WO2009032591A1 - Food effect in treatment of diabetes with vanadium salts - Google Patents

Abstract

The invention relates to a method of increasing the oral bioavailability of vanadium by administration of a therapeutically effective amount of a vanadium source to a patient under fasted conditions, wherein said administration results in an increase in the rate and extent of absorption of said vanadium source as compared to administration under fed conditions. It has also been suggested that the administration results in an increase of the maximum concentration (Cmax) in plasma or whole blood and the extent of absorption of vanadium (AUC) as compared to the administration of the vanadium source under fed conditions. The method further comprises administering the chelated vanadium compounds to diabetic patients and/or an agent selected from an analgesic, an anti-emetic, an anti-spasmodic, or a carminative.

Description

Food Effect in Treatment of Diabetes with Vanadium Salts

Related Applications This application claims the benefit of priority to United States Provisional Patent

Application serial number 60/968,388, filed August 28, 2007; and United States Provisional Patent Application serial number 60/970,076, filed September 5, 2007; both of which are incorporated by reference.

Field of the Invention The invention relates to methods for increasing the oral bioavailability of drug products containing vanadium. Background of the Invention

Outside the hospital setting, the most convenient mode of administering medications to patients is generally orally. The bioavailability of a medication may vary from one individual to another; variations are caused by differences in the extent of absorption, metabolism and excretion. Changes in bioavailability of the same medication may occur even with the same patient; for example, when the medication is taken with or without food. Summary of the Invention One aspect of the invention relates to a method of treating diabetes in a mammal, comprising: administering orally to a mammal in need thereof a therapeutically effective amount of a vanadium source under fasted conditions, wherein said administration results in an increase in the rate and extent of absorption of said vanadium source as compared to administration under fed conditions. In certain embodiments, said vanadium source is selected from the group consisting of BEOV, BMOV, BIOV, VO(DMM)₂, VO(DEM)₂, VO(acac)₂, VO(salen-SO₃), VO(gamma-pga), BFOV, BQOV, VOL and vanadyl sulfate. In certain embodiments, said vanadium source is BEOV. In certain embodiments, said therapeutically effective amount of BEOV is in the range of about 0.5 mg to about 90 mg, per dose, and said dose is administered at least twice weekly. In certain embodiments, said therapeutically effective amount of BEOV is in the range of about 1 mg to about 90 mg, per dose, and said dose is administered at least twice weekly. In certain embodiments, said therapeutically effective amount of BEOV is in the range of about 1 mg to about 5 mg, per dose, and said dose is administered at least twice weekly. In certain embodiments, said mammal is a human. In certain embodiments, the administration to the mammal is at least about 12 hours after the mammal's last meal and at least about 6 hours before the mammal's next meal, hi certain embodiments, the administration to the mammal is at least about 10 hours after the mammal's last meal and at least about 4 hours before the mammal's next meal. In certain embodiments, the administration to the mammal is at least about 8 hours after the mammal's last meal and at least about 3 hours before the mammal's next meal. In certain embodiments, the administration to the mammal is at least about 6 hours after the mammal's last meal and at least about 2 hours before the mammal's next meal. In certain embodiments, the administration to the mammal is at least about 4 hours after the mammal's last meal and at least about 2 hours before the mammal's next meal. In certain embodiments, the administration to the mammal is at least about 2 hours after the mammal's last meal and at least about 1 hour before the mammal's next meal, hi certain embodiments, the administration results in a maximum concentration (C_max) level in plasma or whole blood from about 40 ng/mL to about 600 ng/mL. In certain embodiments, the administration results in a maximum concentration (C_maχ) level in plasma or whole blood from about 80 ng/mL to about 200 ng/mL. In certain embodiments, the administration results in an increase of the maximum concentration (C_max) in plasma or whole blood and the extent of absorption of vanadium (AUC) as compared to the administration of the vanadium source under fed conditions. In certain embodiments, the ratio of C_max following administration without food to C_maχ following administration with food is about 4.0 to about 20.0, and wherein the ratio of AUC following administration without food to AUC following administration with food is about 4.0 to about 20.0. In certain embodiments, the ratio of C_maχ following administration without food to C_maχ following administration with food is about 6.0 to about 18.0, and wherein the ratio of AUC following administration without food to AUC following administration with food is about 6.0 to about 18.0. hi certain embodiments, the ratio of C_max following administration without food to C_013x following administration with food is about 8.0 to about 16.0, and wherein the ratio of AUC following administration without food to AUC following administration with food is about 8.0 to about 16.0. hi certain embodiments, the ratio of C_max following administration without food to C_max following administration with food is about 10.0 to about 14.0, and wherein the ratio of AUC following administration without food to AUC following administration with food is about 10.0 to about 14.0. In certain embodiments, the vanadium source is from a container with printed labeling advising that administration under fasted conditions results in an increase in the maximum concentration (C_max) in plasma or whole blood and the extent of absorption (AUC) as compared to the administration of the vanadium source under fed conditions. Another aspect of the invention relates to a method for treating diabetes, comprising administering orally to a human in need thereof a therapeutically effective amount of a chelated vanadium compound, wherein the human has been instructed (a) to have minimal caloric intake for at least 4 hours before and at least 2 hours after administering the chelated vanadium compound. In certain embodiments, the human has been further instructed (b) to have minimal caloric intake for at least 8 hours before administering the chelated vanadium compound. In certain embodiments, the minimal caloric intake is limited to water.

