MX2008006946A - Intravenous essential fatty acid emulsion - Google Patents

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 EMULSION OF ESSENTIAL FATTY ACIDS Scope of the invention: The present invention relates to compositions that include essential fatty acids suitable for intravenous administration to a patient in need thereof to reduce or eliminate inflammatory responses, as well as methods of preparation and use thereof. More specifically, the present invention relates to compositions that include an emulsion of essential fatty acids suitable for intravenous use prior to or during hemodialysis, to prevent or reduce stenosis and / or thrombosis of a vascular access. BACKGROUND OF THE INVENTION: Hemodialysis is the most common method used to treat advanced and permanent renal insufficiencies. Since the 1960s, when hemodialysis began to be a practical treatment for kidney failure, much progress has been made to make hemodialysis treatments more effective and to minimize side effects. During hemodialysis, a patient's blood is allowed to flow through a catheter, a few grams at a time, into a hemodialysis machine. The hemodialysis machine has three main functions, which include pumping blood and controlling blood flow, cleaning waste substances from the blood and controlling blood pressure and the rate of fluid withdrawal from the blood. After passing through the hemodialysis machine, the clean blood is returned to the patient's body through a catheter. Before the hemodialysis is performed, a vascular access should be prepared in the patient's body, or place from which the blood is withdrawn and returned. Typically, a vascular access is prepared weeks to months before starting hemodialysis. The vascular access must be able to withstand a blood flow of approximately 250 milliliters per minute (ml / min). Two types of vascular access are suitable for hemodialysis: arteriovenous graft (AV graft) and arteriovenous fistula (AV fistula). An AV graft is a vascular access that uses a synthetic tube implanted under the skin, typically in the patient's arm. One end of the implanted tube is attached to an artery and the other end of the tube is attached to a vein. The tube serves as an artificial vein that can be used repeatedly for the placement of a needle and access to blood during hemodialysis. An AV graft can be used for hemodialysis approximately two weeks after implantation. Unfortunately, a high percentage of AV grafts develop a reduced or inadequate blood flow due to stenosis or thrombosis at weeks or months after implantation. A reduced or inadequate blood flow is indicative of coagulation or narrowing of the vascular access. In this case, a surgical procedure, such as an angioplasty to widen the narrowed segment, is required to re-establish a greater or more adequate blood flow for the purpose of hemodialysis. An alternative option, in the case of reduced or inadequate blood flow, is to perform surgery on the AV graft and replace the narrowed segment. Up to 75% of AV grafts fail within 2 years after implantation and some AV grafts require a revision or de-coagulation up to 4 times a year. Antithrombotic or anticoagulant treatments, used in an attempt to reduce the rate of AV graft failures, have met with mixed results. The undesired side effects of antithrombotic or anticoagulant treatments have almost made such approaches impossible to reduce the high incidence of vascular access failures. AV fistulas are less likely to form clots or become infected than AV grafts, and tend to last longer than any other type of vascular access. An AV fistula vascular access is formed by surgically communicating an artery directly with a vein, usually on the forearm. The communication of an artery directly with a vein causes more blood to flow into the vein. As a result, the vein increases in size and becomes stronger, making repeated needle punctures easier for hemodialysis treatments. Unfortunately, AV fistulas also have disadvantages. One of these disadvantages is that it takes some time for the vein to increase in size to generate a strong and dilated "fast flowing blood lake" for the purpose of hemodialysis. At least 6 to 12 months are needed for the vein to mature for use in hemodialysis. Sometimes, it takes up to 24 months for the AV fistula to mature for use in hemodialysis. Complications may arise with both AV grafts and AV fistulas that may require additional treatment or surgery. The most common complications are infection and reduced blood flow due to blood clotting. Compared to AV fistulas, AV grafts tend to have more complications associated with coagulation or infection that require AV graft replacement. Therefore, there is a need to reduce or eliminate AV graft failure induced by thrombosis and stenosis. SUMMARY OF THE INVENTION: The present invention provides compositions that include an effective amount of essential fatty acids (EFAs) suitable for intravenous use in patients before or during hemodialysis to reduce or eliminate the incidence of stenosis and / or thrombosis of vascular accesses. .The present invention also provides methods for reducing or eliminating the incidence of stenosis and / or thrombosis of vascular accesses by intravenous administration to a patient in need of compositions that include an effective amount of AGE to reduce or eliminate the stenosis and / or thrombosis. The present invention further provides a method for reducing or eliminating the incidence of stenosis and / or thrombosis of a vascular access of a hemodialysis patient. The method comprises administering intravenously a suitable composition that includes an effective amount of AGE directly through a vascular access of a patient. The present invention further provides methods of making compositions that include an effective amount of AGE suitable for intravenous use in patients. Accordingly, it is an object of the present invention to provide compositions suitable for intravenous use effective in the prevention, stabilization, reversion and / or treatment of stenosis and / or thrombosis of vascular grafts. Another object of the present invention