Link:  Pharm/Biotech Resources

Title:  Methods and compositions for administration of iron for the treatment of restless leg syndrome

United States Patent:  6,960,571

Issued:  November 1, 2005

Inventors:  Helenek; Mary Jane (Brookville, NY); Lange; Ralf A. (Amagansett, NY); Oldham; Fred B. (West Chester, PA); Tokars; Marc L. (Douglassville, PA)

Assignee:  Luitpold Pharmaceuticals, Inc. (Shirley, NY)

Appl. No.:  389228

Filed:  March 14, 2003

A method of treating Restless Leg Syndrome, includes administering to a subject an iron complex having an iron release rate greater than IDI. The iron release rate is determined at a concentration of at least 2,000 μg/dl.

SUMMARY OF THE INVENTION

In a first aspect, the present invention is a method of treating Restless Leg Syndrome, comprising administering to a subject an iron complex having an iron release rate greater than IDI. The iron release rate is determined at a concentration of at least 2,000 μg/dl.

In a second aspect, the present invention is a method of treating Restless Leg Syndrome, comprising administering to a subject an iron complex having an iron release rate of at least 115 μg/dl at a concentration of 3438 μg/dl by the alumina column test.

In a third aspect, the present invention is a method of treating Restless Leg Syndrome, including administering IDI, the improvement comprising replacing IDI with an iron complex having a greater release rate than IDI.

In a fourth aspect, the present invention is a kit, comprising an iron complex composition having a release rate greater than IDI, a syringe, and a needle for the syringe. The iron release rate is determined at a concentration of at least 2,000 μg/dl.

DETAILED DESCRIPTION OF THE INVENTION

The present invention makes use of the discovery that an iron complex, having a higher release rate of iron than IDI, has the same effect for the treatment of RLS as IDI, at a lower dosage. These iron complexes avoid the risks of anaphylaxis associated with IDI when administered intravenously due to antibodies against the dextran moiety not being present in other iron complexes and, because of the higher release rate, therapadic dosage can be lowered.

An example of such an iron complex is Venofer® (iron sucrose injection USP), an iron sucrose complex that has an incidence of anaphylactoid reactions of 0.0046% (that is, 1 out of 20,000 people; IDI has a rate of anaphylaxis of 1.7%, or almost 2 out of 100 people). However, any iron complex that has a release rate greater than that of IDI is an effective RLS therapeutic.

Iron Compositions for the Treatment of RLS

Iron complexes are compounds which contain iron in (II) or (III) oxidation state, complexed with an organic compound. These include iron polymer complexes, iron carbohydrate complexes, and iron aminoglycosan complexes. These complexes are commercially available, or have well known syntheses (see, for example, (Andreasen and Christensen 2001, Andreasen and Christensen 2001, Geisser et al. 1992, Groman and Josephson 1990, Groman et al. 1989)).

Examples of iron carbohydrate complexes include iron simple saccharide complexes, iron oligosaccharide complexes, and iron polysaccharide complexes, such as: iron sucrose, iron polyisomaltose (iron dextran), iron polymaltose (iron dextrin), iron gluconate, iron sorbital, iron hydrogenated dextran, which may be further complexed with other compounds, such as sorbital, citric acid and gluconic acid (for example iron dextrin-sorbitol-citric acid complex and iron sucrose-gluconic acid complex), and mixtures thereof.

Examples of iron aminoglycosan complexes include iron chondroitin sulfate, iron dermatin sulfate, iron keratan sulfate, which may be further complexed with other compounds and mixtures thereof.

Examples of iron polymer complexes include iron hyaluronic acid complex, iron protein complexes, and mixtures thereof. Iron protein complexes include ferritin, transferritin, as well as ferritin or transferritin with amino acid substitutions, and mixtures thereof. Preferably, the iron complexes have a molecular mass of at least 30,000, more preferably of 30,000 to 100,000 as determined by HPLC/CPG (as described in Geisser et al 1992). Preferably, the iron complexes have a size of at most 0.1 micrometer, more preferably 0.035 to 0.1 micrometer, as determined by filtration.

The most preferred iron complex is iron sucrose (iron sucrose injection USP, Venofer®). This composition also avoids toxicity issues that are associated with smaller sugars, especially gluconates, which have high iron release rates. Iron sucrose compositions balance these toxicity issues with optimal iron release rates.

Determining Iron Complex Iron Release Rates

The methods of the invention take advantage of the discovery that iron complexes having higher release rates of iron than IDI can be effectively administered at lower doses. IDI has an iron release rate of 69.5-113.5 μg/dl. In the present invention, the iron complex must have a release rate of at least 115 μg/dl at a concentration of at least 2000 μg/dl; including 2000, 3000, 3500, 5000, and 10,000 μg/dl. Preferably, at least 120 μg/dl, more preferably, at least 140 μg/dl. Two tests can be implemented to determine iron release rates, that by Esposito et al. (2000) and by Jacobs et al. (1990).

