CN101312712A - Intravenous essential fatty acid emulsion - Google Patents

Intravenous essential fatty acid emulsion Download PDF

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Publication number
CN101312712A
CN101312712A CNA2006800432333A CN200680043233A CN101312712A CN 101312712 A CN101312712 A CN 101312712A CN A2006800432333 A CNA2006800432333 A CN A2006800432333A CN 200680043233 A CN200680043233 A CN 200680043233A CN 101312712 A CN101312712 A CN 101312712A
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fatty acid
compositions
vitamin
administration
acid
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J·D·博茨
R·S·莱温松
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Amag Pharma USA Inc
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Drugtech Corp
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Abstract

A method for preventing stenosis and thrombosis of an AV graft is disclosed. An essential fatty acid emulsion is administered to the patient through the AV graft, preferably during dialysis, whereby the anti-inflammatory properties of the essential fatty acid emulsion prevent complications typical of AV grafts.

Description

Intravenous essential fatty acid emulsion
Invention field:
The present invention relates to comprise be applicable to intravenous administration in the patient's of needs essential fatty acid reducing or the reacted composition that diminishes inflammation, and preparation and using method.More specifically, the present invention relates to comprise be suitable for before the hemodialysis or among the essential fatty acid emulsion that uses of intravenous to prevent or to reduce the narrow and/or thrombotic compositions of vascular access.
Background of invention:
Hemodialysis is the most popular method that is used for treating late period and persistency renal failure.Become practicalness when treatment of renal failure since 1960 ' s hemodialysis first, obtained many progress and made the more effective and minimized side effects of hemodialysis.In blood dialysis, make patient's blood flow in the hemodialyzer once several ounces by pipeline.Hemodialyzer has three main functions, comprises suction blood and monitor blood flow, removes refuse and monitoring blood pressure and remove fluidic speed from blood from blood.Behind hemodialyzer, clean blood is got back in patient's body by pipeline.
Before carrying out hemodialysis, must on patient body, prepare vascular access or from its position of taking out blood and returning.Usually several weeks to the several months are prepared vascular access before the beginning hemodialysis.Vascular access needs to support the blood flow of per minute about 250 milliliters (ml/min).
Two kinds of common vascular access that are applicable to hemodialysis are arteriovenous graft (AV graft) and arteriovenous fistula (AV fistula).Arteriovenous graft is to use implantation subcutaneous, usually the vascular access of the composite tube in patient's arm.One end of implant connects tremulous pulse and the other end connection vein of pipe.This pipe can be recycled and reused for contact pin and blood access in the blood dialysis as artificial vein.Arteriovenous graft can be used for hemodialysis in about two weeks of implantation.Unfortunately, owing to implant several weeks or interior narrow or thrombosis of several months, a high proportion of arteriovenous graft produces low or insufficient blood flow.Low or insufficient blood flow is represented solidifying of vascular access or narrow.In this case, need surgical operation,, widen the part that becomes narrow, to recover the purpose that higher or more competent blood flow is used for hemodialysis as angioplasty.Replaceable selection in low or inadequate blood circumstance is to carry out surgical operation and replace narrow part on arteriovenous graft.
Arteriovenous graft up to 75% implant in 2 years ineffective, and some arteriovenous graft need annual up to 4 times repairing and remove blood clots.Antiplatelet or the anticoagulation regimens used in the trial that reduces the av graft failure rate have run into miscellaneous result.Such method that almost stoped the adverse side effect of antiplatelet or anticoagulation regimens reduces the high rate that vascular access lost efficacy.
The AV fistula may lack than arteriovenous graft and forms grumeleuse or infected, and is easy to continue the longer time than the vascular access of any other type.Directly connect tremulous pulse and vein forms AV fistula vascular access by surgical operation, normally in forearm.Directly connecting tremulous pulse and vein goes in the vein more blood flow.Therefore, it is bigger strongr that vein becomes, and the repetition pin puncture that is used in hemodialysis is easier.Unfortunately, the AV fistula has shortcoming equally.Shortcoming is that vein needs the time to grow up with the blood " lake of flowing fast " of the sturdy expansion that is formed for the hemodialysis purpose.For hemodialysis use, the minimum needs 6 of vein are to ripe over 12 months.Sometimes the AV fistula maturation for hemodialysis use need reach 24 months.
May need further treatment or operating arteriovenous graft and AV fistula to lead to complications.Most common complication is to infect and because the low blood flow that blood coagulation causes.Compare with the AV fistula, arteriovenous graft be easy to have more with solidify or infect relevant complication, need to replace arteriovenous graft.Therefore need to reduce or eliminate the av graft failure of thrombosis and stenosis induced.
Summary of the invention:
The invention provides comprise be suitable for before the hemodialysis or among the intravenous effective dose essential fatty acid (EFA) that is used for the patient to reduce or to eliminate the compositions of the narrow and/or thrombosis incidence rate of vascular access.
The present invention also provides by comprising that effective dose EFA's is used to reduce or eliminate narrow and/or thrombotic compositions intravenous administration reduces or eliminate the narrow and/or thrombosis incidence rate of vascular access in the patient of needs method.
The present invention further provides the method that reduces or eliminate the narrow and/or thrombosis incidence rate of hemodialysis patients vascular access.This method comprises the suitable groups compound that comprises effective dose EFA by the direct intravenous administration of patient vessel's path.