is to provide safe compositions suitable for intravenous use for the prevention, stabilization, reversion and / or treatment of stenosis and / or thrombosis of vascular grafts. Another object of the present invention is to provide an effective method of preventing, stabilizing, reversing and / or treating stenosis and / or thrombosis of vascular grafts before or during hemodialysis. Another object of the present invention is to provide a second method of preventing, stabilizing, reversing and / or treating one or more complications associated with vascular grafts. Another object of the present invention is to provide a method of manufacturing safe compositions suitable for intravenous use for the prevention, stabilization, reversion and / or treatment of one or more complications associated with vascular grafts. Still another object of the present invention is to provide a method of manufacturing compositions that include an effective amount of essential fatty acids suitable for intravenous use for the prevention, stabilization, reversion and / or treatment of one or more complications associated with vascular grafts useful for hemodialysis. These and other objects and advantages of the present invention, some of which are specifically described and others not, will be apparent from the detailed description and the following claims. DETAILED DESCRIPTION: The present invention relates to compositions containing an effective amount of essential fatty acids (AGE) suitable for intravenous use to prevent, reverse, stabilize, reduce and / or eliminate one or more complications associated with vascular accesses, such as stenosis and / or thrombosis. The compositions of the present invention are effective to prevent, reverse, stabilize, reduce and / or eliminate one or more complications associated with vascular accesses by virtue of the anti-inflammatory and antithrombotic effects of the AGEs they contain. The compositions of the present invention are particularly useful in cases in which vascular accesses are used for hemodialysis, although compositions of the present invention can be used with any intravenous access, either for renal or non-renal patients. The compositions of. The present invention is particularly useful for preventing, reversing, stabilizing, reducing and / or eliminating one or more complications associated with AV grafts and / or AV fistulas. Preferred compositions of the present invention include one or more AGE or a fat emulsion containing one or more AGE, such as one or more long chain polyunsaturated omega-3 fatty acids containing from 18 to 22 C atoms, omega fatty acids -6, their pharmaceutically tolerable esters, their pharmaceutically tolerable salts or combinations thereof. Suitable AGEs can be used in their pure forms or as components of oils, highly purified oil concentrates or linseed oil. Additional AGE formulations include omega 3 and omega 6 fatty acids, such as and monounsaturated fatty acids, such as: which contain a single carbon-carbon double bond, whereas polyunsaturated fatty acids contain two or more carbon double bonds. These AGE formulations may also include mixtures of two or more fatty acids together, such as: gamma linolenic acid and EPA and DHA, etc. These various fatty acids can be synthetically produced or found in natural sources. For example, linoleic acid (LA) is found in commonly used cooking oils, including sunflower, safflower, corn, cotton and soybean oils. Omega-6 fatty acids in the form of gamma-linolenic acid (GLA) and LA are found in the seed oils of evening primrose, blackcurrant, borage and fungal oils. Suitable omega-3 fatty acids include, but are not limited to, a-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). The compositions of the present invention may include one or more suitable omega-3 fatty acids. The omega-3 fatty acids can be used in their pure form or in the form of fish oil components. Suitable fish oils include oils that are technically recovered in significant quantities from cold-water fish, such as parchment oil, lacha oil, Peruvian fish oil, sardine oil, salmon oil, herring oil and oil. of mackerel. Preferred are purified fish oil concentrations that are produced from mackerel, sardines, herring or salmon, in which the EPA content of the oil concentration is 20 to 40% and, more preferably, at least 26% by weight. Suitable omega-6 fatty acids include, for example, but not limited to, linoleic acid, α-linoleic acid, dihomo-α-linolenic acid and arachidonic acid, α-linolenic acid and dihomo-β-linolenic acid being preferred. The compositions of the present invention may include one or more suitable omega-6 fatty acids. The omega-6 fatty acids can be used in their pure form or in the form of oil components, for example, evening primrose oil, borage oil or soybean oil, with evening primrose oil being preferred. Suitable esters and pharmaceutically tolerable salts of the designated omega-3 and omega-6 fatty acids can also be used, the pharmaceutically tolerable esters of these acids being particularly preferred. The pharmaceutically tolerable esters of the omega-3 and omega-6 fatty acids include, for example, but without limitation, ethyl esters or glycerin esters, for example, esters of monoglycerides, diglycerides or triglycerides, with triglycerides being preferred. The pharmaceutically tolerable salts of the omega-3 and omega-6 fatty acids include, for example, but without limitation, sodium salts thereof. The compositions of the present invention comprise AGE and / or a fat emulsion of AGE which includes a mixture of fish oil and / or other oils such as evening primrose oil, borage oil or soybean oil, in which the proportion by weight of fish oil with respect to other oils varies, more conveniently, from about 1:50 to about 50: 1. For example, the weight ratio of fish oil to evening primrose oil and / or borage oil, or the ratio of fish oil to soybean oil, can conveniently range from about 1: 2 to about 1: twenty. In some embodiments, the mixtures of the AGEs will comprise at least omega 3 and omega 6 fatty acids at ratios of 1: 1 -1: 40 - The physiologically