar, avicel cellulose, diluent, granule, lubricant, binder and collapse Agent is solved, but in some embodiments, lactose is simultaneously not used.Carrier appropriate also includes powder, capsule, particle and tablet etc.. If necessary, tablet can be coated with by the water of standard or non-aqueous technology.

The binder prepared suitable for the compounds of this invention component and its dosage form includes but not limited to cornstarch, potato The Huang of starch, gelatin, nature or the natural gum of synthesis such as Arabic gum, sodium alginate, alginic acid, other alginates, powder Alpine yarrow glue, guar gum, cellulose and its derivative (such as ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, carboxylic first Base sodium cellulosate), polyvinylpyrrolidone, methylcellulose, gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose and The mixture of itself.

The filler for being suitable for preparing pharmaceutical compound and dosage form disclosed in this patent include but not limited to talcum, mica, Calcium carbonate (such as particle or powdered), microcrystalline cellulose, cellulose powder, dextrates, kaolin, mannitol, silicon The mixture of acid, sorbierite, starch, gelatinized starch and itself.

The use of the purpose of disintegrant can be made when tablet medicine is exposed to water environment in chemicals disclosed in this patent Disintegration of tablet.Disintegrant may excessively be such that tablet is disintegrated in bottle, but can not make tablet disintegration complete very little, may Rate that active constituent is discharged from dosage form and degree can be caused to change.Therefore, the disintegrant content that this patent is announced was both Cannot very little can not be too many, to avoid its to include in combination dosage form disclosed by the invention active component release bring Adverse effect.It is influenced by formulation types and mode of administration, the content of disintegrant may change, this is those skilled in the art Known content.The disintegrant of about 0.5-1.5 weight percent, or about 1-5 weight percent disintegrant energy quilt It is used as Pharmaceutical Compositions.The disintegrant that this patent was announced be used to form pharmaceutical composition and dosage form include but not limited to agar, Alginic acid, calcium carbonate, microcrystalline cellulose, sodium cellulosate, polyvinylpyrrolidone, PVP K30, the poly- dimension of crosslinking Ketone, polacrilin, Explotab, potato or tapioca, other starch, gelatinized starch, other starch, clay, its The compound of its phycocolloid, other celluloses, natural gum or itself.

It includes but not limited to calcium stearate, stearic acid that the present invention announced, which is used to form drug component and the lubricant of dosage form, Magnesium, mineral oil, light mineral oil, glycerine, sorbierite, mannitol, polyethylene glycol, other ethylene glycol, stearic acid, lauryl alcohol sulfuric acid Sodium, talcum powder, hydrogenated vegetable oil (for example, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), The mixture of zinc stearate, ethyl oleate, ethyl laureate, agar or itself.Other lubricants further include such as A kind of syloid silica gel, solidifiable silica spray and the mixture etc. between them.Lubricant can by selectively with Amount less than about 1 weight percent is added in drug ingedient.

If the composition comprising ornithine and/or L-aminobutanedioic acid is used to take orally, in diluent such as water, ethyl alcohol, third In the presence of enediol, glycerine and the various combinations of itself, compound can be with a variety of sweeteners, flavoring agent (Ru Asi Ba Tian, sugar), pigment (such as uranidin), even emulsification and/or suspending agent mixing.

The effect of sweetener or flavoring agent is to increase the sweet taste of food, beverage or drug ingedient, and sweetener can be sugar, sugar Smart or other low content synthetic products (selecting from the non-bowdlerized version of Random House dictionary, the second edition).The non-limit of sweetener or flavoring agent Qualitative example includes Aspartame, 1- oxygen-mogrosides, aspartoyl-alanine turnip ester, jequirity Triterpene Glycosides methyl esters, knob Sweet tea, osladin, SC-45647, two fructose of fiber, two fructose of rough gentian, 4,4', 6,6'- tetra- chloro- 4,4', 6,6- tetra- are gone Oxygen lotion trehalose, sweet protein, Pentadiplandra brazzeana, hydrangenol -4- oxygen glucoside, hydrangenol -8- Oxygen-galactoside, 3,3 '-double deoxidation trehaloses, selligueain A, periandrin V, NC 174, mabinlin, Water betel nut, alitame, blue or green money willow glycosides A, mabilin II albumen, N- (4- cyanophenyls base)-N '-(2- carboxyethyls) urea, stevia rebaudianum are double Glucosides, Adentol, periandradulcin A, periandradulcin B, periandradulcin C, Sweetrex, Mo Neilin, asparagine (22)-glutamine (25)-asparagine (26)-A- chains-asparagine (49)-glucose (50)-B- Chain, thizoma curculiginis albumen, white bacterium disaccharides, polypodoside A, Rubusoside, glycyrrhetyl 3-monoglucuronide, ring Hexanone oxime V, hernandulcin, Nystose, neosugar, Momordia grosvenori aglycone IV, momordica grosvenori glycoside V, momordica grosvenori glycoside V I, coupling Sugar, 4-chlorokynurenine, glucosylsucrose, 6-chlorotryptophan, stevioside A, Paclitaxe be graceful, silk ball Phenol, Palatinitol, Lycasin, cyclo-heptylamino sulfonate, CH 401-N, neohesperidin dihydrochalcone, P4000, malt Sugar alcohol, leaf stripe, miraculin, Synsepalum dulcificum, acesulfame potassium or dulcin.

The tablet that the present invention announces can not be coated with or is coated with using the prior art, and coated purpose is to delay medicine A kind of sustained release can be used for example to make drug reach the function of a lasting medicine in the degradation and absorption of gastrointestinal tract in piece Material such as glycerin monostearate or bi-tristearin reach object above.Hard capsule can be used in the formula of oral drugs, Active constituent therein can be mixed with a kind of inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin；Oral drugs Formula can also be used soft capsule, active constituent therein that can be mixed with water or oil medium such as peanut oil, atoleine, olive oil.

The be used to form medical compounds and the surfactant of dosage form that this patent is announced include but not limited to hydrophily table Face activating agent, lipophilic surfactant and its mixture, that is to say, that may be used hydrophilic surfactant mixture, The mixture of lipophilic surfactant includes at least one hydrophilic and lipophilic surfactant mixture.

A kind of its HLB value of hydrophilic surfactant appropriate is generally at least 10, and a kind of lipophilic surface activity appropriate The HLB value of agent should not exceed 10.Relative hydropathic for characterizing nonionic amphiphilic compound and a lipophilic experience Parameter is hydrophil lipophil balance coefficient (HLB value).With compared with the surfactant of low hlb more lipophilic or hydrophobic, in the oil Solubility bigger, and with, with more hydrophilic feature, there is bigger in aqueous solution compared with the surfactant of high hlb Solubility.Hydrophilic surfactant include HLB value be generally higher than 10 compound and those cannot use HLB parameter characterizations Anion, cation or zwitterionic compound.Equally, the HLB value of lipophilic surfactant's (such as hydrophobic surfactant) Equal to or less than 10.But for industrial prescription, pharmacy and cosmetic emulsions, the HLB value of surfactant is only thick as one Slightly instruct.

Hydrophilic surfactant active can be ionic state or nonionic state, and ionic surface active agent appropriate includes but not office It is limited to alkylammonium salt；Fusidate；The derivative of fatty acid of amino acid, oligopeptides and polypeptide；Amino acid, oligopeptides and polypeptide it is sweet Grease derivative；Lecithin and hydrolecithin；Lysolecithin and hydrogenated lyso lecithin；Lecithin and its derivative；It is molten Blood lecithin and its derivative；Carnitine fatty acid salt；Alkylsurfuric acid sodium salt；Fatty acid salt；Docusate sodium；Acyl chemical combination Object；The single, double acetylation tartrate of diand monoglycerides；Succinated diand monoglycerides；The citric acid of diand monoglycerides Ester；And their mixture.

The above-mentioned ionic surfactant referred to include lecithin, lysolecithin, phosphatide, lysophosphatide and they Derivative；Including meat poisoning sword fatty acid ester salt；Alkylsurfuric acid sodium salt；Fatty acid salt；Docusate sodium；Acyl compound； The single, double acetylation tartrate of diand monoglycerides；Succinated diand monoglycerides；The citrate of diand monoglycerides； And their mixture.

Ionic surfactant can be lecithin, lysolecithin, phosphatidyl choline, phosphatidyl-ethanolamine, phosphatide Acyl glycerine, phosphatidic acid, phosphatidylserine, lysolecithin, lysophosphatidyl ethanolamine, hemolytic phosphatidyl, lysophosphatidic acid, Serium inorganic phosphorus acyl serine, PEG- phosphatidyl-ethanolamines, PVP- phosphatidyl-ethanolamines, aliphatic acid lactoyl ester, octadecanoyl -2- breasts Acid, stearoyl lactate, succinylated monoglyceride, the mono-/bis-acetylation tartrates of diand monoglycerides, mono-/bis-glyceride Citrate, cholylsarcosine, caproate, caprylate, caprate, laruate, myristate, palmitate, oleate, castor Numb hydrochlorate, linoleate, linolenate, stearate, lauric acid sulfuric ester, sodium tetradecyl sulfate, docusate sodium, dodecane Acyl carnitine, hexadecanoyl carnitine, myristoyl carnitine, salt and its mixture.

Hydrophilic non-ionic surfactant includes but not limited to alkyl-glucoside, alkylmaltosides, alkyl sulfide For glucoside, Gelucire 44/14, polyoxyalkylene alkyl such as polyethylene glycol alkyl ether, polyoxyalkylene alkyl phenol Such as polyethylene glycol alkyl phenol, polyalkylene glycol alkyl phenol aliphatic ester such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty Acid diester, polyethylene glycol glycerol aliphatic ester, polyglycerol aliphatic ester, for example poly- second of polyethylene glycol sorbitan aliphatic ester class Glycol sorbitan aliphatic ester, containing at least one by glyceride, vegetable oil, hydrogenated vegetable oil, aliphatic acid and sterols group At unit polyalcohol hydrophily transesterification products；Polyethylene glycol steroid, derivative and the like；Polyoxyethylene is tieed up Raw element and its derivative, polyoxyethylene polyoxypropylene ether copolymer and its mixture, polyethylene glycol sorbitan aliphatic ester and At least one ingredient is by the hydrophilic transesterification products of polyalcohol that triglycerides, vegetable oil, hydrogenated vegetable oil form；Polyalcohol Can be glycerine, ethylene glycol, polyethylene glycol, propylene glycol, pentaerythrite or a kind of saccharide.

