EP2288337A1 - Supplément parentéral avec des éléments traces pour le traitement notamment du syndrome de réponse inflammatoire systémique, de brûlures et de déficits en sélénium - Google Patents

Supplément parentéral avec des éléments traces pour le traitement notamment du syndrome de réponse inflammatoire systémique, de brûlures et de déficits en sélénium

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Publication number
EP2288337A1
EP2288337A1 EP09742543A EP09742543A EP2288337A1 EP 2288337 A1 EP2288337 A1 EP 2288337A1 EP 09742543 A EP09742543 A EP 09742543A EP 09742543 A EP09742543 A EP 09742543A EP 2288337 A1 EP2288337 A1 EP 2288337A1
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EP
European Patent Office
Prior art keywords
unit
trace elements
supplementary
patient
kit
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09742543A
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German (de)
English (en)
Inventor
Mette Berger
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Universite de Lausanne
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Universite de Lausanne
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Filing date
Publication date
Application filed by Universite de Lausanne filed Critical Universite de Lausanne
Publication of EP2288337A1 publication Critical patent/EP2288337A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/16—Fluorine compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0029—Parenteral nutrition; Parenteral nutrition compositions as drug carriers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the general field of parenteral administration of micronutrients, in particular trace elements.
  • the present invention more particularly relates to a kit for parenteral administration of trace elements to a patient, and to a method of providing intravenous trace elements to a patient.
  • Parenteral Nutrition replaces "normal nutrition", which is eating or feeding by the enteral route in patients with gut failure and assimilated conditions. This requires delivering by the intravenous route all the substrates that are required by the body to thrive and which compose normal nutrition.
  • Total parenteral nutrition must deliver the macronutrients (glucose, amino acids, lipids), the micronutrients (electrolytes, vitamins, trace elements), and water.
  • macronutrients glucose, amino acids, lipids
  • micronutrients electrolytes
  • vitamins and trace elements have to be provided separately for stability reasons. Indeed presence of micronutrients in parenteral nutrition solutions generally causes instability.
  • the European industrial products are probably a little closer to requirements for most trace elements, but there have been issues with too much manganese, which causes encephalopathy (neurological toxicity). Indeed, the potential for trace elements to accumulate and cause toxicity is an important issue. Some trace elements also are significant contaminants of industrially produced solutions, and particularly parenteral nutrition such as chromium, copper, manganese, and zinc.
  • an objective of the present invention to provide sufficient trace elements, while preventing excesses, to patients depending on parenteral nutrition, and further to acutely ill patients suffering from systemic inflammatory response syndrome (SIRS), patients suffering from burns, patients undergoing continuous renal replacement therapy, for example veno-venuous hemofiltration (CVVH), and/or, patients living in selenium deficient areas.
  • SIRS systemic inflammatory response syndrome
  • CVVH veno-venuous hemofiltration
  • Individuals of these groups have different requirements with respect to at least one trace elements, compared to other patients obtaining parenteral nutrition that do not belong to on of these groups.
  • kits of bags or containers comprising a basic bag and at least one or more supplemental bag(s), which can be combined with said basic bag, wherein an individual receives the trace elements by parenteral administration of the basic bag and, in dependence on the condition, treatment and/or residence of the individual, only the basic bag or at least one supplemental bag is further parenterally administered.
  • the present inventors learned that individuals suffering from systemic inflammatory response syndrome (SIRS), individuals suffering from burns, individuals undergoing continuous renal replacement therapy, and individuals living in selenium deficient areas have requirements of trace elements that substantially differ from the requirements of other patients receiving parenteral nutrition. While administration of basic trace elements is sufficient for a majority of patients not falling into one of the above-indicated categories, the patients falling in one or more of these categories need to be administered supplemental trace elements in order to meet the patient's needs.