ideal ratio is 1: 1.7, such that a more preferable range would be 1: 1.5-4, also being useful of 1: 4-8. Suitable fat emulsions of the present invention preferably contain one or more omega-3 fatty acids and / or omega-6 fatty acids and / or their pharmaceutically tolerable esters or seals present in amounts ranging from about 5 to about 45% by weight, preferably in amounts ranging from about 10% to about 30% by weight and, more preferably, in amounts ranging from about 10% to about 20% by weight. Useful mixtures include, but are not limited to, mixtures of 10% and 20% by weight dilutions. For suitable fat emulsions containing one or more omega-3 fatty acids, fatty acids, their esters or salts in pure form or in the form of oil components are preferred for use in accordance with the present invention. The fat emulsions of the present invention may also include one or more physiologically safe emulsifiers. Suitable emulsifiers include, for example, but not limited to, phospholipids with an animal or vegetable origin and, preferably, phospholipids containing EPA as a polyunsaturated fatty acid. Ovolecithin is particularly suitable for use in compositions of: the present invention. Other useful emulsifiers include synthetic and semi-synthetic lecithins. Said one or more emulsifiers may be present in the present fat emulsion in amounts ranging from about 1% to about 20% by weight (based on the fat content) and, preferably, in amounts ranging from about 5% up to about 15% by weight (based on the fat content). The compositions may also contain other biologically active compounds, such as antioxidants or agents that are known to eliminate or counteract the effects of toxic free radicals and byproducts of oxidative processes and other chemical manifestations of physiological stress. These include, but are not limited to, Vitamin E, Vitamin C, carotenoids, flavonoids, lipoic acid, any derivatives thereof or mixtures. Vitamin E, natural, synthetic, various tocopherols. Vitamin E, which is preferably in the form of tocopherol or a pharmaceutically safe tocopherol ester, may be used, such as, but not limited to, tocopherol acetate, in the present fat emulsion in amounts ranging from about 0.15. % up to about 1.5% by weight (based on the fat content), to act as an antioxidant. Other compounds may be present. Additional suitable additives such as, for example, but not limited to, conventional isotonic additives (common intravenous salts such as sodium chloride and non-electrolytes such as glucose, pH modifiers (such as acetic acid and sodium acetate) may be included in the present emulsion. and buffers (such as acetate and phosphate buffer systems composed of the acid and an acid salt), emulsion stabilizers such as gelatin, long-chain sugars such as agar and / or co-emulsifiers such as Tweens and Spans, as well as selenium compounds, if desired, it is common to balance the intravenous products up to an osmolarity of approximately 300 milliosmoles / liter and a pH of approximately 7.4, and this can be accomplished by the use of tonicity adjusters and tampons by a specialist in the preparation. of drugs that are to be administered to the patient through the intravenous route of administration. Suitable excipients include, for example, but without limitation, the isotonic agents commonly employed glycerin, glucose, xylose and sorbitol, with glycerin being preferred. For purposes of illustration, but not limitation, two formulations of two fat emulsions suitable for use in compositions of the present invention are described below in Table 1 and Table 2.

Table 1: Fat emulsion formulation Fish oil 100 mg / ml Glycerin (agent isotonic 25 mg / ml) Ovolecithm 12 mg / ml Vitamin E 0.15 mg / ml Water (for injection) levar to 1 ml Table 2: Formulation of fat emulsion EPA / DHA 75 mg / ml Glycerin (isotonic agent 25 mg / ml) Ovolecithin 12 mg / ml Vitamin E 0.15 mg / ml Water (for injection) bring to 1 ml The fish oil used in the formulation of Table 1 above is preferably highly refined fish oil that has been enriched in omega-3 fatty acids as triglyceride components by means of methods known to those skilled in the art such as those described in DE PS 37 22 540. Said preferred fish oils contain at least about 40% by weight of omega-3 fatty acids. The total EPA and DHA content of fish oil as triglyceride components ranges from about 25% to about 50% by weight and, more preferably, ranges from about 35% to about 50% by weight (each value determined in base to the superficial percentage in a gas chromatogram). The EPA and DHA content of the fish oil can be present in varying quantitative proportions, which can be determined by measuring the respective surfaces in the gas chromatogram. The quantitative proportions depend on the nature of the fish oil used and the degree of enrichment of omega-3 fatty acids that is achieved. Fish oils in which EPA and DHA are present as triglyceride components in a quantitative ratio of EPA to DHA from about 0.5: 1 to about 2.6: 1 (surface ratio in the gas chromatogram) are preferred for the present fat emulsions. The fat emulsions which are used according to the invention are oil-in-water (O /) emulsions for which the external phase is constituted by distilled water, suitable for intravenous administration. The intravenous administration of compositions of the present invention which include an effective amount of one or more AGE or fat emulsions including one or more AGE, such as one or more long chain polyunsaturated omega-3 fatty acids, omega-3 fatty acids 6 or its pharmaceutically tolerable esters or salts, through a vascular access before or during dialysis significantly reduces associated complications. In one embodiment, the compositions of the present invention, which include one or more AGE or a fat emulsion, of one or more AGE, are administered intravenously during hemodialysis. In such a case, the composition is administered by intradialysis infusion of a 10% fish oil emulsion. Materials and methods The preparation for infusion during dialysis is an emulsion of fish oil containing 10 cj to 20 g of fish oil, 2.5 g of