IRON COMPOSITIONS AND METHODS OF MAKING AND USING THEM - Patent application

Abstract

1. An injectable iron composition comprising an iron(III)-hydroxide-sucrose complex containing 1 mg / mL to about 2 mg / mL of iron, additional sucrose separate from the sucrose of the iron(III)-hydroxide-sucrose complex, a stabilizing agent, e.g., sodium hydroxide, and water, for use in treating anemia.

Description

[Background technology]

[0001] background

[0001] Iron-containing compositions have been used to treat iron deficiency anemia resulting from iron deficiency or metabolic dysfunction. Iron administered parenterally without other modifications is highly toxic. To overcome this problem, iron carbohydrate complexes have been developed. A water-soluble iron (III) hydroxide sucrose complex is a preparation that has been used frequently and successfully. Intravenous (IV) iron preparations are colloids containing spherical iron-carbohydrate nanoparticles. The core of each particle is an iron-oxyhydroxide gel. The core is surrounded by a carbohydrate shell that stabilizes the iron-oxyhydroxide, releases the bioactive iron in a controlled manner, and maintains the resulting particles in colloidal suspension. Intravenous or parenteral iron preparations share the same core chemistry but differ from each other by the size of the core and the identity and density of the surrounding carbohydrate. The differences in core size and carbohydrate chemistry determine pharmacological and biological differences, including clearance rate after injection, iron release rate in vitro, early demonstration of iron bioactivity in vivo, and maximum tolerated dose and rate of infusion.

[0002]

[0002] Injectable iron compositions are known to be effective in a variety of diseases and conditions including, but not limited to, severe iron deficiency, iron deficiency anemia, intestinal iron absorption, intestinal iron intolerance problems (where regular intake of oral iron preparations is not warranted), iron deficiency (where there is no response to oral treatment (e.g., dialysis patients)), and situations where little or no iron stores are built up but are important for further treatment (e.g., in combination with erythropoietin).

[0003]

[0003] Currently available parenteral iron compositions approved for use in the United States include iron dextran (e.g., InFed®, Dexferrum®), sodium ferric gluconate complex in sucrose (Ferrlecit®), iron sucrose (Venofer®), iron isomaltoside (Monofer®), and nonstoichiometric magnetite (superparamagnetic iron oxide) coated with polyglucose sorbitol carboxymethyl ether (Feraheme®). Of the currently available parenteral iron compositions, serious and life-threatening reactions occur most frequently with iron dextran. In addition, non-life-threatening reactions such as joint pain, back pain, hypotension, fever, muscle pain, pruritus, vertigo, and vomiting may also occur. While these reactions are not life-threatening, they often prevent further dosing and therefore iron repletion.

[0004] Venofer® (iron sucrose injection, USP) 20 mg / mL contains the active pharmaceutical ingredient (API) polynuclear iron(III)-hydroxide in sucrose having a molecular weight of approximately 34,000-60,000 Daltons (Da) and a proposed structural formula: [Na2Fe5O8(OH)·3(H2O)] n ·m(C 12 H 22 O 11 ) where n is the degree of iron polymerization and m is the number of sucrose molecules associated with the polymerized iron(III)-hydroxide.

[0005]

[0005] Venofer® is indicated for the treatment of iron deficiency anemia in patients with chronic kidney disease (CKD). Following intravenous administration, the polynuclear iron(III)-hydroxide-sucrose structure dissociates into iron and sucrose, and the iron is transported to target cells, including erythroid progenitor cells, as a complex with transferrin. The iron in the progenitor cells is incorporated into hemoglobin as the cells mature into erythrocytes. Venofer® IV infusion solution is prepared in 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental iron per mL and is physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C). In addition to Venofer®, other parenteral iron compositions approved in the US include iron dextran (e.g., InFed®, Dexferrum®), sodium ferric gluconate complex in sucrose (Ferrlecit®), and ferric carboxymaltose injection (Injectafer®), iron isomaltoside (Monofer®), and non-stoichiometric magnetite (superparamagnetic iron oxide) coated with polyglucose sorbitol carboxymethyl ether (Feraheme®). Those approved in the UK also include iron sucrose (Sucrofer®, UK Claris).

[0006]

[0006] Some intravenous iron compositions are administered by intravenous infusion. Typically, intravenous infusion uses a larger volume IV bag or IV bottle containing a delivery vehicle, such as saline or dextrose, connected to a delivery tubing set. Intravenous infusion uses gravity or a pump to deliver the medication into the vein over a period of at least 20 minutes to an hour or more.

[0007]

[0007] Intravenous infusion can be time-consuming for medical personnel (e.g., nurses, doctors, etc.) and can require additional steps and equipment. For example, medical personnel must select an IV bag or bottle (e.g., 50 mL to 250 mL or more) with a correct volume of a compatible delivery vehicle (e.g., saline solution) and dilute and inject a dose of the iron composition into the delivery vehicle for administration to the patient. If the wrong delivery vehicle is selected and the medication is incompatible with the selected delivery vehicle, the medication may be unstable, resulting in the formation of an undesirable precipitate, which is not beneficial to the patient. Summary of the Invention [Problem to be solved by the invention]

[0008]

[0008] Thus, there is a need for stable, injectable iron compositions that are ready to use (RTU) for injection. These stable, injectable iron compositions can be administered by direct intravenous administration, which avoids many of the drawbacks associated with slower, larger volume intravenous infusions (e.g., 1000 mL or more). The compositions of the present application address these and other needs by providing premixed, ready to use injectable compositions of iron that are stable and provide the appropriate elemental iron concentration for immediate use without the need for dilution. [Means for solving the problem]

[0009] overview

[0009] Provided is a stable injectable iron composition comprising iron, carbohydrate, a stabilizer, and water. In some embodiments, the injectable iron composition of the present application is a premixed, ready-to-use or ready-to-administer stable injectable composition that achieves an appropriate elemental iron concentration for immediate use without the need for dilution into a larger volume delivery vehicle (e.g., 1000 mL or greater volume).

[0010] In some of these iron compositions, the iron comprises, consists essentially of, or consists of elemental iron, and the carbohydrate comprises a monosaccharide, a disaccharide, an oligosaccharide (e.g., typically containing from 2 to about 10 sugar residues), or a polysaccharide (e.g., typically containing more than 10 sugar residues). In various embodiments, (i) the monosaccharide comprises glucose, galactose, fructose, or a mixture thereof; (ii) the disaccharide comprises sucrose, lactose, maltose, or a mixture thereof; (iii) the oligosaccharide comprises raffinose, stachyose, verbascose, or a mixture thereof; or (iv) the polysaccharide comprises starch, a starch derivative, dextran, cellulose, glycogen, or a mixture thereof.

[0011] In many embodiments, the elemental iron and carbohydrate used in these iron compositions form a colloidal iron (III) carbohydrate complex. Carbohydrates useful for these iron compositions include, but are not limited to, iron carboxymaltose, iron sucrose, iron polyisomaltose, iron polymaltose, iron gluconate, iron sorbitol, iron hydrogenated dextran, iron delisomaltose (e.g., ferric delisomaltose or iron isomaltoside), ferumoxytol (superparamagnetic iron oxide coated with a derivatized carbohydrate), or mixtures thereof. In some cases, the iron composition has a pH of about 10 to about 11.1. In other cases, the iron composition has a neutral pH or a pH of about 7.

[0012]

[0012] In some embodiments, the injectable iron composition comprises, consists essentially of, or consists of iron, a carbohydrate, a stabilizing agent (eg, a buffering agent), and water.

[0013]

[0013] The present application also provides a method for making a stable injectable iron composition. In one aspect, a method for making a stable injectable iron composition is provided, which comprises, consists essentially of, or consists of mixing components, such as iron-carbohydrate colloid and water, to form a mixture, and adding a stabilizing agent to the mixture to form a stable injectable iron composition. The components of the stable injectable iron composition can be added in any order.

[0014]

[0014] In some embodiments, the method for preparing a stable injectable iron composition further comprises adding the composition to a container. The container may be a disposable vial, ampoule or bottle, or bag made of glass (e.g., type I glass, non-treated glass, treated molded glass, etc.) or plastic material (e.g., polypropylene), or the container comprises a vial with a barrier-coated stopper (e.g., 20 mm silicone and / or ethylene tetrafluoroethylene (ETFE) stopper, or 32 mm uncoated stopper) and / or aluminum cap. In other aspects, the method further comprises filtering the composition. In yet other embodiments, the method further comprises sterilization and / or heat treatment of the composition by terminal sterilization or autoclaving.

[0015]

[0015] Also provided is a method of treating a disease, disorder, or condition characterized by iron deficiency or iron metabolic dysfunction, comprising administering to a subject in need of treatment a stable injectable iron composition comprising iron, a carbohydrate, a stabilizer, and water.

[0016] In some cases, the disease, disorder or condition characterized by iron deficiency or iron metabolism dysfunction includes anemia due to iron absorption abnormalities or poor nutrition, or anemia associated with Crohn's disease, gastric surgery, intake of drug products that inhibit iron absorption, and chronic use of calcium. In other cases, the anemia is iron deficiency anemia, such as chronic blood loss, acute blood loss, pregnancy, childbirth, childhood development, psychomotor and cognitive development in children, breath-holding attacks, heavy uterine bleeding, menstruation, chronic recurrent hemoptysis, idiopathic pulmonary siderosis, chronic internal bleeding, gastrointestinal bleeding, parasitic infection, chronic kidney disease, dialysis, surgery or acute trauma, chronic alcohol intake, chronic salicylate intake, chronic steroid intake, chronic nonsteroidal anti-inflammatory drug intake, or chronic erythropoiesis stimulating drug intake. In some embodiments, the anemia is a chronic disease, e.g., rheumatoid arthritis; cancer; Hodgkin's leukemia; non-Hodgkin's leukemia; cancer chemotherapy; inflammatory bowel disease; ulcerative colitis; thyroiditis; hepatitis; systemic lupus erythematosus; polymyalgia rheumatica; scleroderma; mixed connective tissue disease; Sjogren's syndrome; anemia of congestive heart failure / cardiomyopathy; or idiopathic senile anemia.

[0017] In various embodiments, the method treats restless legs syndrome; blood donation; Parkinson's disease; hair loss; or attention deficit disorder.

[0018]

[0018] In some embodiments, an injectable iron composition is present that comprises an iron(III)-hydroxide-sucrose complex; sucrose in an amount greater than 15 mg / mL of the injectable iron composition, a sodium compound comprising sodium acetate, sodium hydroxide, sodium carbonate, sodium bicarbonate or mixtures thereof; and water.

[0019]

[0019] In some embodiments, an injectable iron composition is present, comprising an iron(III)-hydroxide-sucrose complex comprising about 1 mg / mL of iron(III)-hydroxide bound to about 15 mg / mL of sucrose; a stabilizing agent comprising about 80 mg / mL of sucrose and about 0.08 mg / mL of sodium hydroxide; and water.

[0020]

[0020] In some embodiments, an injectable iron composition is present, comprising an iron(III)-hydroxide-sucrose complex comprising about 2 mg / mL of iron(III)-hydroxide bound to about 30 mg / mL of sucrose; a stabilizer comprising about 85 mg / mL of sucrose and about 0.96 mg / mL of sodium hydroxide; and water.

[0021]

[0021] In some embodiments, an injectable iron composition is present that comprises an iron(III)-hydroxide-sucrose complex containing about 1 mg / mL of iron(III)-hydroxide; about 95 mg / mL of sucrose; about 0.08 mg / mL of sodium hydroxide; and water.

[0022]

[0022] In some embodiments, an injectable iron composition is present that comprises an iron(III)-hydroxide-sucrose complex containing about 2 mg / mL of iron(III)-hydroxide; about 115 mg / mL of sucrose; about 0.96 mg / mL of sodium hydroxide; and water.

[0023]

[0023] In some embodiments, there is a method for making a stable injectable iron composition, the method comprising mixing an iron(III)-hydroxide-sucrose complex comprising about 1 mg / mL of iron(III)-hydroxide bound to about 15 mg / mL of sucrose with a stabilizer comprising about 80 mg / mL of sucrose and about 0.08 mg / mL of sodium hydroxide, and water to form a stable injectable iron composition.

[0024]

[0024] In some embodiments, there is a method for making a stable injectable iron composition, the method comprising mixing an iron(III)-hydroxide-sucrose complex comprising about 2 mg / mL of iron(III)-hydroxide bound to about 30 mg / mL of sucrose with a stabilizer comprising about 85 mg / mL of sucrose and about 0.96 mg / mL of sodium hydroxide, and water to form a stable injectable iron composition.

[0025]

[0025] In some embodiments, there is a method of making a stable injectable iron composition, the method comprising mixing an iron(III)-hydroxide-sucrose complex containing about 1 mg / mL of iron(III)-hydroxide with about 95 mg / mL of sucrose and about 0.08 mg / mL of sodium hydroxide and water to form a stable injectable iron composition.

[0026]

[0026] In some embodiments, there is a method of making a stable injectable iron composition, the method comprising mixing an iron(III)-hydroxide-sucrose complex containing about 2 mg / mL iron(III)-hydroxide with about 115 mg / mL sucrose and about 0.96 mg / mL sodium hydroxide and water to form a stable injectable iron composition.

[0027]

[0027] Additional features and advantages of various embodiments will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by the practice of various embodiments. The objectives and other advantages of the various embodiments will be realized and attained by means of the elements and combinations particularly pointed out in the description and appended claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Detailed Description definition

[0028] For the purposes of this specification and the appended claims, unless otherwise indicated, all numbers expressing amounts of ingredients, percentages or proportions of materials, reaction conditions, and other numerical values ​​used in this specification and the appended claims are understood to be modified in all cases by the term "about". Thus, unless otherwise indicated, the numerical parameters set forth in the following specification and the appended claims are approximations that may vary depending on the desired properties sought to be obtained by the present disclosure. At the very least, and without attempting to limit the application of the principle of equivalents to the scope of the claims, each numerical parameter should at least be interpreted in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0029]

[0029] Notwithstanding that the numerical ranges and parameters setting forth the broad ranges of the present disclosure are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are understood to encompass any and all subranges subsumed therein. For example, the range "1 to 10" includes any and all subranges between a minimum value of 1 and a maximum value of 10 (including 1 and 10), i.e., any and all subranges having a minimum value equal to or greater than 1 and a maximum value equal to or less than 10 (e.g., 5.5 to 10).

[0030]

[0030] All scientific and technical terms used herein have the meanings commonly used in the art unless otherwise specified. The definitions provided herein are intended to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of this disclosure.

[0031]

[0031] It is noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless expressly and unambiguously limited to one referent. Thus, for example, reference to a "stabilizer" includes one, two, three or more stabilizers.

[0032]

[0032] As used in this specification and the appended claims, the term "or" is generally used in its sense, including "and / or," unless the content clearly dictates otherwise.

[0033]

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, patent applications, published applications and published materials, websites and other published materials mentioned throughout the disclosure herein are incorporated by reference in their entirety unless otherwise noted. In the event that there are multiple definitions for terms in this specification, those in this section prevail. When a URL or other such identifier or address is mentioned, it is understood that such identifiers may change and specific information on the Internet may come and go, but equivalent information may be found by searching the Internet. Reference thereto evidences the availability and public disclosure of such information.

[0034]

[0034] The term "composition" refers to a cohesive material formed from two or more substances, ingredients, or constituents; the manner in which the whole or mixture is constituted. When referring to a pharmaceutical product, a composition is often referred to as a "formulation."

[0035]

[0035] The term "impurity" refers to a constituent, component or ingredient that impairs the purity of a pharmaceutical active ingredient or pharmaceutical composition.

[0036]

[0036] The terms "injectable" or "injectable composition," as used herein, mean a composition that can be drawn up into a container and injected intravenously, subcutaneously, intramuscularly, intraarterially, intracardially, intrathecally, epidurally, intraparenchymally, intraperitoneally, intraventricularly, etc. into an animal (e.g., a human).

[0037]

[0037] The term "reference list drug" refers to an approved drug product against which generic versions are compared to demonstrate that they are bioequivalent.

[0038]

[0038] The term "stability" refers to the ability of a pharmaceutical active ingredient or pharmaceutical composition to remain within particular criteria or specifications.

[0039]

[0039] The term "stable" as used herein means to remain in a state or condition suitable for administration to a patient and without undergoing substantial changes in the potency of the active agent in the formulation over a specified period of time. In some embodiments, the injectable iron composition of the present application is considered stable if the iron colloid composition can maintain its integrity and required release kinetics at the level specified on the label for the maximum expected shelf life (e.g., the period from the date of manufacture to administration to an animal) under environmental conditions likely to be encountered in practical use. Typically, stability can be determined according to FDA guidelines, such as Guidance for Industry: Drug Stability Guidelines (p. 1-48), December 9, 2008. In some embodiments, the composition is stable for at least 6 months, usually at least 12 months, and generally at least 18, 24, 36, or 48 months when kept at room temperature. In some embodiments, the composition is also preferably stable for longer periods when stored at 25°C. Substantial changes in critical quality attributes are those that affect product quality from the target concentration during a specified period of time. Critical quality attributes include, for example, Mn, Mw, and PDI of the compositions of the present application. In some embodiments, unless otherwise indicated, a stable composition is one that retains at least about 85%, or at least about 90%, or at least about 95%, or at least about 99% of the initial amount of the colloidal iron(III) carbohydrate complex composition in its state (e.g., not substantially precipitated, not substantially decomposed, or not substantially adsorbed to the container) for a period of at least 6 months. In some embodiments, unless otherwise indicated, a stable composition is one that retains at least about 85%, or at least about 90%, or at least about 95%, or at least about 99% of the initial amount of the colloidal iron(III) carbohydrate complex composition in its state (e.g., not substantially precipitated, not substantially decomposed, or not substantially adsorbed to the container) for a period of at least 1 year.In some embodiments, unless otherwise indicated, a stable composition is one that retains at least about 85%, or at least about 90%, or at least about 95%, or at least about 99% of the initial amount of the colloidal iron(III) carbohydrate complex composition in its original state (e.g., not substantially precipitated, not substantially decomposed, or not substantially adsorbed to the container) for a period of two years. In some embodiments, a stable composition has a potency range of 95%-105% or 90%-110% of the labeled amount for a period of up to two years.