Another aspect of the invention relates to a method for treating diabetes, comprising administering orally to a human in need thereof a therapeutically effective amount of a chelated vanadium compound, wherein the human has been instructed (a) to have minimal caloric intake for at least 4 hours before and at least 4 hours after administering the chelated vanadium compound. In certain embodiments, the human has been further instructed (b) to have minimal caloric intake for at least 8 hours before administering the chelated vanadium compound. In certain embodiments, the minimal caloric intake is limited to water. Another aspect of the invention relates to a method for treating diabetes in a human in which the human: (a) orally administers a therapeutically effective amount of a chelated vanadium compound; and (b) ingests a minimal caloric intake for at least 4 hours before and at least 2 hours after administering the chelated vanadium complex. In certain embodiments, the human further (c) ingests a minimal caloric intake for at least 8 hours before administering the chelated vanadium complex. In certain embodiments, the minimal caloric intake is limited to water. In certain embodiments, the method further comprises administering an agent selected from an analgesic, an anti-emetic, an anti-spasmodic, or a carminative. In certain embodiments, the systemic bioavailability of vanadium is at least about 20%. In certain embodiments, the C_max of vanadium in the plasma or blood of the human is at least about 200 ng/mL. In certain embodiments, the C_max of vanadium in the plasma or blood of the human is at least about 100 ng/mL. In certain embodiments, the Cmax of vanadium in the plasma or blood of the human is at least about 50 ng/mL. In certain embodiments, the C_max of vanadium in the plasma or blood of the human is at least about 25 ng/mL. In certain embodiments, the T_max of vanadium in the plasma or blood of the human is less than about 2 hours. Another aspect of the invention relates to a method for treating diabetes in a human in which the human: (a) orally administers a therapeutically effective amount of a chelated vanadium compound; and (b) ingests a minimal caloric intake for at least 4 hours before and at least 4 hours after administering the chelated vanadium complex, hi certain embodiments, the human further (c) ingests a minimal caloric intake for at least 8 hours before administering the chelated vanadium complex, hi certain embodiments, the minimal caloric intake is limited to water. In certain embodiments, the method further comprises administering an agent selected from an analgesic, an anti-emetic, an anti-spasmodic, or a carminative. In certain embodiments, the systemic bioavailability of vanadium is at least about 20%. In certain embodiments, the C_maχ of vanadium in the plasma or blood of the human is at least about 200 ng/niL. In certain embodiments, the C_maχ of vanadium in the plasma or blood of the human is at least about 100 ng/mL. In certain embodiments, the C_max of vanadium in the plasma or blood of the human is at least about 50 ng/mL. In certain embodiments, the C_max of vanadium in the plasma or blood of the human is at least about 25 ng/mL. In certain embodiments, the T_maχ of vanadium in the plasma or blood of the human is less than about 2 hours.

Another aspect of the present invention relates to the use of a chelated vanadium compound in the manufacture of a medicament for the treatment of diabetes in a subject in a fasted state. In certain embodiments, the chelated vanadium compound is selected from the group consisting of BEOV, BMOV, BIOV, VO(DMM)₂, VO(DEM)₂, VO(acac)₂, VO(salen-SO₃), VO(gamma-pga), BFOV, BQOV, VOL and vanadyl sulfate. In certain embodiments, the chelated vanadium compound is BEOV. hi certain embodiments, the medicament is administered in a solid oral dosage form. In certain embodiments, the fasted state is minimal caloric intake for at least 4 hours before and at least 2 hours after administering the medicament, hi certain embodiments, the medicament is administered in the range of about 0.5 mg to about 90 mg, per dose, and the dose is administered at least twice weekly. In certain embodiments, the medicament is administered in the range of about 1 mg to about 90 mg, per dose, and the dose is administered at least twice weekly. In certain embodiments, the medicament is administered in a range of about 1 mg to about 5 mg, per dose, and the dose is administered at least twice weekly.

Another aspect of the present invention relates to a pharmaceutical formulation comprising a chelated vanadium compound for the treatment of diabetes in a human patient in a fasted state and/or the reduction of fasting blood sugar in a human patient and/or the improvement of glucose tolerance in a fasted human patient and/or reduction of glycosylated hemoglobin in a fasted human patient, hi certain embodiments, the chelated vanadium compound is selected from the group consisting of BEOV, BMOV, BIOV, VO(DMM)₂, VO(DEM)₂, VO(acac)₂, VO(salen-SO₃), VO(gamma-pga), BFOV, BQOV, VOL and vanadyl sulfate, hi certain embodiments, the chelated vanadium compound is BEOV. In certain embodiments, the pharmaceutical formulation is administered in a solid oral dosage form. In certain embodiments, the fasted state is minimal caloric intake for at least 4 hours before and at least 2 hours after administering the medicament. In certain embodiments, the pharmaceutical formulation is administered in the range of about 0.5 mg to about 90 mg, per dose, and the dose is administered at least twice weekly. In certain embodiments, the pharmaceutical formulation is administered in the range of about 1 mg to about 90 mg, per dose, and the dose is administered at least twice weekly. In certain embodiments, the pharmaceutical formulation is administered in a range of about 1 mg to about 5 mg, per dose, and the dose is administered at least twice weekly.

Yet another aspect of the present invention relates to a method for reducing fasting blood sugar in a human patient comprising administering a therapeutically effective amount of a chelated vanadium compound to an individual in a fasted state. In certain embodiments, the chelated vanadium compound is in a solid oral dosage form. In certain embodiments, the chelated vanadium compound is selected from the group consisting of BEOV, BMOV, BIOV, VO(DMM)₂, VO(DEM)₂, VO(acac)₂, VO(salen-SO₃), V0(gamma- pga), BFOV, BQOV, VOL and vanadyl sulfate. In certain embodiments, the chelated vanadium compound is BEOV. In certain embodiments, the therapeutically effective amount of BEOV is in the range of about 0.5 mg to about 90 mg, per dose, and the dose is administered at least twice weekly. In certain embodiments, the therapeutically effective amount BEOV is in the range of about 1 mg to about 90 mg, per dose, and the dose is administered at least twice weekly. In certain embodiments, the therapeutically effective amount of BEOV is in the range of about 1 mg to about 5 mg, per dose, and the dose is administered at least twice weekly. In certain embodiments, the human patient has diabetes.

Yet another aspect of the present invention relates to a method for improving the glucose tolerance in a human patient comprising administering a therapeutically effective amount of a chelated vanadium compound to an individual in a fasted state. In certain embodiments, the chelated vanadium compound is in a solid oral dosage form. In certain embodiments, the chelated vanadium compound is selected from the group consisting of BEOV, BMOV, BIOV, VO(DMM)₂, VO(DEM)₂, VO(acac)₂, VO(salen-SO₃), V0(gamma- pga), BFOV, BQOV, VOL and vanadyl sulfate. In certain embodiments, the chelated vanadium compound is BEOV. In certain embodiments, the therapeutically effective amount of BEOV is in the range of about 0.5 mg to about 90 mg, per dose, and the dose is administered at least twice weekly. In certain embodiments, the therapeutically effective amount BEOV is in the range of about 1 mg to about 90 mg, per dose, and the dose is administered at least twice weekly. In certain embodiments, the therapeutically effective amount of BEOV is in the range of about 1 mg to about 5 mg, per dose, and the dose is administered at least twice weekly. In certain embodiments, the human patient has diabetes.