glycerol and 1.2 g of egg yolk lecithin per 100 g. ml (Omegaven®, Fresenius Kabi, Bad Homburg, Germany), which make up a solution of 10 to 20%. Fish oil is highly refined and contains at least 40% long chain omega-3 fatty acids (EPA, DHA) along with other long chain saturated and unsaturated fatty acids. The omega-3: omega-6 ratio can be selected from 1: 2 to 1: 4, depending on the combination of 10-20% ® ® fat and 80-90% of a long-chain basic oil emulsion soy. Omegaven® is available as a commercial product in sterile glass vials containing 50 or 100 ml of the 10% emulsion. The vial should be checked for any precipitation and discarded if it exists. The package should be shaken before use and the contents accessed only by sterile procedures and infusion sets. The content can only be used for infusion through a central or peripheral vein or through a dialysis machine. The emulsion is infused into the drip chamber of: the venous blood line at the distal end of the dialyzer. The Omegaven® infusion should only begin after approximately 15 minutes of dialysis and infused continuously at a rate not to exceed 0, 5 ml / kg / hour in such a way that the hypertriglyceridemia observed with a faster infusion is avoided. A concentration of 20% omega-3 can be infused for 2.5 to 3 hours if the 10% can not meet the dosage requirements of approximately 4 g per dialysis session. Omegaven® can be infused with other emulsions or solutions as long as there is no incompatibility according to the manufacturer's instructions and, preferably, they are administered through the same vascular access orifice during dialysis. The rate of administration may vary, but will generally result in a total dosage of the composition from 25 g to 25 g during the dialysis procedure.

In an alternative embodiment, compositions of the present invention can be administered before or during preparation for hemodialysis. In such cases, the composition is administered intravenously, preferably, to the same dosage as indicated above. In a typical patient, hemodialysis is administered three times a week. The administration of the present compositions is preferred before or during each hemodialysis session, with administration being preferred over hemodialysis. Less frequent administration may be acceptable depending on the patient's particular factors. These factors include the status of the omega-3 fatty acid level of the patient, measured as the content of omega-3 fatty acids in biological tissues, such as red blood cell membranes, platelets and the like, using measures currently validated, such as the index of omega-3 (measure of the amount of EPA + DHA in red blood cell membranes expressed as the percentage of total fatty acids), as well as other conventional and emerging measurement technologies that would give the physician administering the information about the dose or the administration interval of the present invention, to achieve maximum clinical benefits. Some examples of measurements that can be performed to facilitate the adjustment of said medical treatment comprising this invention include, but are not limited to, the evaluation of blood chemistry to determine triglycerides, cholesterol, fatty acids and lipoproteins and apoproteins, coagulation studies and markers. of coagulation, hepatic, renal and electrolyte, cytokines, tissue and membrane phospholipids, eicosanoids such as prostaglandins E2, E3, leukotrienes B4 and B5, to name a few, immune markers, markers of endothelial function such as the activity of NO synthase , nitric oxide, glutamine and other intermediates, adhesion molecules, byproducts of oxidative stress, free radicals and substitute markers for lipooxidation, production of superoxide, markers of inflammation as C-reactive protein, as well as markers of autoimmunity, cell proliferation and any marker measurable or subp metabolic processes, which will allow the prescribing physician to determine if the dose of the present invention is achieving its objective in its present dosage regime or dosage interval. Other physical data such as blood pressure and heart rate can also be used to adjust the dose, as well as tests such as flow-mediated dilation for endothelial function. In a preferred embodiment, a composition of the present invention comprising an effective amount of about 4 grams of one or more essential fatty acids, or about 4 grams of one or more essential fatty acids in a fat emulsion, per dialysis session is administered. . The present invention also facilitates the determination, adjustment or optimization of the dosage of the compositions for individual patients based on the condition and the physical and physiological state of each patient. Factors that may influence the dosage include, for example, age, weight, body mass index, body surface area, gender, racial or ethnic background, personal and family medical history, pre-existing diseases or conditions, risk factors for diseases ! or conditions and the result of laboratory analysis. Based on the consideration of one or more of said factors, a starting dose can be determined and the dose adjusted periodically. For example, patients with hypertriglyceridemia (TG> 250 mg) should start with a lower dose or a slower infusion rate. The reasons for a dose adjustment may include the development of a hypertriglyceridemia of more than 25C mg when measured within 90 minutes after the start of: the infusion, whereas those of an upward adjustment of the dose may include an inadequate increase in the levels of desired omega-3 fatty acids in target tissues or the unsatisfactory suppression of inflammatory markers or metabolic intermediates, which are known to be markers. substitutes, to achieve the clinical benefit of the invention. In addition, it is desirable to monitor the blood chemistry of each patient to determine if the dosages should be modified. The parameters that can be controlled may include triglyceride levels. Dose adjustments that may be based on the results of such control may include. Said blood chemistry measurements may be performed periodically, such as every 3-6 months or, preferably, every 