  • SIRS systemic inflammatory response syndrome
  • the present invention provides, in a first aspect, a kit for parenteral administration of trace elements to a patient, the kit comprising a basic parenteral unit and at least a supplementary unit, wherein the basic parenteral unit comprises a basic composition of trace elements preferably adapted and/or intended to cover the basal requirements in stable patients, and wherein the said supplementary unit comprises supplementary trace elements so as to meet needs in trace elements of specific conditions and/or of a specific patient.
  • the kit is intended to cover daily requirements of trace elements of a patient that is in a specific acute condition.
  • the kit may be administered to patients suffering from acute conditions whether on parenteral or enteral nutrition support and to patients depending on chronic parenteral nutrition (i.e. home PN).
  • the present invention provides, a method of providing trace elements to patient, the method comprising the step of administrating a basic parenteral unit comprising basic trace elements, and, in dependence of diagnosis, treatment and/or geographical residence of the patient at least one further supplementary unit, wherein said supplementary unit comprises additional trace elements to meet, together with the basic unit, the specific needs in trace elements of the patient.
  • Figure 1 is a graphic illustration of the concept according to an embodiment of the present invention.
  • PN means "parenteral nutrition”
  • SIRS means systemic inflammatory response syndrome
  • CVVH means continuous veno-venous hemo filtration.
  • Figure 1 thus illustrates how a basic unit is combined with one or more supplementary units in order to provide sufficient trace elements to patients in different conditions.
  • kits for parenterally adminstrating trace elements to a patient.
  • a “kit”, for the purpose of the present invention refers to a plurality of different elements, which may be combined and/or connected.
  • the term “kit” reflects the possibility of selecting one, two or more of these elements in order to parenterally administrate trace element to an individual, in particular a patient.
  • the kind and quantity of units to be administered intravenously is preferably selected so as to meet or at least as well as possible the requirements of the patient.
  • the kit of the present invention comprises a basic parenteral unit and at least one supplementary unit.
  • a "unit" for the purpose of the present invention relates to an entity, which generally may be provided in the form of a bag, a pouch or any other form of container suitable to harbour a liquid and, dissolved therein, the trace elements to be administered parenterally.
  • the "unit” is such that the contents are kept sterile and are completely protected from any contamination from the outside.
  • Pouches for parenteral administration of nutrients, medicaments or liquid in general are commercially available.
  • trace elements for the purpose of the present invention comprises one or more of the elements selected from the group of chromium, cobalt, copper, fluor, iron, iodine, manganese, molybdenum, selenium, vanadium and zinc. According to a preferred embodiment, the expression “trace elements” comprises all these elements.
  • the kit of the present invention comprises a first unit, also referred to herein as “basic unit”, “basic parenteral unit” and the like.
  • the first unit comprises a basic composition of trace elements intended to provide sufficient trace element to a patient not falling into one or more of the specific categories of patients, which have different requirements at least in one trace element, and in general higher requirements in one or more trace elements.
  • the basic unit comprises trace elements in sufficient amounts for patients who do not suffer from SIRS, who did not suffer from burns, who do not undergo a continued renal replacement therapy, and who are residents of selenium-rich areas.
  • the "PN basis" constitutes the founding element of the kit, whether the patient depends on parenteral nutrition or not.
  • basic unit is thus intended to meet the basic requirements in trace elements of a patient who does not have particular and/or specific requirements due to the circumstantial conditions and/or acute conditions he/she find himself/herself, such as defined, for example, by the specific categories described herein. It is particularly suited for patients on home PN.
  • the basic unit comprises the following trace elements at the indicated amounts: 2- 3 ⁇ g of chromium; 0-5 ⁇ g, preferably 1-4 ⁇ g of cobalt; 0.3-0.4 mg of copper; 1.4-1.5 mg fluor; 0.5-1 mg iron; ⁇ 50 ⁇ g iodine; 20-30 ⁇ g molybdenum; 40-80 ⁇ g selenium; 8-10 mg, preferably 9-10 mg zinc; wherein the indicated amounts correspond to a daily administration dose.
  • the basic unit is free of vanadium or comprises ⁇ 1 ⁇ g vanadium.