Yet another aspect of the present invention relates to a method for reducing glycosylated hemoglobin in a human patient comprising administering a therapeutically effective amount of a chelated vanadium compound to an individual in a fasted state. In certain embodiments, the chelated vanadium compound is in a solid oral dosage form. In certain embodiments, the chelated vanadium compound is selected from the group consisting of BEOV, BMOV, BIOV, VO(DMM)₂, VO(DEM)₂, VO(acac)₂, VO(salen-SO₃), VO(gamma-pga), BFOV, BQOV, VOL and vanadyl sulfate. In certain embodiments, the chelated vanadium compound is BEOV. In certain embodiments, the therapeutically effective amount of BEOV is in the range of about 0.5 mg to about 90 mg, per dose, and the dose is administered at least twice weekly. In certain embodiments, the therapeutically effective amount BEOV is in the range of about 1 mg to about 90 mg, per dose, and the dose is administered at least twice weekly. In certain embodiments, the therapeutically effective amount of BEOV is in the range of about 1 mg to about 5 mg, per dose, and the dose is administered at least twice weekly. In certain embodiments, the human patient has diabetes.

The present invention also relates to an article of manufacture comprising a container containing a chelated vanadium compound and a label with the container, wherein the label instructs the user to administer orally the chelated vanadium compound for the treatment of diabetes; and the label further instructs the user to ingest a minimal caloric intake for at least 4 hours before and at least two hours after administration of the chelated vanadium complex. In certain embodiments, the label further instructs the user to ingest a minimal caloric intake for at least 8 hours before administration of the chelated vanadium complex. In certain embodiments, additional written instructions for use are provided with the container.

In any of the aforementioned aspects and embodiments, the therapeutically effective amount of the chelated vanadium compound is ingested by the patient after fasting overnight and prior to the first meal of the day.

Brief Description of the Drawings

Figure 1 is a plot of the vanadium plasma concentration (nanograms per milliliter) versus time (hours) elapsed from oral administration of 75 mg BEOV to human volunteers. Independent plots are shown for the administration with food (dashed line) and without food (solid line).

Figure 2 is a semi-logarithmic plot of the log of vanadium plasma concentration (nanograms per milliliter) versus time (hours) elapsed from oral administration of 75 mg BEOV to human volunteers. Figure 3 is a plot of the fasting glucose level after oral administration of placebo or

20 mg BEOV to diabetic study volunteers.

Figure 4 is a plot of the extent of absorption of vanadium (AUC) in an oral glucose tolerance test (OGTT) after administration of placebo or 20 mg BEOV to diabetic study volunteers. Figure 5 is shows levels of glycosylated hemoglobin (HbAIc) after administration of placebo or 20 mg BEOV to diabetic study volunteers.

Figure 6 shows euglycemic-hyperinsulinemic clamp results in fasting diabetic study volunteers on days 1 and 28 of the Phase II trial.

Figures 7 A-C shows the level of BEOV in the blood of diabetic study volunteers reaches a steady state within two weeks of treatment initiation. Detailed Description of the Invention

Overview

Unexpectedly, we have discovered that oral administration of vanadium under fasted conditions increases the extent and rate of absorption via the oral dosage form in human subjects.

One aspect of this invention is a method of increasing the bioavailability of vanadium in a human patient receiving vanadium therapy wherein the vanadium is contained in a pharmaceutical composition, which method comprises administering a therapeutically effective amount of vanadium to the patient in a fasted condition. Another aspect of the invention is providing a method of increasing rate and extent of vanadium absorption as measured by the vanadium concentration attained in the blood stream over time of a patient receiving the vanadium in an oral dosage form which method comprises administering a therapeutically effective amount of vanadium to the patient in a fasted condition. The vanadium concentration in the blood of a patient is optionally determined using either whole blood or plasma measurements, although the absolute results from the two types of samples may not be identical due to, for example, differences in the amount of partitioning of vanadium in whole blood versus plasma.

The invention also includes a method of increasing the oral bioavailability of vanadium to a patient receiving vanadium therapy, comprising administering to the patient under fasted conditions a pharmaceutical tablet, capsule or other oral dosage form comprising about 0.5 mg to about 90 mg of a source of vanadium, wherein the administration results in an increase of the maximum concentration (C_m3x) in plasma or whole blood and the extent of absorption of vanadium (AUC) as compared to the administration of vanadium under fed conditions. The invention further includes a method of increasing the oral bioavailability of vanadium to a patient receiving vanadium therapy, comprising administering to the patient under fasted conditions a pharmaceutical tablet, capsule or other oral dosage form comprising about 1 mg to about 90 mg of a source of vanadium, wherein the administration results in an increase of the maximum concentration (C_maχ) in plasma or whole blood and the extent of absorption of vanadium (AUC) as compared to the administration of vanadium under fed conditions.

The invention is also directed to a method for treating diabetes in a patient, which comprises administering orally to a patient in a fasted condition a therapeutically effective amount of vanadium. To this end, a source of vanadium (e.g., containing about 20, 15, 10, or 5 mg of elemental vanadium) is administered orally to a patient, wherein the resulting maximum concentration (C_maχ) in plasma or whole blood of vanadium after administration is at least about 40 ng/mL to about 600 ng/niL of plasma; in certain embodiments, the extent of absorption as measured by AUC (0-infinity) is at least about 20,000 ng h/mL to about 40,000 ng h/mL in plasma or whole blood. The rate of absorption is decreased by the presence of food, as evidenced by the increased T_max in the fed state versus the fasted state. While not wishing to be bound by any particular theory, it is possible that the rate or extent of dissociation of vanadium from the vanadium source (e.g., BMOV or BEOV) in the gastrointestinal tract (i.e., as opposed to in the plasma, with which therapeutic benefit is believed to correlate) is decreased when the vanadium source is administered orally in the fasted state as compared to the fed state. Definitions

As used herein, the term "bioavailability" generally means the rate and extent to which an active ingredient is absorbed from a drug product and becomes available systemically. For oral dosage forms, bioavailability is a composite of a range of inter- related parameters, such as effect on gastrointestinal tract transit time, vascularity of the site of absorption from the gastrointestinal tract, and the composition of any food that may be present. Bioavailability data as measured by drug levels in the plasma/whole blood for a particular formulation provides an estimate of the fraction of the administered dose, for example, an oral tablet, that is absorbed into the systemic circulation.