1 to 3 months, but may also include measurements within the first 24 hours to 30 days after administration. After making a dose adjustment, it is desirable to allow a period of time for the patient's condition to equilibrate or stabilize before determining whether the adjusted dose should be continued or further modified. A desirable waiting period to evaluate the outcome of an adjustment is 3 months, but other periods may be used when circumstances dictate. The compositions of the present invention comprise AGE or AGE in a fat emulsion alone or, alternatively, together with one or more active pharmaceutical ingredients and / or nutritional supplements. Suitable nutritional supplements include, for example, but not limited to, ALA, group B vitamins, derivatives of group B vitamins, vitamin E, vitamin D, vitamin A, carotenoids, alpha lipoic acid, flavonoids, vitamin K, statins, derivatives of fibric acid, iron, erythropoietin, CoQ10, amino acids, creatine, carnitine, zinc, calcium, PTH, FTH analogues, chelating agents, lipids, proteins, carbohydrates and combinations thereof. Said compositions, when present, may be in forms that can be used physiologically. Examples of such agents also include: neuroprotectants, such as nimodipine and related compounds; antibiotics, such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamicin and erythromycin; anti-infectious; antibacterials such as sulfonamides, sulfacetamide, sulfametizole, sulfisoxazole; nitrofurazone and sodium propionate; antiallergics such as antazoline, metapyrillin, chlorpheniramine, pyrilamine and profenpyridamine; bacteriostats or microbiostatic agents or preservatives, anti-inflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrisone, methylprednisolone, prednisolone-21-phosphate, prednisolone acetate, fluorometalone, betamethasone and triminolone; miotics and anticholinesterase agents such as pilocarpine, sterol salicylate, carbacol, diisopropyl fluorophosphate, phospholine iodide and demecarium bromide; mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine and hydroxyamfetamine; sympathomimetics such as epinephrine; and prodrugs such as those described in Design of Prodrugs, edited by Hans Bundgaard, Elsevier Scientific Publishing Company, Amsterdam, 1985, which is incorporated herein by reference. In addition to the above agents, other agents suitable for treating, controlling or diagnosing intravenous conditions in an organism of a mammal may be added to compositions of the present invention as long as they are not incompatible with the other components of the composition. Any conventional pharmaceutical textbook, such as Remington's Pharmaceutical Sciences, can be consulted for the identification of such agents. Because the formulations are to be introduced intravenously, they must necessarily be sterile and, preferably, contain preservatives to maintain sterility. Two kinds of preservatives are useful in particular with emulsions of essential fatty acids edetate (ethylenediaminetetraacetic acid) and pedetate (diethylenetriaminepentaacetic acid). Generally, for edetate, preferred salts include sodium edetate and calcium, edetate disodium being preferred. For the pedetate, the preferred salts will have a lower affinity for the pedetate than calcium, the trisodium calcium pedetate being preferred. Preferably, both salts are present at low concentrations, the edetate being present at 0.03-0.9 millimolar and the pedetate at 0.0005-0.005% by weight. Generally, an effective preservative fulfills the function of preventing a significant proliferation of microorganisms for at least 24 hours in case of accidental extrinsic contamination (for example, preferably an increase of not more than 10 times after a low level of extrinsic contamination, such as of 10-10000 colony forming units at temperatures in the range of 20 degrees-25 degrees C). In a useful assay, broth cultures of preservative efficacy test organisms from one or more conventional USPs (US Pharmacopoeia) are added to preservative containing formulations at approximately 100-200 colony forming units per ml. The test formulations were incubated at 25-30 degrees C and assayed for viable counts after 24 and 48 hours. Intravenous administration of compositions of the present invention without the addition of one or more active pharmaceutical agents may also be beneficial to the patient for indications including hypertension, decreased cardiovascular risk, nutritional supplementation, modulation of inflammation, immunomodulation, neuropsychiatric modulation, acute diseases, arrhythmias and malignant tumors. Compositions of the present invention can be produced using AGEs or commercially available AGE emulsions suitable for intravenous administration. One such emulsion of AGE is Omegaven®, produced by Fresenius Kabi, Bad Homburg, Germany. The qualitative and quantitative composition of 100 ml of an Omegaven® emulsion contains: 10.0 g of highly refined fish oil containing: 1.25-2.85 g of eicosapentaenoic acid (EPA); 1.44-3.09 g of docosahexaenoic acid (DMA); 0.1-0.6 g of myristic acid; 0.25-1.0 g of palmitic acid; 0.3-0.9 g of palmitoleic acid; 0.05-0.2 g of stearic acid; 0.6-1.3 g of oleic acid; 0.1-0.7 g of linoleic acid; 0.2 g of linolenic acid; 0.05-0.4 g of octadecatetraene acid co; 0.05-0.3 g of eicosaenoic acid; 0.1-0.4 g of arachidonic acid; 0.15 g of docosaenoic acid; 0.15-0.45 g of docosapentaenoic acid; 0.015-0.0296 g of dl-a-tocof rol (as an antioxidant); 2.5 g of glycerol; 1.2 g of purified egg phosphatide; total energy: 470 kJ / 100 ml = 112 kcal / 100 ml. PH value: from 7.5 to 8.7. Acidity assessment: < 1 mmol HC1 / 1. Osmolarity: 308-376 mosm / kg. The pharmaceutical form is an emulsion for infusion. Therapeutic indications include supplementing parenteral nutrition with long-chain omega-3 fatty acids, especially eicosapentaenoic acid and docosahexaenoic acid, when it is impossible, insufficient, or nutrition is contraindicated orally or enterally. The maximum infusion rate should not exceed 0.5 ml of Omegaven® / kg body weight / hour, which: corresponds to 0.05 g of fish oil / kg body weight / hour.