[0040]

[0040] The term "buffer" as used herein refers to a solution that resists changes in pH when acid or alkali is added to it. Examples of simple buffering agents used in aqueous buffers are citric acid, acetic acid, sodium or potassium dihydrogen phosphate (NaH2PO4 or KH2PO4), disodium or potassium hydrogen phosphate (Na2HPO4 or K2HPO4), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), potassium carbonate (K2CO3), potassium bicarbonate (KHCO3), CHES (N-cyclohexyl-2-aminoethanesulfonic acid), and boronic acid (borate). Examples of other common buffers are TAPS (3-{[tris(hydroxymethyl)methyl]amino}propanesulfonic acid), bicine (N,N-bis(2-hydroxyethyl)glycine), Tris (tris(hydroxymethyl)methylamine), Tricine (N-tris(hydroxymethyl)methylglycine), HEPES (4-2-hydroxyethyl-1-piperazineethanesulfonic acid), TES (2-{[tris(hydroxymethyl)methyl]amino}ethanesulfonic acid), MOPS (3-(N-morpholino)propanesulfonic acid), PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)), cacodylate 5 (dimethylarsinic acid), SSC (saline sodium citrate), IVIES (2-(N-morpholino)ethanesulfonic acid), and succinic acid (2(R)-2-(methylamino)succinic acid).

[0041]

[0041] The carriers and additives and other components of the pharmaceutical composition must be "pharmaceutical acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient. Thus, the term "pharmaceutical acceptable salts" refers to salt forms of active compounds prepared with counterions that are non-toxic under the conditions of use and compatible with stable formulations. For compounds containing relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a desired base, either without solvent or in a suitable inert solvent. Examples of pharmaceutical acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. Salts derived from pharmaceutical acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines (including natural substituted amines, cyclic amines, ethanolamine, 2-diethylaminoethanol), amino acids and their derivatives, including, but not limited to, lysine, arginine, glycine, and histidine.

[0042]

[0042] The term "pharmaceutically acceptable carrier or excipient" refers to a carrier or excipient that is useful in preparing a pharmaceutical composition, which has an acceptable side effect profile under the conditions of administration in which the composition is formulated or used, and serves to provide a vehicle for storage or administration of the active component. The carrier or excipient is compatible with the other components of the formulation and is not harmful to the recipient thereof. "Pharmaceutically acceptable carrier or excipient" as used herein and in the claims includes both one and more than one such carrier or excipient. A pharmaceutically acceptable carrier is determined in part by the particular composition to be administered and by the particular method used to administer the composition. There are a wide variety of suitable formulations of the pharmaceutical compositions of the present disclosure (see, e.g., Remington's Pharmaceutical Sciences, 20th ed., 2018, supra).

[0043]

[0043] The term "Mn" refers to the number average molecular weight, which is the statistical average molecular weight of all polymer chains in a sample;

number

[0044] The term "Mw" refers to weight average molecular weight;

number

[0045]

[0045] The term "PDI" refers to the polydispersity index of a polymer and is used as a measure of the broadness of the molecular distribution of a polymer. PDI is defined by the ratio of Mw to Mn.

[0046]

[0046] The term "tonicity agent" refers to an agent used to modify the osmolality of a formulation to make it closer to the osmolality of a body fluid, such as blood or plasma. The composition does not require any particular osmolality, provided that the composition is physiologically compatible. Thus, the composition may be hypotonic, isotonic, or hypertonic. Typically, the pharmaceutical composition of the present application has an osmolality of about 200 mOsm / L, 250, 300, 350, 400, 450, 500, 550 to about 600 mOsm / L, which in some embodiments reduces pain, irritation, and tissue damage. The tonicity of the pharmaceutical composition can be adjusted by adjusting the concentration of any one or more of the tonicity agents, cosolvents, complexing agents, buffers, or additives. Suitable tonicity agents include, but are not limited to, anhydrous and hydrous forms of NaCl, dextrose, sucrose, xylitol, fructose, glycerol, sorbitol, mannitol, KCl, CaCl2, MgCl2, or combinations thereof.

[0047]

[0047] The pH of the iron composition can be adjusted to the recited pH range or target pH by adding an acid or acid salt or a base or basic salt as necessary. For example, the pH can be adjusted by an alkalizing agent, such as an alkali metal hydroxide, such as NaOH, KOH, or LiOH, or an alkaline earth metal hydroxide, such as Mg(OH)2 or Ca(OH)2, or a carbonate.

[0048]

[0048] The term "pharmaceutical composition" is intended to encompass products including the active ingredients and the inactive ingredients that constitute the carrier, as well as any product that results directly or indirectly from combination, complex formation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from any other type of reaction or interaction of one or more of the ingredients described herein.

[0049]

[0049] The term "ready-to-use composition" refers to an injectable composition containing the active drug in solution at the required concentration and volume, presented in the final container (syringe, vial, ampoule, bottle, infusion bag, or elastomeric device) and ready to be administered, for example, to a patient in need thereof without the need for further dilution.

[0050]

[0050] The term "therapeutically effective amount" refers to an amount of an agent that, when administered to a subject, either alone or as one of multiple doses, is sufficient to prevent or treat a condition, e.g., low in vivo blood iron levels, anemia, etc. A "therapeutically effective amount" will vary depending on the formulation, the severity of the condition, the age, general health, and weight of the subject being treated.

[0051]

[0051] The term "premixed," as used herein, means a pharmaceutical composition that is already mixed from the time of packaging and / or manufacture prior to sale and does not require reconstitution or dilution prior to administration to a subject.

[0052]

[0052] The term "disposable container" refers to a sealed, pharma- ceutical preparation container that holds a drug product in a sterile environment, intended for use in a single operation to transfer all or substantially all of the contents. It should be recognized that disposable containers are generally preservative-free, and that if multiple transfers are attempted, these should be completed within a short period of time, i.e., less than about 8-10 hours after the initial breach of the sterile environment. In some embodiments, a disposable container may be used to administer all of its contents to one subject in need thereof. In some embodiments, a disposable container may be used to administer its contents to multiple subjects in need thereof.

[0053]

[0053] As used herein, the term "mixing" refers to admixing, contacting, blending, agitating, or allowing for admixture, mixing, blending, agitation, and the like.

[0054]

[0054] The term "dissolved oxygen" refers to the oxygen found in the aqueous carrier of the composition. Distinguished from dissolved oxygen is headspace oxygen. As used herein, the term "headspace oxygen" refers to the oxygen found in the headspace volume of a sealed container that contains the composition.

[0055]

[0055] It will be apparent to those skilled in the art that various modifications and variations can be made to the various embodiments described herein without departing from the spirit or scope of the teachings herein. Thus, the various embodiments are intended to cover other modifications and variations of the various embodiments within the scope of the present teachings.

[0056]

[0056] The headings below are not meant to limit this disclosure in any way. Embodiments under any one heading may be used in conjunction with embodiments under any other heading.

[0057] Iron Composition

[0057] The present application relates to the development of a stable injectable iron composition comprising iron, carbohydrate, a stabilizer and water. More specifically, in some embodiments, the present disclosure is directed to a stable ready-to-use (RTU) pharmaceutical formulation or composition of iron sucrose for parenteral use, for example, by injection or intravenous infusion with or without an intravenous pump.

[0058]

[0058] In some embodiments, the ready-to-use or ready-to-administer stable injectable compositions of the present application reduce preparation time and are convenient to administer. These compositions are pre-made, minimizing potential dosing errors that may occur in mixing the compositions and selecting the appropriate delivery vehicle for injection.

[0059] In some embodiments, the compositions and methods described herein utilize an appropriate alkaline solution and / or buffering agent and / or sucrose to stabilize the formulation and prevent or reduce aggregation and precipitation of iron-sucrose complexes. Those skilled in the art will appreciate that the additives described herein serve only as non-limiting examples of iron carbohydrate stabilizers. Non-limiting agents include buffers, such as carbonate buffers, sugar carbohydrates, sugar-lipids, sodium gluconate or mixtures thereof. The iron compositions of the present application contain active pharmaceutical ingredients related to the iron carbohydrate category, such as iron sucrose for parenteral iron therapy.

[0060]

[0060] In some embodiments, the iron in the stable injectable iron composition of the present application comprises elemental iron. Elemental iron includes the amount of iron present in an iron-carbohydrate complex or an iron-carbohydrate colloid. Elemental iron includes, for example, the amount of iron present in the iron-carbohydrate complex or iron-carbohydrate colloid. +It contains iron in an oxidized state. For example, in the iron-sucrose complex or iron-sucrose colloid of the ready-to-use formulation, in some embodiments, the amount of elemental iron is 1 mg / mL or 2 mg / mL. Carbohydrates useful in the preparation of the iron composition of the present disclosure include monosaccharides, disaccharides, oligosaccharides, or polysaccharides. Examples of useful monosaccharides include, but are not limited to, glucose, galactose, fructose, or mixtures thereof. Useful disaccharides include, for example, sucrose, lactose, maltose, or mixtures thereof. Useful oligosaccharides can include raffinose, stachyose, verbascose, or mixtures thereof. Various polysaccharides include starch, starch derivatives, dextran, cellulose, glycogen, or mixtures thereof. For example, starch derivatives can include dextrins, including maltodextrin, maltose syrup, or glucose syrup, or mixtures thereof. In some embodiments, the maltodextrin can have a DE (dextrose equivalent) of 3 to 20. In some embodiments, the maltose syrup can have a DE of greater than 50 (e.g., 52). In some embodiments, the glucose syrup can have a DE of greater than 20 (e.g., 42). In some aspects, the monosaccharides can include dihydroxyacetone, glyceraldehyde, erythrose, ribose, ribulose, sorbose, xylose, arabinose, fructose, glucose, galactose, mannose, or mixtures thereof. In other aspects, useful disaccharides can be selected from sucrose, maltose, cellobiose, gentiobiose, isomaltose, melibiose, primeverose, rutinose, trehalose, lactose, or mixtures thereof. In other embodiments, carbohydrates useful in the preparation of the stable iron sucrose compositions of the present disclosure include modified sugars, or modified disaccharides, or modified oligosaccharides or modified polysaccharides. Examples of these modified sugars include, but are not limited to, hydroxyethyl starch, deferoxamine, dextran aldehyde, dextran methacrylate, acid modified starch, sucralose, acetylthiosucrose or any other modified sugar. The preferred carbohydrate is sucrose.

[0061] In some embodiments, the iron component of the iron compositions of the present application has a surface interaction with the carbohydrate component, allowing the iron to be in solution as a colloidal particle, and an iron-carbohydrate colloid is formed. In some embodiments, the iron colloid can include an iron oxyhydroxide or iron oxide core complexed with a carbohydrate. In some embodiments, sucrose can interact with the iron core to have an iron-sucrose complex or an iron sucrose-colloid.

[0062] In many embodiments, the elemental iron and carbohydrate of the stable injectable iron composition of the present disclosure form a colloidal iron(III) carbohydrate complex. The colloidal iron(III) carbohydrate complex comprises typically spherical iron-carbohydrate nanoparticles, with the core of each particle being an iron-oxyhydroxide gel surrounded by a carbohydrate shell that stabilizes the iron-oxyhydroxide core (see, e.g., Bo G. Danielson, J Am Soc Nephrol 15: S93-S98, 2004). In other embodiments, the colloidal iron(III) carbohydrate complex comprises an iron monosaccharide complex, an iron disaccharide complex, an iron oligosaccharide complex, an iron polysaccharide complex, or a combination thereof. In yet other embodiments, the iron polysaccharide complex comprises iron carboxymaltose, iron sucrose, iron polyisomaltose, iron polymaltose, iron gluconate, iron sorbitol, iron hydrogenated dextran, iron delisomaltose (e.g., ferric delisomaltose or iron isomaltoside), or a mixture thereof. In various embodiments, the stable injectable composition comprises iron carboxymaltose (iron carboxymaltodextrin), iron sucrose, iron polyisomaltose, iron polymaltose, iron gluconate, iron sorbitol, iron hydrogenated dextran, iron delisomaltose (e.g., ferric delisomaltose or ferric isomaltoside), ferumoxytol (superparamagnetic iron oxide coated with a derivatized carbohydrate), or mixtures thereof.

[0063]

[0063] Examples of iron carbohydrate complexes include iron monosaccharide complexes, iron disaccharide complexes, iron oligosaccharide complexes, and iron polysaccharide complexes, such as iron carboxymaltose, iron sucrose, iron polyisomaltose (iron dextran), iron polymaltose (iron dextrin), iron gluconate, iron sorbitol, iron hydrogenated dextran (e.g., iron dextrin-sorbitol-citrate complex and iron sucrose-gluconate complex), which may be further complexed with other compounds, such as sorbitol, citrate and gluconate, and mixtures thereof.

[0064] In some embodiments, the iron carbohydrate complex may be an iron carboxymaltose complex, an iron mannitol complex, an iron polyisomaltose complex, an iron polymaltose complex, an iron gluconate complex, an iron disaccharide complex, an iron oligosaccharide complex, an iron sorbitol complex, or an iron hydrogenated dextran complex, as described in U.S. Patent Application Serial No. 15 / 958,930 to Helenek et al., which is incorporated herein by reference as if set forth in its entirety. In some embodiments, the iron carbohydrate complex is an iron polyglucose sorbitol carboxymethyl ether complex. In some other embodiments, the iron carboxymaltose complex contains about 24% to about 32% elemental iron, about 25% to about 50% carbohydrate, and is about 100,000 Daltons to about 350,000 Daltons. In various embodiments, the iron carboxymaltose complex is obtained from an aqueous solution of iron(III) salt and an aqueous solution of oxidation products of one or more maltodextrins, using an aqueous hypochlorite solution at pH values ​​in the alkaline range, where when one maltodextrin is applied, its dextrose equivalent is between 5 and 20, when a mixture of several maltodextrins is applied, the dextrose equivalent is between 5 and 20, and the dextrose equivalent of each individual maltodextrin contained in the mixture is between 2 and 20. In other embodiments, the iron carboxymaltose complex is obtained from [FeO x (OH) y (H2O) z ] n [{(C6H 10 O5) m(C6H 12 O7) l ] k wherein preferably the indices x, y, z, n, m, l and k provide a weight average molecular weight of about 100,000 Daltons to about 350,000 Daltons, more preferably n is about 10 3 wherein m is about 8, 1 is about 11, and k is about 4; contains about 28% elemental iron; and has a molecular weight of about 150,000 Da. In many other embodiments, the iron carboxymaltose complex is polynuclear iron(III)-hydroxide 4(R)-(poly-(1→4)-O-α-glucopyranosyl)-oxy-2(R),3(R),5(R),6-tetrahydroxy-hexanoate.

[0065] In various embodiments, the iron carbohydrate complex comprises an iron core having an average iron core size of about 9 nm or less. In some embodiments, the average iron core size is at least about 1 nm but not more than about 9 nm; at least about 3 nm but not more than about 7 nm; or at least about 4 nm but not more than about 5 nm. The iron core size can be determined, for example, by transmission electron microscopy (TEM), X-ray diffraction (XRD), atomic force microscopy (AFM), or Mössbauer spectroscopy, as described in Zou, Peng, et al. "Physicochemical Characterization of Iron Carbohydrate Colloid Drug Products," The AAPS Journal, Vol. 19, No. 5, September 2017, pp. 1359-1376.

[0066] In various embodiments, the average size of the particles of the iron carbohydrate complex is about 35 nm or less. In some embodiments, the average size of the particles is about 30 nm or less. In some embodiments, the average size of the particles is about 25 nm or less. In some embodiments, the average size of the particles is about 20 nm or less; about 15 nm or less; about 10 nm or less; or at least about 6 nm but not more than about 7 nm. The iron core size can be determined, for example, by transmission electron microscopy (TEM), X-ray diffraction (XRD), atomic force microscopy (AFM), or Mössbauer spectroscopy, as described in Zou, Peng, et al. "Physicochemical Characterization of Iron Carbohydrate Colloid Drug Products," The AAPS Journal, Vol. 19, No. 5, September 2017, pp. 1359-1376.

[0067] In some embodiments, iron polymaltose (iron dextrin) has a carbohydrate component that contains glucose molecules linked by α-1,4 linkages. In other cases, iron polyisomaltose has a carbohydrate component that contains long chains of α-1,6 linked glucose residues (i.e., chains of isomaltose), as in dextran. However, unlike dextran, polyisomaltose is linear, while dextran is a branched carbohydrate. In many cases, iron polyisomaltose complexes are substantially non-immunogenic and substantially non-cross-reactive with anti-dextran antibodies. As used herein, the term "iron carbohydrate complexes are substantially non-immunogenic" includes that the iron carbohydrate complexes pose a low risk of anaphylactic / hypersensitivity reactions, where the low risk is a lower incidence of adverse events than iron dextran. As also used herein, the term "substantially non-cross-reactive with anti-dextran antibodies" includes that it does not exhibit substantial binding to anti-dextran antibodies.