Other hydrophilic nonionic type surfactants include but not limited to PEG-10 laurates, PEG-12 lauric acid Ester, PEG-20 laurates, PEG-32 laurates, PEG-32 laurates, PEG-12 oleates, PEG-15 oleates, PEG-20 oleates, PEG-20 dioleates, PEG-32 oleates, PEG-200 oleates, PEG-400 oleates, PEG-15 are hard Resin acid salt, PEG-32 distearates, PEG-40 stearates, PEG-100 stearates, PEG-20 dilaurates, PEG- 25 oleins, PEG-32 dioleates, PEG-20 glyceryl laurates, PEG-30 glyceryl laurates, PEG- 20 stearines, PEG-20 glyceryl oleates, PEG-30 glyceryl oleates, PEG-40 glycerol monolaurates, PEG-40 palm fibres Palmitic acid benevolence oil, PEG-50 rilanit specials, PEG-40 castor oil, Cremophor ELP, PEG-60 castor oil, PEG-40 hydrogenated castors Oil, PEG-60 rilanit specials, PEG-60 corn oils, PEG-6 caprates/caprylate glyceride, PEG-8 caprates/caprylate Glyceride, polyglyceryl laurate, PEG-30 cholesterol, PEG-25 phytol, PEG-30 Sterids, soya hydroxies, tri- oleics of PEG-20 Ester, PEG-40 sorbitan monooleates, PEG-80 sorbitan monolaurates, polysorbate20, poly- sorb Alcohol ester 80, POE-9 lauryl ethers, POE-23 lauryl ethers, POE-10 oleyls ether, POE-20 oleyls ether, POE-20 are stearic Acyl ether, PEG-100 tocopheryl succinates, PEG-24 cholesterol, -10 oleate of glycerine, polysorbate40, polysorbate60, sucrose list are stearic Acid esters, sucrose monolaurate, sucrose palmitic acid ester, PEG-10-100 nonylphenol series, PEG15-100 octyl phenols system Row, poloxamer.

Lipophilic surfactant appropriate includes but is not limited to fatty alcohol, fatty acid glyceride, acetoglyceride fat Acid esters, low ethanol aliphatic ester, cithrol, sorbitan aliphatic ester, polyethylene glycol sorbitan fatty acid Ester, sterol and its derivative, polyethoxy sterol and its derivative, polyethylene glycol alkyl ether, sugar ester, sugar ether, single and double glycerine Polyl lactic acid derivative contains at least one unit being made of glyceride, vegetable oil, hydrogenated vegetable oil, aliphatic acid and sterols Polyalcohol hydrophobicity transesterification products；Oil-soluble vitamin and its derivative, the mixture of themselves.Preferred Lipophilic surfactant includes fatty acid glyceride, methyl glycol fatty acid ester and their mixture, or containing extremely Few polyalcohol hydrophobicity transesterification products at the unit being made of vegetable oil, hydrogenated vegetable oil and triglycerides.

The purpose that mentioned compound contains solubilizer in one embodiment is to ensure solubilising and/or improving dissolving Degree forms precipitation to reduce compound to the greatest extent.This is particularly advantageous for non-oral formulation such as injection compound.Solubilizer also can quilt Dissolubility for increasing hydrophilic medicament and/or other compounds, such as surfactant may be alternatively used for maintaining composition Stability, homogeneity or dispersibility.

Solubilizer appropriate includes but not limited to following substance：Ethyl alcohol and polyalcohol, such as ethyl alcohol, isopropanol, butanol, benzene first Alcohol, ethylene glycol, propylene glycol, butanediol and its isomer, glycerine, pentaerythrite, sorbierite, mannitol, carbitol, two Methyl isobide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin And cyclodextrine derivatives, polyethylene glycol ethers such as tetrahydrofurfuryl alcohol PEG ether (tetrahydrochysene furan of the average molecular weight between 200-600 or so Mutter polyglycol ether) or methoxyl group PEG, amide and other nitrogenous compounds such as 2-Pyrrolidone, 2- piperidones, ε-acyl in oneself Amine, N- alkyl pyrrolidones, N- hydroxyalkylpyrrolidones, N- Alkylpiperidines ketone, N- alkyl caprolactams, dimethylacetylamide and Polyvinylpyrrolidone, esters such as ethyl propionate, citrate, tributylcitrate, acetyl triethyl citrate, acetyl tributyl citrate Tributyl, triethyl citrate, ethyl oleate, ethyl caprilate, ethyl butyrate, glycerol acetate, propylene glycol monoacetate, the third two Alcohol diacetate, 6-caprolactone and its isomer, δ-valerolactone and its isomer, beta-butyrolactone and its is same Other solubilizer that enantiomers and the present invention mention, such as dimethylacetylamide, Isosorbide dimethyl ether, N- methylpyrroles Alkanone, monooctanoin, diethylene glycol monoethyl ether, water.

Solubiliser mix can also use in the method that the present invention refers to, including but not limited to glycerol acetate, lemon Lemon triethylenetetraminehexaacetic acid ester, ethyl caprilate, dimethylacetylamide, N-Methyl pyrrolidone, n-hydroxyethyl pyrrolidone, gathers ethyl oleate Vinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethyl alcohol, polyethylene glycol 200-100, tetrahydrofuran polyethylene glycol Ether, carbitol, propylene glycol and Isosorbide dimethyl ether.Preferred solubilizer includes sorbierite, glycerine, glycerol acetate, second Alcohol, PEG-400, Tetrahydrofurfuryl polyethylene glycol ether and propylene glycol.

The present invention does not do special limitation to the usage amount of solubilizer, and a set solubilizer level can be confined to one A those skilled in the art are easy in determining biologically acceptable amount ranges.In some cases, solubilizer contains The range that amount is more than biological acceptable amount might have certain benefit, for example, drug concentration is made to maximize, is supplied in drug Before individual, routine techniques such as distillation or evaporation technique can be used, excessive solubilizer is added and concentrates drug.Therefore, if this Kind of situation occurs, the content of solubilizer can reach drug (including excipient) total weight 10%, 25%, 50% or about 200%.If it is desired to the solubilizer of denier can also be used, such as 5%, 2%, 1% or less.Most solubilizer makes 1%-100%, the more typically about 5%-25% of gross weight are ranged approximately from content.

The compound that the present invention announces may include one or more pharmaceutically acceptable additives and excipient, including but not It is limited to anti-adhesion agent, anti-foaming agent, buffer, polymer, antioxidant, preservative, chelating agent, gluing conditioning agent, elastic force agent, adjusts Taste agent, colorant, flavouring agent, opacifier, suspending agent, binder, filler, moulding-aid agent, lubricant and their mixture.

For ease of the stability for processing, increasing compound or other reasons, one can be added when preparing this compound Kind acid or alkali.Alkali can be a kind of pharmaceutically acceptable alkali, including amino acid, amino-acid ester, ammonium hydroxide, potassium hydroxide, hydrogen Sodium oxide molybdena, sodium bicarbonate, aluminium hydroxide, calcium carbonate, magnesium hydroxide, aluminum magnesium silicate, the alumina silicate of synthesis, synthesis hydrotalcite, Aluminum magnesium hydroxide, diisopropylethylamine, ethanol amine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, three hydroxyls Aminomethane (TRIS) and the like.Alkali appropriate also includes the salt that pharmaceutically acceptable acid is formed, and this kind of acid includes Acetic acid, acrylic acid, adipic acid, alginic acid, methanesulfonic acid, amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, lemon Acid, aliphatic acid, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, arabo-ascorbic acid, lactic acid, maleic acid, oxalic acid, half bromine Phenylbenzimidazole sulfonic acid, propionic acid, p-methyl benzenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioacetic acid, toluene sulphur Acid, uric acid and the like；Also include salt such as sodium phosphate, disodium hydrogen phosphate, the sodium dihydrogen phosphate that polyacid is formed.If there is Alkali be a kind of salt, cation may be conventional pharmaceutically acceptable cation, for example, ammonium, alkali metal, alkaline-earth metal and Its analog, including but not limited to sodium, potassium, lithium, magnesium, calcium, ammonium.

The acid appropriate being added is pharmaceutically acceptable organic or inorganic acid, inorganic acid appropriate include hydrochloric acid, hydrobromic acid, Hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and the like.Organic acid appropriate includes acetic acid, acrylic acid, adipic acid, seaweed Acid, pyrovinic acid, amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, aliphatic acid, formic acid, fumaric acid, It is gluconic acid, hydroquinone sulfonic acid, arabo-ascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, half bromophenylsulfonic acid, propionic acid, right Toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioacetic acid, toluenesulfonic acid, uric acid and the like.

Compound disclosed by the invention also contains one or more herbaceous plant or replenishers, including but not limited to Brazilian It is the certain kind of berries, clover, aloe, aloe barbadensis Miller, aristolochic acid, asia ginseng, Radix Astragali, lactic acid bacteria, belladonna (herb), beta carotene, double It is discrimination bacillus, Bilberry, biotin, bitter orange, black cohosh root, Asiatic plantain, black tea, bladder-wrack, milk thistle, foreign Asiatic plantain, blueberry, bluish-green It is algae, boron, bromelain, butterbur, calcium, pot marigold, casey that, cartilage (ox and shark), Chinese cassia tree, radix ranunculi ternati, camomile, holy and pure The certain kind of berries, chondroitin sulfate, chromium, cassia bark, cloves, coenzyme q-10, collargol product, mossberry, creatine, dandelion, devil claw root, DHEA, Radix Angelicae Sinensis, Echinacea, ephedrine, Canadian nurse's tea, eucalyptus, European elder, European pavilion parasitism, evening primrose oil, cucurbit Bar, feverfen, fish oil, flaxseed, linseed oil, folic acid, garlic, ginger, ginkgo, ginseng, aminoglucose hydrochloride, gucosamine Sulfate, canada yellow-root, grape seed extract, green tea, hawthorn, butterfly Asia, chestnut, horse hair, hydrazine sulfate, iodine, iron, slips, Lactic acid bacteria, amarogentin, L-arginine, lavender, Radix Glycyrrhizae, matrimony vine, lycopene, magnesium, manganese, epiphysin, Milk Thistle grass, pavilion are parasitic Extract, niacin and niacinamide (vitamin B3), Noni fruit, probiotic oral, pantothenic acid (vitamin B5), passionflower, PC- SPES, peppermint oil, peppermint, phosphate, pomegranate, propolis, pycnogenol, vitamin B6, red clover, rhodotorula, vitamin B2, sieve It is horse camomile, Bradley yeast, s-adenosyl-L-methionine (SAMe), Salvia japonica, match profit palmitic acid, vegetables/sun soup of selection, selenium, big Beans, St. john's wort, sweet orange essence, tea oil, methyllanthionine, tripterygium wilfordii, turmeric, valerian, vitamin A, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, dioscorea japonica, yogimbine, zinc or 5-HTP.