The present invention further provides and made the method for compositions that intravenous is used for the patient that is suitable for that comprises effective dose EFA.
Therefore, the purpose of this invention is to provide effectively preventing of being suitable for that intravenous uses, stable, reverse and/or the narrow and/or thrombotic compositions of treatment arteriovenous graft.
Another object of the present invention provides and is suitable for the safe composition that intravenous uses, and is used for prevention, and is stable, reverses and/or the narrow and/or thrombosis of treatment arteriovenous graft.
Another object of the present invention provides prevention, and is stable, reverse and/or the treatment hemodialysis before or among the narrow and/or thrombotic effective ways of arteriovenous graft.
Another object of the present invention provides prevention, and is stable, reverses and/or treat the safety method of one or more complication relevant with arteriovenous graft.
Another object of the present invention provides the method for making the safe composition that is suitable for the intravenous use, and said composition is used for prevention, and is stable, reverses and/or treat one or more complication relevant with arteriovenous graft.
A further object of the present invention provides makes the method for compositions that comprises the effective dose essential fatty acid, said composition is suitable for intravenous and uses, be used for prevention, stable, reverse and/or treat one or more complication relevant with the arteriovenous graft that is used for hemodialysis.
To know these and other purposes of the present invention and advantage from following detailed description and claim, and specially describe wherein some, other then do not have.
Describe in detail:
The present invention relates to contain the compositions that is suitable for the effective dose essential fatty acid (EFA) that intravenous uses, said composition is used for prevention, reverses, and is stable, reduces and/or eliminates one or more complication relevant with vascular access, as narrow and/or thrombosis.Compositions of the present invention relies on the antiinflammatory of contained EFA wherein and antithrombotic to form effect and can effectively prevent, and reverses, and is stable, reduces and/or eliminates one or more complication relevant with vascular access.Compositions of the present invention is particularly useful in the situation that vascular access is used for hemodialysis, although compositions of the present invention can be used for any intravenous path, no matter be to be used for kidney or non-kidney patient.Compositions of the present invention reverses in prevention, and is stable, reduces and/or eliminates in one or more complication relevant with arteriovenous graft and/or AV fistula particularly useful.
Preferred composition of the present invention comprises one or more EFA, or contain the fats emulsion of one or more EFA, contain the polyunsaturated long-chain omega-fatty acid of 18 to 22C atoms as one or more, ω-6 fatty acid, permissible ester on its materia medica, permissible salt or its compositions on its materia medica.Can be with purified form, or as the component of oil, highly purified oil concentrate or Semen Lini oil use suitable EFA.
Other EFA preparation comprises ω 3 and ω 6 fatty acids, as
ω 6 families
Popular name The numeral title
Linoleic acid 18:2n-6
Acid and gamma-linolenic 18:3n-6
-- 20:2n-6
Two high acid and gamma-linolenics (DHGLA) 20:3n-6
Arachidonic acid 20:4n-6
Docosatetratenoic acid 22:4n-6
-- 22:5n-6
ω 3 families
Popular name The numeral title
Alpha linolenic acid (ALA) 18:3n-3
Parinaric acid 18:4n-3
20:3n-3
Eicosatetraenoic acid 20:4n-3
Eicosapentaenoic acid (EPA) 20:5n-3
Clupanodonic acid (DPA) 22:5n-3
Docosahexenoic acid (DHA) 22:6n-3
And the monounsaturated fatty acid that contains single carbon-to-carbon double bond, as:
Popular name The numeral title
The nutmeg olefin(e) acid 14:1
Do not have 15:1
Palmitoleic acid 16:1
Do not have 17:1
Oleic acid 18:1
Gaducene acid 20:1
Erucic acid 22:1
Nervonic acid 24:1
And polyunsaturated fatty acid contains two or more pairs of carbon bonds.These EFA preparations can also comprise the mixture of two or more fatty acids, as: acid and gamma-linolenic and EPA and DNA etc.Generation can be synthesized or these different fatty acids can be in natural origin, found.For example, find linoleic acid (LA) in cooking oil commonly used, cooking oil commonly used comprises Helianthi, Flos Carthami, corn, Semen Gossypii and soybean oil.At Radix Oenotherae erythrosepalae, black currant has been found ω 6 fatty acids of acid and gamma-linolenic (GLA) and LA form in the plant seed oils of borage and the fungal oil.
Suitable omega-3 fatty acid comprises, such as but not limited to, alpha-linolenic acid, eicosapentaenoic acid (EPA) and docosahexenoic acid (DHA).Compositions of the present invention can comprise the omega-3 fatty acid that one or more are suitable.Can use omega-3 fatty acid with its purified form or with the form of components of fish oils.Suitable fish oil comprises by technology with competent content from cold water fish, as sardine (pilchard) oil, and herring oil, peruvian fish oil, sardine (sardine) oil, trout oil, those oil that herring oil and mackerel oil are collected.Preferably from mackerel, sardine, the purification fish oil concentrate that Mylopharyngodon piceus or salmon produce, wherein the EPA content of oil concentrate is 20 to 40%, more preferably at least 26% weight.
Suitable ω 6 fatty acids comprise, such as but not limited to, linoleic acid, gamma-Linolenic acid, two high acid and gamma-linolenics and arachidonic acid, preferred thus gamma-Linolenic acid and two high acid and gamma-linolenics.Compositions of the present invention can comprise one or more suitable ω 6 fatty acids.Can use ω 6 fatty acids with its purified form or with the form of oil ingredient, for example, primrose oil, borage oil or soybean oil, wherein preferred primrose oil.
