Advanced Magnetics, Inc.

Amag Pharmaceuticals, Inc.

Emulsan Biotechnologies Inc.

Jerome M Lewis

Ernest V Groman

Lee Josephson

Timothy B Frigo

Howard Bengele

Kenneth G Paul

Edward T Menz

Chu W Jung

Philip M Enriquez

Francis E Kenny

George M Whitesides

Kevin R Hrebenar

Stephen Palmacci

Eirik Nestaas

Iron oxide complexes, pharmacological compositions and unit dosage thereof, and methods for their administration, of the type employing an iron oxide complex with a polyol, are disclosed. The pharmacological compositions employ a polysaccharide iron oxide complex, wherein the polysaccharide is a modified polyol such as a carboxyalkylated reduced dextran. The complex is stable to terminal sterilization by autoclaving. The compositions are suitable for parenteral administration to a subject for the treatment of iron deficiencies or as MRI contrast agent. The complex is substantially immunosilent, provide minimal anaphylaxis and undergo minimal dissolution in vivo. The pharmacological compositions of the complex contain minimal free iron which can be quantified by a variety of methods.

Polyol and polyether iron oxide complexes as pharmacological and/or MRI contrast agents

Pharmacological compositions, and methods for administration, of the type employing an iron oxide complex with a polyol or polyether. The methods of administration may comprise parenteral administration of an effective dose of the complex formulated in a biocompatible liquid delivered at a rate of from about 1 mL/sec to less than 1 mL/min and wherein upon administration the complex provides minimal detectable free iron in a subject, and minimal incidence of anaphylaxis. The pharmacological compositions are of the type employing a polyol or polyether iron oxide complex, which, upon parenteral administration to a subject, are substantially immunosilent, provide minimal anaphylaxis and minimal free iron, and undergo minimal dissolution in vivo.

Compositions, methods of making the compositions, and methods of using the compositions are provided for an enhanced magnetic resonance imaging agent and a hematinic agent, the agents comprising carboxyalkylated reduced polysaccharides coated ultrasmall superparamagnetic iron oxides. Methods of use of the carboxymethyl reduced dextran as a plasma extender are provided.

Heat stable colloidal iron oxides coated with reduced carbohydrates and uses thereof

Heat stable colloidal iron oxides coated with reduced carbohydrates and carbohdrate derivatives

This invention is composition comprising a highly purified, substantially endotoxin-free polysaccharide preparation suitable for use as a parenterally administered pharmaceutical, and the method for producing the composition. The process produces a substantially endotoxin-free polysaccharide composition using a size separation technique in which the low molecular weight impurities are removed first, with a subsequent separation of the endotoxin from the polysaccharide, again, by size separation. Suitable size separation techniques include gel fitration, or more preferably, ultrafiltration. In the preferred embodiment of the invention, the polysaccharide arabinogalactan is first ultrafiltered using a 10,000 dalton membrane; the low molecular weight impurities (&lt;10,000 da) are discarded. The retentate is ultrafiltered using a 100,000 dalton membrane; the high molecular weight retentate, which contains the endotoxin, is discarded, leaving a substantially purified endotoxin free arabinogalactan composition in the filtrate. Other polysaccharides such as dextran, mannan, and gum arabic are also well suited for this purification technique. The process and products produced thereby are well suited for use in parenteral pharmacuetical compositions.

Endotoxin-free polysaccharides

This invention relates to a method of directing a therapeutic agent to selected cells, wherein a complex is formed between a polysaccharide capable of interacting with a cell receptor and a therapeutic agent. The resulting complex is administered to a subject, and permitted to be internalized into the selected cells through a process known as receptor mediated endocytosis (RME). The polysaccharide may be, for example, arabinogalactan, gum arabic, mannan or hydrolysis products thereof; the therapeutic agent may be, for example, an antiviral agent, a nucleic acid, hormone, steroid, antibody, chemoprotective or radioprotective agent. The cell receptor may be for example, the asialoglycoprotein receptor or the mannose receptor.