As used herein, the terms "without food," "fasted conditions," and "fasted state" are defined to mean, in general, the condition of not having consumed food during the period from at least about 4 hours before the administration of vanadium to at least about 1 hour after the administration of vanadium. A human patient in a fasted state or a fasted human patient includes a patient who was administered the source of vanadium under fasted conditions, even if the patient subsequently consumes food at the completion of or outside the time period of the fasted conditions.

In contrast, the term "with food" is defined to mean, in general, the condition of having consumed food during the period between from about 60 minutes prior to administration of vanadium to about 60 minutes after the administration of vanadium. "Food" includes anything that a mammal ingests orally that has a metabolic benefit or a caloric value to the mammal. For example, "food" is material, usually of plant or animal origin, that contains or consists of nutrients, such as carbohydrates, fats, proteins, vitamins, or minerals in any ratio, and is ingested and assimilated by an organism to produce energy, stimulate growth, and maintain life.

The phrase "treating diabetes" means controlling or alleviating the symptoms associated with diabetes, as well controlling or alleviating diabetes itself. By way of example, "treating diabetes" includes any one or a combination of the following: (a) normalizing blood glucose levels in a patient suspected to have or diagnosed with diabetes; (b) normalizing blood lipid levels in a patient suspected to have or diagnosed with diabetes; (c) correcting thyroid hormone deficiency in a patient suspected to have or diagnosed with diabetes; (d) improving insulin sensitivity in a patient suspected to have or diagnosed with diabetes; and (e) preventing and/or reversing secondary complications associated with diabetes, including (i) cardiomyopathy; (ii) cataract development; (iii) impaired antioxidant status; (iv) excessive food intake; (v) excessive fluid intake; (vi) kidney disease; and (vii) peripheral neuropathy. "Diabetes" includes both type 1 and type 2 diabetes mellitus.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element is essential to the practice of the invention. Methods of the Invention

So long as one avoids toxicological problems, it is generally desirable to increase the oral bioavailability of a medication, thereby increasing the extent of the therapeutic effect on the user, and reducing the potential for off-target side effects (e.g., gastrointestinal disturbances). A food-drug interaction refers to the change of the bioavailability of drugs caused by intake of food; the interaction may result in reduced, delayed or increased systemic drug availability. Food may interact with a co-administered drug before and during gastrointestinal absorption, during distribution, during metabolism, and/or during elimination. Importantly, studies have not previously been conducted to evaluate the effect of food on the pharmacokinetics of vanadium and vanadium-containing compounds used for the treatment of diabetes.

The present invention is directed to methods for increasing the bioavailability of vanadium in diabetic patients, and for example thereby treating diabetes in these patients. It has been discovered that a source of vanadium can be orally administered to human patients in a regimen that increases the therapeutic effectiveness of vanadium to such patients. Specifically, when administered under fasted conditions, vanadium exhibits increased oral bioavailability in patients. Thus, the present invention is directed to for example the treatment of diabetes in a patient in which the source of vanadium is administered to the patient under fasted conditions.

Therefore, the present invention provides a method of increasing the oral bioavailability of a source of vanadium in a human patient comprising administering to the patient a therapeutically effective amount of vanadium under fasted conditions. In certain embodiments, the human patient has diabetes, and the therapeutically effective amount is therapeutically effective for treating diabetes.

The methods of the present invention are directed to the administration of a therapeutically acceptable amount of vanadium or a pharmaceutically acceptable salt of vanadium. Pharmaceutically acceptable salts of vanadium include any and all forms of vanadium in a non-covalent complex with at least one additional molecule (e.g., a ligand). In certain embodiments, the present invention is directed to the use of a 3-hydroxy-4- pyrone oxovanadium(IV) salt. In certain embodiments, the present invention is directed to the use of a vanadyl complex with bidentate maltol-type ligands. In certain embodiments, the present invention is directed to the use of bis(maltolato)oxovanadium(IV) (BMOV), bis(ethylmaltolato)oxovanadium(IV) (BEOV), bis(isopropylmaltolato)oxovanadium(IV) (BIOV), bisdimethylmalonatooxovanadium(IV) (VO(DMM)₂), bisdiethylmalonatooxovanadium(IV) (VO(DEM)₂), bisacetylacetonatooxovanadium(IV) (VO(acac)₂), cesium aqua (N,N'-ethylene(salicylideneiminato)-5-sulfonato) oxovanadium (IV) dehydrate (VO(salen-SO₃)), poly(gamma-glutamic acid)oxovanadium(IV) complex (VO(gamma-pga)), Bis(alpha-furancarboxylato)oxovanadium(IV) (BFOV), bis(quercetinato)oxovanadium IV (BQOV), N(l)-2,4-dihydroxybenzylidene-N(4)-2- hydroxybenzylidene-S-methyl-thiosemicarbazidato-oxovanadium(IV) (VOL) or vanadyl sulfate as a source of vanadium. In certain embodiments, the present invention is directed to the use of BMOV or BEOV as a source of vanadium. The use of BMOV is described in U.S. Pat. 5,300,496, incorporated herein by reference. The chemical structures of BMOV and BEOV are shown below.

In general, a suitable dose of a therapeutically effective (e.g., therapeutically effective for the treatment of diabetes) amount of BEOV for administration to a patient will be between about 0.5 mg to about 90 mg total daily dose, which may be given in a single dose or multiple doses. In another embodiment, the effective amount of BEOV is between about 1 mg to about 90 mg total daily dose. In another embodiment, the therapeutically effective amount is between about 1 mg and 5 mg total daily dose, which may be given in a single dose or multiple doses. In another embodiment, the therapeutically effective amount is between about 5 mg and 50 mg total daily dose, which may be given in a single dose or multiple doses. In another embodiment, the therapeutically effective amount is about 2 mg total daily dose, which may be given in a single dose or multiple doses. In certain embodiments, the vanadium source is given once a week or twice a week. Alternatively, the dosing may be more or less frequent. In general, the methods encompass any dosing regimen that is efficacious in treating diabetes. In certain embodiments, the source of vanadium is given to a fasted patient in a single dose or multiple doses. The single dose may be administered daily, or multiple times a day, or multiple times a week, or monthly, or multiple times a month. In certain embodiments, the source of vanadium is given in a series of doses. The series of doses may be administered daily, or multiple times a day, weekly, or multiple times a week, or monthly, or multiple times a month.