In some embodiments, it is treat hyperlipidemia or a certain illness related with hyperlipidemia oral that the present invention, which announces, Compound may include ornithine-L-aminobutanedioic acid, citrate, mannitol, polyvinyl pyrrolidone K30, sweet orange essence, sunset yellow Pigment, Aspartame, ethyl alcohol and talcum powder.

In some embodiments, include composition disclosed by the invention provided by the present invention for the pharmaceutical compositions of injection With the pharmaceutical excipient for being suitable for injection, the dosage of composition and excipient component is described herein.

The compound form of injectable provided by the invention includes aqua or oil suspension, by sesame oil, corn oil, cotton seed Emulsion, aseptic aqueous solution and the similar pharmaceutical media that oil, peanut oil, elixir, mannitol, glucose are formed.

Physiological saline is also conventional injection.Equally, ethyl alcohol, glycerine, propylene glycol, polyethylene glycol and the like (with And they itself mixture), cyclodextrine derivatives, vegetable oil can also be used to inject.Suitable mobility can be by using A kind of coating such as lecithin maintains, and for the granular size of dispersed phase to be maintained surfactant can be used.By using Various antibacteriums or antifungal agents such as metagin, methaform, phenol, sorbic acid, thimerosal and other Analog can inhibit the activity of microorganism.

Aseptic parenteral solution together can be by this with the above-mentioned various other ingredients (can filter disinfection in advance if necessary) referred to The compound provided is provided and above-mentioned auxiliary agent is dissolved in solvent appropriate and obtains the content of needs.In general, dispersion Can be obtained by the way that various sterile active ingredients are added in sterile vehicle, this sterile vehicle include basic decentralized medium and Other essential components just as the above-mentioned.By taking aseptic powdery is prepared into aseptic injection as an example, more satisfied preparation method Vacuum drying and Freeze Drying Technique, can produce it is a kind of it is additional be added to obtained from previous sterile filtered solution it is other The powder of the active constituent of desired auxiliary agent.

Compound that is inhalable or being blown into is included in pharmaceutically acceptable, water or organic solvent or the mixing of themselves Solution in object and powder and suspension.This liquid or solid compound may include pharmacy just as the above-mentioned appropriate Acceptable excipient.Certainly, it is the influence for treating locally or systemically, oral or nasal cavity is recommended to suck this ingredient.Component can push away It recommends and is dissolved in pharmaceutically acceptable solvent by being used after borrowing inert gas formation spray.Spray can directly be set from spraying Standby middle absorption, this spraying apparatus can also connect a breathing mask or uninterrupted positive pressure respiration instrument.The solution of ingredient hangs Supernatant liquid or powder morphology can transmit administration in the right way by equipment, but recommend through the sucking of oral and nasal cavity.

Component that this patent provides and be suitable for sublingual, oral cavity, rectum, in bone, intraocular, intranasal, Epidural cavity or backbone to One or more pharmaceutically acceptable excipient open countries of medicine can prepare pharmaceutical composition.These excipient components are to art technology Personnel be also it is well known, it is specific visible below with reference to document：Anderson,Philip O.；Knoben,James E.； Troutman,William G,eds.,Handbook of Clinical Drug Data,Tenth Edition,McGraw- Hill,2002；Pratt and Taylor,eds.,Principles of Drug Action,Third Edition, Churchill Livingston,New York,1990；Katzung,ed.,Basic and Clinical Pharmacology,Ninth Edition,McGraw Hill,20037ybg；Goodman and Gilman,eds.,The Pharmacological Basis of Therapeutics,Tenth Edition,McGraw Hill,2001； Remingtons Pharmaceutical Sciences,20th Ed.,Lippincott Williams&Wilkins., 2000；Martindale,The Extra Pharmacopoeia,Thirty-Second Edition(The Pharmaceutical Press,London,1999).As a whole, the present invention incorporates all of the above bibliography.

It is a kind of or more in serum for reducing that invention also describes the compounds being made of ornithine and/or L-aminobutanedioic acid The level of kind hyperlipidemia risks and assumptions, a kind of adverse reaction of medicine of reduction, and/or the method for reducing serum CPK level. Reducible hyperlipidemia risk factors include triglycerides, cholesterol and low-density lipoprotein.The present invention is to realize to be described herein Purpose, the use of method, composition and/or ornithine and/or L-aminobutanedioic acid is described, for example, reduce individual it is tested One or more hyperlipidemia risks and assumptions are horizontal in person's blood flow or serum.The risk of hypertension factor may include but is not limited to fat Matter and/or lipoprotein.The method of the present invention can be used for increasing the hdl level in individual blood flow or serum, this Individual process including ornithine and/or L-aminobutanedioic acid be also applied for hyperlipemic patients, the individual with hyperlipidemia risk and/or Just by a kind of individual of illness related with hyperlipidemia.In certain scenarios, a kind of medicine announced in medical domain The effective dose of (such as lipid-lowering medicine) can be together with ornithine and/or L-aminobutanedioic acid effective dose to individual co-administered.At some In embodiment, this medicine (such as Statins) can generate a kind of adverse reaction, and (such as the raising of creatine kinase, striated muscle are molten Solution or muscle changes).Method provided herein can also be used for mitigating adverse reaction or improvement caused by these medicines A related condition (such as rhabdomyolysis or muscle changes) is increased with creatine kinase.This patent in conjunction with the embodiments from many ways into Description is gone.

Method provided by the invention includes that the component containing ornithine and/or L-aminobutanedioic acid is implemented into certain individual.It is " a Body " can represent a kind of animal, such as a kind of mammal, a specific such as people.The method and compound component that this patent is announced can For human body therapy, preclinical and veterinary purpose.In some embodiments, individual represents a kind of animal, and in other implementations In example, individual represents the mankind.The age of individual may be not quite similar, it is also possible to be children (such as baby, child, child, youngster It is virgin), teenager or adult (such as young, middle age, the elderly)；The age of human body individual can be between 0~120 years old, even more Always.Specifically, human body individual age may be between 0~12 month, it is also possible between 0~12 years old, it is also possible between 13~19 years old, Such as 14,15,16,17,18 or 19 years old；May between 20~39 years old, such as 20,21,22,23,24,25,26,27,28, 29,30,31,32,33,34,35,36,37,38 or 39 years old；May between 40~59 years old, such as 40,41,42,43,44,45, 46,47,48,49,50,51,52,53,54,55,56,57,58 or 59 years old；May also be more than 59 years old, such as 60,61,62,63, 64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、 89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、 111,112,113,114,115,116,117,118,119 or 120 years old；Human body individual may be 45 years old or greater age, May be 55 years old or greater age.Human body individual is likely to be male it could also be possible that women.

Human body individual may be from different nationalities, geographic area, country, continent and race.For example, human body individual may It is an Asian (for example, Far East portion Asian, central and east Asian, Southeast Asian, people from Northeast Asia or asian ancestry Indian), white Kind people (Canada, the U.S., Europe or Mediterranean), African, Pacific Ocean islander or Spaniard.Human body individual may be from National (geographic center of the Congo's river valley and region), Ban Mubu carry race (Africa in the middle part of Hottentot, Bu Xuman races, the Congo In order to lattice rice), Ku Xite linguistic subfamilies (Ethiopia, Somalia), Mediterranean race (come from mediterranean region), Di Nala races (most of in Balkan Peninsula western part and North of Italy), Alps race, Ladogan races (name, Russia sieve after Ladoga Lapland subspecies near this Tu, including the European arctic), Nuo De races or Northern Europe race, (profit is chatted to race of Armenia by Armenia Sub-, Lebanon and northern Iraq), the blue people of figure (breathing out husky Bolkestein, Hungary, Turkey), Iran-Afghan (Iran, A Fu Sweat, Iraq, Turkey), Indian tribe (Pakistan and north India), Dravidian race (India, Bangladesh, Si Lilan Card), dimension mostly according to race (live in Central India and south other Australians), race of Melanesia (New Guinea, Ba Bu Sub- island, Solomon Islands), Australia-Tasmania race (aborigines), Northeast Asia and the northern Mongols (China, Manchuria, South Korea, Korea, Japan), Southeast Asia or the southern Mongols (China, Indo-China, Thailand, Burma, Ma Laixi Sub-, Indonesia and Philippine), Micronesia-Polynesia race, A Yinu races (Japan the north aborigines), Tungid Race (Mongolia and people from Siberia, Eskimos), American Indian race (American Indian).Human body individual may be from Afghanistan, Albania, Algeria, Andorra, Angola, Antigua and Barbuda, Argentina, Armenia, Australia Big Leah, Austria, Azerbaijan, Bahamas Islands, Bahrein Island, Bangladesh, Barbados, Byelorussia, Belgium, primary Ritz, Benin, Bhutan, Bolivia, Bosnia-Herzegovena, Botswana, Brazil, Brunei, Bulgaria, Bu Ji Nanofarad rope, Burma, Burundi, Cambodia, Cameroon, Canada, Cape Verde, Central African Republic, Chad, Chile, China, brother's human relations Than Asia, the Comoros, the Congo, Costa Rica, Ke Tediya, Croatia, Cuba, Cyprus, Czech Republic, Denmark, Djibouti, the Dominica Republica, East Timor, Ecuador, Egypt, Salvador, Equatorial Guinea, Eritrea, love Sha Niya, Ethiopia, Fiji, Finland, France, Gabon, Gambia, Georgia, Germany, Ghana, Greece, jesse greener Reach, Guatemala, Guinea, Guinea peso, Guyana, Haiti, Holy See, Honduras, Hong Kong, Hungary, Iceland, India, Indonesia, Iran, Iraq, Ireland, Israel, Italy, Jamaica, Japan, Jordan, Kazakhstan, Kenya, Kiribati, South Korea, Kosovo, Kuwait, Kirghizstan, Laos, Latvia, Lebanon, Lesotho, Liberia, Libya, the Dun Sideng that is disbursed from the cost and expenses, Lithuania, Luxembourg, Macao, Macedonia, Madagascar, Malawi, Ma Laixi Asia, Mali, Malta, the Marshall Islands, Mauritania, Mauritius, Mexico, Micronesia, is rubbed at Maldives Er Duowa, Monaco, Mongolia, Montenegro, Morocco, Mozambique, Namibia, Nauru, Nepal, Holland, lotus category The row of peace this, New Zealand, Nicaragua, the Niger, Nigeria, Korea, Norway, Oman, Pakistan, The Republic of PALAU, Palestine, Panama, Papua New Guinea, Paraguay, Peru, Philippine, Poland, Portugal, Qatar, Rome Buddhist nun Asia, Russia, Rwanda, Nevis, St. Lucia, St. Vincent and the Grenadines archipelago, Samoa, holy horsepower Promise, Sao Tome and Principe, Saudi Arabia, Senegal, Serbia, Seychelles, Sierra Leone, Singapore, Si Luo Cut down gram, Slovenia, Solomon Islands, Somalia, South Africa, Korea S, southern the Sudan, Spain, Sri Lanka, the Sudan, Su Li South, Swaziland, Sweden, Switzerland, Syria, Taiwan, Tajikistan, Tanzania, Thailand, East Timor, Togo, The island Tang Jia, Te Linibala and Tobago, Tunisia, Turkey, Turkmenistan, Tuvalu, Uganda, Ukraine, Arab Joint emirate, Britain, Uruguay, Uzbekistan, Vanuatu, Venezuela, Vietnam, Yemen, Zambia, Jin Babu Wei.