Delivery of therapeutic agents to receptors using polysaccharides

A substantially purified arabinogalactan, its degradative products and selected modifications thereof have been found to act as carriers for delivering therapeutic agent to cell receptors capable of receptor mediated endocytosis (RME). The arabinogalactan and its degrative products once derivatived are capable of forming a complex between the therapeutic agent and the polysaccharide such that the complex retains the ability to recognize and bind to the RME receptor.

Arabinogalactan derivatives and uses thereof

The invention relates to a method for the targeting of a therapeutic agent to a specific population of cells, wherein a complex is formed between the therapeutic agent and a polysaccharide capable of interacting with a cell receptor, and wherein the resulting complex is internalized into the cell by receptor mediated endocytosis (RME). In one embodiment of the invention, a complex of a therapeutic agent containing iron and the polysaccharide arabinogalactan may be formed and used to deliver iron specifically to hepatocytes by RME.

Targeting of therapeutic agents using polysaccharides

The preparation and isolation of biodegradable superparamagnetic MR imaging contrast agents for the vascular compartment is described. These aggregates are comprised of individual biodegradable superparamagnetic metal oxide crystals which aggregates have an overall mean diameter less than about 4000 angstroms. The preferred vascular imaging contrast agent is comprised of aggregates of iron oxide crystals having an overall mean diameter less than about 500 angstroms. These contrast agents may be associated with a macromolecular species, which assist, among other things, in the preparation of these extremely small materials, and may be dispersed or dissolved in a physiologically acceptable medium. Preferred media also stabilize the materials against further aggregation even under harsh sterilization conditions. The autoclaved biodegradable superparamagnetic iron oxides of the invention are ideally suited for a pharmaceutical preparation and enjoy several advantages over prior intravascular imaging contrast media including low osmolality, low effective dose requirements, high relaxivities, long blood lifetimes, rapid biodegradability, and versatility with respect to a wide range of applicable MR data acquisition parameters.

Vascular magnetic resonance imaging agent comprising nanoparticles

This invention relates to materials exhibiting certain magnetic and biological properties which make them uniquely suitable for use as magnetic resonance imaging (MRI) agents to enhance MR images of animal organs and tissues. More particularly, the invention relates to the in vivo use of biologically degradable and metabolizable superparamagnetic metal oxides as MR contrast agents. Depending on their preparation, these metal oxides are in the form of superparamagnetic particle dispersoids or superparamagnetic fluids where the suspending medium is a physiologically-acceptable carrier, and may be uncoated or surrounded by a polymeric coating to which biological molecules can be attached. These materials are administered to animals, including humans, by a variety of routes and the metal oxides therein collect in specific target organs to be imaged; in the case of coated particles, the biological molecules can be chosen to target specific organs or tissues. The biodistribution of the metal oxides in target organs or tissues results in a more detailed image of such organs or tissues because the metal oxides, due to their superparamagnetic properties, exert profound effects on the hydrogen nuclei responsible for the MR image. In addition, the dispersoids and fluids are quite stable and, in the case of the fluids, can even be subjected to autoclaving without impairing their utility. Furthermore, the materials are biodegradable and, in the case of iron oxide compounds, can eventually be incorporated into the subject's hemoglobin, making them useful in treating anemia. Thus, the materials are well-suited for in vivo use.

Hydrated biodegradable superparamagnetic metal oxides

This invention relates to the production of oil-in-water emulsifiers and emulsion stabilizers. More particularly, this invention relates to methods for the production of novel hydrophobically modified proteins which may be used as emulsifiers or to stabilize emulsions. This invention also relates to products incorporating these hydrophobically modified protein emulsifiers and emulsion stabilizers. These compounds may be used in many applications such as paints, dyes and cosmetics.

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Newton, MA, United States of America

Jerome M Lewis