[0068]

[0068] Iron ferumoxytol, also known as derivatized carbohydrate coated superparamagnetic iron oxide, refers to an iron complex, where ferumoxytol comprises non-stoichiometric magnetite coated with polyglucose sorbitol carboxymethyl ether.

[0069]

[0069] An example of an iron sucrose injection solution has a molecular weight of approximately 34,000 to 60,000 Da and [Na2Fe5O8(OH)·3(H2O)] n ·m(C 12 H 22 O 11 and Venofer® (iron sucrose injection, USP), 20 mg / mL composed of the active pharmaceutical ingredient (API) polynuclear iron(III)-hydroxide in sucrose having a proposed structural formula of:

[0070]

[0071] Venofer® is indicated for the treatment of iron deficiency anemia in patients with chronic kidney disease (CKD). In the mammalian body, the polynuclear iron(III)-hydroxide-sucrose structure dissociates into iron and sucrose following intravenous administration, and the iron is transported to target cells, including erythroid progenitor cells, as a complex with transferrin. The iron in the progenitor cells is incorporated into hemoglobin as the cells mature into erythrocytes. In addition to Venofer®, other parenteral iron compositions approved in the United States include iron dextran (e.g., InFed®, Dexferrum®), sodium ferric gluconate complex in sucrose (Ferrlecit®), and ferric carboxymaltose injection (Injectafer®). Those approved in the UK also include iron sucrose (Sucrofer®, UK Claris).

[0071]

[0072] Ferric delisomaltose (e.g., ferric delisomaltose or ferric isomaltoside) is another form of iron compound used in the treatment of iron deficiency. The drug is a complex of iron(III) hydroxide and delisomaltose, the latter being an iron carbohydrate oligosaccharide that acts to release iron. The molecular formula of this iron carbohydrate complex is C. 18 H 34 FeO 16 +3 Specifically, ferric del-isomaltose is an iron-carbohydrate complex with a matrix structure composed of alternating layers of ferric hydroxide and the carbohydrate del-isomaltose. Del-isomaltose contains linear, hydrogenated isomaltooligosaccharides with an average molecular weight of 1000 Da. Ferric del-isomaltose has an average molecular weight of 155,000 Da and the following empirical formula: {FeO(1-3X)(OH)(1+3X)(C6H5O 73 -)X}, (HO)T, (CH 10 O6)R(-C6H 10 O5-)Z(C6H 13 O5) R, (NaCl)Y, where X=0.0311; T=0.25; R=0.14; Z=0.49; Y=0.14.

[0072]

[0073] In many embodiments, in the injectable iron compositions described in this disclosure, the stabilizing agent comprises an alkalizing agent, a buffering agent, sucrose, or a mixture thereof. In many embodiments, the stable injectable iron compositions described in this disclosure also comprise an agent that can be selected from an alkaline solution, a buffering agent, or sucrose. Useful alkaline solutions include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, or a mixture thereof. Buffers useful as stabilizing agents in the iron compositions of this disclosure include acidic and basic buffers. Stabilizing agents include, but are not limited to, hydrochloric acid, sodium acetate, acetic acid, sodium citrate, citric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, calcium bicarbonate, or a mixture thereof. Other useful buffers that can be used as stabilizers include, but are not limited to, sucrose, polyisomaltose, sorbitol, citric acid, polymaltose, gluconate, chondroitin sulfate, carboxymaltose, mannitol, polyglucose sorbitol carboxymethyl ether, isomaltoside, delisomaltose, citrate, L-histidine, histidine, glycine, arginine, tyrosine, lysine, or mixtures thereof.

[0073]

[0074] The stabilizing agent in the iron compositions of the present disclosure reduces changes to pH, Mw, Mn, density, T75, and / or PDI over a period of time compared to an iron composition that does not include a stabilizing agent. For example, in some embodiments, unless otherwise indicated, a stable composition is one that retains at least about 85%, or at least about 90%, or at least about 95%, or at least about 99% of the initial amount of the colloidal iron(III) carbohydrate complex composition in its state (e.g., not substantially precipitated, not substantially decomposed, or not substantially adsorbed to the container) for a period of two years. In some embodiments, a stable composition has a potency range of 95%-105% or 90%-110% of the labeled amount for a period of up to two years.

[0074]

[0075] In some embodiments, the stable injectable iron composition comprises elemental iron, the carbohydrate comprises sucrose, and the stabilizer comprises at least one of a sodium compound, L-histidine, or sucrose. The sodium can be provided, for example, by sodium hydroxide, sodium chloride, or sodium gluconate. The sodium compound can also stabilize the iron in the composition.

[0075]

[0076] In some embodiments, the total amount of carbohydrate referred to herein (e.g., total sucrose) includes carbohydrate ligands that are complexed with or bound to iron, as described, for example, in the Examples, and amounts that are not complexed with or bound to iron. In some embodiments, carbohydrate that is not complexed with iron can be added to an already carbohydrate-iron complex. In various embodiments, the iron compositions described in this application contain elemental iron (about 1.0 to about 2.0 mg / mL), total sucrose (about 20 to about 195 mg / mL), a buffer consisting of Na ions (about 2 to about 708 mM or 0.08 to about 28.3 mg / mL as NaOH) to adjust tonicity and / or as a stabilizer, and L-histidine (about 0 to about 0.9 mg / mL) to maintain a pH in the range of about 10 to about 11.1, and water for injection (QS) as a vehicle. In various embodiments, the additives include sucrose, NaOH, and L-histidine, which in some embodiments may be included within the limit concentrations for intravenous compositions within the limits set forth by the FDA Inactive Ingredients Database. For example, the FDA database lists 0.09% mg w / v or less for histidine, 2.83% w / v or less for NaOH, and 19.5% w / v or less for sucrose for intravenous solutions.

[0076]

[0077] In some embodiments, the stable injectable composition comprises elemental iron in an amount of 1.0 mg, total sucrose in an amount of 57.5 mg / mL, sodium hydroxide in an amount of 0.08 mg / mL, and optionally L-histidine in an amount of 0.75 mg / mL. In various embodiments, the stable injectable compositions described in this disclosure have a total volume of 1 mL, which allows their application as direct intravenous administration to patients suffering from anemia-related diseases, disorders, or conditions, thus avoiding the disadvantages resulting from long-term intravenous infusion. However, in some embodiments, the injectable composition with a total volume of 1 mL can be diluted with saline or dextrose 5% in water (also known as D5W solution, suitable for intravenous (IV) injection to replace lost body fluids and provide carbohydrates to the body). In some embodiments, dextrose 5% in water can be used to treat low blood sugar (hypoglycemia), insulin shock, or dehydration.

[0077]

[0078] In some embodiments, the stable iron compositions of the present application can have nano-sized iron particles having an average particle size range of about 7 nm to about 25 nm. For example, the stable iron compositions of the present application can have total iron nano-sized particles having an average particle size range of about 8.0 nm, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.1 to about 10.2 nm. The iron core size can be determined by dynamic light scattering (DLS), atomic force microscopy (AFM), or Mössbauer spectroscopy, for example, as described in Zou, Peng, et al. "Physicochemical Characterization of Iron Carbohydrate Colloid Drug Products," The AAPS Journal, Vol. 19, No. 5, September 2017, pp. 1359-1376.

[0078]

[0079] In various embodiments, the elemental iron and carbohydrate of the stable injectable iron compositions of the present disclosure form a colloidal iron(III) carbohydrate complex. The elemental iron(III) in the colloidal iron carbohydrate complex can be in an amount of about 0.25 mg / mL to about 20 mg / mL (e.g., 1 mg / mL to about 2 mg / mL or 1 mg / mL to about 5 mg / mL). In some embodiments, the amount of elemental iron can range from about 1 mg / mL, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL to about 20 mg / mL.

[0079]

[0080] The carbohydrate may be present in the composition in an amount of about 3 mg / mL to about 250 mg / mL (e.g., about 5 mg / mL to about 200 mg / mL). In some embodiments, the carbohydrate may be present in the composition in an amount of about 3 mg / mL to about 250 mg / mL (e.g., about 5 mg / mL to about 200 mg / mL) per mg or 2 mg of iron. In some embodiments, this can include the total amount of carbohydrate (e.g., total sucrose) that is complexed with or bound to iron, and the amount that is not complexed with or bound to iron, as shown, for example, in Table IV. In some embodiments, the carbohydrate may be part of the stabilizing agent, which may be sucrose in an amount of about 3 mg / mL to about 250 mg / mL (e.g., about 5 mg / mL to about 195 mg / mL).

[0080]

[0081] In some embodiments, sucrose, which may also be a stabilizer, is in some embodiments about 5 mg / mL, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 42.5, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 1 11, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158 , 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199 to about 200 mg / mL in the composition.

[0081]

[0082] In some embodiments, sucrose, which may also be a stabilizer, is in some embodiments about 5 mg / mL, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 42.5, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 120, 121, 122, 9, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 101, 102, 103, 104, 105, 106, 107, 108, 10 9, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157 , 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199 to about 200 mg / mL in the composition.

[0082]

[0083] In some embodiments, the stabilizing agent in the composition comprises an alkalizing agent, a buffering agent or sucrose. The alkalizing agent can comprise sodium hydroxide, potassium hydroxide, calcium hydroxide or a combination thereof. The alkalizing agent may be present in the composition in an amount of about 0.025 mg / mL to about 80 mg / mL (e.g., about 0.08 mg / mL to about 28.3 mg / mL). In some embodiments, the alkalizing agent may be present in the composition in an amount of about 0.025 mg / mL to about 80 mg / mL (e.g., about 0.08 mg / mL to about 28.3 mg / mL) per 1 mg / mL or 2 mg / mL of iron. In various embodiments, a ready-to-use (RTU) IV infusion contains elemental iron in an amount of about 1 mg / mL to about 2 mg / mL (about 18 mM to about 36 mM), sucrose in an amount of about 15 mg / mL to about 195 mg / mL (about 44 mM to about 570 mM), sodium phosphate as provided by NaOH in an amount of about 0.08 to about 28.3 mg / mL (about 2 mM to about 708 mM), and sucrose in an amount of about 15 mg / mL to about 195 mg / mL (about 44 mM to about 570 mM). + ions, and L-histidine in an amount of about 0 to about 0.9 mg / mL (about 0 to about 6 mM) or 0 to about 1.5 mg / mL (about 0 to about 10 mM).

[0083]

[0084] In some embodiments, L-histidine may be present in the composition in an amount of about 0 to about 0.9 mg / mL (about 0 to about 6 mM) or 0 to about 1.5 mg / mL (about 0 to about 10 mM) per 1 mg / mL or 2 mg / mL of iron.

[0084]

[0085] For example, the stabilizer (e.g., sodium hydroxide) may be present in the composition in a range of about 0.08 mg / mL, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 to about 28.3 mg / mL.

[0085]

[0086] In some embodiments, the iron-carbohydrate complex or iron-carbohydrate colloid can be stabilized with a stabilizing agent (e.g., sodium compounds, histidine, and / or carbohydrates, such as sucrose or mixtures thereof) by adding the stabilizing agent to the iron-carbohydrate complex or iron-carbohydrate colloid. Without being bound to any particular theory, it is believed that in some embodiments, sodium compounds and / or unbound sucrose can stabilize the iron-sucrose complex or iron sucrose colloid. For example, the stabilizing agent can reduce or prevent aggregation of iron sucrose resulting from an increase in weight average molecular weight, a decrease in pH, a change in iron species, and precipitation of the iron sucrose complex.

[0086]

[0087] The w / w or w / v ratio of elemental iron (e.g., 1 mg or 2 mg of iron) to carbohydrate (e.g., sucrose) in the stabilized iron compositions of the present application may be about 1:16 w / w or w / v, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85 , 1:90, 1:95, 1:100, 1:105, 1:110, 1:115, 1:120, 1:125, 1:130, 1:135, 1:140, 1:145, 1:150, 1:155, 1:160, 1:165, 1:170, 1:175, 1:180, 1:190, 1:195 to about 1:200 w / w or w / v.

[0087]

[0088] In some embodiments, the buffering agent in the composition can include sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, calcium bicarbonate, L-histidine, glycine, arginine, tyrosine, lysine, or combinations thereof. The buffering agent can be present in the composition in an amount of 0.125 mg / mL to about 5 mg / mL, or 0.125 mg / mL to about 20 mg / mL, or about 1 mg / mL to about 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL to about 2.0 mg / mL. In some embodiments, the buffering agent includes L-histidine, and the L-histidine is present in the composition in a range of about 0 mg / mL, 0.125, 0.25, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 to about 0.9 mg / mL.

[0088]

[0089] In certain embodiments, the colloidal iron(III) carbohydrate complex comprises iron sucrose, where the iron sucrose comprises elemental iron(III) in an amount of about 1 mg / mL to about 2 mg / mL and sucrose in an amount of about 14 to about 31 mg / mL. In some aspects, the sucrose in the colloidal iron(III) carbohydrate complex, prior to the addition of additional sucrose as a stabilizing agent, can range from about 1 mg / mL, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 to about 31 mg / mL.

[0089]

[0090] In some embodiments, the sucrose in the colloidal iron(III) carbohydrate complex, before additional sucrose is added as a stabilizer, is about 1 mg sucrose per mg iron, 2 mg sucrose per mg iron, 3 mg sucrose, 4 mg sucrose, 5 mg sucrose, 6 mg sucrose, 7 mg sucrose, 8 mg sucrose, 9 mg sucrose, 10 mg sucrose, 11 mg sucrose, 12 mg sucrose, 13 mg sucrose, 14 mg sucrose, 15 mg sucrose, 16 mg sucrose, 17 mg sucrose, 18 mg sucrose, 19 mg sucrose, 20 mg sucrose, 21 mg sucrose, 22 mg sucrose, 23 mg sucrose, 24 mg sucrose, 25 mg sucrose, 26 mg sucrose, 27 mg sucrose, 28 mg sucrose, 29 mg sucrose, 30 mg sucrose, 31 mg sucrose, 32 mg sucrose, 33 mg sucrose, 34 mg sucrose, 35 mg sucrose, 36 mg sucrose, 37 mg sucrose, 38 mg sucrose, 39 mg sucrose, 40 mg sucrose, 41 mg sucrose, 42 mg sucrose, 43 mg sucrose, 44 mg sucrose, 45 mg sucrose, 46 mg sucrose, 47 mg sucrose, 48 mg sucrose, 49 mg sucrose, 50 mg sucrose, 51 mg sucrose, 52 mg sucrose, 53 mg sucrose, It can be present in the range of 4 mg sucrose, 15 mg sucrose, 16 mg sucrose, 17 mg sucrose, 18 mg sucrose, 19 mg sucrose, 20 mg sucrose, 21 mg sucrose, 22 mg sucrose, 23 mg sucrose, 24 mg sucrose, 25 mg sucrose, 26 mg sucrose, 27 mg sucrose, 28 mg sucrose, 29 mg sucrose, 30 mg sucrose to about 31 mg sucrose.

[0090]

[0091] A stabilizer of sodium hydroxide can be added to the composition in an amount of about 0.07, or about 0.08 to about 28.3 mg / mL, or about 0.96 mg / mL, L-histidine can be in an amount of about 0 to about 0.9 mg / mL, and additional sucrose can be added as a stabilizer in an amount of about 5 to about 195 mg / mL.

[0091]

[0092] In other embodiments, elemental iron in the stable injectable composition can be in an amount of 1 mg / mL, sucrose, whether bound or unbound, can be in an amount of about 20 to about 95 mg / mL, sodium hydroxide can be in an amount of about 0.08 to about 1.84 mg / mL, and L-histidine can be in an amount of about 0 to about 1.6 mg / mL. In various embodiments, the amount of sucrose in the stable injectable composition of the present disclosure can be greater than 15 mg / mL. In yet other embodiments, the stable injectable iron composition comprises sucrose in a colloidal iron(III) carbohydrate complex in an amount that may vary from about 15 to about 30 mg / mL, and elemental iron in an amount that may be from about 1 to about 2 mg / mL, wherein the amount of sucrose that can be added as a stabilizer to the already formed colloidal iron(III) carbohydrate complex can vary from about 5 to about 195 mg / mL, the amount of sodium hydroxide can vary from about 0.07 to about 28.3 mg / mL or about 0.98 mg / mL, and the amount of L-histidine can vary from about 0 to about 1.6 mg / mL. In some embodiments, the stable injectable iron composition comprises sucrose in a colloidal iron(III) carbohydrate complex in an amount that may vary from about 15 to about 30 mg / mL, and elemental iron in an amount that may be from about 1 mg / mL to about 20 mg / mL.

[0092]

[0093] In certain embodiments, the iron composition comprises a colloidal iron(III) carbohydrate complex comprising iron sucrose in an amount of about 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL to about 10 mg / mL.

[0093]

[0094] In one particular embodiment, the active pharmaceutical ingredient (API) in the iron composition has a molecular weight of approximately 34,000 to 60,000 Daltons (Da) and a proposed structural formula: [Na2Fe5O8(OH)·3(H2O)] n ·m(C 12 H 22 O 11 ) where n is the degree of iron polymerization and m is the number of sucrose molecules associated with the polymerized iron(III)-hydroxide. The sucrose in the polynuclear iron(III)-hydroxide complex may range from about 0.5 mg / mL, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 to about 31 mg / mL. The stabilizing agent sodium hydroxide may be present in the iron compositions of these embodiments in an amount from about 0.07, or about 0.08 to about 28.3 mg / mL, or about 0.96 mg / mL.