For ease of compliance with the therapeutic methods described herein, a patient may be administered a short-term satiety factor during fasting periods. Some examples of satiety factors that may be used in the therapeutic methods described herein include appetite suppressants, such as phentermine, or peptides and proteins that play a role in regulating appetite (e.g., leptin, amylin, bombesin, ghrelin). The satiety factor may be administered orally (e.g., as a liquid) or as an injectable, and should not interfere with the bioavailability of the vanadium source. In addition, the therapeutic methods described herein include as an option the monitoring of vanadium ion accumulation in the patient (e.g., in the patient's plasma or blood).

In certain embodiments, the dosing regimen includes a drug holiday, in which the source of vanadium is not administered to the patient for a pre-determined period of time. At the termination of the drug holiday, the prior treatment regimen or a new treatment regimen is optionally re- initiated. By way of example, a patient is administered a single dose of a chelated vanadium compound daily for "x" consecutive days, followed by a drug holiday of "y" days, after which the dosing/drug-holiday cycle starts again. In some embodiments, "x" is 3 days, 7 days, 10 days, 14 days, 17 days, 21 days, 24 days, 28 days, or 31 days, and "y" is 1 day, 2 days. 3 days, 4 days, 5 days, 6 days, 7 days, 8 days. 9 days or 10 days.

The vanadium-containing complex may be administered for therapy to a patient in any conventional manner. While it is possible for the vanadium-containing complex to be administered as the raw chemical, it is generally presented as a pharmaceutical formulation. Pharmaceutical formulations according to the present invention comprise the vanadium- containing complex or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formula and not deleterious to the recipient thereof. When the individual components of the combination are administered separately, they are generally each presented as a pharmaceutical formulation.

The pharmaceutical formulations of the invention may include one or more other medicinal agents, pharmaceutical agents, carriers, adjuvants, and/or diluents. In one example, a source of vanadium is combined with other active agents for the treatment of diabetes. Suitable oral antidiabetic agents include sulfonylureas, meglitinides, biguanides, thiazolidinediones, and α-glucosidase inhibitors.

Examples of carriers or recipients for oral administration include cornstarch, lactose, magnesium stearate, microcrystalline cellulose and stearic acid, povidone, dibasic calcium phosphate and sodium starch glycolate. Any carrier suitable for the desired administration route is contemplated by the present invention.

In certain embodiments, the compositions of the present invention are contained in a solid dosage form (e.g., a pill, capsule, or tablet), a semi-solid dosage form or a liquid dosage form, each containing a predetermined amount of active ingredient. In certain embodiments, a solid dosage form is coated for ease of swallowing. The compositions of the present invention are optionally in the form of a powder or granules; or as a solution or suspension. For oral administration, fine powders or granules optionally contain diluting, dispersing, and or surface active agents and may be present in a solution or suspension in water or syrup, capsules or sachets in the dry state, in a nonaqueous solution or suspension wherein suspending agents are optionally included, or in tablets wherein binders and lubricants may be included. Components that are optionally added include flavoring, preservative, suspending, thickening or emulsifying agents.

Oral delivery methods are often limited by chemical and physical barriers imposed by the body, such as the varying pH in the gastrointestinal tract, exposure to enzymes, and the impermeability of the gastrointestinal membranes. Methods of the present invention for orally administering the pharmaceutical formulation may also include the co-administration of adjuvants with the compositions of the present invention. For example, nonionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether can be administered with or incorporated into the formulations of the present invention to increase artificially the permeability of the intestinal walls. Other methods include the coadministration of enzymatic inhibitors with the formulations of the present invention. The active ingredients may also be present as a bolus or paste or may be contained within liposomes and emulsions.

Formulations for rectal administration may be presented as a suppository or enema. When administered in the form of an aqueous liquid solution, the formulation will contain the source of vanadium and purified water. Optional components in liquid solution include suitable solvents, buffering agents, sweeteners, anti-microbial preservatives, flavoring agents, and mixtures thereof. A component of the formulation may serve more than one function. For example, a suitable buffering agent may also act as a flavoring agent as well as a sweetener.

Suitable solvents in the liquid solution used in the present invention include, for example, sorbitol, glycerin, propylene glycol, and water. A mixture of two or more solvents may optionally be used. The solvent or solvent system is typically present in an amount of from about 1% to about 90% by weight of the total liquid formulation. Suitable buffering agents include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. A mixture of two or more buffering agents may optionally be used. The buffering agent or mixtures thereof are typically present in an amount of from about 0.001 wt. % to about 4 wt. %. Suitable sweeteners include, for example, saccharin sodium, sucrose, and mannitol.

A mixture of two or more sweeteners may optionally be used. The sweetener or mixtures thereof are typically present in an amount of from about 0.001 wt. % to about 70 wt. %.

Suitable anti-microbial preservatives include, for example, methylparaben, propylparaben, sodium benzoate, benzalkonium chloride. A mixture of two or more preservatives may optionally be used. The preservative or mixtures thereof are typically present in an amount of from about 0.0001 wt. % to about 2 wt. %.

Suitable flavoring agents may be used to the liquid solution a cherry flavor, cotton candy flavor, or other suitable flavor to make the solution easier for a patient to ingest. The flavoring agent or mixtures thereof are typically present in an amount of from about 0.0001 wt. % to about 5 wt. %. Kits of the Invention

The present invention also relates to an article of manufacture comprising a container containing a chelated vanadium compound and a label with the container, wherein the label instructs the user to administer orally the chelated vanadium compound for the treatment of diabetes; and the label further instructs the user to ingest a minimal caloric intake for at least 4 hours before and at least two hours after administration of the chelated vanadium complex. In certain embodiments, the label further instructs the user to ingest a minimal caloric intake for at least 8 hours before administration of the chelated vanadium complex. In certain embodiments, additional written instructions for use (e.g., instructional guidelines for minimal caloric intake) are provided with the container. For example, the chelated vanadium compound may be packaged in a 30-day blister card of tablets. Each pill may contain varying amounts of chelated vanadium compound, if necessary, in order to regulate and maintain stable levels of serum vanadium in the patient.