An embodiment of the present invention for illustrative purposes, but without limitation, is a method for preparing a composition of the present invention which comprises combining an emulsion of fish oil containing from 10 g to 20 g of fish oil, 2.5 g of fish oil. glycerol and 1.2 g of egg yolk lecithin per 100 ml (Omegaven®), which make up a solution from 10% to 20%. Fish oil is highly refined and contains at least 40% long chain omega-3 fatty acids. The ratio of omega-3: omega-6 can be selected from 1: 2 to 1: 4 depending on the combination of 10-20% fat of Omegaven® and 80-90% fat of basic emulsions of long chain oil soy. A method of using the prepared composition comprises administering intravenously the composition containing an effective amount of an AGE emulsion to a patient, before or during hemodialysis, at a rate not exceeding 0.5 ml / kg / hour, in such a way that the hypertriglyceridemia observed with a faster infusion is avoided, for a total dosage of 4 grams of omega-3 fatty acids per dialysis session. A concentration of 20% omega-3 can be infused for 2.5 to 3 hours if the 10% can not meet the dosage requirements determined by the clinical and biochemical target goals, measured from time to time. Omegaven® is available as a commercial product in sterile glass vials containing 50 or 100 ml of a 10% emulsion. The vial should be checked for any precipitation and discarded if there is precipitation. The package should be shaken before use and the contents should be accessed only through a sterile procedure and infusion equipment. Omegaven® can only be used for infusion through a central or peripheral vein or through a dialysis machine. The emulsion can also be infused into the drip chamber of the venous blood line at the distal end of the dialyzer. The Omegaven® infusion should only begin after approximately 15 minutes of dialysis and be infused continuously at a rate not exceeding 0.5 ml / kg / hour, so as to avoid the hypertriglyceridemia seen with an infusion faster. A 20% omega-3 concentration can be infused for 2.5 to 3 hours if the 10% can not meet the dosage requirements of approximately 4 g per dialysis session. Omegaven® can be infused with other emulsifiers or solutions as long as they are not incompatible according to the manufacturer's instructions. Examples Example 1; An emulsion of fish oil is prepared for intravenous administration during hemodialysis.

The fish oil emulsion contains 10 g of fish oil, 2.5 g of glycerol and 1.2 g of egg yolk lecithin per 100 ml, ie Omegaven® (Fresenius Kabi, Bad Homburg, Germany), that make up a 10% solution. Fish oil is highly refined and contains at least 40% long chain omega-3 fatty acids. The ratio of omega-3: omega-6 is 1: 4. The sterile glass vial available in the Omegaven® market is checked for any precipitation and discarded if it exists. The container is shaken well and access to the emulsion contained inside through an infusion set, using conventional sterile procedures. The emulsion is infused into the drip chamber of the venous blood line at the distal end of the dialyzer. Infusion of the Omegaven® emulsion begins after approximately 15 minutes of dialysis. The emulsion is infused continuously at a rate not exceeding 0.5 ml / kg / hour, until 4 g of the emulsion has been infused. Example 2: A concentration of 20% omega-3 is infused for 2.5 to 3 hours, according to Example 1, to satisfy the dosage requirements of approximately 4 g per dialysis session. Example 3: A combination of fish oil emulsions and vegetable oil is prepared for intravenous administration during hemodialysis. The combination of emulsions contains 10 g of fish oil, 2.5 g of glycerol and 1.2 g of egg yolk lecithin per 100 ml, ie Omegaven® (Fresenius Kabi, Bad Homburg, Germany), together with an emulsion of flaxseed oil containing 5 g of linseed oil, ie ALA 75 (BioGin Biochemicals Co., Ltd, Chengdu, China), which make up a 15% solution. Fish oil is highly refined and contains at least 40% long chain omega-3 fatty acids with an omega-3: omega-6 ratio of 1: 4 and flaxseed oil contains at least 70% long chain omega-3 fatty acids, with an omega-3: omega-6 ratio of 4: 1. The emulsion is infused into the drip chamber of the venous blood line at the distal end of the dialyzer. Alternatively, the infusion can also be administered through a central or peripheral venous line. The infusion of the emulsion begins after approximately 15 minutes of dialysis. The emulsion is infused continuously at a rate not exceeding 0.5 ml / kg / hour, until about 4 g of the emulsion have been infused. Example 4: A combination of emulsions is prepared in which omega-3 fatty acids of marine and vegetative origin are combined with a high dose of folic acid (10 mg) and Vitamin B12 (10 μg), for administration via intravenous during hemodialysis. The combination of emulsions contains 10 cf of