The eating pattern of individual simultaneously differs, the eating habit of " diet " acute pyogenic infection of finger tip individual whithin a period of time, one period It may be 3,4,5,6,7,8,9,10,11,12,13 or 14 days；3,4,5,6,7 or 8 weeks；3,4,5,6,7,8,9,10,11 or 12 A month；2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、45、50、55、 60,65,70,75,80,85,90,95 or 100 years.In some embodiments, individual certain diet may cause hyperlipidemia or Person's some symptoms related with hyperlipidemia.Individual may receive the combination described herein being made of ornithine and/L-aminobutanedioic acid The treatment of object and preparation method.In some embodiments, individual may take a kind of high fat diet, High cholesterol diet, high full With fatty acid diets, high-carbonhydrate diet, high-protein diet or low fiber diet.For every a kind of diet, "high" generally means than just The normal higher content of diet, FDA to this carried out description (" Dietary Guidelines for Americans ", 2010).The fat content that high fat diet is included can be higher than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%.High fat diet may also include 60% fat.The eating habit of individual is also possible to that one or more high blood can be caused Fat risks and assumptions increase, and as increased the level of triglycerides, cholesterol, low-density lipoprotein in blood, while putting on weight or high Pionemia.Individual may also may also include containing a large amount of red meat in excessive drinking or diet beef, pork, mutton with And other similar food products.Individual diet may also contain a large amount of converted products.

The weight of individual may and differ, it is possible to overweight or fat.It is overweight or fat mean that whose body weight is higher than Ideal weight range, ideal weight range are BMI between 18-25, and the computational methods of BMI are weight (kg) divided by height (m) square, individual BMI may also between 25-30, such as BMI is 25,25.5,26,26.5,27,27.5,28,28.5, 29,29.5,29.9 or 30.Individual BMI may also be higher than 30, such as BMI be 30.5,31,32,33,34,35,36,37,38, 39 or 40.Individual BMI may also be higher than 40,50,75,100,125,150,160,170,180,190,200,210,220, 230,240,250,260,270,280,290,300,310,320,330,340,350,360,370,380,390 or 400.

Individual may have a certain living habit that may also lack living habit." custom " means the conventional behavior of individual The frequency of generation is higher than normal.In some embodiments, this custom may increase individual hyperlipidemia risk or and with height The risk of other symptoms of related to blood fat.In some embodiments, this custom may also increase in individual blood flow and serum Hyperlipidemia risk factors are horizontal.Individual may have smoking or suck the custom of smog, and the tobacco product sucked of individual includes but not It is confined to cigarette, cigar, small opium pipe.Living environment residing for individual may include smog or secondhand smoke.In certain scenarios, by Do not have the behavioural habits for the risk that certain can reduce hyperlipidemia or certain symptoms related with hyperlipidemia risk in individual, Individual is possible to that hyperlipidemia or the environment of symptom risk related with hyperlipidemia risk can be in.For example, individual may not practised It is used to exercise or carries out constitution activity, the constitution active level of individual exercise or progress may also be less than normal, individual forging Refining frequency may be averaged 1 week 1 time, it is also possible to 1,2,3,4,5,6,7,8,9,10,11,12 month 1 time, it is also possible to be 2,3, 4,5,6,7,8,9,10 years 1 time.The exercise frequency of individual is also possible to 1 week less than 1 time, it is also possible to 1,2,3,4,5,6,7,8, 9, it is less than 1 time within 10,11,12 months, it is also possible to be to be less than 1 time for 2,3,4,5,6,7,8,9,10 years.Individual is also likely to be all one's life All give up doing exercise.

Composition and preparation method thereof containing ornithine and/or L-aminobutanedioic acid can be used for by disease or have disease Some risk individual treatment, this disease may be hyperlipidemia or with the relevant disease of hyperlipidemia.In certain embodiments, Disease related with hyperlipidemia may be thyroid disease, nephrosis, hepatopathy, Cushing syndrome, hyperlipidemia induction fatty liver disease Disease, hypercholesterolemia, obesity, atherosclerosis, diabetes, angiocardiopathy, rhabdomyolysis, muscle changes or drug Related disorders of lipid metabolism such as alcohol, estrogen and the like.In certain embodiments, angiocardiopathy may be coronal dynamic Arteries and veins disease, palsy, hypertension, peripheral artery disease, heart attack, ischemic heart disease or congenital heart disease.Certain In embodiment, compound of this patent and preparation method thereof also is likely used for controlling by the patient of HBV, HCV and HIV infection It treats.

Hyperlipidemia have the raised feature of blood lipid level, including blood flow, blood plasma or cholesterol in serum, cholesteryl ester, Phosphate and triglycerides increase.These lipids may also be transported to blood and form big lipoprotein, lipoprotein can be divided into Lower 5 kinds：Chyle, very low density lipoprotein, medium density lipoprotein, low-density lipoprotein and high density lipoprotein level are divided by density In vain.Most of triglycerides is likely to form chyle or very low density lipoprotein, and most of cholesterol can form low low-density lipoprotein White and high-density lipoprotein.If blood flow or lipids in serum level are too high, then excessive lipid may be accumulated in vascular wall On, the cholesterol accumulated on vascular wall may cause patch to be formed so as to cause narrowed blood vessels.Hyperlipidemia also has certain fat The feature that albumen increases or high-density lipoprotein reduces.Hyperlipidemia risk factors include but is not limited to lipid and/or lipoprotein. By disease or one or more hyperlipidemia risk factors that some risk with disease may have with individual it is horizontal not It is normal related.Composition containing ornithine and/or L-aminobutanedioic acid can be used for the one or more hyperlipidemia wind for improving individual Dangerous factor.In certain embodiments, hyperlipidemia risk factors may be one or more lipoprotein and/or lipid includes but not office It is limited to total cholesterol, triglycerides, high-density lipoprotein, intermediated-density lipoprotein, very low density lipoprotein or low-density lipoprotein In vain.One or more biological markers are also likely to be serum CPK level or blood glucose level.

Method for assessing human body hyperlipidemia risk factors (such as lipoprotein and/or lipid) and CPK activity levels is many It is more.These methods are influenced by the type of sample and the different inspection technologies that use and difference, although some researchs make With red blood cell or tissue samples, but serum and blood plasma are most common sample types.The serum levels of hyperlipidemia risk factors and The conventional method that CPK activity can refer to through the invention measures, and non-limitative example includes immunoassays and enzymatic analysis.It is high The physiological concentrations or CPK activity of blood fat risk factors preferably measure under the conditions of empty stomach, for example, on an empty stomach at least 8h, 10h, 12h, 15h, for 24 hours even longer time.

Preparation method described herein and composition can be used for reduce serum in one or more hyperlipidemia risks because It is plain horizontal.In certain embodiments, this method and composition can be used for reducing total cholesterol, triglycerides or low-density lipoprotein White level；In certain embodiments, this method and composition can be used for reducing the CPK levels of individual；In certain embodiments, should Method and composition can be used for increasing the hdl level of individual；In certain embodiments, this method and composition can For reducing glucose in serum level；Abnormal hyperlipidemia risk factors level mean in individual serum hyperlipidemia risk because Element have exceeded that those skilled in the art think it typically would be desirable to ranges.Total cholesterol, low-density lipoprotein, high-density lipoprotein and Being defined by National Heart, Lung, and Blood Institute, National Institute of Health it typically would be desirable to range for triglyceride levels (refers to Third Report of the Expert Panel on Detection,Evaluation,and Treatment of the High Blood Cholesterol in Adults(Adult Treatment Panel III):Executive Summary, 2011).Total cholesterol level, low-density lipoprotein white level, hdl level and triglyceride levels be hyperlipidemia or With the biological marker of the relevant illness of hyperlipidemia.

In certain embodiments, it is logical that component and preparation method containing ornithine and/or L-aminobutanedioic acid can be used for those Cross total cholesterol, low-density lipoprotein, high-density lipoprotein or triglycerides be accredited as it is high danger, high-risk, boundary is high-risk or connects The individual treatment of nearly normal level.Desired total cholesterol serum levels should be less than 200mg/dL, individual total cholesterol level It is likely to be at that boundary is high-risk between 200~239mg/dL, individual total cholesterol level is that 240mg/dL or more is likely to be at The high-risk stage.For example, component and preparation method containing ornithine and/or L-aminobutanedioic acid can be used for treating elevated cholesterol For 220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237, 238、239、240、241、242、243、244、245、246、247、248、249、250、251、252、253、254、255、256、 257, the individual of 258,259 or 260mg/dL；In certain embodiments, ornithine and/or L-aminobutanedioic acid can be used to treat Individual of the total cholesterol level between 260~270,270~280,280~290 or 290~300mg/dL；In some embodiments In, ornithine and/or L-aminobutanedioic acid can be used to treat the individual that total cholesterol level is higher than 200,240 or 300mg/dL.