"Chelator Test" (Esposito et al 2000)

The release rate of a candidate iron complex is the ability of the candidate complex to donate iron to apotransferrin or to an iron chelator, such as desferrioxamine. To detect such transfer, the probes fluorescein-transferrin (F1-Tf) and fluorescein-desferrioxamine (F1-DFO) can be used, which undergo quenching upon binding to iron (Breuer and Cabantchik 2001). In short, the method involves mobilization of iron from serum with 10 mM oxalate and its transfer to the metallosensor fluoresceinated apotransferrin (F1-aTf). Gallium is present in the assay to prevent the binding of labile plasma iron to the unlabelled apotransferrin in the sample. Labile plasma iron values are derived from the magnitude of quenching of the fluorescence signal of fluoresceinated apotransferrin. Fluorescence may be measured using, for example, 96-well plates and a plate reader operating at 485/538 nm excitation/emission filter pair (gain=25).

"Alumina Column Test" (Jacobs et al. 1990)

In this test, samples (serum and candidate iron composition) are passed over an alumina column to absorb organic and drug-bound iron, the elutants are then collected and reconstituted to a pre-selected volume (e.g., 1.5 ml), and the final iron concentration determined using a chemistry analyzer, such as a Hitachi 717 chemistry analyzer. Ferrozine reagents are used, which included detergent, buffers of citric acid and thiourea, ascorbate, and ferrozine. This test is a non-proteinizing method in which detergent clarifies lipemic samples, buffers lower the pH to <2.0 to free iron as Fe³⁺ from transferrin, ascorbate reduces Fe³⁺ to Fe²⁺, and ferrozine reacts with Fe²⁺ to form a colored complex measured spectophotometrically at 560 nm. From this result the value of a control (blank) sample is subtracted from the experimental sample readings, and the results are recorded as the Δ Tf-bound iron (μg/dl).

Pharmaceutical Compositions

In many cases, the iron complex may be delivered as a simple composition comprising the iron complex and the buffer in which it is dissolved. However, other products may be added, if desired, to maximize iron delivery, preservation, or to optimize a particular method of delivery.

A "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration (Gennaro 2000). Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's Lactate solutions and dextrose solution. Supplementary active compounds can also be incorporated into the compositions. For intravenous administration, Venofer® is preferably diluted in normal saline to approximately 2-5 mg/ml. The volume of the pharmaceutical solution is based on the safe volume for the individual patient, as determined by a medical professional

General Considerations

A iron complex composition of the invention for administration is formulated to be compatible with the intended route of administration, such as intravenous injection. Solutions and suspensions used for parenteral, intradermal or subcutaneous application can include a sterile diluent, such as water for injection, saline solution, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Preparations can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injection include sterile aqueous solutions or dispersions for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, CREMOPHOR EL™ (BASF; Parsippany, N.J.) or phosphate buffered saline (PBS). The composition must be sterile and should be fluid so as to be administered using a syringe. Such compositions should be stable during manufacture and storage and must be preserved against contamination from microorganisms, such as bacteria and fungi. The carrier can be a dispersion medium containing, for example, water, polyol (such as glycerol, propylene glycol, and liquid polyethylene glycol), and other compatible, suitable mixtures. Various antibacterial and anti-fungal agents, for example, benzyl alcohol, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal, can contain microorganism contamination. Isotonic agents such as sugars, polyalcohols, such as manitol, sorbitol, and sodium chloride can be included in the composition. Compositions that can delay absorption include agents such as aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating an iron complex in the required amount in an appropriate solvent with a single or combination of ingredients as required, followed by sterilization. Methods of preparation of sterile solids for the preparation of sterile injectable solutions include vacuum drying and freeze-drying to yield a solid containing the iron complex and any other desired ingredient.

Systemic Administration

Systemic administration can be transmucosal or transdermal. For transmucosal or transdermal administration, penetrants that can permeate the target barrier(s) are selected. Transmucosal penetrants include, detergents, bile salts, and fusidic acid derivatives. Nasal sprays or suppositories can be used for transmucosal administration. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams.

Carriers

Active compounds may be prepared with carriers that protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable or biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such materials can be obtained commercially from ALZA Corporation (Mountain View, Calif.) and NOVA Pharmaceuticals, Inc. (Lake Elsinore, Calif.), or prepared by one of skill in the art.