Exemplification The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and is not intended to limit the invention. Example 1 A Phase I clinical trial using the ethylmaltolato vanadium coordination complex,

BEOV, was done to: (1) assess the safety and tolerability of single, escalating does of orally administered BEOV; (2) determine the pharmacokinetics of modest doses of BEOV from measured plasma, urinary and fecal [V]_totai; and (3) compare the bioavailability of a well-tolerated dose of BEOV and an equivalent molar dose of oral VOSO₄. Human volunteers (n = 40) were healthy and non-diabetic between the ages of 18 and 45.

To assess the food effect on the oral bioavailability of BEOV, eight volunteers received two single BEOV doses of 75 mg (11.1 mg V) on separate occasions, either fasted (overnight and at least 4 h after dosing) or fed (standard breakfast immediately after dosing), separated by approximately 2 weeks.

Table I

Comparison of fed versus fasted parameters for BEOV absorption

Parameter Fasted Fed P values^*

T_max (h)⁸ 0.75 4.00 0.06

C_max (ng/mL)^b 426.1 34.0 0.0001

AUC (ng h/mL)^c 28,777 2,353 0.0001 t-Λ (h)^d 76.83 108.25 NS

% ADurine (0-169 h) 36.1 2.3 - "/o ADfeces (0-168 h) 17.5 108.8

CI_R (L/h)¹ 0.174 0.166 NS

Analysis of variance (ANOVA) was performed using the GLM procedure in SAS (version 6.12) a T_max: time to maximal concentration of vanadium (V). b Cmax." maximal concentration of V c AUC: area under the curve of V disappearance from plasma ([V] vs. time). d t_'/2: half- life of V elimination from the plasma. e % AD: percentage of the administered dose of V. f CI_R: renal clearance of V, estimated from total V excreted in urine over the 168 h collection period (Ae₁₁) and AUC: (Ae_u/AUC) x 100.

The results of the pharmacokinetic analysis of the volunteers' plasma vanadium over time administered under fasted and fed conditions are set forth in Table I and FIGS. 1 and 2. The presence of food had a large negative effect on the bioavailability of BEOV. As Table I illustrates, the C_maχ and AUC (0 - infinity) are significantly greater for BEOV administration without food.

Based on experimental results in animals, the relative bioavailability of vanadium from BEOV relative to vanadyl sulfate was estimated to be three times greater calculated by:

((AUC/Dose)_BEov - (AUC/Dose)_VOso4) x 100.

However, the mean maximum vanadium concentration (C_max) after administration of 75 mg BEOV in the fasted state was approximately 426 ng/mL and for BEOV administration under fed conditions was approximately 34 ng/mL. Thus, the vanadium concentration was approximately 13 times higher from administration in the fasted state than from administration of the same dose in the fed state.

Likewise, the results for AUC (0 - infinity) were similar. The AUC (0 - infinity) after administration of BEOV in the fed state was approximately 2,353 ng h/mL and in the fasted state was approximately 28,777 ng h/mL, approximately 12 times greater. The fasted state also had an observable effect on the rate of vanadium absorption or time to maximal plasma concentration (T_max). T_maχ was achieved in only 45 minutes (mean value of eight data points) when BEOV was administered in the fasted state versus 4 hours (mean value of eight data points) in the fed state; however, the observed ranges for the two sets (fasted and fed) of individual data points overlapped.

Moreover, the food effect influences the observed plasma elimination half life of orally administered BEOV. For example, the elimination plasma half life of oral BEOV (75 mg) administered in the fasted state is roughly thirty hours shorter than the half life when the same dose is administered in the fed state. In other words, when administered under fasted conditions the time taken for the level of vanadium in the plasma derived from BEOV to fall by fifty percent is decreased, which is a desirable improvement because, e.g., it allows for more prompt therapeutic responses to any toxicity or side effects at a particular dosage.

The ANOVA detected statistically significant differences between BEOV fasted and fed conditions for AUC (O-infϊnity) and C_max.

No adverse health affects were observed in any of the volunteers with BEOV administration during the course of this study. Liver and kidney function tests and blood chemistries remained within normal levels in all volunteers in the study. In contrast, oral administration of vanadyl sulfate (50 mg) has been reported to result in sedation, headache, dizziness, or gastrointestinal disturbances (e.g., diarrhea, nausea, and/or cramps) in some subjects when administered in a similar manner.

In sum, the administration of a source of vanadium, BEOV, without food increases the extent of absorption of vanadium when administered as a single 75 mg dose. The bioavailability of a source of vanadium, as BEOV, increased when administered without food as compared to the administration of BEOV with food. For any suitable pharmaceutical dosage form containing a therapeutically effective amount of vanadium, the C_max following administration under fasted conditions is typically at least about 40 ng/mL, and in another embodiment at least about 80 ng/mL. The ratio of C_max for BEOV, in any dosage form, administered without food to C_max for BEOV with food is generally greater than about 4.0 up to about 20.0.

The AUC (O-infϊnity) for BEOV, in any pharmaceutical dosage form, given in a single dose of 75 mg, is typically greater than about 4,000 ng h/mL following administration without food. The ratio of AUC (0-infmity) for BEOV, in any dosage form, administered without food to AUC (O-infϊnity) for BEOV with food is generally greater than about 4.0 up to about 20.0.

Table II

Pharmacokinetic assay results of BEOV

Parameter BEOV VOSO₄

10 mg 25 mg 35 mg 60 mg 90 mg

50 mg

T_max (h)^a 3.1 3.5 3.0 3.5 0.8 6.0

C_max (ng/niL)^b 4.1 38.5 28.7 65.0 170.0 21.6

AUC (ng h/mL)^c 276 1392 1273 3286 8719 1136 t_/2 (h)^d 63.5 45.1 55.1 52.5 61.0 59.2

% AD_uπne (O_-72 h)^e 1.90 5.81 3.11 4.64 11.33 1.04

% ADfeces (0-72 h) 139.8 66.8 40.5 73.8 57.4 40.4

CI_R (L/h)^f 0.237 0.168 0.226 0.204 0.243 0.142

T_max: time to maximal concentration of vanadium (V). b C_max: maximal concentration of V c AUC (0-infinity): area under the curve of V disappearance from plasma ([V] vs. time). ^d t_/2: half- life of V elimination from the plasma. e % AD: percentage of the administered dose of V.