Permissible ester and salt can be used for compositions of the present invention equally on the suitable materia medica of described ω-3 and ω-6 fatty acids, preferred especially thus these acid permissible ester on materia medica.ω-3 and ω-6 fatty acids permissible ester on materia medica comprises, such as but not limited to, ethyl ester or glyceride, for example, single-, two-or triglyceride, preferred thus triglyceride.ω-3 and ω-6 fatty acids permissible salt on materia medica comprises, such as but not limited to its sodium salt.
Compositions of the present invention comprises EFA and/or comprises fish oil and/or the EFA fats emulsion of the mixture that other are oily, and other oil are as primrose oil, borage oil or soybean oil, and fish oil and other oily weight ratios are optimum thus is about 1: 50 to about 50: 1.For example, the weight ratio of fish oil and primrose oil and/or borage oil, or the ratio of fish oil and soybean oil can be about 1: 2 to about 1: 20 suitably.In some embodiments, the mixture of EFA will comprise at least that ratio is 1: 1-1: 40 ω-3 and ω-6 fatty acids.The ratio of physiology coideal is 1: 1.7, and therefore most preferred scope is 1: 1.5-4,1: 4-8 also is useful.
The suitable fats emulsion of the present invention preferably contains permissible ester or salt on one or more omega-fatty acids and/or ω-6 fatty acid and/or its materia medica, amount is about 5 to about 45% weight, preferred amounts is about 10% to about 30% weight, and most preferred amount is about 10% to about 20% weight.Useful mixture includes, but not limited to the dilution of 10% to 20% weight mixture.
For the suitable fat emulsions that contains one or more omega-fatty acids, the fatty acid of pure form preferably used according to the invention or oil ingredient form, its ester or salt.
Fats emulsion of the present invention can also comprise that one or more physiologys go up the emulsifying agent of safety.Suitable emulsifying agent comprises, such as but not limited to, the phospholipid in animal or plant source, and preferably contain EPA those phospholipid as polyunsaturated fatty acid.Lecithin is specially adapted in the compositions of the present invention.Other useful emulsifying agents comprise synthetic and semisynthetic lecithin.Can have one or more such emulsifying agents in the fats emulsion of the present invention, content is about 1% to about 20% weight (based on fat content), and preferred content is about 5% to about 15% weight (based on fat content).
Compositions also can also contain the other biological reactive compound, as antioxidant or the known reagent that can remove or offset other chemical influences that show of toxicity free radical and byproducts of oxidative and physical stress.These include but not limited to vitamin E, vitamin C, Caratenoids, flavonoid, thioctic acid and derivant thereof or mixture.Vitamin E, natural, synthetic, blended tocopherol.Vitamin E preferably on tocopherol or the materia medica Renascin of safety as but be not limited to the form of tocopherol acetate, the content that can be used for fats emulsion of the present invention is about 0.15% to about 1.5% weight (based on fat content), is used as antioxidant.Can there be other chemical compounds.
If desired, can comprise the additive that other are suitable in the fats emulsion of the present invention, such as but not limited to, conventional grade is oozed additive (vein inner salt commonly used is as sodium chloride and non-electrolyte, as glucose), pH regulator agent (as acetic acid and sodium acetate) and buffer agent (as, the salt acetate and the phosphatebuffer buffer system that constitute by acid and acid), emulsion stabilizer is as gelatin, the long-chain saccharide, as agar and/or co-emulsifier, as tween and span, and selenium compound.Usually make the intravenous reconciliation of inventory to about 300 m osmoles/liter Morie osmolarity and about 7.4 pH, this can use tension regulator and buffer agent to realize that this medicine will be sent to the patient by the intravenous administration approach in the preparation medicine by these those skilled in the art.
Suitable grade is oozed additive and is comprised, such as but not limited to, isotonic agent glycerol commonly used, glucose, xylose and sorbitol, preferably glycerine.
The unrestricted purpose for explanation has been listed two kinds of suitable fats emulsion prescriptions that are used for compositions of the present invention in following table 1 and table 2.
Table 1: fats emulsion prescription
Figure A20068004323300121
Table 2: fats emulsion prescription
Figure A20068004323300122
Fish oil used in above table 1 prescription preferably passes through as the purified fish oil of DE PS 37 22 540 disclosed technology heights well known by persons skilled in the art, and this fish oil is rich in the omega-fatty acid of forming as triglyceride.Such preferred fish oil contains at least about 40% weight omega-fatty acid.Be about 25% to about 50% weight as total EPA of components of triglycerides and DHA content in the fish oil, more preferably from about 35% to about 50% weight (is that each value is measured on the basis with the surface percentage in the gas chromatogram).The EPA of fish oil exists with different content ratios with DHA content, measures this ratio by the surface of measuring in the gas chromatogram separately.Content ratio depends on the character of used fish oil, and depends on the enrichment degree of the omega-fatty acid that is obtained.Wherein EPA and the DHA as components of triglycerides is preferred in the fats emulsion of the present invention than the fish oil that exists than the content of DHA about 0.5: 1 to about 2.6: 1 (surface ratio in the gas chromatogram) with EPA.