Kits for Pharmaceutical Compositions

Iron complex compositions can be included in a kit, container, pack or dispenser, together with instructions for administration. When the invention is supplied as a kit, the different components of the composition may be packaged in separate containers, such as ampules or vials, and admixed immediately before use. Such packaging of the components separately may permit long-term storage without losing the activity of the components.

Kits may also include reagents in separate containers that facilitate the execution of a specific test, such as diagnostic tests.

Containers or Vessels

The reagents included in kits can be supplied in containers of any sort such that the life of the different components are preserved and are not adsorbed or altered by the materials of the container. For example, sealed glass ampules or vials may contain lyophilized iron complex or buffer that have been packaged under a neutral non-reacting gas, such as nitrogen. Ampules may consist of any suitable material, such as glass, organic polymers, such as polycarbonate, polystyrene, etc., ceramic, metal or any other material typically employed to hold reagents. Other examples of suitable containers include bottles that arc fabricated from similar substances as ampules, and envelopes that consist of foil-lined interiors, such as aluminum or an alloy. Other containers include test tubes, vials, flasks, bottles, syringes, etc. Containers may have a sterile access port, such as a bottle having a stopper that can be pierced by a hypodermic injection needle. Other containers may have two compartments that are separated by a readily removable membrane that, upon removal, permits the components to mix. Removable membranes may be glass, plastic, rubber, etc.

Instructional Materials

Kits may also be supplied with instructional materials. Instructions may be printed on paper or other substrate, and/or may be supplied on an electronic-readable medium, such as a floppy disc, CD-ROM, DVD-ROM, mini-disc, SACD, Zip disc, videotape, audio tape, etc. Detailed instructions may not be physically associated with the kit; instead, a user may be directed to an internet web site specified by the manufacturer or distributor of the kit, or supplied as electronic mail.

Methods for the Treatment of RLS with Compositions Having Greater Iron Release Rates than IDI

Methods of treatment of RLS with iron complex compositions having greater iron release rates than IDI comprise the administration of the complex, either as doses administered over pre-determined time intervals or in response to the appearance and reappearance of RLS symptoms. In general, dosage depends on the route of administration. The preferred route of administration is intravenous infusion; however, certain iron compounds may be administered intramuscularly such as iron dextran. However, any route is acceptable as long as iron from the iron complex is quickly released (more quickly than IDI administered intravenously) such that RLS symptoms are treated.

An appropriate dosage level will generally be about 10 mg to 1000 mg of elemental iron per dose, which can be administered in single or multiple doses, particularly at least 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, 1000.0, and 2000.0 milligrams of elemental iron, and furthermore up to the maximal tolerated dose (MTD) per administration. Preferably, the dosage level will be about 0.1 to about 1000 mg per dose; most preferably about 100 mg to about 500 mg per dose. The compounds may be administered on various regimes.

For example, a 1000 mg of elemental iron of an injectable intravenous iron sucrose complex (Venofer®) is given as a single dose (as a 1.5-5 mg iron/ml in normal saline) to RLS patients. A single intravenous treatment will provide relief of symptoms for an extended period of time, approximately two to twelve months (Nordlander 1953), although relief may be granted for shorter or longer periods. If desired, post-infusion changes in CNS iron status can be monitored using measurements of CSF ferritin (and other iron-related proteins) and of brain iron stores using MRI. Post-infusion changes in RLS are assessed using standard subjective (e.g., patient diary, rating scale) and objective (e.g., P50, SIT, Leg Activity Meters) measures of clinical status. If desired, to better evaluate RLS symptom amelioration, CSF and serum iron values, MRI measures of brain iron and full clinical evaluations with sleep and immobilization tests are obtained prior to treatment, approximately two weeks after treatment, and again twelve months later or when symptoms return. Clinical ratings, Leg Activity Meter recordings and serum ferritin are obtained monthly after treatment. CSF ferritin changes can also be used to assess symptom dissipation.

The frequency of dosing depends on the response of each individual patient and the administered amount of elemental iron. An appropriate regime of dosing will be once every week to once every eighteen months, more preferably once every two to twelve months, or any interval between, such as once every two months and one day, three, four, five, six, seven, eight, nine, ten and eleven months. Alternatively, the iron complexes may be administered ad hoc, that is, as symptoms reappear, as long as safety precautions are regarded as practiced by medical professionals.

It will be understood, however, that the specific dose and frequency of administration for any particular patient may be varied and depends upon a variety of factors, including the activity of the employed iron complex, the metabolic stability and length of action of that complex, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
 

Claim 1 of 16 Claims

1. A method of treating Restless Leg Syndrome, comprising administering to a subject an iron sucrose having an iron release rate greater than IDI, wherein the iron release rate is determined at a concentration of at least 2,000 μg/dl.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.