CI_R: renal clearance of V, estimated from total V excreted in urine over the 72 h collection period (Ae₁₁) and AUC: (Ae₁₁/ AUC) x 100.

Separate volunteers were given a single oral dose of 10, 25, 35, 60, or 90 mg BEOV. Placebos were used in the presence of food as controls in the presented study. As Table II illustrates, time to maximal concentration, T_maχ, and renal clearance were independent of BEOV dose (with the exception of the 90 mg dose).

Vanadium from VOSO₄ was absorbed at a slower rate, based on T_max, achieved a lower maximal concentration, a lower % AD in urine and had a slower renal clearance, compared to vanadium from BEOV. Example 2

A Phase II clinical trial was conducted to evaluate the pharmacokinetic and pharmacodynamic relationship of BEOV given as two 10 mg capsules q.d. for 28 days, on the insulin sensitivity and the glucose utilization in human volunteers with non-insulin dependent diabetes mellitus. A control group was included in order to assess the variability over 28 days in the sensitivity of type 2 diabetics to insulin as assessed in the euglycemic- hyperinsulinemic clamp model. Study volunteers were normotensive, adult males between the ages of 35-65 diagnosed as having Type 2 diabetes; a baseline hemoglobin AIc (HbAIc) between 6.5% and 10% inclusive; and were either drug naive, or had been taken off prior treatment with either Metformin, or a sulfonylurea (e.g., Glipizide).

Study volunteers received two 10 mg capsules of BEOV for oral administration, after an overnight fast on Day 1 and thereafter once daily through Day 28 for volunteers that constitute the fasted (overnight and 2 hours after dosing), or after fed a standard breakfast (before dosing and a 2 hour fast after dosing). The control group volunteers received two placebo capsules orally after an overnight fast on Day 1 and every day thereafter through Day 28. Figure 3 shows fasting glucose levels in a diabetic study volunteer after administration of either placebo or 20 mg BEOV. Pharmacokinetic evaluation

The pharmacokinetic profile of vanadium released from BEOV was measured in whole blood following a single oral administration of two 10 mg capsules to both fasted and fed volunteers. On Days 1 and 28 pharmacokinetic sampling for total blood vanadium was measured at 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours after drug administration. On Days 7, 14 and 21, following the daily administration of two 10 mg capsules, blood samples were taken at 0.5, 1.0, 1.5, and 2 hr post-dose for the determination of vanadium levels. All study volunteers had a single sample of blood drawn at on Days 35 and 42 after the last dose of BEOV was administered to determine the blood levels of vanadium. Pharmacodynamic Evaluation

Euglycemic-hyperinsulinemic Clamp Procedure On Days 1 and 28, study volunteers receiving either placebo or BEOV in a fasted state were evaluated using a 6-hour euglycemic-hyperinsulinemic clamp evaluation. After an overnight fast, volunteers were given a combination of an intravenous infusion of dextrose, as well as a continuous infusion of insulin at a concentration from 0.8 - 1.2 IU/mL to achieve plasma insulin at a level of 200 μU/mL (1435 pmol/L for the short-acting insulin prep, e.g., HUMILIN®) and a constant level of 5.3-5.8 mM/L (95-105 mg/dL) plasma glucose. Two hours after the start of the infusion, when there was an expectation that endogenous production of insulin had been suppressed and the body's response to the infused insulin had stabilized, blood glucose levels were measured at 5 minute intervals for 3 hours following the administration of either 20 mg BEOV or placebo. Figure 6 shows exemplary glucose clamp data generated in the study.

Oral Glucose Tolerance Test (OGTT)

Study volunteers were tested for oral glucose tolerance based on the following protocol.

On Day -1, pre-treatment baseline glucose tolerance measurements were assessed for volunteers administered placebo or BEOV (both in a fasted and fed state) by administration of 75 g of a glucose solution. Study volunteers administered BEOV in a fed state were tested for glucose tolerance consisting of a defined meal and 30 minute measurements of plasma glucose until the levels return to pre-prandial levels.

All volunteers fasted at least 8 hours prior to the OGTT evaluation. On Day 2, volunteers administered placebo or BEOV (fasting) were given a 2 hour

OGTT evaluation 22 hours from their first dose of medication on Day 1. Subjects were given their second dose of BEOV and discharged from the clinic.

On Days 7, 14, 21, volunteers administered placebo or BEOV (fasting) were given a 2 hour OGTT evaluation 1 hour after dosing. On Days 29, 35 and 42, volunteers administered placebo or BEOV (fasting) were given a 2 hour OGTT prior to discharge.

On Days 1, 7, 14, 21, 28, volunteers administered BEOV (fed) were given an OGTT consisting of a standardized meal (OGTTm) performed 1 hour after administration of BEOV. On days 35 and 42, an OGTTm was performed 2 hours prior to discharge.

The extent of absorption of vanadium (AUC) in an OGTT and levels of glycosylated hemoglobin (HbAIc) after administration of placebo or 20 mg BEOV is shown in Figure 4 and 5, respectively. A summary of HbAIc values and oral glucose tolerance test data from the Phase II study is shown in Tables IV-XIII.

Tables IV-XIII. HbAIc values and oral glucose tolerance test data in study volunteers at times 0.5, I, 1.5 and 2 hours.

Table IV.

Patient taken off drug prior to study.

Table V.

Patient taken off drug prior to study *HbAlc value waived

Table VI.

Table VII.

fPatient taken off drug prior to study.

Table VIII.

fPatient taken off drug prior to study. Table IX.

Table X.

Table XI.

fPatient taken off drug prior to study.

Table XII.

Patient taken off drug prior to study.

Table XIII.

Patient taken off drug prior to study.

Table XIV. Summary of Phase II clinical trial results

Table XIV.