  • the daily administration dose being the dose or amount of trace elements to be administrated to a patient on a daily basis, is preferably contained in one bag.
  • the trace elements of the basic unit are contained in a container containing 25-60 ml of an aqueous solution, preferably a 30-50 ml, and most preferably a 35-45 ml of an aqueous solution of the trace elements to be administrated on a daily basis as indicated above.
  • the patient is administered parenterally one basic unit per day, preferably in the form of a single container.
  • the kit according to the present invention comprises one or more supplementary unit(s) comprising supplementary trace elements.
  • the supplementary unit is administrated in addition to the basic unit in order to meet the specific increased needs in some trace elements of patients suffering from a specific condition, patients undergoing specific therapies and/or patients being residents of a specific region.
  • SIRS severe systemic inflammatory response syndrome
  • the present invention provides a supplementary unit for compensating deficiency in trace elements in patients due to low contents of said trace elements in the area of their residence.
  • CVVH continuous veno-venous hemo filtration
  • the present invention provides at least a first, and optionally a second, a third, a fourth or more supplementary units comprising supplementary trace elements so as to meet needs in trace elements of a specific patient and/or patient population.
  • each supplementary unit is assigned to a specific category of patients, the category grouping patients characterised by similarly changed needs in trace elements with respect to patients of another category or with respect to basic requirements.
  • the supplementary unit for example the first, the second, the third and/or the fourth supplementary unit, comprises trace elements to address the specific needs of a patient selected from the group consisting of: (1) a patient suffering from an intense systemic inflammatory response syndrome (SIRS),
  • SIRS systemic inflammatory response syndrome
  • the patient is preferably a critically ill patient suffering a condition with an intense systemic inflammatory response syndrome.
  • the present invention has the objective to more approximately meet the requirements of patients falling in a category or group of patients who, according to the knowledge of the inventor, have substantially higher need in some specific trace elements.
  • the present invention intends to prevent important deficiencies in trace elements in patients, for example hospitalised individuals and/or patients receiving parenteral nutrition or supplements at home.
  • the present also has the goal of avoiding toxic accumulation of trace elements in a patient.
  • patients falling into one of the categories defined herein form a specific patient population. It is indicated that the present invention also encompasses categories of patients, or patient populations, that are not disclosed herein, but that will be identified later as a group of patients having requirements in trace elements specifically differing from the requirements of any category defined herein.
  • the present invention also encompasses the possibilities that the definition of a specific category of patients and/or patient population as defined therein is refined.
  • the present invention also encompasses the possibility that the amounts of trace elements of the basic unit and any supplementary unit be redefined.
  • the invention encompasses an adaptation of the basic unit, and, if adequate of any of the supplementary units.
  • the kit of the present invention comprises a supplementary unit for providing supplementary trace elements to a patient and/or a patient population suffering from systemic inflammatory response syndrome (SIRS).
  • SIRS systemic inflammatory response syndrome
  • the inventor on the basis of her experience and evidences from medical literature, notes that critically ill SIRS patients are exposed to an increased oxidative stress, due to their condition, to the associated inflammatory response, and also to the side effects of some of the intensive care unit (ICU) treatments such as mechanical ventilation using high inspired fractions of oxygen, transfusion of erythrocytes, and continuous renal replacement therapy. Injured tissues produce free radicals, and inflammation amplifies this reaction.
  • the oxygen derived radicals (ROS) which are produced under normal aerobic metabolism mainly by leukocytes and by the respiratory mitochondrial chain) are essential for cell signaling, and for bacterial defense.
  • the nitric oxide derived radicals (NOS) are normal by-products of endothelial metabolism.
  • ROS activate the nuclear transcription factor kappa B (NFKB), which is one of the steps of the amplification of SIRS. This activation is attenuated by several "antioxidant” micronutriments, such as selenium (Se) zinc (Zn) and vitamins C and E.
  • endogenous antioxidant defenses are largely enzymatic and dependent for activity on trace elements, in particular Cu, Se, Mn, and Zn.