[0094]

[0095] In various aspects, the stable injectable compositions described in the present disclosure have a pH and physiological osmolality of about 10 to about 11.5. In some embodiments, the injectable compositions of the present application have an osmolality of about 200 mOsm / L, 250, 300, 345, 350, 400, 450, 480, 500, 550 to about 600 mOsm / L to reduce pain, irritation and tissue damage.

[0095]

[0096] The pH of the injectable iron composition can be adjusted using a suitable acid, including, but not limited to, sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, acetic acid, citric acid, lactic acid, carboxylic acid, sulfonic acid, or combinations thereof.

[0096]

[0097] The pH of the injectable iron composition can be adjusted using a suitable base, examples of which include, but are not limited to, sodium hydroxide, sodium carbonate, sodium bicarbonate, calcium hydroxide, calcium carbonate, potassium hydroxide, or combinations thereof.

[0097]

[0098] In some embodiments, the pH may range from about 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4 to about 11.5. The average molecular weight (Mw) of the injectable compositions of the present disclosure may vary from about 34 kDa to about 60 kDa. In various aspects, the number average molecular weight (Mn) of these injectable compositions may vary from about 24 kDa to about 60 kDa. The polydispersity index thus obtained of these injectable compositions may vary from about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6 to about 1.7. In some embodiments, the injectable iron compositions of the present disclosure have a density of about 1.027 to about 1.047 g / mL or about 1.037 to about 1.058 g / mL for about 3 months, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 36, or about 48 months.

[0098]

[0099] In some embodiments, there is potential toxicity resulting from increased reduction of Fe(III) to Fe(II) species in injectable compositions containing iron carbohydrate complexes, such as colloidal iron sucrose complexes. To minimize conversion of Fe(III) to Fe(II) and ensure product quality, stabilizers are added, so that in some embodiments, the amount of elemental Fe(II) in these iron injectable compositions can vary from about 0.01 wt / v% to about 0.4 wt / v%, and in other embodiments, from about 0.4 wt / wt% to about 1.7 wt / wt%. In some embodiments, the amount of elemental Fe(II) can vary in the range of about 0.4 wt / v%, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6 to about 1.7 wt / v%.

[0099]

[0100] In some embodiments, the stability of the stable iron compositions of the present application can be compared to an existing FDA approved injectable iron formulation (Venofer®) using an in vitro controlled release test for trivalent ferric iron (T75) to demonstrate therapeutic equivalence over time. The T75 reduction kinetics of iron from Fe+3 to Fe+2 can be tested as described in U.S. Patent No. 6,911,342 to Helenek et al., which is incorporated herein by reference. In various embodiments, the time required for 75% of elemental iron (III) to be released from the iron injectable composition (also known as T75) can vary from about 20 minutes or less to a shelf life of 24 months.

[0100]

[0101] In many embodiments, the storage stability of the injectable iron composition may be about 24 months. In some embodiments, the stability of the injectable iron composition may be about 3 months, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months. In some embodiments, the stability of the injectable iron composition may be about 3 months, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months, and the composition has no detectable precipitate form. In yet other aspects, the stable injectable iron composition of the present disclosure may be at least one of a preservative-free composition, a sterile composition, or a ready-to-use aqueous injectable composition.

[0101] container

[0102] In various embodiments, the injectable iron sucrose composition is placed in a container. The container can have a variety of volumes. Typically, the container can have a volume of about 1 mL to about 250 mL. In some examples, the container can have a volume of about 1 mL, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 to about 250 mL. In other embodiments, the volume of the container can be about 250 mL, 300, 350, 400, 450 to about 500 mL. In many aspects, useful containers for the iron composition of the present disclosure include disposable vials, bottles, ampoules, bags, or any type of container capable of holding a desired volume of the iron composition of the present application in a sterile state. In other aspects, the container can include a vial with a barrier-coated stopper and / or an aluminum cap. In some embodiments, the vial or ampoule includes glass (e.g., Type I glass) or a plastic material (e.g., polypropylene). In other cases, the container for the iron composition of the present disclosure can be made of a variety of materials. Non-limiting materials for the container can include glass, plastic (e.g., polyethylene, polypropylene, polyvinyl chloride, polycarbonate, etc.), the like, or combinations thereof, that can both prevent or reduce oxygen transmission and minimize aluminum, heavy metal, and anion contamination to the composition. In certain embodiments, the container is fabricated from multi-layer plastic (PL2501, PL2040), also known as Galaxy container, which is a plastic container primarily for intravenous use. In other cases, the container can be a bag, which can be PVC- or polypropylene-based.

[0102]

[0103] In other embodiments, the container can be made of glass as a disposable vial, for example, a type I glass vial for injectable products. In other embodiments, the container can be a bag having about 10 mL to about 250 mL. In some embodiments, the pharmaceutical composition of the present disclosure can also be stored in a glass vial or ampoule, for example, a 10 mL disposable glass vial or ampoule.

[0103]

[0104] In some embodiments, the composition comprising iron, carbohydrate, stabilizing agent, and water can be provided in a bag, syringe, vial, or bottle that can hold a volume of 1 mL, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 to about 250 mL. The composition can comprise, for example, 1 mg / mL elemental iron or 2 mg / mL elemental iron, for example, in a ready-to-use formulation in a 100 mL bottle or bag containing carbohydrate, stabilizing agent, and water. The composition bottle or bag can have a stopper (e.g., uncoated or coated bromobutyl stopper, or uncoated or coated chlorobutyl stopper) and / or a vent hole disposed therein that is configured to receive a tubing set that can be vented or non-vented. In some embodiments of the ready-to-use iron composition, the user can spike the stopper, connect the vented or non-vented tubing to the bag or bottle, and administer the composition to a patient in need of iron treatment, with or without an IV pump.

[0104]

[0105] In some embodiments, the iron compositions of the present application are stable in a vial, bottle, or bag at normal storage conditions for extended periods of time. In certain embodiments, the iron compositions of the present application are stable at about 25° C.±2° C., 30° C.±2° C., 40° C.±2° C., 60° C.±2° C., and 60-75±5% RH for at least 6 months, typically at least 12 months, and typically at least 18 months, 24 months, 36 months, or 48 months.

[0105]

[0106] As previously discussed, the pH range for iron carbohydrate IV dosage forms varies from about 10 to about 11.5. This pH can damage plastic or silicon coatings in glass containers, and aluminum, heavy metals, and anions can leach out during the shelf life of the product, especially over extended storage of the product. Elemental impurities monitored in the final drug products described in this disclosure include, but are not limited to, Cd, Pb, As, Hg, Co, V, Ni, Tl, Au, Pd, Ir, Os, Rh, Ru, Se, Ag, Pt, Li, Sb, Ba, Mo, Cu, Sn, and Cr. In some embodiments, the iron-carbohydrate composition contains from 0.0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, or 4.9 to about 5.0 ppb of these impurities. In some embodiments, the iron-carbohydrate composition contains elemental impurities in amounts as defined by the International Council on Harmonization (ICH) guidance, Q3D Elemental Impurities for Industry (ICH Q3D).

[0106] Headspace Oxygen

[0107] In certain embodiments, the composition is present in a container at about 0.5 v / v% to about 5.0 v / v%, or about 0.5 v / v% to about 4.0 v / v%, or about 0.5 v / v% to about 3.5 v / v%, or about 0.5 v / v% to about 3.0 v / v%, or about 0.5 v / v% to about 2.5 v / v%, or about 0.5 v / v% to about 2.0 v / v%, or about 0.5 and further comprising a headspace gas containing oxygen in an amount of about 0.5 v / v% to about 1.5 v / v%, or about 0.5 v / v% to about 1.0 v / v%, or in some cases about 0.1 v / v% to about 0.5 v / v%, or about 0.1 v / v% to about 0.4 v / v%, or about 0.1 v / v% to about 0.3 v / v%, or about 0.1 v / v% to about 0.2 v / v%. For clarity and ease of discussion and measurement, these values ​​are taken for the iron composition at the time of its manufacture (the "time zero" data point) or at and up to one month from time zero. Additional time points beyond one month from the time zero data point may achieve similar headspace oxygen levels.

[0107]

[0108] Without being bound by any particular theory, the dissolved oxygen levels and headspace oxygen levels in a sealed container of the iron compositions described herein may reach equilibrium at some time during its shelf life. Such equilibrium may be maintained for a very short time, i.e., a few seconds, or for a very long time, i.e., several months. Such equilibrium may be disturbed from time to time by simple agitation. Thus, it should be recognized that the dissolved oxygen levels and headspace oxygen levels may vary in absolute numbers from one time point to another. However, the numbers are expected to remain within the ranges disclosed herein. At times, a number (e.g., dissolved oxygen) may be above or below a particular range (e.g., about 0.5 to about 3.0 PPM) at the 15 day time point, but fall within that range at some other time point (e.g., at or after the 30 day time point). Thus, in some embodiments, the ranges, subranges, and specific data points disclosed and discussed herein are appropriate for the time points beyond time zero and the one month time point. In one embodiment, the time points may extend to about 2 months, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, and up to about 24 months.

[0108]

[0109] In some cases, the total amount of oxygen in a sealed container may be a suitable measure to assess the stability of an iron composition. In many embodiments, the compositions described in this application are not oxygen sensitive. In certain embodiments, the dissolved oxygen level ranges from about atmospheric to about 0.5 mg / L.

[0109]

[0110] The amount of oxygen present in the headspace of the container can be controlled by filling the headspace with an inert gas, such as nitrogen or argon. Alternatively, the headspace oxygen can be controlled by a vacuum operation without using an inert gas. In another embodiment, the headspace oxygen can be controlled by a combination of vacuum operation and inert gas overlay. In one particular embodiment, the headspace oxygen is controlled by repeated pulses of vacuum and inert gas overlay in succession, the process can start with a vacuum operation first, followed by an inert gas overlay, followed by a vacuum operation. The combination of vacuum operation and inert gas overlay (or inert gas overlay and vacuum operation) is considered to be one pulse when both steps are used together. A typical headspace control operation can include 1 to 8 pulses. Typically, there can be 2, 3, 4, or 5 pulses. Each pulse can last from about one-tenth of a second to 5 seconds, or from 5 to 15 seconds, when performed by automated high-speed equipment custom designed for this specific purpose. In some embodiments, the pulses may last from about 0.1 to about 2.0 seconds. In some embodiments, the pulses may last from about 0.1 to about 1.0 seconds, or from about 0.1 to about 0.4 seconds. When performed using manual methods, each pulse may take up to 30 to 60 seconds or more.

[0110]

[0111] During the manufacturing process, in one embodiment, dissolved oxygen levels are controlled by sparging with an inert gas. Additionally, a blanket of inert gas (e.g., nitrogen, argon, helium) can be maintained throughout manufacturing and storage to control exposure to atmospheric oxygen, while opaque containers (stainless steel or amber glass) are selected to protect the formulation from exposure to light.

[0111]

[0112] In some embodiments, the iron composition is preservative-free. As used herein, preservative-free includes compositions that do not contain preservatives. Thus, the composition does not contain, for example, benzalkonium chloride, methyl, ethyl, propyl or butyl paraben, benzyl alcohol, phenylethyl alcohol, or benzethonium. The pH of the iron composition ranges from about 10 to about 11.5, and the iron composition can exhibit antimicrobial properties (e.g., antibacterial properties) at this alkaline pH in the absence of preservatives.

[0112]

[0113] In some embodiments, one or more antioxidants can be incorporated into the injectable pharmaceutical composition described in the present disclosure.Antioxidants can be introduced into pharmaceutical compositions to inhibit or delay the potential oxidation of active ingredients.Examples of antioxidants that can also be present in injectable pharmaceutical compositions include, but are not limited to, acetone sodium hydrogen sulfate, ascorbate, ascorbic acid, alpha-tocopherol, sodium hydrogen sulfate, butylated hydroxyanisole, butylated hydroxytoluene, cysteine, cysteinate HCl, sodium dithionite, gentisic acid, gentisic acid ethanolamine, monosodium glutamate, sodium formaldehyde sulfoxylate, potassium pyrosulfite, sodium metabisulfite, monothioglycerol, propyl gallate, sodium sulfite, sodium thioglycolate, or combinations thereof.

[0113]

[0114] In some embodiments, one or more preservatives can be incorporated into the injectable pharmaceutical compositions described in this disclosure. Preservatives can be introduced into the pharmaceutical solution to kill bacteria, yeast, and mold.

[0114]

[0115] Several preservatives are available that can kill or prevent the growth of commonly encountered contaminants; these contaminants include, but are not limited to, the bacteria Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli (E. coli), and Staphylococcus aureus (S. aureus); the yeast Candida albicans (C. albicans); and the mold Aspergillus niger (A. brasiliensis).

[0115]

[0116] The presence of at least one preservative, in some embodiments, allows the injectable pharmaceutical composition to be used for at least 2 days, 7 days, or even 1 month or more once the container holding the composition is opened. The injectable pharmaceutical composition has a minimum opened vial antimicrobial effectiveness of at least 1 day, and in some cases, the opened vial antimicrobial effectiveness includes 7 days or more.

[0116]

[0117] The incorporation of one or more preservatives in the pharmaceutical composition should not interfere with the solubility of the iron composition and the final composition can still pass the test methods of the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation (meeting at least criterion B for parenteral products) and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products.

[0117]

[0118] In some embodiments, at least one preservative is present in the pharmaceutical composition and may be selected from the group including, but not limited to, m-cresol, chlorocresol, parabens (including, but not limited to, methylparaben, ethylparaben, propylparaben, butylparaben), derivatives and salts thereof, chlorobutanol, quaternary ammonium compounds, derivatives and salts thereof (including benzethonium chloride, benzalkonium chloride), boric acid, benzyl alcohol, cetylpyridinium chloride, cetrimide, phenol, phenylethanol, phenoxyethanol, or mixtures thereof.

[0118]

[0119] The preservative or preservatives are present in an amount effective to impart the desired preservative characteristics and that enables the final composition to comply with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation (meeting at least criterion B for parenteral products), and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products.

[0119] Method for preparing an iron composition

[0120] The stable injectable iron compositions of the present application can be made by mixing iron with a carbohydrate and water to form a mixture and adding a stabilizer to the mixture to form a stable injectable iron composition.

[0120]

[0121] In some embodiments, the iron compositions of the present application have an iron core bound to carbohydrate ligands to form an iron-carbohydrate complex or an iron-carbohydrate colloid. The iron core can be, for example, a polynuclear iron-oxyhydroxide core that can be bound to the carbohydrate ligands by van der Waals forces, nonionic hydrogen bonding, ionic hydrogen bonding, and / or coordinate bonds.

[0121]

[0122] The stable iron compositions of the present application can be prepared using commercially available iron-carbohydrate complexes or iron-carbohydrate colloids that can be mixed with water and a stabilizing agent as discussed herein to form the stable ready-to-use or ready-to-administer iron compositions of the present application. Suitable commercially available iron-carbohydrate complexes or iron-carbohydrate colloids that provide a source of elemental iron that can be used to make the stable iron compositions of the present application are listed in Table A below.

[0122] [Table 1]

[0123]

[0123] The commercially available iron-carbohydrate complexes or iron-carbohydrate colloids listed in Table A are available from the following manufacturers listed in Table B below.

[0124] [Table 2]

[0125]

[0124] Referring to Table A above, iron sucrose contains sucrose, a disaccharide, e.g., a low molecular weight carbohydrate, as a ligand. The drug product contains 20 mg elemental iron / mL and approximately 30% sucrose w / v (300 mg / mL), e.g., 15 mg sucrose / mg iron. The drug product has a pH of 10.5-11.1. The proposed structural formula is [Na2Fe5O8(OH)·3(H2O)] n ·m(C 12 H 22 O 11 ). Sodium ferric gluconate comprises the sodium salt of the ferric ion carbohydrate complex in alkaline aqueous solution with 12.5 mg iron / mL and approximately 20% sucrose w / v, e.g., 16 mg sucrose / mg iron. In contrast to iron sucrose, the drug product has a pH of 7.7-9.7. The structural formula is [NaFe2O3(C6H 11 O7)(C 12 H22 O 11 )5] n≒200 According to this formula, this contains 1 gluconate (also a low molecular weight ligand) for every 2 iron or 1.7 mg gluconate / mg iron.

[0126]

[0125] The low molecular weight iron dextran contains 50 mg iron / mL. The pH of the solution is 4.5-7.0. The content of the iron(III)-hydroxide dextran complex is 312.5 mg / mL. The dextran content is approximately 206 mg / mL or 4.1 mg dextran / mg iron.

[0127] Ferric delisomaltose, also called iron isomaltoside 1000, contains 100 mg of iron / mL. Isomaltoside 1000 contains 3-5 glucose units and is derived from the chemical modification of isomaltooligosaccharides present in dextran 1. Ferric delisomaltose has the empirical formula: {FeO (1-3X) (OH) (1+3X) (C6H5O7 3- )} X , (H2O) T , (CH 10 O6) R (-C6H 10 O5 - ) Z (C6H 13 O5) R , (NaCl) Y ;X=0.0311;T=0.25;R=0.14;Z=0.49;Y=0.14. The iron carbohydrate complex contains approximately 2.3 mg delisomaltose / mg iron. The iron citrate isomaltooligosaccharide alcohol-hydrate complex, ferric delisomaltose, also contains citrate as an additional ligand at a concentration of approximately 10 mg / mL or 0.1 mg citrate / mg iron. The drug product is a solution having a pH of 5.0-7.0.