The rational low-density lipoprotein serum levels that individual has should be less than 100mg/dL, individual serum levels between 100~129mg/dL is close to normal level, and individual serum levels are that boundary is high-risk between 130~159mg/dL, individual blood It is high-risk that clear water, which is put down between 160~189mg/dL, and individual serum levels are 190mg/dL and higher level is high danger.Contain The component and preparation method of ornithine and/or L-aminobutanedioic acid can be used for treat low-density lipoprotein white level be 100,101,102, 103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、 122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、 141、142、143、144、145、146、147、148、149、150、151、152、153、154、155、156、157、158、159、 160、161、162、163、164、165、166、167、168、169、170、171、172、173、174、175、176、177、178、 179, the individual of 180,181,182,183,184,185,186,187,188,189 or 190mg/dL；In some embodiments, contain Have the component of ornithine and/or L-aminobutanedioic acid and preparation method can be used for low-density lipoprotein white level be 190mg/dL or higher, 160mg/dL or higher, 130mg/dL or higher, 100mg/dL or higher individual treatments.

In certain embodiments, component and preparation method containing ornithine and/or L-aminobutanedioic acid can be used for passing through blood Aloof from politics and material pursuits density lipoprotein is accredited as high-risk or high-risk boundary individual treatment.Desired high-density lipoprotein serum levels answer height In 60mg/dL, individual serum levels are high-risk less than 50mg/dL or lower.In certain embodiments, the height of an example male individual Density lipoprotein levels are that 40mg/dL or lower is high-risk；In certain embodiments, the hdl level of a women It is high-risk for 50mg/dL or lower；Individual serum levels are that boundary is high-risk between 50~60mg/dL, and what this patent was announced includes The method and component of ornithine and/or L-aminobutanedioic acid can be used for treat hdl level be 60,59,58,57,56, 55、54、53、52、51、50、49、48、47、46、45、44、43、42、41、40、39、38、37、36、35、34、33、32、31、 30、29、28、27、26、25、24、23、22、21、20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、 2, the individual of 1 or 0mg/dL；In certain embodiments, individual high-density lipoprotein be likely lower than 60,50,40mg/dL.

In certain embodiments, component and preparation method containing ornithine and/or L-aminobutanedioic acid can be used for passing through blood Clear triglycerides is accredited as high danger, high-risk or high-risk boundary individual treatment.Desired triglycerides serum levels are answered low In 150mg/dL, individual serum levels are that boundary is high-risk between 150~199mg/dL, individual serum levels between 200~ 499mg/dL is high-risk, and individual serum levels are 500mg/dL or higher is high danger, such as individual serum triglyceride Level may be 150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165, 166、167、168、169、170、171、172、173、174、175、176、177、178、179、180、181、182、183、184、 185,186,187,188,189,190,191,192,193,194,195,196,197,198,199 or 200mg/dL；Certain In embodiment, individual triglyceride levels between 200~225,225~250,250~275,275~300,300~325, 325~350,350~375,375~400,400~425,425~450,450~475or, 475~500mg/dL；Certain In embodiment, individual triglyceride levels could possibly be higher than 150,200 or 500mg/dL.

The composition and preparation method thereof containing ornithine and/or L-aminobutanedioic acid that the present invention announces can be used for treating individual CPK levels in serum increase, increase a related illness extremely or with CPK level activities.Including ornithine and/or door winter The composition of propylhomoserin may be decreased the CPK activity of individual serum, delay to lead to the raised unfavorable factor of CPK activity；Phosphocreatine Kinases (CPK) may be a biological marker of certain class illness, it is also possible to and it is related with the condition that certain class illness occurs, it is this kind of Illness includes but is not limited to rhabdomyolysis, muscle changes, cerebral injury or palsy, twitch, delirium tremens, dermatomyositis, polymyarian Inflammation, electric shock, heart attack, myocarditis, lung infraction, muscular atrophy, hypothyroidism, hyperthyroidism and by Suck adverse reaction and the heart disease pericarditis caused by caused by certain class drugs or drug.It is this kind of to cause the increasing of CPK activity The drugs or drug of high this adverse reaction include but is not limited to amphotericin B, Ampicillin, arcotic, lipid-lowering medicine (such as he Spit of fland, fibrates, Clofibrate, ezetimibe), dexamethasone, furosemide, alcohol, cocaine, cardiovascular drugs such as blood Diluent and drug for hypertension, anti-infectives such as antibacterium medicine and antifungal, Anti-HBV drugs, anti-HCV medicament or anti- HIV drugs, antipsychotics, anti-diabetic class drug, immune formulation, gastrointestinal drug, medicine for respiratory system.

In certain embodiments, the composition containing ornithine and/or L-aminobutanedioic acid and its preparation side that the present invention announces Method can be used for treating since the use of statin causes individual serum CPK is horizontal to increase.This kind of statin may cut down him including atropic Spit of fland, Lovastatin sustained-release agent, Lovastatin+niacin, Pitavastatin, Pravastatin, Rosuvastatin, pungent is cut down Fluvastatin Statin, Simvastatin+niacin, Simvastatin+ezetimibe.Statins may cause one or more adverse reactions, Existing clinical evidence shows that statin can cause rhabdomyolysis and muscle changes, and feature is exactly that CPK levels increase, it is this not Good reaction may induced muscle pain and weak, refer to document (Beth A.Parker et al., " Effect of Statins on Skeletal Muscle Function/Clinical Perspective,“Circulation.2013；127:96- 103).In addition to that can increase CPK activity in serum, statin intake may also can increase blood glucose or glucose level, can further lead The onset risk of diabetes, the disturbance of consciousness, cataract is caused to increase.Compared with median dose and short-term administration, this adverse reaction It is more close with high dose or the administration of chronic long statin.The statin side effect evidence of the reports such as Preiss and Machan is more detailed (Risk of incident diabetes with intensive-dose compared with moderate-dose to the greatest extent statin therapy:a meta-analysis,”Journal of the American Medical Association, 2011:305(24):2556-64；Machan et al.,“Age-Related Cataract Is Associated with Type 2Diabetes and Statin Use,”Optometry&Vision Science,2012:89(8):1165- 1171.)；Due to these adverse reactions, the Clinical practice of statin is possible to limited.

Composition containing ornithine and/or L-aminobutanedioic acid can also be used for individual CPK activity beyond ideal or normal range (NR) Treatment, ideal or normal serum CPK activity level may be 10~120U/L or 20~199U/L；May also 350~ 175U/L or 95~140U/L.In certain embodiments, the composition containing ornithine and/or L-aminobutanedioic acid can also be used for controlling Treat individual CPK activity exceed 120,130,140,150,160,170,175,180,190,200,210,220,230,240,250, 260,270,280,290,300,350,400,450,500,550,600,650,700,750,800,850,900,950 or 1000mg/L；In certain embodiments, individual serum CPK activity could possibly be higher than 200,210,220,230,240,250,260, 270、280、290、300、310、320、330、340、350、360、370、380、390、400、450、500、550、600、650、 700,750,800,850,900,950 or 1000U/L；In certain embodiments, individual CPK activity levels could possibly be higher than 400U/L。

In one embodiment, one can be given by just suffering from the individual of certain disease or the individual with certain sick onset risk The ornithine and/or L-aminobutanedioic acid treatment, this effective dose for determining effective dose can be packed by certain dosage form；It is expected to reach Physiologic effect, this effective dose can also be a range of ornithine and/or L-aminobutanedioic acid physiology usage amount.Another In some outer embodiments, including the composition of ornithine and/or L-aminobutanedioic acid can be effectively reduced one or more hyperlipidemia wind The physiological concentrations or level of dangerous factor, one or more hyperlipidemia risk factors such as lipoprotein and/or lipid include but not It is limited to triglycerides, low-density lipoprotein or cholesterol.In certain embodiments, the use agent of ornithine and/or L-aminobutanedioic acid Amount can effectively make individual Triglycerides in Serum baseline concentrations reduce by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59% or 60% or higher；Compound is it is also possible that triglycerides baseline concentrations Reduce by 19%~24%, 14%~29%, 12%~35%, 10~40%, 8%~45%, 5%~50%, 2%~60% or 1%~70%.In certain embodiments, the effective dose of ornithine and/or L-aminobutanedioic acid ingredient can make triglycerides from high Risk is down to high risk, boundary high risk or ideal range；Also triglycerides can be made to be down to boundary high risk or reason from high risk Think range；It is also possible to that triglycerides is made to be down to ideal range from boundary high risk.

In some embodiments, ornithine and/or L-aminobutanedioic acid can make in individual baseline serum low-density lipoprotein at least Reduce by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% or more It is high；Low-density lipoprotein white level may also reduce by 19%~24%, 14%~29%, 12%~35%, 10~40%, 8%~ 45%, 5%~50%, 2%~60% or 1%~70%.In certain embodiments, ornithine and/or L-aminobutanedioic acid ingredient Effective dose can make low-density lipoprotein be down to high risk, boundary high risk, close to normal range (NR) or ideal model from high risk It encloses；Also low-density lipoprotein can be made to be down to boundary high risk, close to normal range (NR) or ideal range from high risk；It is also possible to make low Density lipoprotein is down to from boundary high risk close to normal range (NR) or ideal range；It is also possible that low-density lipoprotein is from close to just Normal range is down to ideal range.

In some embodiments, ornithine and/or L-aminobutanedioic acid can make individual baseline serum middle-high density lipoprotein at least Increase by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% or more It is high.Hdl level can also increase by 19%~24%, 14%~29%, 12%~35%, 10~40%, 8%~ 45%, 5%~50%, 2%~60% or 1%~70%.In some embodiments, ornithine and/or L-aminobutanedioic acid ingredient Effective dose can make high-density lipoprotein be down to boundary high risk or ideal range from high risk；It is also possible to make high-density lipoprotein From boundary, high risk is down to ideal range.

In some embodiments, ornithine and/or L-aminobutanedioic acid can make in individual baseline serum total cholesterol level at least Reduce by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% or more It is high；Total cholesterol level can also be lowered 19%~24%, 14%~29%, 12%~35%, 10~40%, 8%~45%, 5%~50%, 2%~60% or 1%~70%.In certain embodiments, the effective agent of ornithine and/or L-aminobutanedioic acid ingredient Amount can make total cholesterol be down to high risk, boundary high risk or ideal range from high risk；Also total cholesterol can be made from high wind Boundary high risk or ideal range are down in danger；It is also possible to that total cholesterol is made to be down to ideal range from boundary high risk.

After giving ornithine and/or L-aminobutanedioic acid treatment, the physiological concentrations of lipoprotein are preferably surveyed under the conditions of empty stomach It is fixed, such as at least 8h, 10h, 12h, 15h, for 24 hours even longer time on an empty stomach.