fish oil, 2.5 g of glycerol and 1.2 g of egg yolk lecithin for 100 ml, ie Omegaven® (Fresenius Kabi, Bad Homburg, Germany), together with an emulsion of flaxseed oil containing 5 g of linseed oil, ie ALA 75 (BioGin Biochemicals Co., Ltd, Chengdu, China), which make up a 15% solution. Fish oil is highly refined and contains at least 40% long chain omega-3 fatty acids with an omega-3: omega-6 ratio of 1: 4 and flaxseed oil contains at least 70% long chain omega-3 fatty acids, with an omega-3: omega-6 ratio of 4: 1. Folic acid is in the form of 5-formylH4folate (folinic acid) and is administered clinically under the trade name of Leucovorin ™ Calcium Leucovorin 10 mg / ml in solution for intravenous injection. The emulsion is infused into the drip chamber of the venous blood line at the distal end of the dialyzer or through a central access or a peripheral venous line. The infusion of the emulsion begins after approximately 15 minutes of dialysis. The emulsion is infused continuously at a rate not exceeding 0.5 ml / kg / hour, until approximately 4 g of the omega-3 fatty acids and 10 mg of folinic acid have been infused. Based on measurements of endothelial function, such as flow-mediated dilation (FMD), folinic acid can be increased or decreased to achieve the desired clinical outcome. Additional examples may be added, on paper or based on experimental results, showing: other formulations, other routes of administration, use of blood chemistry control to determine the appropriate dosage, various optimized dosages, etc. The invention having been described in detail, those skilled in the art will understand that modifications of the invention can be made without departing from its spirit and scope. Therefore, it is not intended to limit the scope of the invention to the specific embodiments described. Rather, it is intended that the appended claims and their equivalents determine the scope of the invention. It is evident that many modifications and variations of the invention can be made, as described above in this document, without departing from the spirit and scope thereof. The specific embodiments described are provided by way of example only and the invention is limited only by the terms of the appended claims.

Claims (42)

1. CLAIMS 1. A composition comprising: an effective amount of essential fatty acids in pure form or a fatty emulsion of said essential fatty acids in pure form suitable for intravenous administration, before or during hemodialysis.
2. 2. The composition of claim 1, wherein: said essential fatty acids in pure form are selected from the group consisting of omega-3 fatty acids, salts of omega-3 fatty acids, omega-3 fatty acid esters, omega-3 fatty acids, 6, salts of omega-6 fatty acids, omega-6 fatty acid esters and combinations thereof.
3. 3. The composition of claim 1, wherein said fat emulsion is an oil in water emulsion.
4. 4. The composition of claim 1, wherein said essential fatty acids in pure form include eicosapentaenoic acid and docosahexaenoic acid.
5. 5. The composition of claim 1, wherein said essential fatty acids in pure form include eicosapentaenoic acid and docosahexaenoic acid in a ratio of eicosapentaenoic acid to docosahexaenoic acid from about 0.5: 1 to about 2.6: 1.
6. 6. The composition of claim 1, wherein the composition is suitable for intravenous administration three times a week.
7. 7. The composition of claim 1, wherein said effective amount is about 4 grams.
8. 8. The composition of claim 1, further comprising a component selected from the group consisting of active pharmaceutical ingredients, nutritional supplements and mixtures thereof.
9. 9. The composition of claim 1, further comprising a component selected from the group consisting of vitamins of group B, vitamin derivatives of group B, vitamin E, vitamin D, vitamin A, vitamin K, statins, fibric acid derivatives, iron, erythropoietin, CoQlO, lutein, creatine, carnitine, zinc, calcium, PTH, PTH analogs, chelators, lipids, proteins, catrbono hydrates and mixtures thereof.
10. 10. The composition of claim 1, wherein the administration of said composition is useful in the treatment of at least one indication selected from the group consisting of hypertension, decreased cardiovascular risk, nutritional supplementation, modulation of inflammation, immunomodulation, neuropsychiatric modulation, acute diseases, arrhythmias and malignant tumors.
11. 11. The composition of claim 1, further comprising essential fatty acids in oils.
12. 12. A method of preventing, stabilizing, reversing and / or treating one or more complications associated with a vascular access comprising: administering intravenously a composition that includes essential fatty acids or a fatty emulsion of essential fatty acids, through vascular access .
13. 13. The method of claim 2, wherein the vascular access is used for hemodialysis.