  • Cu, Zn and Mn are required by the superoxide dismutases (SOD), Se by the glutathione peroxidases (GPX), and Cu and/or Fe by catalase.
  • SOD superoxide dismutases
  • GPX glutathione peroxidases
  • Cu and/or Fe by catalase.
  • the antioxidant enzymes exert their activities in the cytosol, in mitochondria, or in plasma.
  • the SODs initiate the antioxidant process, transforming the superoxide anion into hydrogen peroxide.
  • the later is metabolized by catalase, and further by the different types of GSHPx, which neutralize the various peroxides.
  • Tissue concentrations of these antioxidants is strongly depressed after burn injury in a rat model and in burned patients.
  • Selenium appears to be particularly affected by the alterations caused by SIRS, while being central in the antioxidant defence as part of the GPX.
  • the activity of the plasma GPX is highly dependent on selenium whatever the condition. It is particularly depressed in patients with an intense inflammation such as sepsis, pancreatitis, major burns and acute and chronic renal failures.
  • Antioxidant and immune defenses are closely linked. It was demonstrated that selenium deficiency favors the development of virus virulence and subsequent infections through the reduction of GPX activity. The present inventor thus find that "oxidation” and "antioxidation” are an essential step in defenses against infection. In addition a series of trace elements, in particular Cu, Se, Fe, and Zn, and vitamins in particular vitamins C et E may be involved in immune defenses, probably through antioxidant mechanisms.
  • the present invention provides a supplementary unit for the category of patients suffering from SIRS.
  • This supplement mainly aims at reinforcing endogenous antioxidant defences.
  • SIRS is found in specific severe critical care conditions, for example those selected from severe sepsis or septic shock of any origin, pancreatitis, acute respiratory distress syndrome (ARDS), major trauma and organ transplantation, in particular heart, kidney, liver and/or lung transplantation.
  • the supplementary unit to be administered, in addition to the basic unit, to patients sustaining SIRS comprises 200-500 ⁇ g selenium, for example 200-300 ⁇ g selenium, 5-10 mg zinc, and 10-20 ⁇ g chromium, wherein these amounts correspond to a daily administration dose for patients diagnosed with SIRS.
  • These trace elements may be dissolved, for example in about 20-40 ml water and filled in a corresponding bag.
  • the kit of the present invention comprises a supplementary unit for providing supplementary trace elements to patients suffering from burns.
  • Deficiencies in various trace elements have been repeatedly described since 1960 in patients suffering from major burns. They are proportional to the burn surface (i.e. to burned % of body surface area, abbreviated BSA hereafter) and are associated with wound healing and infectious complications.
  • BSA body surface area
  • the oxidative stress caused by burns stimulates the expression of the transport protein metallothionein (MT) which increases in the liver due to the rapid raise of the expression of its MT-I mRNA: this stimulation is probably caused by the increase in lipid peroxides.
  • MT transport protein metallothionein
  • the serum concentrations of most trace elements and of their carrier proteins decrease, causing an unbalance in circulating antioxidants, which are supposed to be able to limit the release of NFkB caused by increased ROS. It has been hypothesized that the redistribution of trace elements occurring during the acute phase response may be deleterious if prolonged.
  • the inventor finds, on the basis of her knowledge and information from selected literature, that copper deficiency is specific of burns and has been described for many years both in children and in adults.
  • the injury involves 30% BSA or more, patients can lose 20-40% of their body Cu content within the first week of injury with their exudates.
  • a further study in severely burned children confirmed exudative Cu and Zn losses.
  • Plasma Cu concentration remains low for weeks, proportionally to burn size. The deficiency may be severe enough to cause fatal arrhythmias.
  • oxidative stress and lipid peroxidation is particularly intense in burns, and caused in part by the direct effect of the burn on skin lipids, and by an increased free radical production, which is initiated directly by the burn, and indirectly by leukocytes.
