PAMENTERAL NITTRITION COMPOSITION CONTAINING IRON
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This application claims flie benefit under 35 U.S.C. 119(e) of U.S. Provisional Patent Application 6(V753,81S, filed December 23, 200S, the entire disclosure of which is incoipoiated herein reference.
The invention relates to a con^Kisiticni cantaining bioavailable iron suitable for parenteral nutritimi.
Background of the Invention
Parenteral nutrition (PN), also known as parenteral hyperalimentation, is a medical treatment that siq>plies nutrition-maintaining compositions intravenously, and is indicated for a variety of mammalian disorders, such as cancer, gastrointestinal diseases, major body bums, extensive wounds, and AIDS. Partial paicnteial nutrition supplies only part of daily nutritional requirements, supplementing oral intake. Many hospitalized patients receive dextrose or amino acid solutions by ttiis method. Total parenteial nutrition treatment (TPN) supplies all daily nutritional requirements intravenously, circumventing Ac gut. TFN may be employed following surgeiy, when feeding by moulfa or using the gut is not possible, when a patient's digestive system cannot absoib nutrients due to chronic disease, or, if nutrition cannot be met by enteral feeding and supplementatioa Premature and sick infants often require extended periods of TPN.
Compositions for paienterel nutrition generally contain at least water, gjucose, amino acids, and optionally emulsified fiits. They may be aseptically compounded firom amino acid solutions, dextrose soluti'ons, and/or lipid emulsions. PN compositions may fiirtiier contain vitamins, electrolytes and essential trace elements.
FN compositions gpneratly contain only negligible amounts of iron. Because of concerns about hicompatibility and toxicity, iron is not routinely added to PN admbctuies.
Patients who lequire TPN may develop iron deficient anemia despite adminislratioD of hematopoietic nutrients (e.g., folate, vitamin B12, pyridoxine, ascorbic acid, copper, zinc, and amino acids). Inm deficiency is a primary cause of anemia in patients receiving TPN and reflects a patient's inability to compensate for blood losses associated with underlying disease, multiple sui:gerie^ or frequent phlebotomies.
Iron deficiency is^conscted by tfieadmiiiistcation of iron-corrtaining compounds, hi general, healtiiy subjects who suffer fixnn iron deficiency ingest oral preparations containnig iron salts as a safe, cheap and effective means of replenishing iron stores. Patients, however, are frequently non-compliant with oral iron supplements due to associated gastnointestinal side-effects, e.g., nausea, vomiting, bloating, discomfort, indigestion, heartburn, and constipation. In patients receiving TPN, administration of oral iron may not be fbasibk eifter because flie mechanical fiuMors that preclude use of enteral nutrition also preclude the use of oral and/or enteral iron, or patients may not be able to absoib oral iron, such as patients witti malabsorption syndrome. Furfheimoie, oral iron administration is commonly associated wifii uiqileasant and/or deleterious gastrointestinal side effects therdiy resulting in poor compliance.
Various forms of iron have been suggested for intravenous administration, including, by way of example, low molecular weight ferrous iron con^unds, such as ferrous citrate or ferrous gjhicotute, and iron bound to polymeric materials, such as iron dextran and iron saccharafees. Formulations containing shnple iron salts, such as iron chloride, sul&te or ascoibate, are considered too toxic for parenteral administration, ance transfer of diese iron salts to die patient's blood liberates fiee iron, i.e., iron Uiat is not bound to a natural or syntfietic ligand, such as tcansferrin, or ferritin. Free iron, wheOier in its +2 (ferrous) or +3 (ferric) oxidation state, is a transition element capable of catalyzing fi«e radical generation and I^id peroxidation. Hie ferrous (Fe(II)) ion is reactive, and by a series of cyclic redox reactions, leads to the production of highly reactive hydroxyl radicals by the Fenton reaction, or alkoxyl and peraxyl radicals from the breakdown of lipid peroxides. Likewise, the highly charged ferric (Fe(ni)) aquo ion will tend to precipitate at physiological pH due to hydrolysis reactions to fomi insoluble hydroxides, and its interactioxis widi plasma proteins may result in fiieir denaturation and partial precipitation. All of tfiese actions are toxicities wiA serious adverse effects and have prevented clinical use of conventional fisxious or ferric iron sahs in finmulations that arc adnunistered intravenously.
Colloidal iron compounds fiiat are iron-caibohydrate complexes aie currently fbmiulated for paienteial administiation of iron. In the United States, colloidal iron compounds approved by ttie U.S. Food and Drug Administration Jar i.v. administiation include inm dextran (INPeD(S>, Watson Phaima, Inc.; Dexfemim®, American Regent, Inc.), iron gluconate (FerrleciVB). Watson Fharma, Inc.), or iron sucrose (Venofer®, American Regent, Inc.)- Intravoaous administiation of coltoidal iron compounds such as these is known to cause serious adverse efSscts, including pain, severe and/or life-threatening anaphylactoid reactions, organ toxicity, release of catalytically active iron tiut is associated with higher risk of or exaceifoation of infection and possibly cancer, and oxidative stress and chnmic inflammation that is causatively associated with a&eioscleiosis, coronary arteiy disease, and strobes {Physicians' Desk Reference, SZ^ Ed., pages 568-570, 3319-3322 (2004)). Furthermore, parenteral formulations containing conventional colloidal iron inepaiations have potent but hi^ily variable, cytotoxic potentials (Zager et al., 2004, Kidney Jntl. 66: 144-156). Zager et cd. concluded that parenteral foimuIati(His of colloidal iron complexes have potrait cytotoxic potentials that can be exhibited at clinically relevant iron concentrations. The persistence of polymeric iron complexes in te circulation for several days following i.v. infusion may allow uptake by microorgamsms and thereby promote microbial growth. Recent studies have also shown tiiat i.v. administration of colloidal iron compoimds may be associated with an increased morbidity arxl mortality from infections (Collins et al., 1998, J. Am. Soc. NephroL 9: 205A). Therefore, the use of i.v. colloidal iron requires close mortitoring for adverse patient responses with each administiation.
It has been proposed that maintenance parenteral nutrition patients receive intravenous polymeric iron supplements. A prospective study to evahiate file intravenous inm dextian (Imferon®, Merrill National Laboratories, Cincinnati, Ohio, US) dosage needed to restore serum iron levels in patients receiving TEN diowed that 87.S-17S mgAveek iron effectively raised serum iron levels over a 3 week period (Noiton et al,1983, Journal of Parenteral and Enteral Nutrition 7:457-461). For ease of administration polymeric iron dextian has been administered as an additive to parenteral nutrition mixtures (Porter et al, 1988, Journal of American College of Nutrition IQ)-. 107-110).
The compatibiUty of iion willi parenteral nutrition admixtures, however, has not been clearly establidied. One study has shown 1-day compatibility of fenous citrate, a moaametic fenous sah; with a single parenleral-nutrition component; amino acid solution (Sayers et al., 'l983, J. Parenter. Enteral Nutr. 7(2):117-120). A second study has ^wn compatibility of iron dextran with amino acid-dextrose parenteral admixtures (Wan et. cd., 1980, Am. J. Hosp. Pharm. 37: 206-210.) In contrast, several studies found that iron dextran added to TPN formulation caused breakdown of die adnuxture, coalescence of lipid dt<^lets, and cracking and creaming of the lipid component (Driscoll et al, 199S, Am. J. HeahhSyst. Pharm. 52:623-634; Vaugjian et al., 1990, Am. J. Hosp. Pharm. 47:1745- 1748). The effect of colloidal iron dextnm on the std>ility of parenteral nutritional (PN) emulsions has been analyzed (Driscoll et oL, 1995, supra). Driscoll et al (1995, supra) determined that ttie trivalent cation content derived fiom colloidal iron dextran was flie only variable that affected the stability of nutritional emulsions, accounting for approximately 60% of a potentially dangerous increase in fiit particle sizes observed. In addition, a percentage of large &t particles (i.e., fat particles greater ttian 5 Mm in diameter; PFATS) fiiat was greater tfian 0.4% was observed to be associated with unstable PN emulsions and dismption of Iheir integrity.