The lipid-lowering medicine for the treatment of hyperlipidemia or other illnesss related with hyperlipidemia may lead to various side effects, These side effects include but not limited to myalgia, weakness, hepatic injury, blood glucose increase, diabetes, the disturbance of consciousness, gastrointestinal tract not It is suitable, reduce the absorption in gastrointestinal tract of other medicines or vitamin, cataract.Provided by the invention includes ornithine and/or door winter Composition of propylhomoserin and preparation method thereof can reduce one or more hyperlipidemia risk factors such as lipoprotein and/or lipid, one In a little embodiments, gives individual ornithine and/or L-aminobutanedioic acid treatment has no effect on its internal blood glucose level；In some implementations In example, ornithine and/or L-aminobutanedioic acid will not increase individual CPK activity levels；In some embodiments, ornithine and/ Or L-aminobutanedioic acid will not cause one or more adverse reactions related with other lipid-lowering medicines, this is ornithine and/or door winter ammonia Acid treatment hyperlipidemia or the advantage place for having related disorders with hyperlipidemia.

In some embodiments, ornithine and/or L-aminobutanedioic acid are for alleviating or reducing by one caused by other lipid-lowering medicines Kind or a variety of side effects, these side effects include rhabdomyolysis, muscle changes, CPK levels increase, myalgia and weakness, Hepatic injury, diabetes generation, the disturbance of consciousness, gastrointestinal discomfort, reduces other medicines or vitamin in stomach and intestine at blood sugar concentration increase The absorption in road, cataract.In some embodiments, ornithine and/or L-aminobutanedioic acid can reduce CPK activity levels, can also Delay the other diseases illness for causing CPK to increase.

The increase of CPK activity levels may be the side effect of one or more medicines, including ornithine and/or door winter The composition of propylhomoserin can be used for the side effect for reducing the initiation of these medicines, by ornithine and/or L-aminobutanedioic acid and one kind Or the medication simultaneously of a variety of medicines, the side effect of these medicines initiation can be reduced, these medicines include but unlimited In amphotericin B, Ampicillin, arcotic, lipid-lowering medicine (such as statin, fibrates, Clofibrate), dexamethasone, furans aniline Acid, alcohol, cocaine, cardiovascular drugs such as blood thinners, Anti-HBV drugs, anti-HCV medicament or inverase.

The composition and preparation method comprising ornithine and/or L-aminobutanedioic acid that the present invention announces can with it is one or more Lipid-lowering medicine cooperativing medicine-feeding；In some embodiments, the effective dose of one or more lipid-lowering medicines can reduce one or more high blood Fat risk factors；In some embodiments, the effective dose of one or more lipid-lowering medicines can lead to one or more influences, including Cholesterol levels are reduced, low-density lipoprotein white level is reduced, reduce triglycerides or increases hdl level；At some In embodiment, one or more lipid-lowering medicines may will produce adverse reaction.

In some embodiments, including the compound of ornithine and/or L-aminobutanedioic acid may be effectively reduced individual CPK work Property it is horizontal.For example, the compound can make individual baseline CPK levels reduce by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% or higher；In some embodiments, including ornithine and/or door winter CPK can be effectively decreased down to ideal or normal level by the compound of propylhomoserin；In some embodiments, individual CPK levels may Down to 400U/L or less；In some embodiments, individual CPK levels may be down to 200U/L or less.

In some embodiments, the composition containing ornithine and/or L-aminobutanedioic acid may also include one or more controls Treat an effective dose of drug such as lipid-lowering medicine.The method of part description includes ornithine and/or L-aminobutanedioic acid administration, one kind Or a variety of medicine administrations.In some embodiments, these medicines may be lipid-lowering medicine；In some embodiments, bird Propylhomoserin and/or L-aminobutanedioic acid may be administered with one or more medicines with same time and same way；In some implementations In example, ornithine and/or L-aminobutanedioic acid may respectively be administered with one or more medicines, in some embodiments, bird ammonia Acid and/or L-aminobutanedioic acid first may can be wanted ornithine and/or door winter ammonia with one or more medicine consecutive administrations One or more medicines can also be first administered in acid；In some embodiments, ornithine and/or L-aminobutanedioic acid may be with one Kind or a variety of medicine cooperativing medicine-feedings；In some embodiments, the administration route of ornithine and/or L-aminobutanedioic acid with it is a kind of or A variety of medicines are identical；In some embodiments, the administration route of ornithine and/or L-aminobutanedioic acid and one or more treatments Drug simultaneously differs；For example, ornithine and/or L-aminobutanedioic acid are administered orally, and other medicines are then noted by vein Penetrate administration.The administration route of one or more medicines can identical can also be different.

In addition, in some cases, the continued treatment time of ornithine and/or L-aminobutanedioic acid is identical as other medicines Or it is longer.For example, the continued treatment time of ornithine and/or L-aminobutanedioic acid is 30, and the administration time of other medicines It is 10.Individual can first give other medicines treatment a period of time before ornithine and/or L-aminobutanedioic acid administration.

To improve the body condition of individual, the method and composition that the present invention refers to includes using a kind of condition by ornithine And/or L-aminobutanedioic acid is administered to individual, also includes by one or more medicines administration (such as lipid-lowering medicine) to individual.By bird Propylhomoserin and/or L-aminobutanedioic acid be administered to individual there is a possibility that individual body condition improve 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%；It will One or more medicines administration (such as lipid-lowering medicine) to individual there is a possibility that individual body condition improve 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%；In some embodiments, the improvement of situation can be more than 50%；In some cases, ornithine and/or door Winter propylhomoserin and one or more medicine tunables exert one's influence to body condition；In some cases, ornithine and/or L-aminobutanedioic acid is administered alone the improvement of body condition than the two with one or more medicines (such as statin) administering drug combinations It becomes apparent；Biological marker level or the risk factors level of individual can be used to weigh in the degree that situation improves, and can also adopt With organ dysfunction before administration after improvement degree compare.

Example 1：Ornithine and/or L-aminobutanedioic acid are on rat plasma triglycerides and the active influences of CPK

This experiment has carried out the correlative study of the purposes of the composition comprising ornithine and/or L-aminobutanedioic acid, the group It includes aspartic acid ornithine salt to close object also, and the composition can be used for treating the hyperlipidemia of individual, reduce triglyceride levels. In addition, lipid-lowering medicine such as taking for Atorvastatin are likely to result in CPK raisings, the combination containing aspartic acid ornithine in blood plasma Object may have reduction effect for CPK raisings, we have also carried out correlative study accordingly.

Male Wistar rat (is purchased from Beijing Hua Fukang Co., Ltds, Beijing, China), and every weighs about 180~250g, It is divided into five groups of raisings in environment temperature (about 21 ± 1 DEG C) and the good animal house of humid control, illumination 12h and dark is given once daily It is protected from light and (starts to illuminate when the morning 7), cycle raising, diet and water inlet are unlimited, and food can be normal diet or high fat diet.

Rat, which gives high fat diet (60% fat), can induce out hyperlipemia model on 10th, big to hyperlipidemia after 10 days Mouse orally administration aspartic acid ornithine (Wuhan Qirui Pharmaceuticals Co., Ltd., Wuhan, Hubei, China, using 0.5%CMC-Na It prepares)；Negative control group gives 0.5%CMC-Na；Positive controls give fat-reducing medicament Atorvastatin and (open auspicious medicine company in Wuhan Co., Ltd, Wuhan, Hubei, China are prepared using 0.5%CMC-Na).In the afternoon 3 when -5 when, the successful rat of modeling is given It gives aspartic acid ornithine, negative control and positive control drug gavage to handle, 1 day 1 time, continuous 30 days；Aspartic acid ornithine Dosage be 945mg/kg, which is equivalent to the 9g of human body routine clinical dosage；Positive control drug atropic cuts down him Spit of fland includes 2 dosage, respectively 1.05 and 2.1mg/kg, which is respectively equivalent to the 10g of human body routine clinical dosage And 20g；The rat of 2 groups of negative control groups of this experimental setup, negative control group is given only normal diet processing.

0,10,20, the 30 day tail portion blood for acquiring all experimental rats upon administration, measure the blood plasma of rat in all groups/ Serum triglyceride level and CPK are horizontal.

There is hyperlipidemia in rat after giving high fat diet 10,20 and 30 days.Experimental result is shown, with negative control group phase Than high fat diet can dramatically increase the triglyceride levels (table 1) of mouse blood plasma；Compared with negative control, orally administration door winter ammonia The high triglyceride that sour ornithine can significantly reduce high fat diet induction is horizontal, reduces almost up to 50% (P<0.01)；With feminine gender Control is compared, and the Atorvastatin (1.05 and 2.1mg/kg) of two kinds of dosage of orally administration has been significantly reduced triglycerides water Flat, the range of decrease is respectively up to 31% and 37% (P<0.05).

By result as it can be seen that although between group and no difference of science of statistics (P>0.05), aspartic acid ornithine is for triglycerides Horizontal reduction effect is more more effective than the Atorvastatin of two kinds of dosage；Meanwhile aspartic acid ornithine and Atorvastatin Administering drug combinations can reduce triglyceride levels, but without significant compared with aspartic acid ornithine or Atorvastatin folk prescription are administered Significant difference (table 1).

Rat plasma triglyceride levels (mmol/L)

Group	10days	20days	30days
				A	1.23±0.51	1.22±0.86	0.87±0.12
B	2.9±1.27**	2.22±0.7**	1.83±0.14**

C	1.56±0.21##	1.56±0.7#	0.97±0.27##
				D	1.98±0.44#	1.63±0.9#	1.25±0.39#
E	2.08±0.92	1.79±0.85#	1.15±0.32#
				F	1.64±0.64##	1.2±0.57##※	0.84±0.16##
G	1.75±0.55##	1.24±0.7##※	1.18±0.37#

Table 1:Orally administration aspartic acid ornithine folk prescription and its with Atorvastatin administering drug combinations to rat plasma glycerine The influence of three esters level.The level of plasma triglyceride is indicated with mean ± s.e.；N=8~10；

P*<0.05 and * * P<0.01, B group is compared with A groups；#P<0.05,##P<0.01, C, D, E, F or G groups and B group ratios Compared with；※P<0.05, F or G groups are compared with D groups；P<0.05 (being obtained using Dunnett's variance analyses).A groups：Medium+normal drink Food；B groups：Medium+high fat diet；C groups：Aspartic acid ornithine 945mg/kg；D groups：Atorvastatin 2.1mg/kg；E groups：Ah Atorvastatin 1.05mg/kg；F groups：Aspartic acid ornithine 945mg/kg+ Atorvastatins 2.1mg/kg；G groups：L-aminobutanedioic acid Ornithine 945mg/kg+ Atorvastatins 1.05mg/kg.Investigational agent and positive control drug give gavage processing.