  • burns involving more than 20% BSA the inflammatory response spreads rapidly to the whole body, resulting in a general capillary leak syndrome, with edema formation.
  • Experimental studies have shown that there is a close relationship between a lipid peroxide reaction and secondary pathological changes following burns. As long as wounds are not closed, inflammation is reactivated by microorganism proliferation, endotoxin production and surgery.
  • the supplementary unit to be administrated, in addition to the basic unit, to a patient and/or a patient population suffering from burns comprises: 3-4 mg copper; 300-500 ⁇ g selenium; and 30-40 mg zinc, wherein these amounts correspond to a daily administration dose for these patients.
  • This daily dose is preferably to be administered for 7-8 day in patients with burns on 20-30% of BSA, for 14-21 days, for example 14-15 days, in burns of 30-50% of BSA, and for 21-30 days, for example 21-25 days, with burns exceeding 50% of BSA.
  • percentage of the body surface affected by burns preferably determines the length of administration of the supplementary unit for patients suffering from burns.
  • the dose to be delivered is first adapted to the child's size (total BSA): the above figures were determined for adults having a body surface of 1.8 m 2 . Thereafter the burned size is taken into account as in adults (see above).
  • the supplementation may have to be resumed later based on low plasma in case of persistent open burn wounds.
  • the trace elements of the supplementary unit for patients suffering for burns may be dissolved, for example, in about 100-200 ml water and filled in corresponding bags. Patients suffering from burns are preferably provided with enteral nutrition, with the trace elements of the kit of the present invention being administered by the intravenous route.
  • the present invention provides a supplementary unit to be administered in addition to the basic unit comprising: all the elements of the basic unit at the indicated quantities, and, in addition + 100-200 ⁇ g of selenium per daily administered dose.
  • patients undergoing continuous renal replacement therapy receive two basic units and a supplementary unit comprising 100-200 ⁇ g, preferably 100- 150 ⁇ g of selenium per day.
  • the trace elements of the supplementary unit for patients undergoing a renal replacement therapy may be dissolved, for example, in about the same amount of water as the basic unit, preferably in at least about 35 ml water and filled in an appropriate bag.
  • the supplementary unit for patients undergoing continuous renal replacement therapy comprises, in addition to selenium as indicated above zinc, for example, 7-10 mg zinc.
  • the continuous renal replacement therapy is continuous veno-venuous hemof ⁇ ltration (CVVH).
  • CVVH continuous veno-venuous hemof ⁇ ltration
  • the present invention provides a supplementary unit for providing supplementary trace elements to a patient and/or a patient population living in Se- def ⁇ cient geographic areas, said supplementary unit comprising 150-250 ⁇ g, preferably 180- 220 ⁇ g selenium per daily administered dose.
  • the trace element for this supplementary unit may, for example be dissolved in about 15-25 ml water and filled in an appropriate bag, or into the basic unit pouch or bottle.
  • Selenium deficiency affects the muscles and squelettal system. It results in cardiomyopathy (Keshan disease), which can be lethal, and musculo-squelettal disorders (Kashin Beck disease), and in late stages hair and nail alterations. They typically occur in areas with extremely low soil content.
  • Some areas of the globe are characterized by very low soil contents of selenium. Europe is one of these areas, and low plasma concentrations have repeatedly been shown in the general population of many European countries. One European country, Finland, has taken action and used fertilization to successfully improve the status of cattle and then humans, by altering the complete food chain's selenium content and adapting progressively the fertilization dose to the observe responses. Other areas are New Zealand and Australia, California, and the Chinese Keshan province. In contrast, some other areas of the world are seleniferous such as most of the US, Canada, Venezuela and some areas of China, with their populations having high-supra normal plasma concentrations of selenium. The supplementation of the selenium should therefore integrate these geographic differences.
  • the daily administration dose of a supplementary unit is preferably contained in one container, for example a pouch.
  • the trace elements of the supplementary unit destined for SIRS patients are within a 20-40 ml container of an aqueous solution of the trace elements to be administrated on a daily basis as indicated above.