Used fats emulsion is emulsion oil-in-water (O/W) according to the present invention, and the foreign minister is made of the distilled water that is suitable for intravenous administration for this reason.Before the dialysis or among the intravenous administration of compositions of the present invention by vascular access significantly reduced relevant complication, said composition comprises one or more EFA of effective dose or comprises one or more EFA such as one or more polyunsaturated long-chain omega-fatty acids, the fats emulsion of permissible ester or salt on ω-6 fatty acid or its materia medica.
In one embodiment, in blood dialysis with the compositions intravenous administration that comprises the fats emulsion of one or more EFA or one or more EFA of the present invention.Under these circumstances, come administration composition by inculcating (Intradialysis Infusion) 10% Fish Oil Emulsion in the dialysis.
Material and method
Being used for the preparation that dialysis procedure inculcates is that the every 100ml that makes 10% to 20% solution contains 10g to 20g fish oil, the Fish Oil Emulsion of 2.5g glycerol and 1.2g Ovum Gallus domesticus Flavus lecithin (
Figure A20068004323300131
Fresenius Kabi, Bad Homburg, Germany).With fish oil highly purified and contain at least 40% long-chain omega-fatty acid (EPA, DHA), and the saturated and unsaturated fatty acid of other long-chains.According to 10%-20% from
Figure A20068004323300132
Fat and 80-90% from the combination of the basic long-chain emulsion of soybean oil, selecting ω-3: ω-6 ratio is 1: 2 to 1: 4.
Can be used as contain 50 or the aseptic vial of 100ml 10% emulsion in commercial product obtain
Figure A20068004323300141
Should detect any precipitation in the bottle, and if exist and just to abandon.Before using, should rock container, and only import content by sterile procedure and infusion set.Content is only to be used to inculcate by central authorities or peripheral vein or by dialysis apparatus.Emulsion is inculcated to instillator, be used for the venous blood system of dialyser far-end.
Should be only in dialysis beginning after about 15 minutes
Figure A20068004323300142
Inculcate, and to be no more than 0.5ml/kg/ hourSpeed inculcate continuously, therefore avoid faster inculcating the hypertriglyceridema that causes.If 10% can not satisfy the dosage demand of the about 4g of each dialysis period, can in 2.5 to 3 hours, inculcate 20% ω-3 concentration.
If there is not incompatibility in the explanation according to manufacturer, can come together to inculcate with other emulsions or solution
Figure A20068004323300143
And preferably come administration by the same vessel path mouth in the dialysis procedure.Can change the speed of administration, but in the dialysis procedure process, obtain the total dosage of composition of 25g to 25g usually.
In interchangeable embodiment, can be in administration compositions of the present invention before the hemodialysis or in the preparation in hemodialysis.In such a case, preferably with above-mentioned same dose intravenous administration compositions.
In typical patient, carry out three hemodialysis weekly.Preferably before each hemodialysis or among administration compositions of the present invention, the most preferably administration in the blood dialysis.According to patient's specific factor, less administration frequency is acceptable.Such factor comprises the condition of patient's omega-fatty acid state, as by biological tissue such as erythrocyte membrane, omega-fatty acid content in the platelet etc. is measured, use the measured value of current confirmation, as (the measurement of EPA+DHA content in the erythrocyte membrane of ω-3 index, be expressed as total fatty acids percentage ratio) and other routines and emerging measuring technique, these technology will give the dosage or the information at interval of of the present invention administration of administration doctor about obtaining the maximum clinical benefit.Can come to assist described some practical measuring examples of medical scheme of the present invention that comprise of adjustment to include but not limited to triglyceride, cholesterol, the hematochemistry evaluation of fatty acid and lipoprotein and apoprotein, solidify the labelling of research and coagulability, liver, kidney and electrolyte, cytokine, film and organize phospholipid, eicosane class such as PGE2, E3, leukotrienes B4 and B5, propose that some are immune labeled, the labelling of endothelial function such as eNO synthase activity, nitric oxide, glutamate, Glu or other intermediums, adhesion molecule, the by-product of oxidisability stress, free radical and lipid oxidation, the surrogate markers that peroxide produces, markers of inflammation, as c-proteins C reactive and autoimmune, the labelling of cell proliferation, with the by-product of any measurable labelling or metabolic process, these can make the doctor who prescribes determine whether dosage of the present invention satisfies the target in dosage of the present invention or the dosing interval scheme.Other healths find as blood pressure, and heart rate also can be used for adjusting dosage, and the test that is used for endothelial function, as the expansion of flow mediated.In preferred embodiments, each dialysis period administration comprises that about 4 of effective dose restrains the compositions of the present invention of about 4 one or more essential fatty acid of gram in one or more essential fatty acid or the fats emulsion.
The present invention also provides mensuration, and adjustment or optimization are used for the dosage of the compositions of individual patient, based on each patient's body and physiological condition and situation.The factor that can influence dosage comprises, for example, and age, body weight, body-mass index, body surface area, sex, race or ethnic background, individual and family disease history, the disease of preexist or disease, the risk factor of disease or disease and the result of laboratory work.Based on the consideration of one or more such factors, can determine starting dose, and according to cycle adjustment dosage.For example, (patient of TG>250mg) should begin with lower dosage or slower infusion rate to suffer from hypertriglyceridema.The basis that dosage reduces can comprise and begins to inculcate the generation that is higher than the hypertriglyceridema of 250mg when measuring in 90 minutes, and the basis that dosage raises can comprise that the rising deficiency of required omega-fatty acid in the destination organization or the inhibition of markers of inflammation or metabolic intermediate are unsatisfied with, and known these metabolic intermediates are the surrogate markers that obtain clinical benefit of the present invention.In addition, the hematochemistry that it is desirable to monitor each patient determines whether changing dosage.The parameter that can monitor comprises triglyceride levels.Can comprise dose titration based on such monitoring result.Can be according to cycle such as every 3-6 month, or preferred per 1 measure to carrying out such hematochemistry over 3 months, but also can comprise measurement in the administration 24 hours to 30 days.After carrying out dose titration, it is desirable to before whether mensuration should continue or further change the dosage of adjusting, permission patient's disease is balance or stable for some time.In order to estimate the result of adjustment, ideal waiting time section is 3 months, but according to shown in the situation, can use the other times section.