Product labeling for each of the conventional colloidal iron-containing formulations warns specifically diat flie formulation is not to be added to parenteral nutrition solutions for intravenous administration (physicians' Desk Reference, 58*^ Ed., pages 568-570, 3319- 3322 (2004)). There is also concern tiiat proltmged iron administration in parenteral nutrition may have undesirable adverse effects. Iron overload has been reported in children receiving prolonged iron supplementation in TPN (Ben Hariz et al., 199^, JPediatr. 123: 238-241)
Consequently, there is a need for an altenuitive and more pl^rsiologic metiiod of administering bioevailable iron intravenously as a component of a parenteral nutrition composition. The present invention addresses that need.
SUMMARY OFTHE INVENTION
The invention provides a composition comprising bioavailable iron suitable for parenteral nutrition. In one embodiment, the composition comprises a flierapeutically effective amount of soluble ferric pyrophosphate: amino acids; carbohydrate; and a phaimaceutically acceptable earner. another embodiTnent, the composition fin&er comprises lipid. The composition is characterized by physico-chemically stability. In one imbodiment, the composition is physico-chemically stable for at least about 24 hours bllowing preparation, when tiie composition is maintained at a tempeiatuie of about 25 ''C.
In one embodiment of the invention, the mean drqplet size of the composition is less han about 500 nanometers for at least about 30 hours following preparation, when the somposition is maintained at a temperature of about 25 In another embodiment, the nean droplet size of the composition is less dian about 285 nancnneters for at least about 30 lours following preparation, when the composition is maintained at a temperature of about
In anoAer embodiment, globule size distribution of the composition, expressed ts the volume-weighted percent of &t greater than 5 pm in the conposition, is less than ibout 0.05% at about 30 hours following preparation, when the composition is maintained It a temperature of about 25 In yet ano&er embodiment, the globule size distribution of he composition, ejqiressed as the volume-weighted percent of &t greatnr ttian 5 pm in the sompositioi), is less dian about 0.03% at about 30 hours following preparation, when the x>mposition is maintained at about 25
In one embodiment of die im'enticHi, the soluble ferric pyrophosphate is added to the somposition such tiliat the iron content present in ttie composition in the range of about 1 mg^ to about 150 mg/L.
In certain embodimei^ of the composition of die invention, amino acids are present in the range fix>m about 2.5% to about 7% (w/v), and carbohydrate is present in the range from about 5% to about 20% (w/v). In some embodiments of the invention, the carbohydrate comprises dextrose. In certain embodiments of the invention where the Bonq>osition comprises l^id, die lipid is present in the range fiom about 2% to about 5% (w/v).
A method for prqiaring a composition suitable for parenteral nutrition is provided, comprising aseptically combining soluble feme pyrophosphate, amino acids, caibohydrate and a phannaceutically acceptable carrier, and c^tionally, lipid.
A method for providing parenteral nutrition comprising bioavailable iron is also provided, by admnustering to an individual, a composition according to die present invention.
A &i1her method for providing paientetal nutritioii conqnising bioavailable iron to m individual is pio^dded. The melhod comprises intravenously administering a first sompoBttion comprising amino acids, caibohydrates and a pharmaceutically acceptable sanrier, and intravenously administering a second composition comprising lipid. At least one of the first and second compositions contains soluble FePPi.
A kit is provided for providing paientetal nutrition comprising a first container containing a first c(»nposition comprising amino acids, caAoIiydiates and a pharmaceuticdly acceptable carrier, a second container containing a second conq)osition comprising lipid. At least one of fte first and second compositions contains soluble FePPi, or said soluble FePPi is contained in'ihe kit in a third container
DETAILED DESCRIPTION OF THF- nWTT.^^N
Definitioiis
As used herein, flie singular forms "a", "an" and 'ihe" include die plural, unless the context clearly dictates otfierwise.
The term "individual" (as in the subject of a treatment) means both mammals and non-mammals. Mammals include, for instance, humans, non-human primates, cattle, horses, dieep, pigs and goats.
As used herein, "bioavailable iron" lefeis to iron in a chemical and physical form that allows it to be absoibed and used by flw boify of an organism.
As used herein, an "insliuctional material" includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of Hie kit for its designated use in practicing a method of tiie invention. The instructional material of die kit of the inventira may, for example, be a£Gxed to a container which contains flie composition or be shi{q)ed together wiOi a container which contains the composition. Alternatively, fiie instnictional material may be shipped separately fiom the container with the intention tiiat the instmctional material and the composition be used cooperatively by die recipient
The terms "sterile" and "sterilized" as used herein have their conventional meanings as understood by skilled artisans when referring to the sterility required pharmaceutically for intravenous preparations. Sterilization is achieved conventionallv. either by application >f heat (e.g., high-pressuite steam sterilization or high-temperature short time steam sterilization) or finou^ the use of filteis having a poie-size sufiiciently small to exclude jathogens.
The tsim "suitable for tntiavenous injection" as used herein has its conventional neaning as understood by ^led artisans when referring to a composition that meets the general lequirements for solutions for injection as presented in the General Chapter of the U.S. Hiaimacopoeia entitled "Injections." (U.S. Phannacopoeia, U.S. Pharmacopeias Convention, Inc., Rockville, MD, 2004.)
The tenns "treating" and "treatment and the like are used herein to generally mean obtaining a desired phatmacologica] and physiological effect The effect may be proptqrlactic in trams of preventing or partially preventing a disease, symptom or condition thereof and/or may be ttwiapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to tiie disease. The term "treatment" as used herein encoiiq)asses any treatment of a disease in a mammal, particulaily a human and includes: (a) preventing fte disease fiom occuziing in a subject which may be predisfiosed to the disease but has not yet been diagnosed as havmg it; (b) inhibiting the disease or arresting its development; (c) relieving die disease, causing regression of the disease and/or its symptoms or conditions, or (d) returning a clinical value to the concentration range normally found in a subject
The phrase 'therapeutically efifective" is intended to qualify the amount of soluble ferric pyrophosphate for use in the intravenously administered flierapy which will achieve the goal of providing a biologically available Q.e., bioavailable) concentration of ferric iron to effect abating, mitigating, reducing or preventing, for example, an iron deficiency disorder, while avoiding adverse side effects typically associated witfi conventional low molecular weigjit iron salts or polymeric iron-saccharate preparations.
By die term "parenteral nutrition composition" is meant a Iqqieralimentation composition for intravenous administzation comprising one or more components selected ftom ttie group consisting of a carbohydrate solution, an amino acids solution, and lipid.
By the temi *'ph}^co-chemically compatible" with respect to a component of a parenteral nutrition coRqx)sition is meant tiiat a disruption of the composition is not observed, as determined by the observation of phase separation, creaming, particulate formation, an increase in die pereentage of lipid globules htiving a diameter greater than S
Mm as measured by conventional light scattering. light obscuration, or particle-sizing schniques, or the like.
It is undeiBtood that any and all w^le or partial integers between any lamges set oith herein are included herein.
'areateral Nntrition Composition
The inventor has discovered, unexpectedly and uniquely, that parenteral nutrition impositions and soluble ferric pyroidiosphatB are pfaysico-chemically compatible. Specifically, the soluble ferric pyrophosphate-containing compositions of the present nvention are physicoHshemically stable and do not undergo degradation, increases in the lize of fat globules, creaming, or phase, sqiaration over at least about 30 hours at room emperature (about 25 °C.). In contrast, conventional polymeric iron complexes, when iseptically compounded with PN admixtures containing lipid, cause degradation and neakdown of die resulting PN admixture, increasos in tiie size of fat globules, creaming, or ihase-separation within a few hours (Driscoll et al., 1995, supra).
Accordingly, the invention provides an iron-containing composition that is useful for parenteral nutrition and far total parenteral nutrition therapies. In one embodiment, the :OTiposition comprises soluble ferric pyrophosphate, amino acids, and caibolQ^te. Li one smbodiment, the composition further comprises lipid. In a preferred embodiment, die wbofaydrate is dextrose. The components of the cooqsosition are present in nutritionally sffective amounts, as hereinafter exemplified.