The results show that compared with negative control, the Atorvastatin of two dosage can be shown for oral Atorvastatin administration Write the CPK activity (P for increasing rat plasma<0.01)；Aspartic acid ornithine and low dosage Atorvastatin (1.05mg/kg, P.o.) administering drug combinations can significantly alleviate the CPK activity raising (P caused by Atorvastatin<0.01)；Aspartic acid ornithine with High dose Atorvastatin (2.1mg/kg, p.o.) administering drug combinations can significantly reduce the CPK activity liter caused by Atorvastatin Height decreases by 20% or so.

The CPK of rat plasma is active (U/mL)

A:Normal Diet	0.508±0.19
		B:High Fat Diet	0.492±0.17
C:LOLA	0.49±0.11
		D:Atorvastatin(High)	0.812±0.21**
E:Atorvastatin(Low)	0.738±0.14**
		F:LOLA+Atorvastatin(High)	0.657±0.34
G:LOLA+Atorvastatin(Low)	0.529±0.13#

2. orally administration aspartic acid ornithine folk prescription of table and its with Atorvastatin contact administration to rat plasma CPK water Flat influence.Mean ± s.e. the expressions of plasma C PK levels, unit U/mL；N=8~10；P*<0.05 and * * P<0.01, D Group or E groups are compared with B groups；##P<0.01, G group is compared with E groups；P<0.05 (being obtained using Dunnett's variance analyses).A groups：Matchmaker Jie+normal diet；B groups：Medium+high fat diet；C groups：Aspartic acid ornithine 945mg/kg；D groups：Atorvastatin 2.1mg/ kg；E groups：Atorvastatin 1.05mg/kg；F groups：Aspartic acid ornithine 945mg/kg+ Atorvastatins 2.1mg/kg；G groups： Aspartic acid ornithine 945mg/kg+ Atorvastatins 1.05mg/kg.Investigational agent and positive control drug give gavage processing.

This experimental result clearly indicates that oral administration aspartic acid ornithine can significantly reduce the rat of high fat diet induction Plasma triglyceride level, which, which also provides tangible proof, proves that aspartic acid ornithine can effectively treat hyperlipemia Disease, drug effect may be better than Atorvastatin.Aspartic acid ornithine can slow down with Atorvastatin administering drug combinations to be cut down by atropic The adverse reaction such as rhabdomyolysis and muscle changes that statin generates, the activity that biological marker is CPK increase.

Example 2：The formula and preparation process of aspartic acid ornithine tablet

Including the composition of ornithine and/or L-aminobutanedioic acid can be prepared to tablet form, this experiment describes winter ammonia The preparation process of sour ornithine tablet, the formula of tablet are as shown in table 3.

First 302.7g povidone, 0.5g sweet oranges essence, 0.0025g sunset yellows are mixed containing 80% ethyl alcohol with 135g It closes, simple ultrasound mixing is prepared into a kind of grume mixture.Then the grume mixture is added to by 150g winter ammonia It is thorough again in the mixture that sour ornithine, 7.5g citric acids, 105g mannitol and 2.5g Aspartames are formed after being thoroughly mixed Bottom is mixed to form soft material, and then dry, formation particle simultaneously uses 18 mesh mesh screens by this pellet through sieves.Particle after sieving Piece agent is prepared after the thorough mixing of 5g talcum powder is added.

The formula of 3. aspartic acid ornithine tablet of table

Aspartic acid ornithine	150g
		Citric acid	7.5g
Mannitol	105g
		Povidone	302.7g
Sweet orange essence	0.5g
		Sunset yellow	0.0025g
Aspartame	2.5g
		80% ethyl alcohol	135g
Talcum powder	5g

Example 3：The formula and preparation process of aspartic acid ornithine capsule

Including the composition of ornithine and/or L-aminobutanedioic acid can be prepared to capsule, this experiment describes L-aminobutanedioic acid The formula of the preparation process of ornithine capsule, capsule is as shown in table 4.

First 302.7g povidone, 0.5g sweet oranges essence, 0.0025g sunset yellows are mixed containing 80% ethyl alcohol with 135g It closes, simple ultrasound mixing is prepared into a kind of grume mixture.Then the grume mixture is added to by 150g winter ammonia It is thorough again in the mixture that sour ornithine, 7.5g citric acids, 105g mannitol and 2.5g Aspartames are formed after being thoroughly mixed Bottom is mixed to form soft material, and then dry, formation particle simultaneously uses 18 mesh mesh screens by this pellet through sieves.Particle after sieving It is prepared into granule after the thorough mixing of 5g talcum powder is added, is then filled into capsule and prepares aspartic acid ornithine capsule Agent.

The formula of 4. aspartic acid ornithine capsule of table

Aspartic acid ornithine	150g
		Citric acid	7.5g
Mannitol	105g
		Povidone	302.7g
Sweet orange essence	0.5g
		Sunset yellow	0.0025g
Aspartame	2.5g
		80% ethyl alcohol	135g
Talcum powder	5g

Example 4：The formula and preparation process of aspartic acid ornithine granule

Including the composition of ornithine and/or L-aminobutanedioic acid can be prepared to granular form, this experiment describes a winter The preparation process of propylhomoserin ornithine granule, the formula of granule are as shown in table 5.

First 302.7g povidone, 0.5g sweet oranges essence, 0.0025g sunset yellows are mixed containing 80% ethyl alcohol with 135g It closes, simple ultrasound mixing is prepared into a kind of grume mixture.Then the grume mixture is added to by 150g winter ammonia It is thorough again in the mixture that sour ornithine, 7.5g citric acids, 105g mannitol and 2.5g Aspartames are formed after being thoroughly mixed Bottom is mixed to form soft material, this particulate matter is simultaneously sieved using 12 and 60 mesh mesh screens by then dry, formation particle, after sieving Particulate matter be added the thorough mixing of 5g talcum powder after be prepared into granule.Granule through packing after the assay was approved.

The formula of 5. aspartic acid ornithine granule of table

Aspartic acid ornithine	150g
		Citric acid	7.5g
Mannitol	105g

Povidone	302.7g
		Sweet orange essence	0.5g
Sunset yellow	0.0025g
		Aspartame	2.5g
80% ethyl alcohol	135g
		Talcum powder	5g

Example 5：The influence of ornithine and/or L-aminobutanedioic acid to rat plasma triglyceride levels

This experiment has carried out the correlative study of the purposes of the composition comprising ornithine and/or L-aminobutanedioic acid, the packet Composition containing ornithine and/or L-aminobutanedioic acid may include ornithine, L-aminobutanedioic acid or aspartic acid ornithine salt.The chemical combination Object component can be used for treating the hyperlipidemia of individual and reduce the triglyceride levels of individual.

Male Wistar rat (is purchased from Beijing Hua Fukang Co., Ltds, Beijing, China), and every weighs about 180~250g, It is divided into five groups of raisings in environment temperature (about 21 ± 1 DEG C) and the good animal house of humid control, illumination 12h and dark is given once daily It is protected from light and (starts to illuminate when the morning 7), cycle raising, diet and water inlet are unlimited, and food can be normal diet or high fat diet.

Rat, which gives high fat diet (about 60% fat), can induce out hyperlipemia model in 10 days, to hyperlipemia after 10 days Disease rat oral give ornithine, L-aminobutanedioic acid, aspartic acid ornithine (Wuhan Qirui Pharmaceuticals Co., Ltd., Wuhan, Hubei, China is prepared using 0.5%CMC-Na)；Control group gives medium 0.5%CMC-Na；Bird ammonia is given to the successful rat of modeling Acid, L-aminobutanedioic acid, aspartic acid ornithine, the processing of vehicle control gavage, 1 day 1 time, continuous 30 days；Aspartic acid ornithine Dosage is 945mg/kg, which is equivalent to the 9g of human body routine clinical dosage；The dosage of ornithine is 472.5mg/kg, the dosage are equivalent to the 4.5g of human body routine clinical dosage；The dosage of L-aminobutanedioic acid is 472.5mg/kg, the dosage are equivalent to the 4.5g of human body routine clinical dosage.

The tail portion blood that all experimental rats are acquired when being administered 30 days, measures the plasma/serum glycerine of rat in all groups Three esters are horizontal.

Give high fat diet 10 days or longer time can modeling go out hyperlipidemia rats.Experimental result is shown, with normal drink Phase of an eclipse ratio gives the triglyceride levels (P that high fat diet can dramatically increase mouse blood plasma<0.01)；With high fat diet control group phase Than orally administration aspartic acid ornithine can significantly reduce the high triglyceride level (P of high fat diet induction<0.05)；With height Fat diet control group is compared, and orally administration L-aminobutanedioic acid is significantly reduced the serum triglyceride level (table of hyperlipidemia rats 6)。

Triglyceride levels (mmol/L)

The shadow of 6. oral administration aspartic acid ornithine of table, L-aminobutanedioic acid and ornithine to rat blood serum triglyceride levels It rings.The level of plasma triglyceride is indicated with mean ± s.e.；N=8~10；**P<0.01, B group and A group ratios；#P<0.05, C Group or D groups and B group ratios, P<0.05 (being obtained using Dunnett's variance analyses).

This experimental result shows that orally administration aspartic acid ornithine and its free state L-aminobutanedioic acid can be by reducing by height The high triglyceride level of fat diet induced achievees the purpose that treat hyperlipidemia.This experiment also further confirms that L-aminobutanedioic acid exists A pivotal player is played in terms of the effect of aspartic acid ornithine mechanism.

Example 6：Influence of the aspartic acid ornithine to rat plasma cholesterol and low-density lipoprotein white level

This experiment has carried out the use for including aspartic acid ornithine salt of the composition comprising ornithine and/or L-aminobutanedioic acid The correlative study on the way compound component can be used for treating individual hyperlipidemia and triglycerides, the courage of reduction individual are solid Alcohol, low-density lipoprotein white level.

Male Wistar rat (is purchased from Beijing Hua Fukang Co., Ltds, Beijing, China), and every weighs about 180~250g, It is divided into five groups of raisings in environment temperature (about 21 ± 1 DEG C) and the good animal house of humid control, illumination 12h and dark is given once daily It is protected from light and (starts to illuminate when the morning 7), cycle raising and is intake unlimited at diet, and food can be that the courage of conventional food or standard is solid Alcohol butter diet.