  • the patient is administered parenterally one supplementary unit per day, preferably in the form of a single container.
  • the supplement units may also be presented in dry powder form to be diluted with the basic unit. An exception is formed by the patients undergoing continuous renal replacement therapy, which receive, in total, two doses of the basic unit and in addition, a bag containing 100 ⁇ g selenium.
  • the supplementary unit may be administered in the form of two separate bags. It could also be envisaged to provide a supplementary unit in the form of a single bag for patients on continuous renal replacement therapy, which contains all the elements of the basic unit and, in addition, the additional selenium.
  • a supplementary unit according to the present invention may be administered directly through a suitable intravenous line.
  • it may be conceived to be susceptible of being branched, for example via a tube, to a receiving port of the basic unit.
  • the contents of the supplementary unit may be guided through the pouch of the basic unit. This is possible, for example, if the mixing of the contents of the basic unit and the supplementary unit occurring in this case does not cause any stability problem or other kind of non- compatibility.
  • the basic and any supplementary unit may be administered successively, by infusing the contents of a container comprising the basic unit or of a supplementary unit through an intravenous catheter into a patients blood stream, and, once the container is empty, de-branching the empty container from the catheter and branching another container comprising a basic unit or a supplementary units, as adequate, through the same catheter.
  • the supplementary units may also be presented as a concentrate or a dry powder to be diluted or dissolved, respectively.
  • a concentrate or dry powder may be diluted with the basic unit.
  • Different ways of administrating the basic unit and any supplementary unit may be conceived by the skilled person, which are encompassed by the present invention.
  • the different supplementary units may all be administrated in the same way, so that medical personnel or a patient at home is not required to use different administration procedures depending on which supplementary unit is administrated.
  • the kit of the present invention may comprise the basic unit and only one single supplementary unit of trace elements.
  • the kit comprises two, three, four, or generally n supplementary units, with n being an integer from 5 upwards.
  • n being an integer from 5 upwards.
  • the present invention provides that the supplementary unit for patients of Se-def ⁇ cient areas can be combined with one of the complementary parenteral units selected from the unit designed to patents suffering from SIRS and the unit designed for patients undergoing continuous renal replacement therapy.
  • the expression "can be combined with” means that the supplementary unit for patients from Se-def ⁇ cient areas can be administered in addition to (or together with) a supplementary unit selected from the supplementary unit for SIRS patients and the supplementary unit for patients on continuous renal replacement therapy.
  • supplementary units disclosed herein only the one for patients residing in Se- poor regions are designed to be combined with other supplementary units, namely with the one for SIRS patients and the one for patients undergoing continuous renal replacement therapy, as illustrated in Figure 1.
  • Other supplementary units are not designed to be combined with each other. Such combination not specifically mentioned herein could lead to toxic accumulation of trace elements.
  • the kit of the present invention is preferably designed for parenteral administration to a critically ill patient and/or a acutely ill patient, whether or not the patient receives total parenteral nutrition.
  • the kit of the present invention is preferably administered to patients over a central venous line, as trace elements are irritant to small peripheral veins.
  • the basic unit is generally parenterally administered for the same time period as the total parenteral nutrition, if applicable, while the supplementary units (in combination with the basis) are administered for the duration of the acute condition but at least for 5 days, even in patients not requiring parenteral nutrition.
  • the supplementary unit(s) that is (are) administered may need to be adapted. For example, if the condition of a patient suffering from burns improves substantially, administration of the corresponding supplementary unit may be stopped as determined by the medically trained person in charge for the patient.
  • the basic unit and, preferably, any supplementary unit is substantially free of macronutrients, in particular, the units are substantially free from glucose sources, lipids, and more preferably also from proteinogenic sources, such as proteins, peptides, and amino acids.
  • “Substantially free of macronutrients” refers to ⁇ 10% by weight of dry matter, preferably ⁇ 5%, more preferably ⁇ 3% by weight of dry matter of macronutrients.