[0128] Ferric carboxymaltose contains 50 mg iron / mL. The complex has the empirical formula: [FeO x (OH)y (H2O) z ] n [{(C6H 10 O5) m (C6H 12 O7) l ] k , where n≒10 3 where m≈8, l≈11, and k≈4 (l represents the average branching degree of the ligand). The ligand carboxymaltose is obtained from maltodextrin by oxidation. The drug product is a solution having a pH of 5.0-7.0. The complex contains approximately 75 mg carboxymaltose / mL (approximately 1.5 mg carboxymaltose / mg iron).

[0129] Ferumoxytol contains 30 mg iron / mL. The complex is iron oxide coated with polyglucose sorbitol carboxymethyl ether. The chemical formula of Ferumoxytol is Fe 5874 O 8752 -C 11719 H 18682 O 9933 Na 414 Based on this formula, the complex contains approximately 0.97 mg carbohydrate / mg iron. Polyglucose sorbitol carboxymethyl ether is a dextran with a low degree of branching (1-2%), partially carboxymethylated at the C-2, C-3, or C-4 positions in the glucan backbone, and reduced non-carboxymethylated C-1 chain end units. Ferumoxytol drug product is formulated with mannitol (1.5 mg mannitol / mg iron). It has a pH of 6-8.

[0130]

[0129] The commercially available iron-carbohydrate complexes or iron-carbohydrate colloids listed in Table A have the iron-carbohydrate contents and pHs listed in Table C below.

[0131] [Table 3]

[0132]

[0131] The commercially available iron-carbohydrate complexes or iron-carbohydrate colloids listed in Table A have the following physicochemical properties, which are listed in Table D below.

[0133] [Table 4]

[0134] The iron-carbohydrate complexes or iron-carbohydrate colloids listed in Table A can be used to provide a source of elemental iron as the iron-carbohydrate complexes or iron-carbohydrate colloids for the stable iron compositions of the present application. The iron-carbohydrate complexes or iron-carbohydrate colloids can be mixed with water and a stabilizer to obtain the stable iron compositions of the present application. Stabilizing agents include, but are not limited to, hydrochloric acid, sodium acetate, acetic acid, sodium citrate, citric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, calcium bicarbonate, sucrose, sucrose gluconate, sorbitol, citric acid, polymaltose (dextrin), gluconate, chondroitin sulfate, carboxymaltose (carboxymaltodextrin), maltose, mannitol, polyglucose sorbitol carboxymethyl ether, isomaltoside, delisomaltose, citrate, L-histidine, histidine, glycine, arginine, tyrosine, lysine, or mixtures thereof. In some embodiments, the stabilizing agent may be a sodium compound, such as sodium acetate, sodium chloride, sodium hydroxide, sodium carbonate, sodium bicarbonate, or mixtures thereof.

[0135] Such mixing may result in one or more chemical reactions (e.g., further colloid formation); however, mixing of the components in the iron composition may be in any order. In some embodiments, the stable injectable compositions of the present application may be prepared by mixing an iron carbohydrate colloid with water to form a mixture to which a stabilizing agent is added to form a stable injectable iron composition. In some embodiments, mixing may be performed in which a carbohydrate (e.g., sucrose) is added to water to form a mixture of water and carbohydrate, then a stabilizing agent (e.g., sodium hydroxide) is added to the mixture, and then iron is added to the mixture with or without further stabilizing agent to form a stable injectable iron composition (e.g., at a pH range of about 10.1 to 11.1). The injectable iron composition may then be filtered and / or autoclaved, placed into a container (e.g., a vial, an ampoule, an IV bottle, an IV bag, etc.) and sealed.

[0136]

[0134] In many cases, the carbohydrate, which itself may be a stabilizer, may be a monosaccharide, a polysaccharide, such as a disaccharide, or an oligosaccharide. The monosaccharide may be glucose, galactose, fructose, or a mixture thereof. Useful disaccharides include, for example, sucrose, lactose, maltose, or a mixture thereof. Useful oligosaccharides may include ferric delisomaltose or ferric isomaltoside, raffinose, stachyose, verbascose, or a mixture thereof. Various polysaccharides include starch, starch derivatives, dextran, cellulose, glycogen, or a mixture thereof. For example, starch derivatives may include dextrins, including maltodextrin, maltose syrup, or glucose syrup, or a mixture thereof. In some embodiments, the monosaccharide may include dihydroxyacetone, glyceraldehyde, erythrose, ribose, ribulose, sorbose, xylose, arabinose, fructose, glucose, galactose, mannose, or a mixture thereof. In other embodiments, useful disaccharides can be selected from sucrose, maltose, cellobiose, gentiobiose, isomaltose, melibiose, primeverose, rutinose, trehalose, lactose, or mixtures thereof.

[0137]

[0135] In some embodiments, the iron present in the stable injectable iron sucrose composition is elemental iron. In various embodiments, the elemental iron and carbohydrate of the stable injectable iron composition of the present disclosure form a colloidal iron (III) carbohydrate complex. In many cases, the colloidal iron (III) carbohydrate complex comprises an iron monosaccharide complex, an iron disaccharide complex, an iron oligosaccharide complex, an iron polysaccharide complex, or a combination thereof. In yet other embodiments, the iron polysaccharide complex comprises iron carboxymaltose, iron sucrose, iron polyisomaltose, iron polymaltose, iron gluconate, iron sorbitol, iron hydrogenated dextran, iron delisomaltose (e.g., ferric delisomaltose or iron isomaltoside), or a mixture thereof. In various embodiments, the stable injectable composition comprises iron carboxymaltose, iron sucrose, iron polyisomaltose, iron polymaltose, iron gluconate, iron sorbitol, iron hydrogenated dextran, iron delisomaltose (e.g., ferric delisomaltose or ferric isomaltoside), ferumoxytol (superparamagnetic iron oxide coated with a derivatized carbohydrate), or isomers thereof or mixtures thereof.

[0138]

[0136] The stable iron compositions of the present application include isomers, such as structural isomers, enantiomers or diastereomers, of the carbohydrates described herein, and their derivatives. Isomers include two or more compounds with the same formula but different atomic arrangements in the molecule and different properties.

[0139] In some embodiments, the iron present in the injectable iron sucrose composition comprises a polymerized iron(III)-hydroxide complex, a polynuclear iron(III)-hydroxide complex, an iron(III)-hydroxide sucrose complex, a polymerized iron(III)-hydroxide colloid, a polynuclear iron(III)-hydroxide colloid, or an iron(III)-hydroxide sucrose colloid, or a combination thereof. In some embodiments, this can provide 1 mg or 2 mg of elemental iron.

[0140]

[0138] In many embodiments, the stable injectable iron composition described in this disclosure also includes a stabilizing agent that can be selected from an alkalizing agent, a buffering agent, and / or sucrose. Useful alkalizing agents (e.g., alkaline solutions) include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, or mixtures thereof. Buffering agents useful as stabilizing agents include sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, calcium bicarbonate, or mixtures thereof. Other buffering agents can be selected from L-histidine, histidine, glycine, arginine, tyrosine, or lysine.

[0141]

[0139] In some embodiments, a stabilizer (e.g., sodium hydroxide) can be added in an amount of about 1 mM / mL, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 to about 50 mM / mL of the iron composition.

[0142]

[0140] In some embodiments, a stabilizer (eg, histidine) can be added in an amount of about 0.25, 0.5, 0.75, 0.8, 1.0, 1.25, 1.5 to about 2.0 mg / mL of the iron composition.

[0143]

[0141] A buffering agent is also used to adjust the pH of the injectable iron composition in this alternative embodiment. The pH of the composition is optionally 9.5 to 11.5 or 10 to 11.5. In other embodiments, the pH of the composition is 10.5 to 11.1.

[0144]

[0142] In some embodiments, the stable injectable iron composition of the present application can be made from a starting material that can be an injectable iron-(III)-hydroxide-sucrose complex, which is then stabilized to obtain the stable injectable iron composition of the present application. A suitable injectable iron-(III)-hydroxide-sucrose complex that can be used as a starting material in the present application can be, for example, 1 mg or 2 mg Venofer®, available from Vifor(International)AG, Switzerland / American Regent, Shirley, New York, USA. In some embodiments, the starting material for the iron-(III)-hydroxide-sucrose complex or iron-(III) oxyhydroxide-sucrose complex can be prepared by reacting a ferric salt (e.g., ferric chloride) with an inorganic base (e.g., NaOH) at pH 3.5-7.0 to provide ferric oxyhydroxide, which is then added to a solution of sucrose, followed by adjusting the pH of the mixture to 9.0-13.0 with an inorganic base to yield the iron-(III)-hydroxide-sucrose complex, which can then be isolated by partial concentration of the aqueous mixture and precipitation by addition of an organic solvent or mixtures thereof to isolate the iron-(III)-hydroxide-sucrose complex.

[0145]

[0143] The method of making the iron-(III)-hydroxide-sucrose complex or iron-(III) oxyhydroxide-sucrose complex used as starting material in this application is described in many references, including U.S. Patent No. 7,964,568; U.S. Patent No. 7,674,780; U.S. Patent No. 8,053,470; U.S. Patent Application Publication No. 20080167266; ​​U.S. Patent Application Publication No. 20180147238; U.S. Patent No. 8,030,480 and U.S. Patent No. 8,053,470. The entire disclosures of these are incorporated by reference into this disclosure. The iron-(III)-hydroxide-sucrose complex or iron-(III) oxyhydroxide-sucrose complex can then be mixed with a stabilizer and water as discussed herein to obtain the stable injectable iron composition of this application.

[0146]

[0144] In some embodiments, a method for making a stable injectable iron composition is provided, the method comprising mixing iron-(III)-oxyhydroxide or iron-(III)-hydroxide with sucrose to form a mixture; and adding a stabilizing agent to the mixture to form a stable injectable iron composition.

[0147] It is understood that in some embodiments, the components of the iron composition (e.g., iron, carbohydrate, stabilizer, water and / or iron-carbohydrate complex) can be mixed in any order. After mixing and addition of the components, the pharmaceutical iron composition can be sterilized, for example, by filtering it through one or more filters (e.g., 0.22 μm sterile filters). The sterilized iron composition can then be filled into a suitable container (e.g., vial, ampoule, bag, etc.) and stoppered and sealed under a reduced oxygen headspace, for example, 5% oxygen (balance nitrogen) or 10% oxygen (balance nitrogen). In certain embodiments, the oxygen headspace in the container can range from about atmospheric to about 0.5 mg / L. In some embodiments, the iron composition can be packaged in a pharma- ceutically acceptable container, for example, an intravenous bag, syringe, vial, or ampoule. The pH of the composition is, in some embodiments, 9.5-11.5 or 10-11.5.

[0148]

[0146] The present disclosure also relates to methods for preparing such compositions. In this other aspect, the term "premixed" as used herein means a pharmaceutical iron composition that is already mixed from the time of manufacture and does not require dilution or further processing before administration. In various embodiments, the premixed injectable may be a disposable, ready-to-use isotonic solution for intravenous administration. No further dilution is required. Prior to administration, the premixed injectable should be visually inspected for particulate matter and discoloration whenever possible depending on the solution and container. The premixed injectable is usually a clear amber to dark brown solution.

[0149]

[0147] In some cases, the iron composition is added to a disposable container, which may be, for example, a disposable vial or ampoule, or the container comprises a vial with a barrier coated stopper and / or an aluminum cap. As noted above, the vial, ampoule, bag may be made of glass or plastic-based materials.

[0150]

[0148] In various embodiments, the iron composition prepared by mixing iron with a carbohydrate and water to form a mixture and adding a stabilizer to the mixture to form a stable injectable iron composition can be further filtered followed by terminal sterilization and autoclaving.

[0151]

[0149] In various embodiments, gamma radiation can be used in the final sterilization step, which involves utilizing ionizing energy from gamma radiation to penetrate deep into the vial containing the iron composition of the present disclosure. Gamma radiation is highly effective in killing microorganisms, they do not leave residues, and do not have enough energy to radioactive the instrument. Gamma radiation can be used when the iron composition is in a vial, ampoule, or bag. This is because gamma sterilization does not require high pressure or vacuum conditions, and therefore the container of the iron composition is not subjected to stress. In some aspects, the vial or ampoule can be made of glass or plastic material, and in other aspects, the vial, ampoule, or bag can be prepared from a plastic material, such as polypropylene.

[0152]

[0150] In other embodiments, electron beam (e-beam) radiation may be used to sterilize the iron compositions described in this disclosure. E-beam radiation comprises a form of ionizing energy that is generally characterized by low penetration and high dose rates. E-beam irradiation is similar to gamma ray processing in that it alters various chemical and molecular bonds on contact, including the reproductive cells of microorganisms. The beam generated for e-beam sterilization is a concentrated, highly charged stream of electrons resulting from the acceleration and conversion of electricity.

[0153]

[0151] High pressure steam sterilization is usually carried out in an autoclave. Autoclaves use pressurized steam as their sterilizing agent. The basic concept of an autoclave is to sterilize each item (whether it is a liquid, plasticware, or glassware) by directly contacting it with steam at a specific temperature and pressure for a specific time. Time, steam, temperature, and pressure are the four main parameters required for successful sterilization using an autoclave.

[0154]

[0152] The time and temperature required for sterilization of vials or ampoules containing iron compositions can be higher and require shorter times for sterilization. The most common temperatures used are 121°C and 132°C. In order for the steam to reach these high temperatures, it must be pumped into the chamber at a pressure higher than standard atmospheric pressure. Standard atmospheric pressure is approximately 101,325 Pascals (roughly 14.6959 pounds per square inch). In some embodiments, the vials can be heat treated at temperatures from about 60°C to about 132°C.

[0155]

[0153] The iron compositions of the present disclosure are preferably packaged in a pharma- ceutically acceptable container in many aspects. Pharmaceutically acceptable containers include intravenous vials, ampoules, and syringes. In some embodiments, the iron compositions of the present disclosure can be, but are not required to be, further diluted with dextrose, saline, or a combination thereof.

[0156]

[0154] In some embodiments, it is also desirable to protect the pharmaceutical composition from light. Thus, the container may optionally further comprise a light barrier. In certain embodiments, the light barrier may be an aluminum pouch exterior.

[0157] In many aspects, the present disclosure also provides a method for preparing sterile pharmaceutical compositions.Examples of suitable procedures for producing sterile pharmaceutical products include, but are not limited to, terminal moist heat sterilization, ethylene oxide, radiation (i.e., gamma and electron beam), and aseptic processing techniques.Any one of these sterilization procedures can be used to produce the sterile pharmaceutical compositions described herein.

[0158]

[0156] Sterile pharmaceutical compositions may also be prepared using aseptic processing techniques. Sterility is maintained by using sterile materials and a controlled working environment. All containers and equipment are preferably sterilized by heat sterilization before filling. The containers are then filled under aseptic conditions, such as by passing the composition through a filter and filling the units. Thus, the composition can be aseptically filled into the container to avoid the heat stress of terminal sterilization. In some embodiments, the iron sucrose composition of the present application can be heated, for example, to about 60°C to about 132°C after being placed in a container (e.g., a vial) as part of the stabilization and / or terminal sterilization process of the drug product.

[0159]

[0157] As noted above, the iron compositions of the present application may be sterile, which is in accordance with United States Pharmacopoeia 40-NF35. <71> ("40 USP"). Further regulations on sterility of final products include the European Pharmacopoeia (European Pharmacopoeia section 2.6.1), and the Japanese Pharmacopoeia (JP section 54). These sterility methods have been harmonized with the USP methods, and results generated under these sources are consistent with USP <71> Preferably, the therapeutically acceptable iron composition of the present application is in accordance with the United States Pharmacopoeia 40-NF35. <71> or USP41 <71> These have been produced by a process that provides assurance of sterility by

[0160] Methods of using iron compositions The iron compositions described in this disclosure can be used for the treatment of diseases, disorders, or conditions characterized by iron deficiency or iron metabolic dysfunction. The method of treatment includes administering a stable injectable iron composition comprising iron, carbohydrate, a stabilizing agent, and water to a subject in need of treatment. In some embodiments, the iron composition is administered intravenously and can be injected in a single direct dose over a period ranging from 1 minute to about 150 minutes. In some embodiments, the IV administration can be over a period ranging from about 1 minute, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 40, 45, 60, 75, 90, 105, 120, 135, and 150 minutes. In many cases, the injectable iron composition can be administered in a single dosage unit of at least 1 mg / mL elemental iron, which does not require further dilution, does not require an IV bag or bottle, and does not require an IV tubing set or pump. In other embodiments, the injectable iron composition is a single dosage unit of at least 1 mg / mL elemental iron, which can be administered in less than 25 minutes, less than 10 minutes, or less than 5 minutes, or less than 1 minute.