Compositions of the present invention comprises the EFA in EFA or the fats emulsion, separately or unite one or more active pharmaceutical ingredients and/or supplementary.Suitable supplementary comprises, such as but not limited to, ALA, vitamin B group, vitamin B group derivant, vitamin E, vitamin D, vitamin A, Caretenoids, alpha lipoic acid, flavonoid, vitamin K, Statins, the special acid derivative of shellfish, ferrum, erythropoietin, CoQ10, aminoacid, sarcosine, carnitine, zinc, calcium, PTH, PTH analog, chelating agen, lipid, protein, carbohydrate or its combination.When existing, such compositions can be a spendable form on the physiology.
The example of reagent also comprises like this: neuroprotective, as nimodipine and relevant chemical compound; Antibiotic, as tetracycline, duomycin, bacitracin, neomycin, polymyxin, Gramicidin, oxytetracycline, chloromycetin, gentamycin and erythromycin; Anti-infective; Antimicrobial drug is as chlorobenzene sulfanilamide, sulfacetamide, sulfamethizole, bacteresulf; Nitrofural, and sodium propionate; Antiallergic agent, as antazoline, methapyrilene, chlorobenzene chlorphenamine, pyrilamine and Fei Ni Lamine; Antibacterial or inhibition microorganism agent or antiseptic, antiinflammatory, as hydrocortisone, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone acetonide, medrysone, methyl meticortelone, meticortelone 21-phosphate, predniso lone acetate, fluorometholone, betamethasone and triminolone; Miotic and anticholinergic, as pilocarpine, physostigmine, carbachol, diisopropyl fluorophosphate (DFP), echothiopate iodide and demecarium bromide; Mydriatic, as atropine sulfate, Ciclolux, melyltropeine, scopolamine, N-ethyl-N-(.gamma.-picolyl)tropamide, eucatropine and hydroxyamphetamine; Sympathomimetic is as epinephrine; And prodrug, those described in Design ofProdrugs (prodrug design), Hans Bundgaard edits, ElsevierScientific Publishing Company, Amerstdarn, 1985, be hereby incorporated by.Except above-mentioned medicament, other can be applicable to intravenous therapy, the medicament of disease adds compositions of the present invention in control or the diagnosis mammalian organism, as long as do not have incompatibility with other components of compositions.Can as Remington ' s Pharmaceutical Sciences, be used to identify such medicament with reference to the textbook of any standard.
Because the preparation intravenous will be introduced, they must be aseptic, and preferably contain antiseptic and keep aseptic.For the useful especially two class antiseptic of the emulsion of essential fatty acid is edetate (ethylenediaminetetraacetic acid) and pedetate (diethylene triamine pentaacetic acid).Usually, for edetate, preferred salt comprises sodium ethylene diamine tetracetate and Ca-EDTA, preferred disodiumedetate.For pedetate, preferred salt will present the affinity lower than calcium to pedetate, preferably ca lciumtrisodium pedetate.Two kinds of salt preferably exist with low concentration, and edetate exists with the 0.03-0.9 mM, and pedetate exists with 0.0005-0.005% weight.Usually, effectively antiseptic realizes in indefinite extraneous contamination situation preventing that at least 24 hours function of the remarkable growth of microorganism is (for example, behind the low-level extraneous contamination, 20 ℃-25 ℃ temperature range, preferably being no more than 10-doubly increases, as 10-10000 colony-forming units).In useful mensuration, the broth culture of one or more standards USP (American Pharmacopeia) preservative efficacy test organisms added contain in the preparation of antiseptic the about 100-200 of an every ml colony-forming units.Test formulation is hatched at 25-30 ℃, and the live organism of testing after 24 hours and 48 hours is counted.
The intravenous administration of compositions of the present invention that does not add one or more active agents is more useful to patient's indication, these indications comprise hypertension, cardiovascular risk reduces, nutritional supplementation, inflammation is regulated, immunomodulating, neuropsychopathic adjusting, acute illness, arrhythmia and malignant tumor.