Low-dose iron parenteral nutrition Iheiapy, as provided administering Aie soluble ferric pyrophosphate-containing parenteral nutrition admixture of the present invention, Eiffords numerous benefits to the rec^ient The soluble fisrric pyrophosphate-containing parmteral nutrition admixture provides a slow, continuing transfer of biocompatible iron to the patient during infusion. The amount of iron in the admixture can be readily and repeatedly adjusted accordii^ to the patient's need. Once a steady state is reached, patients are likely to need less intensive monitoring of iron stores dian patients receiving oral or conventional i.v. colloidal iron ttierapy.
Following ^ir intravenous administration, prior art conventional colloidal iron compounds (e.g., iron dextran, iron sucrose and iron gluconate (Mr 45 -350 kDa)) must be processed in the reticuloendottielial system of tihe recipient before iron is delivered to transfeirin. In genend, only about SO - 8S% of Ifae iion deliveied hitiavenoiisly as a colloidal hon complex is bioavailable and utilized for hemoglobin generation (Gupta et al, 2000, J. Lab. Clin. Med. 136: 371-378). In contrast, fbs soluble feme pyiophosphate- containing compositions of flie present invention are cleated fixnn the circulation more mpidly, since fetric pyrophospbate binds directly to transfenin. Wben soluble ferric pyxophospbate is administered to patients via a paienteral nutrition admixture in accordance witii the present invention, slow administration of inm is fecilitated, and iron status is easier to monitor. Moreover, parenteral nutrition compositions of tiie invention are easily administered to patients at home. In patients receiving TPN, administration of oral iron may not be feasible eitiier because the mechanical fectors tiut preclude use of ente^ nutrition also preclude tiie use of oral and/or enteral iron, or patients may not be able to absorb oral iron, such as patients with malabsorption syndrome. Furthermore, oral iron administration is ccnnmonly associated with unpleasant and/or deleterious gastrointestinal side effects tiierd^ resulting in poor compliance. By eliminating or reducing the need fisr oral inm supplementation and tiiereby the pill burden, die parenteral nutrition composition of the present invention will likely improve quality of life and increase cc»npliance with other medications.
The composition of the invention in one embodiment is an admixture of soluble ferric pyrophosphate and a conventional parenteral nutrition preparation. Conventional parenteral nutrition preparations may contain a variety of nutritional components,.which are varied based on the particular needs of the recipient individual. As is known tiie skilled artisan, patient-q)eciflc fiactors should be considered when selecting an appropriate parenteral formulation. Patient variables mclude but are not Ihnited to: nutritional status and requirements, electrolyte balance, digestive and absorptive capacity, disease state, renal fimction, and medical or drag therapy. One of doll in tiie art is femiliar with determining tiie appropriate parenteral fomnilation for a person in need of parenteral nutrition and doing so is routine in the art.
Conventional parenteral nutrition preparations usefbl in preparing tiie iron- containing compositions of tiie invention generally provide the following quantities of components on a daily basis: water at about 30 to about 40 milliliter per kilogram body weight (ml/kg); energy at about 20 to about 60 kilocalorie per kilogram body weight (kcal/kg), depending on energy expenditure of the patient; and amino acids at about 0.8 to about 3.0 gram per kUogram body weig^ (^kg), depending on the degree of catabolism of the patient. Energy is provided primarily by caibohydiate, and when present, lipid components of flie paienteral nutrition composition. Optional components include vitamins, minerals and electrolytes.
According, clinically useful parenteral nutrition preparations useful in preparing the composition of tiie invention may be aseptically compounded to contain amino acids (range, 2.5-7% (wAr)) and caibdiydrate, such as hydrated glucose or dextrose, (range, S- 20% (w/v)). Lipid is optionally and preferably present m ttw fomi of an emulsion (range, 2- 5% (wAr)). Additives, such as trace-element solutions and multi-vitamin solutions not containing iron, are optionally included. The composition of fiie mvention conqmses soluble ferric pyrophosphatB in a tilBrapeutically efifective amount
About lS-20% of patients witii acute pancreatitis develop hypertriglyceridemia. Some of these patients witii fulminant or protracled acute pancreatitis cannot be fed orally for prolonged periods and require parenteral nutrition. Administmtion of lipids, as a ccHnponoit of parenteral nutrition mixture, would be contmindicated in such patients. For patients in whom lipid adnumstration is contiaindicated, parentBtal nutriticxi prepaxatioins usefiil in preparing a composition of tiie present invention are aseptically compounded to contain amino acids (range, 2.5-7% (w/V) and cariJolQ^te, such as Iqrdrated glucose or dextrose, (range, 5-20% (w/v)); but are lacking ui lipid. Additives, such as trace-element solutions and multi-vitamin solutions not contuning iron, are optionally included. The composition of tiie invention furtiber comprises soluble ferric pyrophosphate in a tiierapeuticaUy effective amount
Soluble ferric pyrt^hosphate
Ferric pyrophosphate is a monomeric iron conqiound tint is available in two different forms. Pure ferric pyrophoqjiiate CFePyP") is a tan powder having the molecular formula a molecular wei^t (MW) of 745.2, and CAS Reg. No. 10058-44-3,
FePyP is insoluble in water. The second form, soluble ferric pyrophosphate C'sohible FePPi") is a green to yellow-green powder, has a molecular composition of (CittBtB)4 • 2 Fe • (P2O7) • X Na, CAS Reg. No. 1332-96-3, and an approximate molecular weight of about 1000 - 1500. Soluble FdPPi is a chelate in which fenic iron is chelated to pyrophosphate and citrate; the chelate is rendered water-soluble by the presence of citrate. The solubility
of soluble FePPi in water is greater flian 1000 ms^ml, and finis exceeds die solubility needed for low-dose iiDn-npletion via paventetal nutrition administtatioa Thus, soluble FeFPi dilEfeis fiom FePyP in its composition, color, molecular weight, and solubili^ in water.
Soluble FePPi occurs as thin, apple green, transparent scales, or pearls or granules or powder. Soluble FePPi can be piepaied a number of ways kirown in the ait, including treating fenic citrate with sodium i^nophosphate in solution {Ferri Pyrophosphas SobihiUs, in United States Pharmacopeia, vol. 8, New Yoik, 1907, p. 161) or by chemically reacting FePyP with citric acid and sodium hydroxide. Soluble FePPi is available comraeroially as a food grade chemical (£)r. Paul Lohmann Chemische Fabrik GmbH, Emmerttial, Germany).
Solid>le FePPi has a variable molecular weig^ and contains a variable amount of iron, ranging from 10.5 to 12.594 (w/w). Because of the variability in tiie peccenti^ of iron content it is routine practice in the art to refer to the content of demental iron rather Oan the conesponding amount of the iron chelate or complex since it is tiie amount of iron that is clinically relevant. Iherefore, in this application, imless stated otherwise, the amount of soluble ferric pyrophosphate refers to ttie amount of elemental iron provided by the chelate, and not die amount of flie chelate itself. The concoitration of soluble FePPi in the parenteral nutrition conqmsition of Ae invention will depend on tiie recipiott's needs. The calculation of iron need is well known to those drilled in the art Generally, the concentration of elemental iron (as soluble fenic pyrophosphate) in the parenteral nutrition ' composition of the invention is preferably in the range of about I to about ISO mg/L (conesponding to about 0.0001% to about 0.015% (w/v)), and preferably fixnn about 1 to about SO mg^ or as needed by the recipient The skilled artisan is femiliar with assessing iron deficiency and determining the quantity necessary to replete iron stores in iron deficient patients and maintain iron stores in those with ongoing iron losses that caimot be met by diet or nutritional f, when present, is generally provided in the form of a lipid emulsion Ibat comprises animal and/or vegetable oil and an emulsifier agent The oil advantageously comprises a source of essential fetty acids (linoleic acid and linolenic acid).