[0161] There are many diseases, disorders or conditions characterized by iron deficiency or iron metabolic dysfunction that can be treated with the injectable iron composition described in this application.For example, in some embodiments, the disease, disorder or condition is anemia, and in some cases, the anemia is iron deficiency anemia.In other embodiments, the iron deficiency anemia is associated with chronic blood loss; acute blood loss; chronic kidney disease; pregnancy; childbirth; childhood development; psychomotor and cognitive development in children; breath-holding attacks; heavy uterine bleeding; menstruation; chronic recurrent hemoptysis; idiopathic pulmonary siderosis; chronic internal bleeding; gastrointestinal bleeding; parasitic infection; chronic kidney disease; dialysis; surgery or acute trauma; chronic alcohol intake, chronic salicylate intake, chronic steroid intake, chronic nonsteroidal anti-inflammatory drug intake, or chronic erythropoiesis stimulating drug intake, or combinations thereof.

[0162]

[0160] In various embodiments, the iron compositions described in the present disclosure can be used to treat anemia of chronic diseases, such as rheumatoid arthritis; cancer; Hodgkin's leukemia; non-Hodgkin's leukemia; anemia from chemotherapy; inflammatory bowel disease; ulcerative colitis; thyroiditis; hepatitis; systemic lupus erythematosus; polymyalgia rheumatica; scleroderma; mixed connective tissue disease; Sjogren's syndrome; anemia of congestive heart failure / cardiomyopathy; or idiopathic senile anemia.

[0163] In some cases, the disease, disorder or condition characterized by iron deficiency or iron metabolism dysfunction is anemia caused by abnormal iron absorption or poor nutrition, or the anemia is associated with Crohn's disease; gastric surgery; taking drug products that inhibit iron absorption; and chronic use of calcium. In other cases, the method of treatment described in this application treats anemia. In some embodiments, the anemia is associated with iron deficiency anemia, such as chronic blood loss; acute blood loss; pregnancy; childbirth; childhood development; psychomotor and cognitive development in children; breath-holding attacks; heavy uterine bleeding; menstruation; chronic recurrent hemoptysis; idiopathic pulmonary siderosis; chronic internal bleeding; gastrointestinal bleeding; parasitic infection; chronic kidney disease; dialysis; surgery or acute trauma; chronic alcohol intake, chronic salicylate intake, chronic steroid intake, chronic nonsteroidal anti-inflammatory drug intake, or chronic erythropoiesis stimulating drug intake. In some aspects, the anemia is a chronic disease, such as rheumatoid arthritis; cancer; Hodgkin's leukemia; non-Hodgkin's leukemia; cancer chemotherapy; inflammatory bowel disease; ulcerative colitis; thyroiditis; hepatitis; systemic lupus erythematosus; polymyalgia rheumatica; scleroderma; mixed connective tissue disease; Sjogren's syndrome; anemia of congestive heart failure / cardiomyopathy; or idiopathic geriatric anemia. In some embodiments, the anemia is due to anemia associated with iron absorption abnormalities or poor nutrition, such as Crohn's disease; stomach surgery; taking drug products that inhibit iron absorption; and chronic use of calcium. In various embodiments, the method treats restless legs syndrome; blood donation; Parkinson's disease; hair loss; or attention deficit disorder.

[0164]

[0162] These and other aspects of the present application will be further appreciated in light of the following examples, which are intended to illustrate certain embodiments of the present application, but are not intended to limit its scope as defined by the claims.

[0165] Embodiment

[0163] 1. An injectable iron composition comprising iron, a carbohydrate, a stabilizer and water.

[0166]

[0164] 2. An injectable iron composition described in embodiment 1, wherein the iron is elemental iron.

[0167]

[0165] An injectable iron composition as described in embodiment 1, wherein the carbohydrate comprises: (i) a monosaccharide, a disaccharide, an oligosaccharide or a polysaccharide; or (ii) a modified monosaccharide, a modified disaccharide, a modified oligosaccharide or a modified polysaccharide.

[0168]

[0166] 4. An injectable iron composition described in embodiment 2, wherein the elemental iron and the carbohydrate form a colloidal iron(III) carbohydrate complex.

[0169]

[0167] 5. An injectable iron composition as described in embodiment 1, wherein the composition comprises iron carboxymaltose, iron sucrose, iron polyisomaltose, iron dextrin, iron gluconate, iron sorbitol, iron hydrogenated dextran, iron delisomaltose, superparamagnetic iron oxide coated with derivatized carbohydrate or an isomer thereof or a mixture thereof.

[0170]

[0168] 6. An injectable iron composition as described in embodiment 3, wherein (i) the monosaccharide comprises glucose, galactose, fructose, an isomer thereof or a mixture thereof; (ii) the disaccharide comprises sucrose, lactose, maltose or an isomer thereof or a mixture thereof; (iii) the oligosaccharide comprises raffinose, stachyose, verbascose or an isomer thereof or a mixture thereof; or (iv) the polysaccharide comprises starch, a starch derivative, dextran, cellulose, glycogen or an isomer thereof or a mixture thereof.

[0171]

[0169] 7. An injectable iron composition as described in embodiment 3, wherein (i) the monosaccharide comprises dihydroxyacetone, glyceraldehyde, erythrose, ribose, ribulose, sorbose, xylose, arabinose, fructose, glucose, galactose, mannose, or an isomer or a mixture thereof; or (ii) the disaccharide comprises sucrose, maltose, cellobiose, gentiobiose, isomaltose, melibiose, primeverose, rutinose, trehalose, lactose, or an isomer or a mixture thereof.

[0172]

[0170] 8. An injectable iron composition as described in embodiment 6, wherein the starch derivative comprises dextrin including maltodextrin, maltose syrup, glucose syrup or a mixture thereof.

[0173]

[0171] 9. An injectable iron composition described in embodiment 1, wherein the stabilizing agent comprises an alkalizing agent, a buffering agent or sucrose.

[0174]

[0172] 10. An injectable iron composition as described in embodiment 1, wherein the iron comprises elemental iron, the carbohydrate comprises sucrose, and the stabilizer comprises at least one of a sodium compound, L-histidine, sucrose, or a combination thereof.

[0175]

[0173] 11. An injectable iron composition as described in embodiment 1, wherein the composition has a total volume of (i) 1 mL or more, or (ii) about 1 mL to about 250 mL, or (iii) about 250 mL to about 500 mL.

[0176] 12. (i) elemental iron in an amount of about 1.0 mg / mL or more; total sucrose in an amount of 95 mg / mL; sodium hydroxide in an amount of 0.96 mg / mL, and optionally L-histidine in an amount of 1.5 mg / mL; (ii) elemental iron in an amount of about 1.0 mg / mL to about 20 mg / mL; (iii) elemental iron in an amount of about 1.0 mg / mL to 2.0 mg / mL, sucrose in an amount of about 15 mg / mL to 195 mg / mL or 15 mg / mL to 115 mg / mL, sodium hydroxide in an amount of about 0.08 mg / mL to 0.96 mg / mL or 0.08 mg / mL to 28.3 mg / mL, and optionally L-histidine in an amount of about or (iv) elemental iron in an amount of about 1.0 mg / mL to 2.0 mg / mL, sucrose in an amount of about 15 mg / mL to 195 mg / mL or 15 mg / mL to 115 mg / mL per mg or 2 mg of iron, sodium hydroxide in an amount of about 0.08 mg / mL to 0.96 mg / mL or 0.08 mg / mL to 28.3 mg / mL per mg or 2 mg of iron, and optionally L-histidine in an amount of about 0 mg / mL to about 1.5 mg / mL per mg or 2 mg of iron.

[0177]

[0175] 13. An injectable iron composition described in embodiment 9, wherein the alkalizing agent comprises sodium hydroxide, potassium hydroxide, calcium hydroxide or a combination thereof.

[0178]

[0176] 14. An injectable iron composition as described in embodiment 9, wherein the buffering agent comprises sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, calcium bicarbonate or a mixture thereof.

[0179]

[0177] 15. An injectable iron composition described in embodiment 9, wherein the buffering agent comprises L-histidine, glycine, arginine, tyrosine, lysine or a mixture thereof.

[0180]

[0178] 16. An injectable iron composition described in embodiment 10, wherein the sodium compound is sodium hydroxide, sodium chloride, sodium gluconate or a combination thereof.

[0181]

[0179] 17. An injectable iron composition as described in embodiment 4, wherein the elemental iron in the colloidal iron(III) carbohydrate complex is from about 1 mg / mL to about 2 mg / mL, and the injectable iron composition comprises total sucrose in an amount of from about 5 to about 195 mg / mL, sodium hydroxide in an amount of from about 0.08 to about 28.3 mg / mL, and L-histidine in an amount of from about 0 to about 1.5 mg / mL.

[0182]

[0180] 18. An injectable iron composition as described in embodiment 4, wherein the iron(III) carbohydrate complex comprises iron sucrose, the iron sucrose comprising from about 1 mg / mL to about 2 mg / mL elemental iron(III) and from about 15 to about 30 mg / mL sucrose, and the injectable iron composition comprises a stabilizer comprising from about 0.07 to about 0.97 mg / mL sodium hydroxide, from about 0 to about 1.5 mg / mL L-histidine and from about 15 to about 195 mg / mL total sucrose.

[0183]

[0181] 19. An injectable iron composition as described in embodiment 16, wherein the elemental iron is 1 mg / mL, the total sucrose is about 57.5 to about 95 mg / mL, the sodium hydroxide is about 0.07 to about 0.97 mg / mL, and the L-histidine is about 0 to about 1.5 mg / mL.

[0184]

[0182] 20. An injectable iron composition described in embodiment 10, wherein the sucrose is in an amount greater than 15 mg / mL.

[0185]

[0183] 21. The injectable iron composition of embodiment 4, wherein the injectable iron composition has one or more of the following characteristics (i) to (viii): (i) a pH of about 10 to about 11.1; (ii) an average molecular weight (Mw) of the colloidal iron(III) carbohydrate complex of about 34 kDa to about 60 kDa; (iii) a number average molecular weight (Mn) of the colloidal iron(III) carbohydrate complex of about 24 kDa to about 60 kDa; (iv) a polydispersity index of the colloidal iron(III) carbohydrate complex of about 1.0 to about 1.7; (v) an amount of elemental Fe(II) in the composition of about 0.01% to about 0.04%; (vi) an amount of elemental Fe(II) in the composition of about 0.01% to 0.4% or less; (vii) a time required for release of 75% of elemental iron from the iron composition from about 20 minutes or less; or (viii) a storage stability of about 24 months.

[0186]

[0184] 22. An injectable iron composition as described in embodiment 4, wherein (i) the iron(III) carbohydrate complex comprises an iron monosaccharide complex, an iron disaccharide complex, an iron oligosaccharide complex, an iron polysaccharide complex or a combination thereof; or (ii) the iron polysaccharide complex comprises iron carboxymaltose, iron sucrose, iron polyisomaltose, iron polymaltose, iron gluconate, iron sorbitol, iron hydrogenated dextran, iron delisomaltose or a mixture thereof.

[0187]

[0185] 23. An injectable iron composition as described in embodiment 21, which is at least one of a preservative-free composition, a sterile composition, or a ready-to-use injectable aqueous composition.

[0188]

[0186] 24. An injectable iron composition described in embodiment 1, which is (i) placed in a container; (ii) heated to about 60°C to about 132°C; or (iii) held at room temperature.

[0189]

[0187] 25. An injectable iron composition as described in embodiment 24, wherein the container comprises a disposable vial or ampoule or bag, or the container comprises a vial having a barrier coated stopper and / or an aluminum cap.

[0190]

[0188] 26. An injectable iron composition as described in embodiment 25, wherein (i) the vial or ampoule comprises a glass or plastic material; (ii) the bag comprises a plastic material; (iii) the vial or ampoule comprises coated glass; or (iv) the injectable iron composition is in a container that is a syringe.

[0191]

[0189] 27. An injectable iron composition as described in embodiment 24, wherein the container has (i) 0.5 v / v% to 5.0 v / v% from the time of manufacture to about 6 months from manufacture when stored at a temperature of 25°C to 60°C; (ii) 0.5 v / v% to 10.0 v / v% from the time of manufacture to about 6 months from manufacture when stored at a temperature of 25°C to 60°C; or (iii) headspace oxygen containing from about atmosphere to about 9 mg / L, and dissolved oxygen present in the composition in an amount of from about 0.1 parts per million (ppm) to about 9 ppm from the time of manufacture to about 1 month from manufacture when stored at room temperature, and the composition is sealed in a disposable container having a volume of (a) more than 1 mL to about 10 mL; or (b) about 10 mL to about 250 mL.

[0192]

[0190] 28. A method for making a stable injectable iron composition comprising: (i) mixing iron and / or a colloidal iron(III) carbohydrate complex with a carbohydrate and water to form a mixture, and adding a stabilizing agent to the mixture to form the stable injectable iron composition; or (ii) mixing a colloidal iron(III) carbohydrate complex with a carbohydrate and water to form a mixture, and adding a stabilizing agent to the mixture to form the stable injectable iron composition.

[0193]

[0191] 29. The method of embodiment 28, wherein the carbohydrate comprises a monosaccharide, a disaccharide, an oligosaccharide or a polysaccharide.

[0194]

[0192] 30. The method of embodiment 28, wherein the iron is elemental iron, and the elemental iron and the carbohydrate form a colloidal iron(III) carbohydrate complex.

[0195]

[0193] 31. The method described in embodiment 28, wherein the colloidal iron(III) carbohydrate complex comprises iron carboxymaltose, iron sucrose, iron polyisomaltose, iron polymaltose, iron gluconate, iron sorbitol, iron hydrogenated dextran, iron delisomaltose, superparamagnetic iron oxide coated with a derivatized carbohydrate or a mixture thereof.

[0196]

[0194] 32. The method of embodiment 28, wherein the stabilizing agent comprises an alkalizing agent, a buffering agent, sucrose or a mixture thereof.

[0197]

[0195] 33. The method of embodiment 28, wherein the iron comprises elemental iron, the carbohydrate comprises sucrose, and the stabilizing agent comprises at least one of sodium, L-histidine, or sucrose.

[0198]

[0196] 34. The method of embodiment 28, further comprising adding the composition to a container.

[0199]

[0197] 35. The method of embodiment 28, further comprising filtering the composition.

[0200]

[0198] 36. The method of embodiment 34, further comprising sterilizing the composition by terminal sterilization or autoclaving.

[0201]

[0199] 37. The method of embodiment 28, wherein the composition has a pH of about 10 to about 11.5.

[0202]

[0200] 38. The method of embodiment 34, wherein the container comprises a disposable vial or ampoule or bag, or the container comprises a vial having a barrier coated stopper and / or an aluminum cap.

[0203]

[0201] 39. The method of embodiment 38, wherein (i) the vial or ampoule comprises a glass or plastic material, or (ii) the bag comprises a plastic material.

[0204]

[0202] 40. The method of embodiment 38, wherein the container has (i) 0.5 v / v% to 5.0 v / v% from the time of manufacture to about 6 months from manufacture when stored at a temperature of 25°C to 60°C; (ii) 0.5 v / v% to 10.0 v / v% from the time of manufacture to about 6 months from manufacture when stored at a temperature of 25°C to 60°C; or (iii) headspace oxygen comprising from about atmosphere to about 9 mg / L, and dissolved oxygen present in the composition in an amount from about 0.1 parts per million (ppm) to about 9 ppm from the time of manufacture to about 1 month from manufacture when stored at room temperature, and the composition is enclosed in a disposable container having a volume of (a) more than 1 mL to about 10 mL; or (b) about 10 mL to about 250 mL.

[0205]

[0203] 41. A method for treating a disease, disorder, or condition characterized by iron deficiency or iron metabolic dysfunction comprising administering to a subject in need of treatment a stable injectable iron composition comprising iron, carbohydrate, a stabilizer and water.

[0206]

[0204] 42. The method of embodiment 41, wherein the composition is administered intravenously.

[0207]

[0205] 43. The method of embodiment 41, wherein the composition is administered by direct intravenous administration over (i) about 1 minute to about 15 minutes, or (ii) 1 minute to about 150 minutes.

[0208]

[0206] 44. The method of embodiment 41, wherein the stable injectable iron composition is administered in a single dosage unit of at least 1 mg / mL elemental iron.

[0209]

[0207] 45. The method of embodiment 44, wherein the dosage unit does not require dilution prior to use.

[0210]

[0208] 46. The method of embodiment 44, wherein the single dosage unit of at least 1 mg / mL elemental iron is administered in less than 25 minutes, less than 10 minutes, or less than 5 minutes or less than 1 minute.

[0211]

[0209] 47. The method of embodiment 41, wherein (i) the disease, disorder, or condition is anemia; (ii) the disease, disorder, or condition is iron deficiency anemia; or (iii) the disease, disorder, or condition is iron deficiency anemia associated with chronic blood loss; acute blood loss; pregnancy; childbirth; childhood development; psychomotor and cognitive development in children; breath-holding attacks; heavy uterine bleeding; menstruation; chronic recurrent hemoptysis; idiopathic pulmonary siderosis; chronic internal bleeding; gastrointestinal bleeding; parasitic infection; chronic kidney disease; dialysis; surgery or acute trauma; chronic alcohol intake, chronic salicylate intake, chronic steroid intake, chronic nonsteroidal anti-inflammatory drug intake, or chronic erythropoiesis-stimulating agent intake.

[0212]

[0210] 48. The method of embodiment 41, wherein (i) the disease, disorder or condition is anemia of chronic disease; (ii) the disease, disorder or condition is a chronic disease including rheumatoid arthritis; cancer; Hodgkin's leukemia; non-Hodgkin's leukemia; anemia from chemotherapy; inflammatory bowel disease; ulcerative colitis; thyroiditis; hepatitis; systemic lupus erythematosus; polymyalgia rheumatica; scleroderma; mixed connective tissue disease; Sjogren's syndrome; congestive heart failure / cardiomyopathy; or (iii) idiopathic senile anemia.