Can use EFA that is suitable for intravenous administration or the EFA emulsion that to buy to produce compositions of the present invention.A kind of such EFA emulsion is By Fresenius Kabi, Bad Homburg, Germany produces.100ml The highly refined fish oil of consisting of of the qualitative, quantitative of emulsion: 10.0g, it contains: eicosapentaenoic acid (EPA) 1.25-2.82g; Docosahexenoic acid (DHA) 1.44-3.09g; Myristic acid 0.1-0.6g; Palmic acid 0.25-1.0g; Palmitoleic acid 0.3-0.9g; Stearic acid 0.05-0.2g; Oleic acid 0.6-1.3g; Linoleic acid 0.1-0.7g; Linolenic acid 0.2g; Parinaric acid 0.05-0.4g; Eicosenoic acid 0.05-0.3g; Arachidonic acid 0.1-0.4g; Docosenoic acid 0.15g; Clupanodonic acid 0.15-0.45g; D1-a-tocopherol (as antioxidant) 0.015-0.0296g; Glycerol 2.5g; The lecithin 1.2g of purification; Gross energy: 470kJ/100ml=112kcal/100ml.PH value: 7.5-8.7.Titratable acidity:<1mmolHCL/I.Osmolality: 308-376mosm/kg.Medicament forms is the emulsion that is used to inculcate.When oral or enteral nutrition is impossible, during not enough or taboo, the treatment indication comprises that non-enteral nutrition replenishes long-chain omega-fatty acid, especially eicosapentaenoic acid and docosahexenoic acid.Maximum infusion rate should be no more than 0.5ml
Figure A20068004323300173
/ kg body weight/hour, corresponding to 0.05g fish oil/kg body weight/hour.
The embodiment that the present invention is illustrative rather than definitive thereof is the method for preparing the present composition, and it comprises that mixing every 100ml contains 10g to 20g fish oil, the Fish Oil Emulsion of 2.5g glycerol and 1.2g Ovum Gallus domesticus Flavus lecithin (
Figure A20068004323300181
), make 10% to 20% solution.Fish oil is highly refined, and contains at least 40% long-chain omega-fatty acid.Can select ω-3: ω-6 ratio is 1: 2 to 1: 4, depend on from
Figure A20068004323300182
10-20% fat and from the combination of the 80-90% fat of the basic long-chain emulsion of soybean oil.The using method of obtained compositions be included in before the hemodialysis or among will contain the EFA emulsion of effective dose compositions deliver medicine to the patient with the speed that is no more than 0.5ml/kg/ hour, therefore avoid faster inculcating the hypertriglyceridema that causes.The accumulated dose of each dialysis period is 4 gram omega-fatty acids.If 10% can not satisfy the dosage demand, can in 2.5 to 3 hours, inculcate 20% ω-3 concentration, measure the dosage demand by the clinical and biochemical target of the object of real-time measurement.
Can be used as contain 50 or the aseptic vial of 100ml 10% emulsion in commercial product obtain
Figure A20068004323300183
Should detect any precipitation in the bottle, and if exist precipitation just to abandon.Before using, should rock container, and only import content by sterile procedure and infusion set.
Figure A20068004323300184
Only to be used to inculcate by central authorities or peripheral vein or by dialysis apparatus.Emulsion can also be inculcated to instillator, be used for the venous blood system of dialyser far-end.
Should be only in dialysis beginning after about 15 minutes Inculcate, and inculcate continuously, to avoid faster inculcating the hypertriglyceridema that causes with the speed that is no more than 0.5ml/kg/ hour.If 10% can not satisfy the dosage demand of the about 4g of each dialysis period, can in 2.5 to 3 hours, inculcate 20% ω-3 concentration.
If there is not incompatibility in the explanation according to manufacturer, can come together to inculcate with other emulsions or solution
Figure A20068004323300186
The specific embodiment
Embodiment 1:
The preparation Fish Oil Emulsion is used for the intravenous administration of blood dialysis.The every 100ml of Fish Oil Emulsion contains 10g fish oil, 2.5g glycerol and 1.2g Ovum Gallus domesticus Flavus lecithin, promptly (Fresenius Kabi, Bad Homburg Germany), make 10% solution.Fish oil is highly purified, and contain at least 40% long-chain omega-fatty acid.ω-3: ω-6 ratio is 1: 4.
The aseptic vial that detection is purchased
Figure A20068004323300188
Whether there is any precipitation, just abandons if exist.Container thoroughly rocked and use standard sterile procedures to obtain wherein contained emulsion by inculcating to be provided with.Emulsion is inculcated to instillator, be used for the venous blood system of dialyser far-end.
In dialysis beginning after about 15 minutes
Figure A20068004323300191
Inculcating of emulsion.Inculcate emulsion continuously with the speed that is no more than 0.5ml/kg/ hour, until inculcating the 4g emulsion.
Embodiment 2:
According to embodiment 1, in 2.5 to 3 hours, inculcate the emulsion of 20% ω-3 concentration, satisfy the dosage demand of the about 4g of each dialysis period.
Embodiment 3:
Prepare fish oil and trials of emulsion of plant oil fluid composition, be used for the intravenous administration of blood dialysis.The every 100ml of composition emulsion contains 10g fish oil, 2.5g glycerol and 1.2g Ovum Gallus domesticus Flavus lecithin, promptly
Figure A20068004323300192
(Fresenius Kabi, Bad Homburg Germany), unite the Semen Lini oil emulsion that contains the 5g Semen Lini oil, and promptly (Chengdu China), makes 15% solution to ALA75 for BioGin BiochemicalsCo., Ltd.Fish oil is highly purified, and contain at least 40% long-chain omega-fatty acid, ω-3: ω-6 ratio is 1: 4, and Semen Lini oil contains at least 70% long-chain omega-fatty acid, and ω-3: ω-6 ratio is 4: 1.
Emulsion is inculcated to instillator, be used for the venous blood system of dialyser far-end.Perhaps, can also be to inculcate by central authorities or peripheral vein.