Oils useful for the preparation of a Upid emulsion suitable as the lipid component in the parenteral nutrition composition of the invention include, but are not limited to, cotton seed oil, sesame oil, peanut oil, olive dl, safflower oil, soybean oil, fish cA and medium- chain triglycerides. Methods of extracting and refining animal or vegetable oils are well known in the art For example. International Patent Application No. PCT/CAOO/00028 describes a method of refining animal or vegetable oils using low heat The use of low temperature meftods minimizes the amount of detrimental oxidized and trans-fatty acids diat arc present in the purified oil. Other methods are available in the art and well known to one of skill in the art
. Emulsifying agents usefiil for preparing a lipid emulsion suitable as the lipid component in the parenteral nutrition composition of the invention are preferably phospholipids of natural, synthetic or semi-synttietic origin. Examples of such phoq)holipids include, but are not limited to, egg phosphatidylcholine, egg lecithin, soy lecitiiin, L-o-dipalmitoyl phosphatidylcholine (DPPC), DL-a-dipahnitoyl phosphatidylethanolamine (DPPE), and dioleoyl pho^hatidylcholine (IX)PC).
Methods of preparing lipid emulsions using purified oil are also well known in the art See for instance U.S. Patent Publication No. 20060127491. In general, fbe cote lipid is first muced with an emulsifier and, optionally, an antioxidant The emulsion is then prepared by slowly adding tfiis oil phase into water with constant agitation. If an osmolality modifier is being used, it is added to the water prior to mucture with tiw oil phase. The pH can be adjusted at this stage, if necessary, and fiiul volume adjusted with water, if required.
Conunorcially-available lipid emulmons usefal in preparing fha paxenteial nntrition composition of die invention include, but are not limited to, INTRALIPID and STRUCTOLIPID ^resenius, Germany), LIPO^YN, UPOSYN n and UPOSYN m (Hospira Inc.), TRAVAMULSION (Baxter), SOYACAL (Alpha Theiapeutics) and UPOFUNDIN (B. Btaun Medical Inc.). These lipid emulsions are composed of a vegetable oil, such as soybean oil or safQower oil, an emulnfying agent, such as egg phoqihoUpids, ^ycerol, and water. OMEGAVEN CFresenius, Germany) is a 10% fish oil emulsion with a high percentage of omega-3 &tly acids, eicosapentaenoic acid (EPA) and docosapentaenoic acid (DHA). Commercially available lipid emulsions are typically provided in 10%, 20% and 30% (w/v) concentrations. A 10% lipid emulsion has about 1.1 kcal per mniiliter (kcaVml). A 20% lipid emulsion has about 2.0 kcal/ml and a 30% lipid emulsion has about 2.9 kcal/ml.
Current nati«ia] guiddines recommend limiting intake to less ttian 30% of total daily kcals. Parenteral nutrition compositions of flw invention preferably comprise between about 2% to about 5% (w/v) lipid. This range corresponds to about 0.2 kcal/ml to about 0.55 kcal/ml, which is generally sufGcient to sadsfy ^ daily requirement for lipid-derived kcals of a patient
Carbohydrate
Carbohydrates are the roost important source of energy in parenteral nutrition. Any caxbohydrate (CHO) that is metabolized and utilized as a calorie source in vivo may be used in the conqx>sition of the invention. The catbcdiydrate may be simple monosaccharides, disaccharides, oligosaccharides, or complex carbohydrates. Carbohydrate sources which may be utilized in the formulation of the invention include hydrolyzed or nonhydrolyzed starches. Examples of carbohydrates useful in ^ composition of tfie invention include, but are not linuted to, glucose, particular^ D-ghicose (dextrose); fructose; maltodextrin; com syrup; com starch; and s^litol. In one embodiment, flie carbohydrate comprises D-glucose. In anoflier embodiment, the carbohydrate comprises hydrated D-glucose.
The parenteral nutrition composition of die invention preferably comprises about 5% to about 20% (w/v) carbohydrate. This range is generally sufficient to provide the daily requnement for caibohydrate-derived kcals of a patient Depending on flw needs of the recipient, cariiohydrate may provide, for example, between about 10% to about 80% of the total daily kcal, and pie&rably about 15% to about 60%. Dextrose for i.v. use provides 3.4 kcal/gcam. Caloiic values of other caibol^diates are known in the art or readily detennined using conventional methods in flie art Commercially availid)le sources of dextrose suitable for use in a parenteral nutrition compositions of die invention typically range from about 10% to about 70% (w/v) dextrose in sterile, nonpyrogenic, hypertomc, aqueous solution.
Amino adds
L-Amino acids provide a biologically-available source of nitrogen. Preferably, the amino acid component of ttie parenteral nutrition composition of the invention comprises the anuno acids, particularly the Lpamino acids, that cannot be produced by fiie body. These nine essential amino acids are isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tiyptcqihan, histidine and valine. Non-essential' amino acids may also be included, such as alanine, glycine, arginine, proline, tyrosine, glutamic acid, aqiartic acid and serine. Glutamine is important in stcess metabolism, such as nuiy occur due to severe illness, and tiierefoie is usefid in parenteral nutrition compositions in some embodiments. The amino acids contained in fte amino acid component may be in a firee form or in a form of a salt Thus, as used herein, "amino acid" includes ttie free form and the salt form. An example of flus salt of an amino acid is a salt thereof with an organic acid such as malic acid, oleic acid, acetic acid, ^utamic acid or hydrochloric acid.
The ratio of individual amino acids in Ae coitq)osition of to invention is not particularly limited and can be determined according to any known index in the art Exemplary indices are disclosed, for instance, m U.S. Patent No. 5,767,123.
Amino acids are present in the composition of tiie invention in a range, fi>r example, of about 2.5% to about 7% (w/v). Commerciany available amino acid solutions usefUl in ttie compoation of fiie invention include AMINOSYN, AMINOSYN U and AMINOSYN specialty amino acid solutions (Hospira Inc.), FREAMINE n (B. Braun Medical), AMINVEN (Fresenius Kabi, Oemiany) and PRIMENE and SYNTHAMIN (Baxter aintec).
Additional Components
The composition of Oe invention may fiiiflier comprise <^onal components including, but not limited to, vitamins, dectrolytes, trace minerals and medicaments, such as heparin, insulin and H? antagonists.
Vitamins usefiil in a paimteral composition of fiie invention include both &t soluble vitamins and water soluble vitamins. Fat soluble vitamins include retinol (vitamin A), 25- hydioxycholecalcifeiol (vitamin D), alpha- and/or gamma-tocopheiol (vitamin E), and phylloquinone (vitamin K). Water soluble vitamins include thiamin (vitamin Bl), riboflavin (vitamin B2), pyridoxin (vitamin B6), niacin (vitamin B3), folic acid, cobalamin (vitamin B12), biotin, panlhothenic acid (vitamin B5), and ascorbic acid (vitamin C). Vitamins may be provided in daily amounts consistent wi^ FDA Recommended Allowances for intravenous vitamins, as ^own in Table 1, or as needed.
Table 1
Vitamin FDA daily amount
Thiamin 6 milligram (mg)
Riboflavin 3.6 mg
Pyridoxine 6mg
Cobalamin 5 microgram (meg)
Niacin 40 mg
Folic acid 600 meg
Pantothenic acid ISmg
Biotin 60 meg
Ascorbic acid 200 mg
Vitamin A 3300 International Units ([U)
Vitamin D 200 lU
Vitamin E 10 lU
Vitamin K ISO meg

Electrolytes useful in a parenteral composition of tiie invention include, for example, calcium, chloride, magnesium, phosphate, potassium, acetate, gluconate and sodium. Guidelines for daily requirements for electrolytes are provided in Table 2. Acetate
is provided as needed to maintain acid-base balance. AppropriatB compounds to pro^dde any pazticular electrolyte are well known In the ait
Table 2
Electrolyte Paily requirement
Sodium 60-150 mEq
Potassium 60-240 mEq
Chloride 60-150 mEq
Magnesium 8-24 mEq
Phosphate 15-30 mEq (or about 7-10 mMol per 1000 kcal) f
Calcium 9-22 mEq

In one emibodiment, the composition comprises monovalent cations (e.g., sodium and potassium) in tiie range of about 0 to about ISO m£q/L and divalent cations (e.g., calcium and magnesium) in fiie nuige of about 4 to about 20 mEq/L.