[0213]

[0211] 49. The method described in embodiment 47, wherein (i) the anemia is due to iron absorption abnormalities or poor nutrition; or (ii) the anemia is associated with Crohn's disease; gastric surgery; ingestion of medicinal products that inhibit iron absorption; and chronic use of calcium.

[0214]

[0212] 50. The method of embodiment 41, wherein the disease, disorder, or condition comprises blood donation, Parkinson's disease, hair loss, restless legs syndrome, or attention deficit disorder.

[0215]

[0213] 51. The method of embodiment 41, wherein the iron is elemental iron.

[0216]

[0214] 52. The method of embodiment 41, wherein the carbohydrate comprises a monosaccharide, a disaccharide, an oligosaccharide or a polysaccharide.

[0217]

[0215] 53. The method of embodiment 51, wherein the elemental iron and the carbohydrate form a colloidal iron(III) carbohydrate complex.

[0218]

[0216] 54. The method described in embodiment 41, wherein the composition comprises iron carboxymaltose, iron sucrose, iron polyisomaltose, iron polymaltose, iron gluconate, iron sorbitol, iron hydrogenated dextran, iron delisomaltose, superparamagnetic iron oxide coated with derivatized carbohydrate, or a mixture thereof.

[0219]

[0217] 55. The method of embodiment 52, wherein (i) the monosaccharide comprises glucose, galactose, fructose or a mixture thereof; (ii) the disaccharide comprises sucrose, lactose, maltose or a mixture thereof; (iii) the oligosaccharide comprises raffinose, stachyose, verbascose or a mixture thereof; or (iv) the polysaccharide comprises starch, a starch derivative, dextran, cellulose, glycogen or a mixture thereof.

[0220]

[0218] 56. The method of embodiment 52, wherein (i) the monosaccharide comprises dihydroxyacetone, glyceraldehyde, erythrose, ribose, ribulose, sorbose, xylose, arabinose, fructose, glucose, galactose, mannose, or a mixture thereof; or (ii) the disaccharide comprises sucrose, maltose, cellobiose, gentiobiose, isomaltose, melibiose, primeverose, rutinose, trehalose, lactose, or a mixture thereof.

[0221]

[0219] 57. The method of embodiment 55, wherein the starch derivative comprises dextrin including maltodextrin, maltose syrup or glucose syrup.

[0222]

[0220] 58. The method of embodiment 41, wherein the stabilizing agent comprises an alkalizing agent, a buffering agent, sucrose, or a mixture thereof.

[0223]

[0221] 59. The method of embodiment 41, wherein the iron comprises elemental iron, the carbohydrate comprises sucrose, and the stabilizer comprises at least one of a sodium compound, L-histidine, sucrose, or a combination thereof.

[0224]

[0222] 60. The method of embodiment 41, wherein the composition has a total volume of (i) 1 mL or more, or (ii) 1 mL to about 10 mL; or (iii) about 10 mL to about 250 mL.

[0225]

[0223] 61. The method described in embodiment 58, wherein the composition comprises elemental iron in an amount of 1.0 mg, total sucrose in an amount of about 95 mg, sodium hydroxide in an amount of about 0.08 mg, and optionally L-histidine in an amount of about 0.75 mg / mL.

[0226]

[0224] 62. The method of embodiment 58, wherein the alkalizing agent comprises sodium hydroxide, potassium hydroxide, calcium hydroxide, or a combination thereof.

[0227]

[0225] 63. The method of embodiment 58, wherein the buffer comprises sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, calcium bicarbonate or a mixture thereof.

[0228]

[0226] 64. The method of embodiment 58, wherein the buffer comprises L-histidine, glycine, arginine, tyrosine or lysine.

[0229]

[0227] 65. The method of embodiment 59, wherein the sodium compound is sodium hydroxide or sodium chloride.

[0230]

[0228] 66. The method described in embodiment 59, wherein the elemental iron in the colloidal iron carbohydrate complex is about 1 mg / mL to about 2 mg / mL, the sucrose is about 5 to about 195 mg / mL, the sodium hydroxide is about 0.07 to about 28.3 mg / mL or about 0.96 mg / mL, and the L-histidine is about 0 to about 0.9 mg / mL.

[0231]

[0229] 67. The method of embodiment 65, wherein the colloidal iron carbohydrate complex comprises iron sucrose, the composition comprises from about 1 mg / mL to about 2 mg / mL of elemental iron(III), the iron sucrose comprises sucrose in an amount of from about 15 to about 30 mg / mL, the composition comprises from about 0.08 to about 28.3 mg / mL of sodium hydroxide, from about 0 to about 0.9 mg / mL of L-histidine, and the composition has a total sucrose content of from about 15 to about 195 mg / mL.

[0232]

[0230] 68. The method described in embodiment 65, wherein the iron content in the composition is 1 mg / mL, the total sucrose content in the composition is about 57.5 to about 95 mg / mL, the sodium hydroxide content in the composition is about 0.08 to about 0.08 mg / mL, and the L-histidine content in the composition is about 0 to about 0.75 mg / mL.

[0233]

[0231] 69. The method described in embodiment 59, wherein the amount of sucrose in the composition is greater than 15 mg / mL.

[0234]

[0232] 70. The method of embodiment 53, wherein the composition has one or more of the following characteristics (i) to (viii): (i) a pH of about 10 to about 11.1; (ii) an average molecular weight (Mw) of the colloidal iron(III) carbohydrate complex of about 34 kDa to about 60 kDa; (iii) a number average molecular weight (Mn) of the colloidal iron(III) carbohydrate complex of about 24 kDa to about 60 kDa; (iv) a polydispersity index of the colloidal iron(III) carbohydrate complex of about 1.0 to about 1.7; (v) an amount of elemental Fe(II) in the composition of about 0.01% to about 0.04%; (vi) an amount of elemental Fe(II) in the composition of about 0.01% to 0.4% or less; (vii) a time required for release of 75% of the trivalent iron element from the iron composition from about 20 minutes or less; or (viii) a storage stability of about 24 months.

[0235]

[0233] 71. The method of embodiment 53, wherein (i) the iron(III) carbohydrate complex comprises an iron monosaccharide complex, an iron disaccharide complex, an iron oligosaccharide complex, an iron polysaccharide complex or a combination thereof; or (ii) the iron polysaccharide complex comprises iron carboxymaltose, iron sucrose, iron polyisomaltose, iron polymaltose, iron gluconate, iron sorbitol, iron hydrogenated dextran, iron delisomaltose or a mixture thereof.

[0236]

[0234] 72. The method described in embodiment 41, wherein the composition is at least one of a preservative-free composition, a sterile composition, or a ready-to-use aqueous composition for injection.

[0237]

[0235] 73. The method of embodiment 41, wherein the composition is placed in a container.

[0238]

[0236] 74. The method of embodiment 73, wherein the container comprises a disposable vial or ampoule or bag, or the container comprises a vial having a barrier coated stopper and / or an aluminum cap.

[0239]

[0237] 75. The method of embodiment 74, wherein the vial, ampoule or bag comprises a glass or plastic material.

[0240]

[0238] 76. The method of embodiment 75, wherein the container has (i) 0.5 v / v% to 5.0 v / v% from the time of manufacture to about 6 months from manufacture when stored at a temperature of 25°C to 60°C; (ii) 0.5 v / v% to 10.0 v / v% from the time of manufacture to about 6 months from manufacture when stored at a temperature of 25°C to 60°C; or (iii) headspace oxygen comprising from about atmosphere to about 9 mg / L, and dissolved oxygen present in the composition in an amount from about 0.1 parts per million (ppm) to about 9 ppm from the time of manufacture to about 1 month from manufacture when stored at room temperature, and the composition is enclosed in a disposable container having a volume of (a) more than 1 mL to about 10 mL; or (b) about 10 mL to about 250 mL.

[0241]

[0239] 77. A composition described in any one of embodiments 1 to 27, administered to a human.

[0242]

[0240] 78. The method of any one of embodiments 28 to 76, wherein the composition is administered to a human.

[0243]

[0241] 79. An injectable iron composition comprising a colloidal iron-carbohydrate complex, a stabilizer and water.

[0244]

[0242] 80. An injectable iron composition described in embodiment 79, wherein the carbohydrate is a sugar including glucose and fructose.

[0245]

[0243] 81. An injectable iron composition as described in embodiment 4, wherein the colloidal iron-carbohydrate complex comprises iron sucrose and the weight ratio of elemental iron(III) to (i) sucrose is from about 1:15 to about 1:200; (ii) Na+ ions is from about 1:0.04 to about 1:28.5; and / or (iii) L-histidine is from about 1:0 to about 1:1.5.

[0246]

[0244] 82. An injectable iron composition as described in embodiment 4, wherein the colloidal iron-carbohydrate complex comprises iron sucrose and the molar ratio of elemental iron(III) to (i) sucrose is from about 1:2.4 to about 1:32; (ii) Na+ ions is from about 1:0.05 to about 1:39.3, or (iii) L-histidine is from about 1:0 to about 1:0.55.

[0247]

[0245] 83. An injectable iron composition according to any one of embodiments 1 to 27, which maintains a density of about 1.027 to about 1.047 g / mL or about 1.037 to about 1.058 g / mL for a period of up to 24 months.

[0248]

[0246] 84. An injectable iron composition described in any one of embodiments 4 to 27, wherein the colloidal iron(III) carbohydrate complex has an average molecular weight (Mw) of about 34 kDa to about 60 kDa for a period of up to 24 months.

[0249]

[0247] 85. An injectable iron composition described in any one of embodiments 4 to 27, wherein the colloidal iron(III) carbohydrate complex has a number average molecular weight (Mn) of about 24 kDa to about 60 kDa for a period of up to 24 months.

[0250]

[0248] 86. An injectable iron composition described in any one of embodiments 4 to 27, wherein the colloidal iron(III) carbohydrate complex has a polydispersity index of about 1.0 to about 1.7 for a period of up to 24 months.

[0251]

[0249] 87.(i) An injectable iron composition as described in embodiment 2, comprising elemental iron in an amount of at least 1.0 mg / mL and up to 2.0 mg / mL, total sucrose in an amount of about 5 mg / mL to about 160 mg / mL, sodium hydroxide in an amount of about 0.08 mg / mL to about 0.96 mg / mL, and optionally L-histidine in an amount of about 0.75 mg / mL to about 1.5 mg / mL.

[0252]

[0250] 88. An injectable iron composition comprising: an iron(III)-hydroxide-sucrose complex containing 1 mg / mL to 2 mg / mL of elemental iron in said injectable iron composition; a sodium compound containing sucrose, sodium acetate, sodium hydroxide, sodium carbonate, sodium bicarbonate or a mixture thereof in an amount greater than 15 mg / mL; and water.

[0253]

[0251] 89. An injectable iron composition as described in embodiment 88, wherein the iron(III)-hydroxide-sucrose complex comprises 1 mg / mL to 15 mg / mL of sucrose complexed with the iron(III)-hydroxide.

[0254]

[0252] 90. An injectable iron composition described in embodiment 89, comprising about 1 mg / mL to 185 mg / mL of sucrose added to the iron(III)-hydroxide-sucrose complex.

[0255]

[0253] 91. An injectable iron composition described in embodiment 89, wherein the sodium compound comprises sodium hydroxide in an amount of about 0.08 mg / mL to about 28.3 mg / mL of the injectable iron product.

[0256]

[0254] 92. The injectable iron composition described in embodiment 89, further comprising L-histidine in an amount of about 0.01 mg / mL to about 1.5 mg / mL of the injectable iron composition.

[0257]

[0255] 93. An injectable iron composition described in embodiment 89 having a pH of about 9.6 to about 11.4.

[0258]

[0256] 94. An injectable iron composition described in any one of embodiments 88 to 93 providing from about 1 mg / mL to about 2 mg / mL of elemental iron.

[0259]

[0257] 95. An injectable iron composition comprising an iron(III)-hydroxide-sucrose complex comprising about 1 mg / mL elemental iron bound to about 15 mg / mL sucrose; a stabilizing agent comprising about 80 mg / mL sucrose and about 0.08 mg / mL sodium hydroxide; and water.

[0260]

[0258] 96. An injectable iron composition comprising an iron(III)-hydroxide-sucrose complex comprising about 2 mg / mL elemental iron bound to about 30 mg / mL sucrose; a stabilizing agent comprising about 85 mg / mL sucrose and about 0.96 mg / mL sodium hydroxide; and water.

[0261]

[0259] 97. An injectable iron composition comprising an iron(III)-hydroxide-sucrose complex containing about 1 mg / mL iron; about 95 mg / mL sucrose; about 0.08 mg / mL sodium hydroxide; and water.

[0262]

[0260] 98. An injectable iron composition comprising an iron(III)-hydroxide-sucrose complex containing about 2 mg / mL iron; about 115 mg / mL sucrose; about 0.96 mg / mL sodium hydroxide; and water.

[0263]

[0261] 99. An injectable iron composition described in any one of embodiments 95 to 98, having a pH of about 9.6 to about 11.4.

[0264]

[0262] 100. An injectable iron composition described in any one of embodiments 95 to 99 providing from about 1 mg / mL to about 2 mg / mL of elemental iron.

[0265]

[0263] 101. An injectable iron composition described in any one of embodiments 95 to 100, packaged in a disposable container and having a volume of 100 mL.

[0266]

[0264] 102. An injectable iron composition described in any one of embodiments 95 to 101, which is useful for treating a disease, disorder, or condition characterized by iron deficiency or iron metabolic dysfunction.

[0267]

[0265] 103. A method for making a stable injectable iron composition, comprising mixing an iron(III)-hydroxide-sucrose complex comprising about 1 mg / mL of iron bound to about 15 mg / mL of sucrose with a stabilizer comprising about 80 mg / mL of sucrose and about 0.08 mg / mL of sodium hydroxide, and water to form the stable injectable iron composition.

[0268]

[0266] 104. A method for making a stable injectable iron composition, comprising mixing an iron(III)-hydroxide-sucrose complex comprising about 2 mg / mL of iron bound to about 30 mg / mL of sucrose with a stabilizer comprising about 85 mg / mL of sucrose and about 0.96 mg / mL of sodium hydroxide, and water to form the stable injectable iron composition.

[0269]

[0267] 105. A method for making a stable injectable iron composition, comprising mixing an iron(III)-hydroxide-sucrose complex containing about 1 mg / mL of iron with about 95 mg / mL of sucrose and about 0.08 mg / mL of sodium hydroxide and water to form the stable injectable iron composition.

[0270]

[0268] 106. A method for making a stable injectable iron composition, comprising mixing an iron(III)-hydroxide-sucrose complex containing about 2 mg / mL of iron with about 115 mg / mL of sucrose and about 0.96 mg / mL of sodium hydroxide and water to form the stable injectable iron composition.

[0271]

[0269] 107. The method of any one of embodiments 103 to 106, wherein the stable injectable iron composition has a pH of about 9.6 to about 11.4.

[0272]

[0270] 108. A method according to any one of embodiments 103 to 107, wherein the injectable iron composition provides from about 1 mg / mL to about 2 mg / mL of elemental iron.

[0273]

[0271] 109. The method of any one of embodiments 103 to 108, further comprising packaging the stable injectable iron composition in a disposable container, wherein the injectable iron composition has a volume of 100 mL.

[0274]

[0272] An injectable iron composition comprising an iron(III)-hydroxide-sucrose complex containing 110.1 mg / mL to about 2 mg / mL of iron, additional sucrose separate from the sucrose in the iron(III)-hydroxide-sucrose complex, a stabilizer, and water.

[0275]

[0273] 111. An injectable iron composition comprising an iron(III)-hydroxide-sucrose complex containing about 1 mg / mL iron; a stabilizer containing about 80 mg of sucrose per mg of iron and about 0.08 mg of sodium hydroxide per mg of iron; and water.

[0276]

[0274] 112. An injectable iron composition comprising an iron(III)-hydroxide-sucrose complex containing about 2 mg / mL iron; a stabilizer containing about 85 mg of sucrose per 2 mg of iron and about 0.96 mg of sodium hydroxide per 2 mg of iron; and water.

[0277]

[0275] 113. An injectable iron composition comprising an iron(III)-hydroxide-sucrose complex containing about 1 mg / mL iron; about 95 mg of sucrose per mg of iron; about 0.08 mg of sodium hydroxide per mg of iron; and water.

[0278]

[0276] 114. An injectable iron composition comprising an iron(III)-hydroxide-sucrose complex containing about 2 mg / mL iron; about 115 mg sucrose per 2 mg iron; about 0.96 mg sodium hydroxide per 2 mg iron; and water.

[0279]

[0277] 115. An injectable iron composition comprising iron in an amount of at least 1.0 mg / mL to 2.0 mg / mL, total sucrose in an amount of about 5 mg to about 160 mg per 1 mg or 2 mg of iron, sodium hydroxide in an amount of about 0.08 mg to about 0.96 mg per 1 mg or 2 mg of iron, and optionally L-histidine in an amount of about 0.75 mg to about 1.5 mg per 1 mg or 2 mg of iron.

[0280]

[0278] 116. An injectable iron composition described in embodiment 110, wherein the additional sucrose other than the sucrose of the iron(III)-hydroxide-sucrose complex contains at least about 5 mg to about 185 mg per 1 mg or 2 mg of iron, sodium hydroxide in an amount of about 0.08 mg to about 28.3 mg per 1 mg or 2 mg of iron, and optionally L-histidine in an amount of about 0.75 mg to about 1.5 mg per 1 mg or 2 mg of iron.