Rat gives standard cholesterol and butter diet is added to can induce out within 10 days hyperlipemia model, and wherein butter diet is daily 2 times, each 0.5mL；(the limited public affairs of auspicious medicine company are opened in Wuhan to hyperlipidemia rats orally administration aspartic acid ornithine after 10 days Department, Wuhan, Hubei, China are prepared using 0.5%CMC-Na)；Negative control group gives medium 0.5%CMC-Na；Positive control Give Atorvastatin (Wuhan Qirui Pharmaceuticals Co., Ltd., Wuhan, Hubei, China are prepared using 0.5%CMC-Na)；This reality It tests and is also provided with parallel negative control, this group of animal is raised only with regular diet.Rat is given when in the daily afternoon 3-5 Aspartic acid ornithine, negative control medium, positive control drug processing, one time a day, continue 30.Aspartic acid ornithine Dosage is 945mg/kg, which is equivalent to the 9g of human body routine clinical dosage；Positive control drug Atorvastatin Including 2 dosage, respectively 1.05 and 2.1mg/kg, the dosage be respectively equivalent to human body routine clinical dosage 10g and 20g；

The Tail blood samples of all experimental rats are acquired when being administered 30 days, the plasma/serum for measuring rat in all groups is sweet Oily three esters, cholesterol and low-density lipoprotein white level.

This experimental result shows that compared with conventinal breeding group, the cholesterol for giving standard adds butter diet that can dramatically increase Triglycerides, cholesterol and the low-density lipoprotein white level of rat plasma.Aspartic acid ornithine can be significantly reduced by standard Cholesterol adds the high triglyceride, cholesterol and low-density lipoprotein white level (P of butter diet induced<0.01)；Orally administration two The Atorvastatin of kind dosage (1.05 and 2.1mg/kg) can also be significantly reduced adds butter diet induced by the cholesterol of standard High triglyceride, cholesterol and low-density lipoprotein white level (P<0.05 and P<0.01) (table 7)；With aspartic acid ornithine group phase Than, while the Atorvastatin for giving aspartic acid ornithine and two kinds of dosage will not further decrease the level (P of three kinds of lipids >0.05)。

This experimental result shows that orally administration aspartic acid ornithine can be reduced adds butter diet to lure by the cholesterol of standard High triglyceride, cholesterol and the low-density lipoprotein white level led, this experiment also provide tangible proof and show L-aminobutanedioic acid Ornithine is possible to have the effect of alleviating clinical hyperlipidemia.

The blood lipid level (mmol/L) of rat plasma

	TG	TC	LDL
				A	1.12±0.81	3.22±0.92	1.37±0.22
B	2.86±1.06**	5.18±0.76**	2.87±0.35**
				C	1.34±0.21##	3.97±0.89#	1.88±0.34##
D	1.86±0.56##	3.76±0.78##	1.64±0.42##
				E	2.15±0.49#	3.98±0.85#	1.78±0.63#
F	1.54±0.56##	3.58±0.86##	1.54±0.32##
				G	1.60±0.82##	3.74±0.91##	1.52±0.53#

7. orally administration aspartic acid ornithine folk prescription of table and its with Atorvastatin drug combination to rat blood serum glycerine The influence of three esters (TG), cholesterol (TC) and low-density lipoprotein white level.Plasma triglyceride, cholesterol and low-density lipoprotein It is indicated with mean ± s.e., unit mmol/L, n=8~10, * * P<0.01, B group is compared with A groups；#P<0.05, ##P< 0.01, C, D, E, F or G group are compared with B groups, P<0.05 (being obtained using Dunnett's variance analyses).A groups：Medium+normal diet； B groups：Medium+high fat diet；C groups：Aspartic acid ornithine 94.5mg/kg；D groups：Atorvastatin 2.1mg/kg；E groups：Atropic Cut down statin 1.05mg/kg；F groups：Aspartic acid ornithine 94.5mg/kg+ Atorvastatins 2.1mg/kg；G groups：L-aminobutanedioic acid bird Propylhomoserin 94.5mg/kg+ Atorvastatins 1.05mg/kg.Administering mode is gastric infusion.

Example 7：Influence of the low dosage aspartic acid ornithine to rat plasma triglyceride levels

The purposes of the composition of the aspartic acid ornithine containing various dose is studied in this experiment, the group It includes aspartic acid ornithine salt to close object also.The composition can be used for treating the hyperlipidemia of individual and reduce the glycerine of individual Three esters are horizontal.

Male Wistar rat (is purchased from Beijing Hua Fukang Co., Ltds, Beijing, China), and every weighs about 180~250g, It is divided into five groups of raisings in environment temperature (about 21 ± 1 DEG C) and the good animal house of humid control, illumination 12h and dark is given once daily It is protected from light and (starts to illuminate when the morning 7), cycle raising, diet and water inlet are unlimited, and food can be that conventional food or high fat diet (contain There is about 60% fat).

Rat, which gives high fat diet, can induce out hyperlipemia model in 10 days；To hyperlipidemia rats orally administration after 10 days Aspartic acid ornithine (Wuhan Qirui Pharmaceuticals Co., Ltd., Wuhan, Hubei, the China, using 0.5% of three kinds of various doses CMC-Na is prepared) raising；The dosage of aspartic acid ornithine is that 47,94.5 and 283.5mg/kg (it is daily to be respectively equivalent to human body 0.5,1 and 3g of clinical administration dosage, C-E groups)；Negative control group gives high fat diet and adds medium 0.5%CMC-Na (door winter ammonia The carrier of sour ornithine, B groups)；Positive control give 2.1mg/kg Atorvastatins (Wuhan Qirui Pharmaceuticals Co., Ltd., Wuhan, Hubei, China, is prepared, F groups using 0.5%CMC-Na)；This experiment also analyzes aspartic acid ornithine and Atorvastatin The aspartic acid ornithine of synergy, 3 kinds of dosage combines oral administration (G-I groups) with 2.1mg/kg Atorvastatins respectively, This experiment is also provided with parallel negative control, organizes interior rat and adds 0.5%CMC-Na media to raise (A groups) only with regular diet. Aspartic acid ornithine, negative control medium, positive control drug are given when in the daily afternoon 3-5 to rat to handle, daily 1 It is secondary, continue 30.

The Tail blood samples of all experimental rats are acquired when being administered 30 days, while measuring blood plasma/blood of rat in all groups Clear triglycerides, cholesterol and low-density lipoprotein and CPK are horizontal.

This experimental result shows that compared with conventinal breeding group, giving the high fat diet containing 60% fat content can significantly increase Add the triglyceride levels of rat plasma, increment rate is up to 100%.Orally administration contains the L-aminobutanedioic acid bird of 94.5 and 283.5mg/kg It is horizontal that propylhomoserin can significantly reduce the high triglyceride induced by high fat diet, reduction amplitude be respectively 40% and 50% (D groups or E groups P compared with B groups<0.05)；The Atorvastatin of orally administration 2.1mg/kg can make the high glycerine three induced by high fat diet Ester level reduces by 31% (F groups P compared with B groups<0.05).Compared with Atorvastatin is administered alone, 94.5 or 283.5mg/kg Aspartic acid ornithine and Atorvastatin drug combination can further decrease triglyceride levels (P<0.01) (table 8).

This experimental results showed that, orally administration low dosage aspartic acid ornithine can reduce induced by high fat diet it is high in fat High triglyceride in mass formed by blood stasis rat plasma is horizontal, prompts aspartic acid ornithine that can effectively treat hyperlipidemia, drug effect can Atorvastatin can be higher than.This experimental result also suggests that aspartic acid ornithine can be used clinically for hyperlipidemia strongly；Together When, low dosage aspartic acid ornithine can generate synergistic effect with Atorvastatin combination therapy hyperlipidemia.

Triglyceride levels (mmol/L) in rat plasma

A	1.07±0.34
		B	2.09±1.02**
C	2.06±0.72
		D	1.20±0.32#
E	1.11±0.31#
		F	1.45±0.33#
G	1.58±0.37#
		H	0.88±0.14##※※
I	0.95±0.21##※※

8. orally administration aspartic acid ornithine folk prescriptions of Table and its with Atorvastatin drug combination to rat blood serum The influence of triglyceride levels.Plasma triglyceride concentration mean ± s.e. expressions, unit mmol/L, n=8~10, * * P <0.01, B group is compared with A groups；#P<0.05, ##P<0.01, C, D, E, F, G, H group or I groups are compared with B groups；※※P<0.01,H Group or I groups are compared with F groups；P<0.05 (using Dunnett's variance analyses).A groups：Medium+normal diet；B groups：Medium+height Fat diet；C groups：Aspartic acid ornithine 47mg/kg；D groups：Aspartic acid ornithine 94.5mg/kg；E groups：L-aminobutanedioic acid bird ammonia Sour 283.5mg/kg；F groups：Atorvastatin 2.1mg/kg；G groups：Aspartic acid ornithine 47mg/kg+ Atorvastatins 2.1mg/kg；H groups：Aspartic acid ornithine 94.5mg/kg+ Atorvastatins 2.1mg/kg；I groups：Aspartic acid ornithine 283.5mg/kg+ Atorvastatins 2.1mg/kg.Administering mode is gastric infusion.

It is aobvious to those skilled in the art although the preferred embodiments of the invention are shown and described in present specification And what is be clear to is that these embodiments are merely exemplary.Numerous deformations, the change that those skilled in the art are presently contemplated that And it substitutes and all belongs to the scope of protection of the present invention.It should be appreciated that in the practice of the invention can be to described in present specification Scheme carries out some replacements.Appended claims of the present invention are intended to limit protection scope of the present invention, but its equivalents is also answered It is likewise covered by protection scope of the present invention.

Claims (6)

1. combination product, which includes active constituent, and the active constituent is：

(a) statins antilipemics medicine is selected from Atorvastatin；

(b) composition of the ornithine of medicine effective doses and L-aminobutanedioic acid, wherein the composition includes at least ornithine (O) and the compound salt form of L-aminobutanedioic acid (A) (OA).

2. combination product according to claim 1, wherein active constituent (b) are the aspartic acid ornithine of medicine effective dose Salt.

3. the purposes in reducing individual hyperlipidemia risk drug is being prepared according to the combination product of claims 1 or 2, it is described Hyperlipidemia risk includes triglyceride levels and/or creatine phosphokinase activity level in individual blood plasma.

4. purposes according to claim 3, wherein the hyperlipidemia risk further includes that LDL in blood plasma is horizontal or courage is solid Alcohol level.

5. pharmaceutical composition, which includes the combination product and pharmaceutically acceptable load according to claims 1 or 2 Body.

6. the purposes of aspartic acid ornithine salt in medicine preparation, the drug for reducing Atorvastatin side effect, The side effect refers to that individual takes the CPK activity levels increase generated after Atorvastatin.