I^Ace minerals useful in a patentBial composition of die invention include, for example, chromium, copper, manganese, selenium, iodine, molybdenum and anc. Trace minerals are provided in daily amounts consistent widi FDA Recommended Allowances or as needed. The recommended daily amount for intravenous trace mineral for the most comnum trace minerals added to parenteral compositions for an adult is shown in Table 3.
Tables
Trace mineral Recommended adult daily amount
Chromium 10-15 meg
Copper 03-0.5 mg
Manganese 60-100 meg
Selenium 20-60 meg
Zinc 2.5-5.0 mg

Otiier optional components which may be added to the composition of the invention include, but are not limited to, nucleotides, beta-carotene, carnitine, taurine,
and medicaments, such as insulin, heparin and H2 antagonists (e.g.. ranitidine hydrochloride).
Preparation pf parefftff-ai Nytrition gomppyi^piy
The piepaiation of flie parenteral nutrition composition of the invention follows conventional methods for preparing aseptic compositions suitable for intravenous administration. In one embodiment, appropriate amounts of separate, sterile concentrated solutions of soluble FePPi, amino acids, caibohydrate, a phaxmaceutically acceptable carrier, and optionally lipid, aie aseptically admixed to prepare a parenteral nutrition composition with die desired quantity of each component In anotiier embodiment, soluble FePPi is aseptically added to an already-admixed conventional parmtBFal nutrition formulation. In one aspect of the prermixed embodiment, the admixed parenteral nutrition formulation comprises amino acids and carbohydrate, and is sui^lemented with boQi soluble FePPi and lipid to prepare a parenteral nutrition con^xisition of the invention. Ii another aspect, flie pre-mbced parenteral nutrition formulation comprises lipid, amino acids
V
and caibohydrate, and is supplemented witti soluble FePPi to prepare a soluble FePPi- containing composition of the invention. Optional components, such as vitamins, tiace minerals olfaer than iron and electrolytes, are also aseptically added.
As shown herein, the admixed soluble Fe-PPi-contaiiung parenteral nutritiIant8.
The soluble FePPi may be added to tin parenteml nutrition composition or a ximpoDBnt thereof as a concentrated sterile aqueous solution. Preferably the soluble FePPi miution is non-pyrogenic. A sterile solution of sohible fenic pyrophosphate is prepared by iddtng soluble ferric pyn^hosphate to a pbarmaceutically acceptable carrier widi agitation snd sterilizing ttn resultmg solution. The {diaxmaceutical carrier is preferably water, preferably sterilized and non-pyrogenic water. Ottier pbarmaceutically acceptable carriers coDopatible with the iron composition may also be employed. Optionally, the water contains a buffer to maintain die pH value with die range fram about 5 to about 8. Optionally, the pH of the resulting soluble FdE^ solution is adjusted widi an aqueous alkali metal tr/dnndde solution to any pH vahie within fee range of from about 5.0 to about 8.0, and prefembly about 7.0. Ibe alkali metal hydroxide is, for example, sodium iQ^droxide or potassium hydroxide, preferably sodium l^droxide.
In some embodiments of the soluble FePPi solution, the phannaceutical carrier is an aqueous solution containing water for injection and one or mote pharmaceutica] auxiliaries and excipients that are added for conventional pharmaceutical purposes, sudi as increasing the osmolality, acting as anti-oxidants, and fee Eke. The concentration of elemental iron (as soluble feme pyroidiosphatB) in fee phaimaceutical carrier is generally in fee range of about 0.1 to about SO m^ml. OpticMially, during manufecture, the ifearmaceutical carrier is spaiged widi an inert gas, such as niliogea or argon, to reduce the concentration of oxygen in fee phannaceutical carrier and die resulting soluble FePPi solution. Optionally, die exposure of the resulting solution to li^t is limited during manufecture and storage. The resulting sokluble FePPi sohition is sterilized using conventional mefeods known to those skilled in fee pharmaceutical art Sterilized soluticms are packaged and stored in containers such as ampoules, syringes, ^dld8, infusion bottles, flexible containers, etc. These manufecturing conditions nu^ be scaled by one of skill in the art using fiilly conventional considerations to prepare small and large volumes.
A multiple-chamber bag may be used to fecilitate fee aseptic compounding of soluble FePPi and other solutions to pr^pmre fee parenteral nutrition compositions of the invention. Such multiple-duunber containers are well known in fee art and are advantageous in reducing fee risk of contamination and mixing errors, while offering rapid nd accurate prqpaiation of admixtuies. The bag chambers are serrated, fi>r instance, by eptums, by separation rods, fiangible valves or oHier openable seals. To admix the olutions, the seals aze opened, and the contents of the chambers aie mixed. For instance, a tuee-chamber bag containmg a sterile solution of FePPi in one chamber, a sterile arbohydiate solution in a second chamber and a stsnle ammo acid solution in a third ihannel is contemplated. Sufficient room is provided to permit optional addition of ipids. Also contemplated is a tinee-chamber bag mefliod whev^ one chamber contains ipid, a second chamber contains a sterile carbohydrate solution, and a third chamber iontains a sterile amino acid solution, and a separate container comprises soluble FePPi. rhe soluble FePPi may be a sterile sohition, or m another embodiment, is in a solid form hat can be aseptically solubilized with a pharmaceutically accq>tBble excipient prior to iddition to the paienteial nutrition composition. Similariy, a four-chamber bag is Kmtemplated, where one chamber contains a sterile solution of soluble FePPi, a second shamber contains a sterile cazbohydiatB solution, a fiiird chamber contains a sterile amino icid solution and a fourth chamber contains lipid. Other components may be added iubsequent to admixing or may be added to a solution, for instance, to the carbohydrate Kilutim, prior to admixing.
The invention fiutber provides Idts for pnwtice of ttie present invention. In (uie smbodiment. a kit is provided comprising a first contamer containing a first conq)08ition comprising amino acids, caibohydrates and a pharmaceutically acceptable carrier, and a second container containing a second composition comprising lipid. At least one of die first uid second compositions cmitains soluble FePPi, or soluble FePPi is contained in a separate container for addition to either the fiist or second containers. The combined amount of soluble FePPi in the first and second containers provides a flierapeutically efifective amount t>f iron to the subject, in the fbim of soluble FePPi. The kit is adapted for sqMiate intravenous infusion of ttie first and second conq>ositions, when soluble FePPi is contained in at least one of fliem. Instructions for use, for providing parenteral nutrition to a subject, Eue optionally provided in the kit
In anotiier embodiment of the invention, a kit comprises a single container comprising soluble ferric pyrophosphate, amino acids,, carbohydrate, lipid, a pharmaceutically acceptable carrier, and optional instructions for use fin- providing paienteial nutrition to a subject though administration of the composition
In another embodiment, a kit comprises at least soluble FePPi in a fiist container and lipid in a second ccmtainer. The Idt also comprises instructional material regarding the preparation of a parenteral nutrition composition comimsing soluble FePPi and lipid present in the kit and exogenously provided amino acids and caibohydrate. This embodiment of the kit is ttierefore useful wift dual-chamber bags, wherein one chamber comprises a sterile anuno acid solution and tfie second chamber contains a sterile carbohydrate solution. Such dual-chamber bags axe commercially available. In another embodiment, the kit fiirther comprises one or mote of a sterile solution of amino acids and a sterile carbohydrate solution. In an embodiment, a kit comixises separate sterile containers of soluble FePPi, lipid, amino acids and carbohydrate, and instructional material describing dw prepamtion of a parenteial nutrition ctnnposidon using the components provided in the kit
The soluble FePPi in the kits of the invention may be present in the kit as a sterile solution in a pharmaceutically acc^table excipient or in solid form that can be aseptically solubilized witti a pharmaceutically acceptable excipient prior to admixing to prepare a parenteral nutrition composition of the invention. A containo* of a phannaceutically acceptable excipient is optionally provided in fte kit wilh soluble FePPi in solid form. Lipid in a kit of die invention is preferably in flie form of a lipid emulsion. The carbohydrate in a kit of the invention is prefisrid>ly dextrose.