14. 14. The method of claim 12, wherein the composition is administered during hemodialysis.
15. 15. The method of claim 12, wherein the composition is administered prior to hemodialysis.
16. 16. The method of claim 12, wherein the composition is administered three times per week.
17. 17. The method of claim 12, wherein approximately 4 grams of essential fatty acid are administered.
18. 18. The method of claim 12, wherein the composition is administered together with a component selected from the group consisting of active pharmaceutical ingredients, nutritional supplements and mixtures thereof.
19. 19. The method of claim 12, wherein the composition is administered together with at least one additive selected from the group consisting of group B vitamins, derivatives of group B vitamins, vitamin E, vitamin D, vitamin A, vitamin K, statins , derivatives of fibric acid, iron, erythropoietin, CoQlO, lutein, creatine, carnitine, zinc, calcium, PTH, PTH analogs, chelating agents, lipids, proteins, carbohydrates and mixtures thereof.
20. 20. The method of claim 12, wherein the administration of the composition is useful for at least one indication selected from the group consisting of hypertension, decreased cardiovascular risk, nutritional supplementation, modulation of inflammation, immunomodulation, neuropsychiatric modulation, acute diseases, arrhythmias and malignant tumors.
21. 21. The method of claim 12, wherein the composition is administered to a patient who does not have a kidney disease.
22. 22. The method of claim 12, wherein the composition includes Omegaven®.
23. 23. A method for preventing stenosis or thrombosis of a vascular access of a hemodialysis patient comprising: administering an emulsion of essential fatty acids through the vascular access.
24. 24. The method of claim 23, wherein the emulsion includes Omegaven®.
25. 25. The method of claim 23, wherein the emulsion is administered at a rate of no more than about 0.5 ml / kg / hour.
26. 26. The method of claim 23, wherein the emulsion is administered until about 4 g of the emulsion has been administered to the patient.
27. 27. The method of claim 23, wherein the emulsion is administered together with a component selected from the group consisting of active pharmaceutical ingredients, nutritional supplements and mixtures thereof.
28. 28. The method of claim 23, wherein the emulsion is administered together with at least one additive selected from the group consisting of group B vitamins, derivatives of group B vitamins, vitamin E, vitamin D, vitamin A, vitamin K, statins , derivatives of fibric acid, iron, erythropoietin, CoQlO, lutein, creatine, carnitine, zinc, calcium, PTH, PTH analogs, chelating agents, lipids, proteins, carbohydrates and mixtures thereof.
29. 29. The method of claim 23, wherein the administration of an essential fatty acid is also indicated in at least one of the indications selected from the group consisting of hypertension, decreased cardiovascular risk, nutritional supplementation, modulation of inflammation, immunomodulation, modulation neuropsychiatric, acute diseases, arrhythmias and malignant tumors.
30. 30. A method of prevention, stabilization, reversal and / or treatment of one or more complications associated with a vascular access in a patient, as well as preventing complications of the administration of essential fatty acids, comprising: administering a predetermined dose intravenously of a composition that includes essential fatty acids or a fatty emulsion of essential fatty acids through vascular access or intravenously through another access; monitor said patient for a response to said dose; and adjust subsequent doses up or down based on the response observed in said control.
31. 31. The method of claim 30, wherein the predetermined initial dose is 4 grams of essential fatty acid administered to a patient.
32. 32. The method of claim 31, wherein the predetermined initial dose is based on a medical history of said patient.
33. 33. The method of claim 31, wherein the medical history includes one or more factors selected from the group consisting of age, weight, body mass index, body surface area, gender, racial or ethnic background, personal and family medical history. Pre-existing diseases or conditions, risk factors for diseases or conditions, and results of laboratory tests, and the predetermined initial dose were adjusted upwards or downwards based on said one or more factors.
34. 34. The method of claim 31, wherein said patient is undergoing dialysis and the predetermined initial dose is provided to a patient at a frequency prior to, at the same time as or after each dialysis session.
35. 35. The method of claim 34, wherein the frequency and / or predetermined initial dose is varied based on a medical history taken from the patient.
36. 36. The method of claim 35, wherein the medical history includes one or more factors selected from the group consisting of age, weight, body mass index, body surface area, gender, racial or ethnic background, personal and family medical history. , pre-existing diseases or conditions, risk factors for diseases or conditions and results of laboratory tests, and the frequency and / or predetermined initial dose is adjusted upward or downward based on said one or more factors.
37. 37. The method of claim 30, wherein the control of said patient includes the control of blood chemistry.
38. 38. The method of claim 38, wherein control includes control of triglyceride levels.
39. 39. The method of claim 37, wherein the dose or frequency of administration is adjusted up or down based on the results of the blood chemistry control.
40. 40. The method of claim 37, wherein said control is carried out periodically before, during or after administration of the essential fatty acid compositions.
41. 41. The method of claim 37, wherein the control is performed during a program based on the condition of the patient or on the results of the control.
42. 42. The method of claim 41, wherein the control is performed after said patient has had time to equilibrate after the dose or frequency has been changed.