Begin inculcating of emulsion after about 15 minutes in dialysis.Inculcate emulsion continuously with the speed that is no more than 0.5ml/kg/ hour, until inculcating about 4g emulsion.
Embodiment 4:
The preparation emulsion compositions is used for the intravenous administration of blood dialysis, wherein mixes from the omega-fatty acid of marine product and plant origin, the folic acid of high dose (10mg) and vitamin B12 (10mcg).The every 100ml of combination emulsion contains 10g fish oil, 2.5g glycerol and 1.2g Ovum Gallus domesticus Flavus lecithin, promptly
Figure A20068004323300193
(Fresenius Kabi, Bad Homburg Germany), unite the Semen Lini oil emulsion that contains the 5g Semen Lini oil, and promptly (Chengdu China), makes 15% solution to ALA75 for BioGinBiochemicals Co., Ltd.Fish oil is highly purified, and contain at least 40% long-chain omega-fatty acid, ω-3: ω-6 ratio is 1: 4, and Semen Lini oil contains at least 70% long-chain omega-fatty acid, and ω-3: ω-6 ratio is 4: 1.Folic acid is 5-formyl H 4The form of folic acid (folinic acid) is clinically with Leucovorin TMThe title of calcium leucovorin 10mg/ml intravenous injection liquid is come administration.
Emulsion is inculcated to instillator, be used for the venous blood system of dialyser far-end, or be to inculcate by central authorities' inlet or peripheral vein.
Begin inculcating of emulsion after about 15 minutes in dialysis.Inculcate emulsion continuously with the speed that is no more than 0.5ml/kg/ hour, until inculcating about 4g omega-fatty acid and 10mg folinic acid.Measurement based on the expansion (FMD) of endothelial function such as flow mediated can increase or reduce folinic acid and obtain required clinical effectiveness.Increase other embodiment, paper or based on experimental result demonstrates: other preparations, other administration route uses hematochemistry to monitor and measures suitable dosage, various optimization dosage etc.
Described the present invention in detail, those skilled in the art will learn and can change the present invention and do not break away from its spirit and scope.Therefore, determine that scope of the present invention is not limited to described particular.On the contrary, determine that appended claim and equivalent thereof have determined scope of the present invention.
Be clear that and carry out aforesaid many changes of the present invention and variation, and do not break away from its spirit and scope.Described particular just illustrates, and the present invention only is subject to appended claim.

Claims (42)

1. compositions comprises:
Be suitable for before the hemodialysis or among the essential fatty acid of the pure form of effective dose of intravenous administration or the fats emulsion of described purified form essential fatty acid.
2. the compositions of claim 1, the essential fatty acid of wherein said purified form is selected from omega-fatty acid, the salt of omega-fatty acid, the ester of omega-fatty acid, ω-6 fatty acid, the salt of ω-6 fatty acid, the ester and the combination thereof of ω-6 fatty acid.
3. the compositions of claim 1, wherein said fats emulsion is an emulsion oil-in-water.
4. the compositions of claim 1, the essential fatty acid of wherein said purified form comprises eicosapentaenoic acid and docosahexenoic acid.
5. the compositions of claim 1, the essential fatty acid of wherein said purified form comprises about 0.5: 1 eicosapentaenoic acid and the docosahexenoic acid to about 2.6: 1 eicosapentaenoic acid ratio docosahexenoic acid ratio.
6. the compositions of claim 1, wherein compositions is suitable for weekly intravenous administration three times.
7. the compositions of claim 1, wherein said effective dose are about 4 grams.
8. the compositions of claim 1 further comprises being selected from active pharmaceutical ingredient the component of supplementary and composition thereof.
9. the compositions of claim 1 further comprises being selected from vitamin B group vitamin B group derivant, vitamin E, vitamin D, vitamin A, vitamin K, Statins, the special acid derivative of shellfish, ferrum, erythropoietin, CoQ10, phylloxanthin, sarcosine, carnitine, zinc, calcium, PTH, PTH analog, chelating agen, lipid, protein, the component of carbohydrate and composition thereof.
10. the compositions of claim 1, wherein said compositions be administered at least a following indication that is selected from: hypertension, cardiovascular risk reduces, nutritional supplementation, inflammation is regulated, immunomodulating, neuropsychopathic adjusting, acute illness, arrhythmia and malignant tumor.
11. the compositions of claim 1 further comprises the essential fatty acid in the oil.
12. prevention is stable, reverses and/or treat the method for one or more complication relevant with vascular access, comprising: the compositions that comprises the fats emulsion of essential fatty acid or essential fatty acid by the vascular access intravenous administration.
13. the method for claim 12 wherein uses vascular access to be used for hemodialysis.
14. the method for claim 12, wherein administration composition in blood dialysis.
15. the method for claim 12, wherein administration composition before hemodialysis.
16. the method for claim 12, wherein administration composition three times weekly.
17. the method for claim 12, the wherein about 4 gram essential fatty acid of administration.
18. the method for claim 12 is wherein united and is selected from active pharmaceutical ingredient, the component of supplementary and composition thereof is come administration composition.
19. the method for claim 12 is wherein united at least a vitamin B group that is selected from, vitamin B group derivant, vitamin E, vitamin D, vitamin A, vitamin K, Statins, the special acid derivative of shellfish, ferrum, erythropoietin, CoQ10, phylloxanthin, sarcosine, carnitine, zinc, calcium, PTH, PTH analog, chelating agen, lipid, protein, the additive of carbohydrate and composition thereof comes administration composition.