Physico-chemical stability
The composition of the invention is physico-chemically stable for at least about 24 hours, preferably at least about 30 hours, following preparation, when maintained at about 25 "C. Physico-chemical stability may be assessed, for raian^le, by assessing flie globule size distribution and emulsion integrity of tiie composition, including examining die composition for cracking and creaming of the lipid component and phase-separation (Driscoll et a/., 1995, Am. J. HeaUhSyst Pharm. 52:623-634; Vaughan et aL, 1990, Am. J. Hosp. Pharm. 47:1745-1748).
Two criteria have been proposed by the U.S. Pharmacopeiea CUSF*) to verify the stability of lipid emulsions C'Globule Size Distribution in Lipid Injectable Emulsions" (Chapter <729>), Proposed chapter. In-process revision, Pharm. Forum 31:1448-1453). The first criterion is the intensity-weighted mean droplet size (MDS), which is expressed in nanometers (nm) and is measured using dynamic light scattering. MDS is an important qualitative measure of the extent of homogenizatioii of a lipid emulsion. The second measure, the laige-diameter tail of flie globule size distribution (GSD), is expressed as the volume-weighted percent of M greater than 5 (im ("PFAT5^ and is determined using light extinction enq)loying a single-paiticle optical sensing technique. Globule size data arc normalized to report die percentage of fet in die test articles that is present as particles of greats than S |im in diameter. A S-ftm dimension was chosen as the determinant of emulsion stabQity in testing fiie compositions of the invoation. Five-fim represents the niiuunum size capable of obstzucting the smallest pulmonaiy capillaries, which have an internal diameter of 4-9 fim, and causing an embolic syndrome.
For lipid injectable emulsions suitable for pharmaceutical applications, the upper USP limit for MDS is 500 nm and for PFATS is 0.05%. The FFAT5 criterion is a reproducible measure of die extreme globule outlier population of the globule size distribution and reflects changes in the laige-diameter tail long bdbre changes in the MDS are measurable. Furthermore, die population of diese large-diameter &t globules Q.e., greater than 5 fun) in stabte lipid emulsions has been reported to be uniformly less dian 0.05%, and when the FFAT5 population increases to 0.4%, visual evidence of instability (i.e., phase separation) is often detected. Accordingly, the PFAT5 criterion provides a quantitative measurement of globule size distribution and is die stability-indtcating measurement indicated in <729> for lipid iiyectable emulsions.
The compositions of the invention are characterized by an intensity-wei^ted MDS of less dian about 500 nm, preferably less than about 300 nm, when the conqx)sition is maintained at a temperature of about 25 The compositions of the invention are also characterized by a large-diameter tail of die GSD, expressed as the FFAT5, of less dian about 0.05%, preferably less dian about 0.03%, when the con^osition is maintained at a temperature of about 25
The compositions of die invention may be administered to provide parenteral nutrition comprising bioavailable iron to an individual. In an embodiment of the invention, the individual requires bioavailable iron to maintain an acceptable nutritional status. In another embodiment, the individual requites bioavailable iron to treat an iron deficiency disorder.
. The compositions of Hie tavention may be administeced to animals, fiarticulaily a watm-blooded animal. Pieferably, tlie individual is a primate. More preferably, the individual is a human.
Candidates fen* paioateial nutrition comprising bioavailable iran include, for exan^le, patienls sufEbring fixnn Crohn's disease, ischemic bowel disease, gastrointestmal motiliiy disoideis, congenital bowel defbct, hypeiemesis gravidarum, cbnmic pancreatitis, radiation oiteritis, chronic adhesive obstructions, cystic fibrosis, cancer, and AIDS. Patients with critical illnesses such as bums, abdommd trauma or sui:^ry, and sepsis also aiB also candidates for parenteral nutrition therapy comprising bioavailable iron.
The iron-containing parenteral nutrition compositions of die present invention are admiinsteied parenteF^y, principally intravenously. Generally, details of administration, such as rate of administration, total volume to be administBied, frequency of adimnistration and duration of administration, axe determined by considerations tiiat axe conventional finr parenteral nutritional compositions and treatment of iron deficiency and are known to tin skilled artisaa
The components of tiie parenteral nutrition compositions of the invention may be administeied in admbcture as a single composition. It is also contemplated that tiie components may be administered sqwrately, in separate infusions, although this may be less convenirait.
According to one embodiment of sqMoate infusions, tbe metiiod of parenteral nutrition comprises administering a first conq>osition comprising amino acids, caibohydrates and a pharmaceutically acceptable carrier, and administering a second composition comprising lipid. At least one of the first and second compositions contains a therapeutically effective amount of soluble FeFH. The separate conq>ositions m^ be provided in kit finm, as described above.
The particular dose for each specific patient depends on diverse fiictors, including, for example, the age, the body weigjht, tiie general state of health, die sex, and Ihe diet of the patient on tiie time and route of administration; on the rate of iron loss; on the combination of medications bemg taken by tiie patient; and on tiie severity of the particular disorder for which therapy is being given, e.g., the hemoglobin level of the patient, level of senmi transferrin saturation, ferritin concentration, etc. The skilled artisan is femiliar vrift tiie guidelines for tiie amount, fipequency and duration of iron therapy for maintaining nutrition or for treating an iron deficiency disoider. In geneial, anemic patients will receive a higher dose of iron, which may be administered more fiequenfly and for a longer treatment duration. Suitable dosages by any method of administration may be conventionally determined in accordance with routine experiments, clinical tests and/or conventional procedures in consideration of fee iron levels desired to be achieved, e.g., in preventing or treating iron deficiency or iron deficiency anemia. Generally, daily iron dosage of about 1- 1000 mg is suitable. This dosage range is intended to be non-limiting since, in all cases, higher or lower amounts may be administered when appropriate.
While not wishing to be bound by any partiknUar rationale or theory, it is believed that tiie iron-containing compositions of fbe present invention exhibit iron bioavailability and absence of toxicities, following their intravenous administration to a subject, because they deUver iron diTectly to circulating transfi^n m a physiological manner that prevents an increase in the concentration of fiee iron in tiie qrstemic cticulatilex to pyrophosphate tiian does stannous ion or calcium ion, hypocalcemia is not expected to be a side affect of soluble ferric pyrt^ho^hate administration. Indeed, soluble FePPi may inhibit calcification by providing pyrophosidiate, a very potent inhibitor of vascular and soft-tissue calcification.
The practice of the invention is illustrated by the following non-limiting example.
ff^ypiwpig 1: Preparation of a soluble FePPi solntion suitable for admixture with a parenteral nutrition composition
A foimulation of soluble FePPi in sterile water is ptepated in the following manner. Two hundred (200) grams of soluble fisrrio pyrophosphate (equivalent to ~ 20 grams of elemental iron) is added to a glass-lined vessel containing 4 liters of purified water that has been sparged wift nitrogen USP for fhirty minutes to redu(\e the oxygen content Nitrogen overpressure is maintained during manu&oturing. When dissolution is coiiq>lete. the green solution is passed through a nylon filter having a 0.22 pm pore-size (a sterilizing filter) and collected in a sterile glass-lined vessel. Amber vials aie filled aliquots of the sterile formulation and are closed with PTFE-lined stoiqiers and capped with ahiminum crimp seals. Vials containing SO mg/ioil soluble fisiric pyrophosphate solution (about 5 mg of elemental iron/ml) are dius obtained.
Example 2: Parenteral nutrition composition comprisinc soluble FePPi and lipid
To study the effect of soluble FdPPi on nutritional emulsions during storage under typical conditions, ttw studies of Driscoll et al. (199S), stq>ra^ were duplicated, using soluble FePPi rather than colloidal iron dextran.