[0281]

[0279] 117. An injectable iron composition described in any one of embodiments 111 to 116 having a pH of about 9.6 to about 11.4.

[0282]

[0280] 118. An injectable iron composition described in any one of embodiments 111 to 117 providing from about 1 mg / mL to about 2 mg / mL of elemental iron.

[0283]

[0281] 119. An injectable iron composition described in any one of embodiments 1-27, 79-102, or 110-118, having a pH adjusted using an acid.

[0284]

[0282] 120. The method of any one of embodiments 28-40, or 103-109, wherein the injectable iron composition has a pH adjusted using an acid. EXAMPLES

[0285] Working Example Examples 1, 2, 3, 4, and 5

[0283] Examples of stable, ready-to-use injectable iron sucrose compositions containing 1 mg / mL elemental iron are described below in Examples 1-4. Also included is a comparative example, Example 5, illustrating the Venofer® intravenous admixture.

[0286]

[0284] In Examples 1, 2, 3, and 4, 1 mL of each formulation contained the following:

[0287] [Table 5]

[0288] In some embodiments, the iron sucrose compositions (Examples 1-4) can be heated, for example, to about 60° C. to about 132° C. after being placed in a container (e.g., a vial) or can be held at room temperature.

[0289]

[0285] Venofer® intravenous admixture (1 mg / mL, elemental iron) diluted with 0.9% NaCl was prepared as a control solution to evaluate the effectiveness of selected excipients in stabilizing the formulation. The control Venofer® composition is summarized below.

[0290] [Table 6]

[0291] The iron compositions were prepared using the same compounding process and filled into the same container closure system (5 mL molded type I glass vials with 13 mm Teflon rubber stoppers and aluminum caps / flip-off seals) under ambient conditions, and the stability of each composition was then evaluated. The only difference between the iron compositions of Examples 1-4 and the comparative formulation was the presence and concentration of the included stabilizing additives, sucrose, NaOH, and L-histidine. For example, Example 3 illustrates an iron composition with an increased amount of sucrose by comparison with the Venofer® IV admixture of Example 5. The stability of the compositions in Examples 1, 2, 3, and 4 was evaluated by monitoring parameters such as Mw, Mn, PDI, pH, appearance, iron(II) content as an impurity, and controlled release testing for ferric iron (T75) to demonstrate equivalence when compared to the currently approved formulation, Venofer®. The results for the compositions of Examples 1, 2, 3, 4, and Comparative Example 5 are summarized below in Tables I, II, and III.

[0292] [Table 7]

[0293] [Table 8]

[0294] [Table 9]

[0295] The stabilized ready-to-use (RTU) iron compositions of Examples 1, 2, 3, and 4 met the acceptance criteria set forth in the current USP monograph (Venofer® Iron Sucrose Injection) for Mw, Mn, PDI, iron [Fe(II)] limits, and absence of low molecular weight iron [Fe(II) and Fe(III) complexes] at 25±2°C / 60±5% RH (long-term), 30±2°C / 65±5% RH (intermediate), and 40±2°C / 75±5% (accelerated) storage conditions for up to 6 months. Specifically, the polydispersity of the iron compositions of Examples 1, 2, 3, and 4 did not exceed a value of 1.7. The Fe(II) content in the iron compositions of Examples 1, 2, 3, and 4 did not exceed 0.4%. The control formulation of Comparative Example 5 (Venofer® intravenous admixture) showed less favorable values ​​for pH, Mw, and PDI specifications at 25±2° C. / 60±5% RH (long-term) within 3 months and at 40±2° C. / 75±5% RH (accelerated) within 1 month.

[0296] As can be seen from Tables I, II, and III above, the addition of sucrose, NaOH, and / or L-histidine enhanced the storage stability (long-term, intermediate, and accelerated conditions) of the iron sucrose compositions. Without being bound by theory, it is believed that the addition of sucrose, sodium ions, and / or buffer stabilizers, such as those provided by sodium hydroxide and / or L-histidine, prevents aggregation of iron sucrose resulting from an increase in weight average molecular weight, a decrease in pH, a change in iron speciation, and precipitation of the iron sucrose complex.

[0297] The ready-to-use (RTU) iron or iron sucrose compositions of Examples 1, 2, 3, and 4 demonstrated greater stability of the iron sucrose colloid at a concentration of 1 mg / mL elemental iron compared to currently available formulations for IV administration of 20 mg / mL iron sucrose injection, which is diluted with 0.9% NaCl for IV infusion at the time of administration. The 20 mg / mL iron sucrose injection was physically and chemically stable for 7 days at controlled room temperature of 20-25° C. (USP 10001) when added to an IV infusion bag containing 0.9% NaCl at concentrations ranging from 1 mg / mL to 2 mg / mL elemental iron. <659> Packaging and Storage Requirements), whereas the above admixture stability studies exemplified in Tables I, II, and III have shown that the iron compositions of the present application are chemically stable for greater than 7 days and for at least 6 months, and in many cases for at least 24 months.

[0298]

[0290] The iron compositions described herein achieve at least an improvement because the stabilized RTU iron sucrose injection 1 mg / mL compositions containing sucrose, NaOH, and / or L-histidine prevent destabilization of the iron sucrose complex and maintain the physiochemical properties of the active agent and / or environment at accelerated and long-term storage conditions. This ensures that the bioavailability of the iron composition remains unchanged upon administration, as monitored by the T75 test.

[0299]

[0291] Furthermore, the stabilized RTU iron sucrose injection 1 mg / mL composition eliminates the risk for errors in dilution and eliminates the preparation steps required to facilitate other iron sucrose intravenous admixture solutions, further ensuring a reduction in the total patient time for administration of each IV infusion.

[0300]

[0292] Table IV provides several ready-to-use formulations of the stable iron sucrose IV infusion compositions of the present application. These formulations are expressed in Table IV in mg / mL and also in millimoles.

[0301] [Table 10]

[0302] In some embodiments, the iron sucrose compositions (Formulations 1-4) can be heated, for example, to about 60° C. to about 132° C. after being placed in a container (e.g., a vial), or can be kept at room temperature. Those skilled in the art will appreciate that the additives described herein serve only as non-limiting examples of iron carbohydrate stabilizers. Such non-limiting agents include, for example, carbonate buffers, sugar carbohydrates, and sugar-lipids. Additionally, iron sucrose serves as a non-limiting example of an active pharmaceutical ingredient that belongs to the category of iron carbohydrates for parenteral iron therapy.

[0303] Example 6 Twenty-one ready-to-use injectable iron sucrose compositions containing 1 mg / mL or 2 mg / mL elemental iron are listed below in Table VI. Their stability at 0 hours, 3 months, 6 months and 18 months at 25±2° C. / 60±5% RH, 30±2° C. / 60±5% RH and 40±2° C. / 60±5% RH are shown in Tables VII and VIII.

[0304]

[0296] The iron compositions in Table VI can be prepared for injection at 20°C-25°C in a tank by adding the desired amount of sucrose to water and mixing the additives to form a mixture. To this mixture, sodium hydroxide and optionally histidine are added and mixed. Iron (1 mg iron complexed with about 15 mg sucrose or 2 mg iron complexed with about 30 mg sucrose) is then added to the mixture while mixing, and then 40 w / v % sodium hydroxide and / or hydrochloric acid is added to adjust the pH to a range of 9.6-11.1 to form a stable injectable iron composition. If required to maintain the pH in the range of 9.6-11.1, sodium bicarbonate can be added as an additive. The formed injectable iron composition can then be filtered and / or autoclaved, placed in vials, bottles or bags and sealed.

[0305] [Table 11]

[0306] [Table 12]

[0307] [Table 13]

[0308] [Table 14]

[0309] [Table 15]

[0310] As shown in Tables VII and VIII, all iron compositions had acceptable stability as indicated by pH, Mw, Mn, and / or PDI over an 18 month period when stored at 25° C., 30° C., and 40° C. at 60±5% RH. Iron compositions QBD12 in Table VII and QBD19 in Table VIII were selected as desirable because they had minimal amounts of sodium and sucrose for sodium- and sucrose-restricted patients. These compositions had less additive loading and consistent pH, Mw, Mn, density, and / or PDI over an 18 month period.

[0311] Example 7 An exemplary ready-to-use iron composition using iron composition QBD12 of Table VII and QBD19 of Table VIII is shown below in Table IX.

[0312] [Table 16]

[0313] Example 8 Exemplary compliance limits for the ready-to-use iron composition of Example 7 are shown below in Tables X and XI.

[0314] [Table 17]

[0315] [Table 18]

[0316] Tables X and XI show acceptable compliance limits for iron compositions at 1 mg / mL and 2 mg / mL concentrations based on appearance, pH range, density range, and potency based on label amount. These iron compositions have little or no bacterial growth (acceptable bioburden) and are suitable for injection.

[0317] Example 9

[0305] The RTU iron compositions at 1 mg / mL and 2 mg / mL concentrations in Table XII can be prepared by adding the desired amount of sucrose to water for injection in a tank at 20°C to 25°C and mixing the additives to form a mixture. Sodium hydroxide is added to the mixture and mixed. Iron is then added to the mixture while mixing, and then 40 w / v % sodium hydroxide and / or hydrochloric acid is added and the pH is adjusted to a range of 10.9 to 11.1 to form a stable injectable iron composition. The formed injectable iron composition can then be filtered and / or autoclaved, placed in vials, bottles or bags and sealed.

[0318] [Table 19]

[0319] The RTU iron compositions in Table XII at 1 mg / mL and 2 mg / mL concentrations have about 3 times less sucrose than Venofer® Concentrate Injection (20 mg / mL) but about 6-8 times more sucrose than Venofer® IV Infusion. Venofer® IV Infusion is diluted in sodium chloride, whereas the other compositions do not contain sodium chloride. The RTU iron compositions at 1 mg / mL and 2 mg / mL concentrations have sodium (e.g., NaOH) and sucrose as stabilizers.

[0320] Example 10 The stability of two RTU iron compositions of the present application (1 mg / mL iron and 2 mg / mL iron) from Table XII of Example 9 was compared with a) concentrated commercial formulation Venofer® 20 mg / mL, and b) Venofer® IV Injection, which is concentrated Venofer® 20 mg / mL diluted in 0.9% sodium chloride to a concentration of 1 mg / mL for IV infusion. The compositions were evaluated by monitoring parameters such as pH, Mw, Mn, PDI, appearance, and controlled release test (T75) for ferric iron. The stability results including pH, Mw, Mn, PDI, appearance, and T75 are shown in Table XIII.

[0321] [Table 20]

[0322]

[0310] Table XIII shows the acceptable compliance limits for the RTU iron compositions at 1 mg / mL and 2 mg / mL concentrations based on appearance, pH range, density range, and potency based on the label amount at 6 months of storage, where the RTU iron compositions are at 1 mg / mL and 2 mg / mL concentrations. This is a significant improvement when compared to Venofer® IV infusion, which is concentrated Venofer® 20 mg / mL diluted in 0.9% sodium chloride to a concentration of 1 mg / mL for IV infusion, which had a precipitate formed in about 1 month and became unstable and unusable due to a drop in pH below 10 after about 1 month of storage. The RTU iron compositions at 1 mg / mL and 2 mg / mL concentrations had no detectable precipitate formation.

[0323]

[0311] Since modifications will be apparent to those of skill in the art, it is intended that this disclosure be limited only by the scope of the appended claims.

Claims

1. An injectable iron composition comprising iron, a carbohydrate, a stabilizer, and water.

2. 2. The injectable iron composition of claim 1, wherein the iron is elemental iron.

3. 2. The injectable iron composition of claim 1, wherein the carbohydrate comprises: (i) a monosaccharide, a disaccharide, an oligosaccharide, or a polysaccharide; or (ii) a modified monosaccharide, a modified disaccharide, a modified oligosaccharide, or a modified polysaccharide.

4. 3. The injectable iron composition of claim 2, wherein the elemental iron and the carbohydrate form a colloidal iron (III) carbohydrate complex.

5. 2. The injectable iron composition of claim 1, wherein the composition comprises iron carboxymaltose, iron sucrose, iron polyisomaltose, iron dextrin, iron gluconate, iron sorbitol, iron hydrogenated dextran, iron delisomaltose, derivatized carbohydrate-coated superparamagnetic iron oxide, or isomers thereof, or mixtures thereof.

6. 4. The injectable iron composition of claim 3, wherein (i) the monosaccharide comprises glucose, galactose, fructose, an isomer thereof, or a mixture thereof; (ii) the disaccharide comprises sucrose, lactose, maltose, an isomer thereof, or a mixture thereof; (iii) the oligosaccharide comprises raffinose, stachyose, verbascose, an isomer thereof, or a mixture thereof; or (iv) the polysaccharide comprises starch, a starch derivative, dextran, cellulose, glycogen, an isomer thereof, or a mixture thereof.

7. 4. The injectable iron composition of claim 3, wherein (i) the monosaccharide comprises dihydroxyacetone, glyceraldehyde, erythrose, ribose, ribulose, sorbose, xylose, arabinose, fructose, glucose, galactose, mannose, or an isomer or mixture thereof; or (ii) the disaccharide comprises sucrose, maltose, cellobiose, gentiobiose, isomaltose, melibiose, primeverose, rutinose, trehalose, lactose, or an isomer or mixture thereof.

8. 7. The injectable iron composition of claim 6, wherein the starch derivative comprises dextrin, including maltodextrin, maltose syrup, glucose syrup, or mixtures thereof.

9. 2. The injectable iron composition of claim 1, wherein the stabilizing agent comprises an alkalizing agent, a buffer, or sucrose.

10. 2. The injectable iron composition of claim 1, wherein the iron comprises elemental iron, the carbohydrate comprises sucrose, and the stabilizer comprises at least one of a sodium compound, L-histidine, sucrose, or a combination thereof.

11. 10. The injectable iron composition of claim 1, wherein the composition has a total volume of (i) 1 mL or more, or (ii) about 1 mL to about 250 mL, or (iii) about 250 mL to about 500 mL.

12. (i) elemental iron in an amount of about 1.0 mg / mL or greater; sucrose in an amount of 95 mg / mL; the sodium compound is sodium hydroxide in an amount of 0.96 mg / mL, and optionally L-histidine in an amount of 1.5 mg / mL; (ii) elemental iron in an amount of about 1.0 mg / mL to about 20 mg / mL; (iii) elemental iron in an amount of about 1.0 mg / mL to 2.0 mg / mL, sucrose in an amount of about 15 mg / mL to 195 mg / mL or 15 mg / mL to 115 mg / mL, the sodium compound is sodium hydroxide in an amount of about 0.08 mg / mL to 0.96 mg / mL or 0.08 mg / mL to 28.3 mg / mL; and 11. The injectable iron composition of claim 10, optionally comprising L-histidine in an amount of about 0 mg / mL to about 1.5 mg / mL; or (iv) elemental iron in an amount of about 1.0 mg / mL to 2.0 mg / mL, sucrose in an amount of about 15 mg / mL to 195 mg / mL or 15 mg / mL to 115 mg / mL per 1 mg or 2 mg of iron, the sodium compound being sodium hydroxide in an amount of about 0.08 mg / mL to 0.96 mg / mL or 0.08 mg / mL to 28.3 mg / mL per 1 mg or 2 mg of iron, and optionally comprising L-histidine in an amount of about 0 mg / mL to about 1.5 mg / mL per 1 mg or 2 mg of iron.

13. 10. The injectable iron composition of claim 9, wherein the alkalinizing agent comprises sodium hydroxide, potassium hydroxide, calcium hydroxide, or a combination thereof.

14. 10. The injectable iron composition of claim 9, wherein the buffering agent comprises sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, calcium bicarbonate, or a mixture thereof.

15. 10. The injectable iron composition of claim 9, wherein the buffering agent comprises L-histidine, glycine, arginine, tyrosine, lysine, or a mixture thereof.

16. 11. The injectable iron composition of claim 10, wherein the sodium compound is sodium hydroxide, sodium chloride, sodium gluconate, or a combination thereof.

17. 5. The injectable iron composition of claim 4, wherein the elemental iron in the colloidal iron(III) carbohydrate complex is from about 1 mg / mL to about 2 mg / mL, the injectable iron composition comprises a total sucrose content in an amount of from about 5 to about 195 mg / mL, and the stabilizer comprises sodium hydroxide in an amount of from about 0.08 to about 28.3 mg / mL, and L-histidine in an amount of from about 0 to about 1.5 mg / mL.

18. 5. The injectable iron composition of claim 4, wherein the iron(III) carbohydrate complex comprises iron sucrose, the iron sucrose comprising about 1 mg / mL to about 2 mg / mL elemental iron(III) and about 15 to about 30 mg / mL sucrose, the stabilizing agent comprises about 0.07 to about 0.97 mg / mL sodium hydroxide, about 0 to about 1.5 mg / mL L-histidine, and the injectable iron composition comprises a total sucrose content of about 15 to about 195 mg / mL.

19. 17. The injectable iron composition of claim 16, wherein the elemental iron is 1 mg / mL, the injectable iron composition has a total sucrose content of about 57.5 to about 95 mg / mL, sodium hydroxide of about 0.07 to about 0.97 mg / mL, and L-histidine of about 0 to about 1.5 mg / mL.

20. 11. The injectable iron composition of claim 10, wherein the sucrose is in an amount greater than 15 mg / mL.