  • the basic and/or supplementary unit(s) is/ are completely free of macronutrients, that is, do not contain any trace elements.
  • Each unit may contain stabilisers, buffers and other additives, as adequate.
  • an additive could be a "macronutrient" in the large sense of the term, if a patient can derive energy from metabolising the additive.
  • the additive would not fall under the expression "macronutrient” as defined herein, because the stabilisers and/or buffers are generally provided in small quantities not designed to meet nutritional requirements of a patient and because the additive is added for the purpose of fulfilling a specific function in the unit, generally for stabilising or conserving the unit in its container, or for making the contents of the container compatible for parenteral administration to humans, which function is not directly related to the nutrition of a patient.
  • the basic unit and any supplementary unit according to the invention is preferably not intended to provide macronutrients in amounts sufficient to provide complete nutrition to a patient.
  • one or more units, and in particular one, several or all of the supplementary units may comprise nutrients, including macronutrients, in particular those which are conditionally essential for the patient and/or patient population for which the supplementary unit is provided.
  • the basic unit and/or a supplementary unit according to the present invention essentially consist of the trace elements mentioned herein in the indicated amounts and is free of further nutrients.
  • the trace elements are generally added in the form of a salt comprising the trace element in ionic form together with another ion of opposed charge.
  • the salt is then added in corresponding amounts to an aqueous solution so as to prepare the basic unit or any supplementary unit according to the present invention.
  • the trace elements can be prepared as salts or as organic compounds (gluconate).
  • each unit comprises an aqueous solution of one or more trace elements, each trace element being added in the preparation of the solution in the form of a salt, wherein a counterion in the salt is selected so as not to affect negatively, in the corresponding amounts, the health of the individual. It may also be useful to provide salts consisting of an anionic and a cationic trace element, so as to avoid the use of trace elements that are not specifically needed.
  • compositions, units, kits, aqueous solutions and so forth of the present invention are typically sterile formulations and are prepared according to conventional manufacturing techniques using for example aseptic manufacture or terminal sterilisation by autoclaving.
  • all components of the compositions, units, kits, aqueous solutions and so forth of the present invention are preferably at least United States Pharmacopeia (USP)-grade purity, which is generally a purity of about 95%.
  • USP United States Pharmacopeia
  • the recommended duration of administration is intended to be different for the various supplements:
  • Burns for the duration specified above in dependence of the affected BSA. It may have to be resumed for about 5 days periods in patients with document low plasma copper, zinc or selenium levels;
  • CVVH for the duration of renal replacement therapy
  • SIRS for 5 days.
  • Example 1 Preparation of a basic unit according to the present invention
  • a basic unit for parenterally administrating trace elements to a patient is prepared by dissolving trace elements as shown in Table 1 under aseptic conditions in 40 ml water:
  • Table 1 Composition of an exemplary basic unit
  • the aqueous solution is aseptically filled in a sterile 40 ml bag.
  • Example 2 Supplementary unit for patients diagnosed with SIRS
  • a supplementary unit for parenterally administrating supplementary trace elements in addition to the basic unit of example 1 to a patient suffering from SIRS is prepared by dissolving trace elements as shown in Table 2 under aseptic conditions in 40 ml water:
  • Table 2 Composition of an exemplary supplementary unit for SIRS patients Trace element Amount
  • the aqueous solution is aseptically filled in a sterile 40 ml bag.
  • Example 3 Supplementary unit for patients suffering from burns
  • a supplementary unit for parenterally administrating supplementary trace elements, in addition to the basic unit of example 1 to a patient suffering from burns is prepared by dissolving, under aseptic conditions, trace elements as shown in Table 3 in 200 ml water:
  • Table 3 Composition of an exemplary supplementary unit for patients suffering from burns
  • the aqueous solution is aseptically filled in a sterile 200 ml bag.