Foity-five (4S) clinically-relevant, intravenous nutritional formulations were prq)ared (Table 4). The formulations contained the following: (1) amino acids (range, 2.5> 7% (w/v)); (2) hydmted ^uoose (range, 5-20% (w/v)); (3) lipid emulsion (range, 2-5% (w/v)); (4) monovalent cations (sodium and potassium, range, 0-150 mEq/L); (S) divalent cations (calcium and magnesium, range, 4-20 mEq/L) and (6) iron (0-10 mg of elemental iron/L) supplied as soluble FePPi. The ranges of concentrations selected le^Resent amounts fiequently used in patients receiving parenteral nutrient therapy.
Each formulation, wifliout sohible F^i, was aseptically prepared as a 1.5-L prqnration in ethylene-vinyl acetate inftision bags under sterile conditions in a Class 100 laminar-airflow hood using an automated compoutuler. Formxilations were prepared in triplicate. A sohition of soluble FePPi in water was prqpared by dissolving 100 mg of soluble FePPi m 5 mL of sterile water. An appropriate volume of a solution of soluble FePPi in water was then added manually to the final admbcture to obtain 6ie desired concentration of iron as soluble FePPi in the PN test preparation (last cohmin of Table 4). After compounding, the formulations were immediately transferred to the laboratory for
analysis at Time 0, and then placed in a tempeiatuie-contiolled chamber set at 25 db 2 tiiroui^out each 30 hour investigation.
• Table 4 Composition of Paientnd Nutrition Test Prepaxations
Formulation No. Amino Acids (% w/v) Dextrose (%w/v) Fat(% w/v) Monovalent Cations (mEq/1) Divalent Cations (mEq/l) Iron (mg/1)
1 7 12.5 3.5 75 12 5
2 4.75 5 3.5 75 12 5
3 3.4 17 4.4 30 7.2 2
4 3.4 17 2.6 30 16.8 2
5 6.1 17 2.6 105 12, 8
6 3.4 17 4.4 105 16.8 2
7 4.75 12.5 3.5 75 12 0
8 3.4 17 2.6 105 16.8 8
9 3.4 17 4.4 105 7.2 8
10 4.75 12.5 3.5 75 12 10
11 3.4 17 4.4 30 16.8 8
12 4.75 12.5 3.5 150 12 5
13 6.1 17 2.6 30 16.8 8
14 6.1 17 2.6 105 16.8 2
15 3.4 8 2.6 105 16.8 2
16 4.75 12.5 3.5 75 4 • 5
17 6.1 8 2.6 30 16.8 2
18 6.1 8 2.6 105 7.2 2
19 4.75 12.5 3.5 75 12 5
20 6.1 8 4.4 30 7.2 2
21 3.4 17 2.6 30 7.2 8
22 3.4 8 4.4 105 16.8 8
23 2.5 12.5 3.5 75 12 5
24 6.1 8 2.6 30 7.2 8
25 3.4 8 4.4 30 16.8 2
26 6.1 8 4.4 105 16.8 2
27 6.1 17 2.6 30 7.2 2
28 6.1 8 4.4 105 7.2 8
29 6.1 8 4.4 30 16.8 8
30 4.75 12.5 2 75 12 5
31 4.75 12.5 3.5 0 12 5
32 6.1 17 4.4 30 16.8 2
33 6.1 17 4.4 105 16.8 8
34 3.4 17 2.6 105 7.2 2
35 3.4 8 4.4 30 7.2 8
36 3.4 8 2.6 30 16.8 8
37 6.1 17 4.4 30 7.2 8
38 3.4 8 2.6 30 7.2 2

Formulation No. Amino Acids (% w/v) Dextrose (%w/v) Fat(% w/v) Monovalent Cations (mEq/1) Divalent Cations (mEq/0 Iron (mg/1)
39 3.4 8 2.6 105 • 7.2 8
40 4.75 20 3.5 75 12 5
41 4.75 12.5 3.5 75 20 5
42 4.75 12.5 5 75 12 5
43 6.1 8 2.6 30 16.8 8
44 3.4 8 4.4 105 7.2 2
45 6.1 17 4.4 105 7.2 2

Physical assessments of the formulations included dynamic li^t scattering (DLS) for the submicron population of droplets for MDS of the dispersed lipid phase, and pH at ttie outset and end of stu^. Large fiit globules (S (jm), indicative of the stability of the admixture, were measured using a light obscuration or extinction mefliod, employing a single-particle optical sen^ng technique (LE/SPOS). The large-diameter data were expressed as the volume-weighted percentage of &t greater tfian five micrometers diameter (PFAT5). These measurements were prafonned at Time 0 (immediately after preparBtion of the fbrmidations), and then at Time 6,24 and 30 hours storage at 25 "C ± 2
Continuous variables were expressed as mean ± S.D, and tested by appropriate parametric analyses. Dichotomous variables were conq>ared by chi-square analysis. The lig^t obscuration data were analyzed by multiple stepwise regression analysis. To assist in identi^ing and grouping stable versus unstable test emulsi(nis, sensitivity and specificity analyses and chi-squaie axulysis were performed to rule out flie lot number or source of intravenous &t emulsion as a fictor influencing emulsion stability. The percentage of fat particles of greater than 5 fun in diameter present at each interval was ttie dependent variable afifected by the sbc fectois that are independent variables. Data obtained from dynamic light scatter and physical assessments were analyzed by eiflier unpaired t tests of independent groups when emulsions are sqiarable into stable vs. unstable groups. Chi- square analysis was also used to assess the tnfluenoe of tfie expression based on the Schultze-Hardy rule, termed the critical aggregation number, in predicting stability. The a priori level of significance was 0.05. Commercial statistical analysis software was used for statistical analysis.
The results are summarized in Table 5.
Table S Stability of Parenteral Nutrition Admbctiuea Containing Soluble FePPi
Population of &t g^bules exceeding 5 vm CFF ATS) C%) Mean droplet size (MDS) (nm)
Formulation No. {Note 1) TimeCHr) Time (Hr)
0 6 24 30 0 30
I 0.007 0.017 0.008 0.014 273 274
2 0.018 0.017 0.007 0.006 277 276
3 0.007 0.011 0.009 0.047 274 276
4 0.013 0.011 0.007 0.005 279 276
5 0.022 0.018 0.010 0.009 276 276
6 0.028 0.021 0.006 0.004 276 277
7 0.010 0.007 0.003 0.003 283 284
8 0.017 0.013 0.007 0.009 289 253
9 0.027 0.022 0.008 0.008 285 281
10 0.010 0.006 0.003 0.002 273 278
11 0.014 0.012 0.006 0.006 285 279
12 0.040 0.027 0.009 0.009 284 281
13 0.004 0.004 0.004 0.004 274 274
14 0.026 0.023 0.010 0.007 282 283
15 0.011 0.008 0.005 0.004 283 279
16 0.016 0.013 0.007 0.006 282 286
17 0.017 0.019 0.003 0.006 188 285
18 0.007 0.008 0.004 0.004 284 192
19 0.013 0.010 0.004 0.003 285 189
20 0.010 0.009 0.006 0.005 289 194
21 0.031 0.020 0.008 0.007 285 190
22 0.011 0.013 0.005 0.022 274 182
23 0.015 0.011 0.015 0.030 275 182
24 0.005 0.011 0.002 0.004 275 183
25 0.015 0.010 0.004 0.004 287 159
26 0.045 0.029 0.013 0.009 285 190
27 0.080 0.123 0.008 0.008 289 192
28 0.050 0.041 0.017 0.010 282 188
29 0.007 0.017 0.006 0.017 273 183
30. 0.006 0.004 0.004 0.014 269 181
31 0.003 0.004 0.004 0.017 278 223
32 0.006 0.009 0.010 0.009 278 185
33 0.039 0.028 0.019 0.010 281 187
34 0.011 0.016 0.006 0.018 277 182
35 0.008 0.011 0.005 0.019 278 185
36 0.008 0.011 0.010 0.020. 271 182
37 0.006 0.020 0.010 0.012 278 187
38 0.017 0.013 0.014 0.009 279 186

Formulation No. {Note T) Population of fiit globules exceediAg 5 |im (PFAT5) C%) Mean droplet size (MDS)(nm)
TimeCHr) Time(Eir)
0 6 24 30 0 30
39 0.018 0.013 0.005 0.009 274 181
40 0.063 0.040 0.085 0.013 281 188
41 0.024 0.037 0.010 0.017 273 180
42 0.008 0.007 0.011 0.014 280 185
43 0.082 0.033 0.013 0.027 285 188
44 0.008 0.012 0.009 0.020 277 185
45 0.081 0.042 0.009 0.008 285 193
Note h The composition of each jfonnulatirai is provided in Table 4.