20. the method for claim 12, wherein compositions be administered at least a following indication that is selected from: hypertension, cardiovascular risk reduces, nutritional supplementation, inflammation is regulated, immunomodulating, neuropsychopathic adjusting, acute illness, arrhythmia and malignant tumor.
21. the method for claim 12 wherein delivers medicine to compositions the patient who does not suffer from nephropathy.
22. the method for claim 12, wherein compositions comprises
Figure A2006800432330003C1
23. the narrow and thrombotic method of the vascular access of preclude blood dialysis patient comprises:
Emulsion by vascular access administration essential fatty acid.
24. the method for claim 23, wherein emulsion comprises
Figure A2006800432330003C2
25. the method for claim 23, wherein speed administration emulsion to be no more than about 0.5ml/kg/ hour.
26. the method for claim 23, wherein administration emulsion is until delivering medicine to the about 4g emulsion of patient.
27. the method for claim 23 is wherein united and is selected from active pharmaceutical ingredient, the component of supplementary and composition thereof is come administration composition.
28. the method for claim 23 is wherein united at least a vitamin B group that is selected from, vitamin B group derivant, vitamin E, vitamin D, vitamin A, vitamin K, Statins, the special acid derivative of shellfish, ferrum, erythropoietin, CoQ10, phylloxanthin, sarcosine, carnitine, zinc, calcium, PTH, PTH analog, chelating agen, lipid, protein, the additive of carbohydrate and composition thereof comes administration composition.
29. the method for claim 23, wherein essential fatty acid be administered at least a following indication that is selected from: hypertension, cardiovascular risk reduces, nutritional supplementation, inflammation is regulated, immunomodulating, neuropsychopathic adjusting, acute illness, arrhythmia and malignant tumor.
30. prevention is stable, reverses and/or treat one or more complication relevant with patient vessel's path, and the method for preventing the complication that caused by the administration essential fatty acid, comprising:
The compositions of the fats emulsion that comprises essential fatty acid or essential fatty acid by vascular access intravenous administration predetermined close to intravenous through another path;
Monitor described patient replying to described dosage; With
Raise or downward modulation dosage subsequently based on observed replying in the described monitoring.
31. the method for claim 30, wherein initial predetermined close is for delivering medicine to patient's 4 gram essential fatty acid.
32. the method for claim 31, wherein initial predetermined close is based on described patient's medical history.
33. the method for claim 31, wherein medical history comprises that one or more are selected from following factor: age, body weight, body-mass index, body surface area, sex, race or ethnic background, individual and family disease history, the disease of preexist or disease, the risk factor of disease or disease and the result of laboratory work, and based on described one or more factors rises or the initial predetermined predose of downward modulation.
34. the method for claim 31, wherein said patient is accepting dialysis and with before each dialysis period, while or frequency afterwards give the patient with predetermined predose.
35. the method for claim 34, wherein the medical history based on the patient changes frequency and/or initial predetermined predose.
36. the method for claim 35, wherein medical history comprises that one or more are selected from following factor: age, body weight, body-mass index, body surface area, sex, race or ethnic background, individual and family disease history, the disease of preexist or disease, the risk factor of disease or disease and the result of laboratory work, and based on described one or more factors rises or downward modulation frequency and/or initial predetermined predose.
37. the method for claim 30, wherein said patient's monitoring comprises the monitoring of blood chemistry.
38. the method for claim 38, wherein monitoring comprises the monitoring of triglyceride levels.
39. the method for claim 37, wherein the result based on the hematochemistry monitoring raises or reduces the dosage or the frequency of administration.
40. the method for claim 37, wherein before administration essential fatty acid compositions, among or periodically carry out described monitoring afterwards.
41. the method for claim 37 is wherein monitored as per the schedule based on patient's situation or monitoring result.
42. the method for claim 41 is wherein monitored after described patient has equilibration time after changing dosage or frequency.
CNA2006800432333A 2005-12-09 2006-12-06 Intravenous essential fatty acid emulsion Pending CN101312712A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104739763A (en) * 2013-12-31 2015-07-01 中国科学院上海药物研究所 Intravenous injection lipid emulsion having anti-inflammatory and anti-thrombosis functions as well as preparation method and application thereof
CN114712307A (en) * 2021-01-05 2022-07-08 上海交通大学医学院附属第九人民医院 Fat emulsion dialysate, preparation method and application thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104739763A (en) * 2013-12-31 2015-07-01 中国科学院上海药物研究所 Intravenous injection lipid emulsion having anti-inflammatory and anti-thrombosis functions as well as preparation method and application thereof
CN104739763B (en) * 2013-12-31 2018-12-11 健康元药业集团股份有限公司 It is a kind of with anti-inflammatory and anti-thrombosis function intravenous lipid emulsion and its preparation method and application
CN114712307A (en) * 2021-01-05 2022-07-08 上海交通大学医学院附属第九人民医院 Fat emulsion dialysate, preparation method and application thereof
WO2022147962A1 (en) * 2021-01-05 2022-07-14 上海交通大学医学院附属第九人民医院 Fat emulsion dialysate, and preparation method therefor and use thereof
CN114712307B (en) * 2021-01-05 2023-06-09 上海交通大学医学院附属第九人民医院 Fat emulsion dialysate and preparation method and application thereof

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