  • Example 4 Supplementary unit for patients on continuous renal replacement therapy
  • a supplementary unit for parenterally administrating supplementary trace elements, in addition to the basic unit of example 1 to a patient on CVVH is prepared by dissolving, in addition to all the trace elements of Table 1 in the amounts indicated in Table 1 , 100 ⁇ g selenium in 40 ml water.
  • This supplementary unit thus differs from the basic unit only in that more selenium is present.
  • the patient is administered the basic unit and this supplementary unit, which means twice that basic unit and, additionally, 100 ⁇ g selenium are daily administered to a patient on CVVH.
  • the aqueous solution is aseptically filled in a sterile 40 ml bag.
  • Example 5 Supplementary unit for patients from selenium poor areas
  • a supplementary unit for parenterally administrating supplementary trace elements, in addition to the basic unit of example 1 to a patient generally residing in a selenium poor area is prepared by dissolving, under aseptic conditions, 100 ⁇ g selenium in 20 ml water.
  • the aqueous solution is aseptically filled in a sterile 20 ml bag.
  • a female 38 years old patient is admitted to the intensive care unit of a hospital for deep surgical burns involving 40% of her body surface to the right arm, back and the abdomen.
  • Her weight is 70 kg.
  • the patient is put on enteral nutrition and the kit of the present invention is used to parenterally provide trace element - delivering one basic kit + 1 burns supplement for 21 days through a central parenteral line.
  • the patient thus is administered the basic unit of example 1 and the supplementary unit for patients suffering from burns of example 3.
  • the patient receives sufficient trace elements over the whole period of treatment.
  • she will not experience any deficiencies in copper, selenium and zinc.
  • Bratter P Negretti de Bratter VE: Influence of high dietary selenium intake on the thyroid hormone level in human serum. J Trace Elem Med Biol 1996; 10:163-166 Anderson RA, Sandre C, Bryden NA, et al: Burn- induced alterations of chromium and the glucose/insulin system in rats. Burns 2006; 32:46-51
  • Voruganti VS, Klein GL, Lu HX, et al Impaired zinc and copper status in children with burn injuries: need to reassess nutritional requirements. Burns 2005; 31(6):711-716 Shenkin A: Trace elements and inflammatory response: implications for nutritional support. Nutrition 1995; 11 :100-105

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Abstract

La présente invention répond au problème de déficiences aiguës en éléments traces observé chez les patients en phase critique et/ou les patients recevant une alimentation parentérale - les problèmes de toxicité sont intégrés. La présente invention concerne, en vue de résoudre le problème, un kit d’administration parentérale d’éléments traces à un patient, le kit comprenant une unité basique d’éléments traces et au moins une unité supplémentaire, l’unité supplémentaire comprenant des éléments traces supplémentaires de manière à répondre aux besoins spécifiques en éléments traces d’un patient particulier. Selon un mode de réalisation, l’invention propose une unité supplémentaire pour les patients chez qui un SIRS a été diagnostiqué, souffrant de brûlures, pour les patients suivant une thérapie continue de remplacement rénal et pour les patients résidant dans des pays pauvres en sélénium.
EP09742543A 2008-05-07 2009-05-06 Supplément parentéral avec des éléments traces pour le traitement notamment du syndrome de réponse inflammatoire systémique, de brûlures et de déficits en sélénium Withdrawn EP2288337A1 (fr)

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PCT/IB2009/051858 WO2009136370A1 (fr) 2008-05-07 2009-05-06 Supplément parentéral avec des éléments traces pour le traitement notamment du syndrome de réponse inflammatoire systémique, de brûlures et de déficits en sélénium

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US4326523A (en) * 1980-08-25 1982-04-27 International Minerals & Chemical Corp. Method of supplying micronutrients to animals
ATE59298T1 (de) * 1982-09-17 1991-01-15 Human Oltoanyagtermelo Praeparate zur behandlung von wunden der hautoberflaeche und verfahren zur herstellung derartiger praeparate.
RU2427364C2 (ru) * 2005-12-23 2011-08-27 Аджай Гупта Композиции для парентерального питания, содержащие железо

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