A balanced fiactional fikctorial design was used to study the influence of six independent fiustois on the stability of 45 clinicaUy-relevaiit, intravenous nutritional fbimulations during storage under typical conditions. The data indicate that soluble FePPi did not significantiy alter the stability of nutritional emulsions or disrupt Iheir integrity. No increases in mean droplet sizes (MDS) were observed. No increases in ttie percentage of &t particles > S pm in diameter (PFAT5) weie observed. Unexpectedly, during the 30-hour period of testing, no unstable emulsions were observed. Notably, there were no disruptions of emulsion integrity, such as creaming, phase-separation, or visible &t globule formation.
This experiment dius demonstrates that formulations that arc compounded aseptically from soluble FePPi and parenteral nutrient compositions are stable. This result is in staik contrast to what is observed wifli paienteial nutrition conqxisitions containing conventional colloidal iron compounds (Diiscoll e/ a/., 1995, siqn-a).
Examine 3: CUnlcal administration of parenteral nutrition composition with soluble FePPi to anemic subjects
A patient wifli a history of bowel resection, secondary to inflammatory bowel disease is currendy receiving TPN flierapy at home. The patient develops iron deficiency anemia, secondary to ongoing bloody diarrhea and malabsorption of iron. The patient is unable to take iron supplements by mouth due to bloating and diarrhea. Eiythropoietin therapy is not effective, since flie patient has iron deficiency.
Aaeptic addition of 15 mg soluble FePPi to a conventional parenteral nutrition conq>osition provides an iron-ieplete paienteial nutrition admixture that is administered to die patient intravenously over 6 hours eveiy day. Treatment in this manner efifectively corrects iron deficiency anemia over a period of 3 months. Subsequently, die dose of soluble FePPi is reduced to 20 mg per liter of parenteral nutrition composition administered 3 times per week.
AD references discussed herein are incoipomted by reference. One sldlled in the art
e
will readily i^reciate that the present invention is well adapted to cany out the objects and obtain die ends and advantages mentioned, as well as those inherent therein. The present invention may be embodied in odier qjecific forms widiout departing from die spirit or essential attributes thereof and, according, reference should be made to the appended claims, ndier than to the finegoing specification, as indicating die sc(^ of flie invention.

CXAIMS
I claim:
1. AcompositicmsmtablefbrpBrenterBlmtritioncompm
a therapeutically effective amount of soluble ferric pyrophosphate; amino acids; caibohydiate and a pbarmaceutically acceptable carrier.
2. The composition according to claim 1, further comprising lipid.
3. The composition accoiding to claim 2, wherein the composition is physico- chemically stable for at least about 24 houis followii^ piepaxation, when ttie composition is maintained at about 25
4. . The composition accoiding to chum 2, wherein the mean droplet size of die composition is less than about 500 nanometers for at least about 30 hours foUowing prepaiation, when the composition is maintained at about 25 "C.
5. The composition acccndhig to claim 2, wherein the globule size distribution of ttie composition, exfnessed as the volume-weighted percent of &t greater than 5 ^m in the composition, is less than about 0.05% at about 30 hours following piepamtion, when the composition is maintained at about 25 "C.
6. The conqiosition accoiding to claim 1, wherein elemental iron as soluble ferric pyrophosphate is present in tfie range of about 1 mg/L to about 150 mg^.
7. The composition accoiding to claim 6, wherein elemental iron as soliible ferric pyn^hosphate is present in flie lange of about 1 m^ to about 50 m^.
8. The composition according to claim 1, wherein the amino acids are present in ttie langB fiom about 2.5% to about 7% (w/v).
9. The composttjan accoiding to daim 2, wherein the lipid is present in the range from about 2% to about S% (w/v>.
10. The composition accoiding to cUum 1. wherein the caibohydrate is present in the range ftom about 5% to about 20% (w/v).
11. The composition accoiding to claim 1. wherein the cafbohydrate comprises dextrose.
12. The composition according to claim 1, fiit^ comprising one or more additional components selected from ttie group consisting of electrolytes, medicaments, vitamins and trace minerals not containing tion.
13. A method for preparing a composition suitable for parentBral nutrition, the metfiod comprising aseptically combining soluble ferric pyrophosphate, amino acids, caibohydrate and a phaimaceutically acceptable carrier.
14. The method of claim 13, further comprising combining lipid in Mit composition.
15. The method of claim 14, C(Miq>rising first fonning a compositian comprising amino acids, caibohydrate and a phaimaceutically acceptable carrier and mixing therewith soluble ferric pyrophosphiOe and lipid.
16. Ttw mediod of claim 14, comprising combining soluble ferric pyropho^hate widi a composition comprising lipid, amino acids, caibohydrate and a phaimaceutically acceptable cairier.
17. Hie method according to claim 14, wherein elemental iron, as the soluble ferric pyrophosphate, is present in the composition in the range from about 1 mg/L to about 150 mg^
18. The mediod accoiding to claim 17, wlieiein elementBl iron, as flw soluble feme pyrophosphate, is present in Ihe composition in the range frcMn about 1 mg/L to about SOmg/L.
19. The method accoiding to claim 14, wherein the composition is physico- chemacally stable for at least about 24 hours following preparation, when the composition is maintained at about 25
20. The meOiod accoiding to claim 14, wherein the mean droplet size of tiie composition is less than about SOO nanometers for at least about 30 hours following preparation, when the composition is maintained at about 25
21. The mediod accoiding to claim 14, wherein the globule size distribution of die composition, expressed as the volume-weighted percent of fat greater dian 5 ^m in the composition, is less than about 0.05% at about 30 hours following preparation, when the composition u maintained at about 25 °C.
22. The method according to claim 14, wherein said carbohydrate comprises dextrose.
23. A method for providing parenteral nutrition comprising bioavailable iron to an individual, Oie meOiod comprising intravenously administering a composition according to claim 1.
24. A method for providing parenteral nutrition comprising bioavailable iron to an individual, die mefliod comprising intravenously administering a composition according to claim 2.
25. The mediod according to claim 23, wherein elemental iron, as soluble ferric pyrophosphate, is present in the administered composition in the range from about 1 mg/1 to about ISO mg^.
26. The meOiod accoiding to claim 24, wheietn the composition is physico- chemically stable fi»r at least about 24 hours fbllowing preparation, when the composition is maintained at about 25
27. The method accoiding to claim 24, wheiein Ae mean droplet size of tiie composition is less than about 500 nanometers for at least about 30 hours following preparation, when the composition is maintained at about 25 'C.
28. The metttod according to claim 24, wfaerdn the ^obule size distribution of the composition, expressed fu the volume-weigJitBd percent of &t greater dian 5 (im in tfie composition, is less than about 0.05% at about 30 hours fbllowing preparation, when the composition is maintained at about 25
29. A method for providing parenteral nutiiticm comprising bioavailable iron to an individual, the meUiod comprising intravenously administering a first compositirai comprising amino acids, carbol^drates and a phamuiceutically accqytable carrier, and intravenously administering a second composition comprising lipid, at least one of the first and second compositions containing soluble FePPi.
30. A kit for providing patenteral nutrition comprising a first container containing a first composition comprising amino acids, carbohydrates and a pharmaceuticaUy acceptable carrier, a second container containing a second conqiosition comprising lipid, wherein at least one of die first and second compositions contains soluble FePPi, or said soluble FePPi is contained in (he kit in a fliird container.