AEs: adverse events FBS: fasting blood sugar GMR: geometric mean ratio LLOQ: lower limit of quantitation

EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. INCORPORATION BY REFERENCE

All of the US Patents and US Patent Application Publications cited herein are hereby incorporated by reference.

Claims

What is claimed is:

1. A method of treating diabetes in a mammal, comprising: administering orally to a mammal in need thereof a therapeutically effective amount of a vanadium source under fasted conditions, wherein said administration results in an increase in the rate and extent of absorption of said vanadium source as compared to administration under fed conditions.

2. The method of claim 1, wherein said vanadium source is selected from the group consisting of BEOV, BMOV, BIOV, VO(DMM)₂, VO(DEM)₂, V0(acac)₂, VO(salen-SO₃), VO(gamma-pga), BFOV, BQOV, VOL and vanadyl sulfate.

3. The method of claim 1 , wherein said vanadium source is BEOV.

4. The method of claim 3, wherein said therapeutically effective amount of BEOV is in the range of about 0.5 mg to about 90 mg, per dose, and said dose is administered at least twice weekly.

5. The method of claim 3, wherein said therapeutically effective amount of BEOV is in the range of about 1 mg to about 90 mg, per dose, and said dose is administered at least twice weekly.

6. The method of claim 3, wherein said therapeutically effective amount of BEOV is in the range of about 1 mg to about 5 mg, per dose, and said dose is administered at least twice weekly.

7. The method of claim 1, wherein said mammal is a human.

8. The method of claim 1, wherein the administration to the mammal is at least about 12 hours after the mammal's last meal and at least about 6 hours before the mammal's next meal.

9. The method of claim 1, wherein the administration to the mammal is at least about 10 hours after the mammal's last meal and at least about 4 hours before the mammal's next meal.

10. The method of claim 1, wherein the administration to the mammal is at least about 8 hours after the mammal's last meal and at least about 3 hours before the mammal's next meal.

11. The method of claim 1 , wherein the administration to the mammal is at least about 6 hours after the mammal's last meal and at least about 2 hours before the mammal's next meal.

12. The method of claim 1 , wherein the administration to the mammal is at least about 4 hours after the mammal's last meal and at least about 2 hours before the mammal's next meal.

13. The method of claim 1 , wherein the administration to the mammal is at least about 2 hours after the mammal's last meal and at least about 1 hours before the mammal's next meal.

14. The method of claim 4 or 5, wherein the administration results in a maximum concentration (C_max) level in plasma or whole blood from about 40 ng/mL to about 600 ng/mL.

15. The method of claim 4 or 5, wherein the administration results in a maximum concentration (C_maχ) level in plasma or whole blood from about 80 ng/mL to about

200 ng/mL.

16. The method of claim 4 or 5, wherein the administration results in an increase of the maximum concentration (Cm_ax) in plasma or whole blood and the extent of absorption of vanadium (AUC) as compared to the administration of the vanadium source under fed conditions.

17. The method of claim 16, wherein the ratio of C_max following administration without food to C_max following administration with food is about 4.0 to about 20.0, and wherein the ratio of AUC following administration without food to AUC following administration with food is about 4.0 to about 20.0.

18. The method of claim 16, wherein the ratio of C_max following administration without food to C_maχ following administration with food is about 6.0 to about 18.0, and wherein the ratio of AUC following administration without food to AUC following administration with food is about 6.0 to about 18.0.

19. The method of claim 16, wherein the ratio of C_max following administration without food to C_max following administration with food is about 8.0 to about 16.0, and wherein the ratio of AUC following administration without food to AUC following administration with food is about 8.0 to about 16.0.

20. The method of claim 16, wherein the ratio of C_max following administration without food to Cmax following administration with food is about 10.0 to about 14.0, and wherein the ratio of AUC following administration without food to AUC following administration with food is about 10.0 to about 14.0.

21. The method of claim 1, wherein the vanadium source is from a container with printed labeling advising that administration under fasted conditions results in an increase in the maximum concentration (C_max) in plasma or whole blood and the extent of absorption (AUC) as compared to the administration of the vanadium source under fed conditions.

22. A method for treating diabetes, comprising administering orally to a human in need thereof a therapeutically effective amount of a chelated vanadium compound, wherein the human has been instructed (a) to have minimal caloric intake for at least 4 hours before and at least 2 hours after administering the chelated vanadium compound.

23. The method of claim 22, wherein the human has been further instructed (b) to have minimal caloric intake for at least 8 hours before administering the chelated vanadium compound.

24. The method of claims 22 or 23, wherein the minimal caloric intake is limited to water.

25. A method for treating diabetes, comprising administering orally to a human in need thereof a therapeutically effective amount of a chelated vanadium compound, wherein the human has been instructed (a) to have minimal caloric intake for at least

4 hours before and at least 4 hours after administering the chelated vanadium compound.

26. The method of claim 25, wherein the human has been further instructed (b) to have minimal caloric intake for at least 8 hours before administering the chelated vanadium compound.

27. The method of claim 25 or 26, wherein the minimal caloric intake is limited to water.

28. The method of claim 22 or 25, wherein the systemic bioavailability of vanadium is at least about 20%.

29. The method of claim 22 or 25, wherein the C_maχ of vanadium in the plasma or blood of the human is at least about 200 ng/mL.

30. The method of claim 22 or 25, wherein the C_maχ of vanadium in the plasma or blood of the human is at least about 100 ng/mL.

31. The method of claim 22 or 25, wherein the C_maχ of vanadium in the plasma or blood of the human is at least about 50 ng/mL.

32. The method of claim 22 or 25, wherein the C_max of vanadium in the plasma or blood of the human is at least about 25 ng/mL.

33. The method of claim 22 or 25, wherein the T_max of vanadium in the plasma or blood of the human is less than about 2 hours.

34. A method for treating diabetes in a human in which the human:

(a) orally administers a therapeutically effective amount of a chelated vanadium compound; and

(b) ingests a minimal caloric intake for at least 4 hours before and at least 2 hours after administering the chelated vanadium complex.

35. The method of claim 34, wherein the human further (c) ingests a minimal caloric intake for at least 8 hours before administering the chelated vanadium complex.

36. The method of claim 34 or 35, wherein the minimal caloric intake is limited to water.

37. The method of claim 34 or 35, further comprising administering an agent selected from an analgesic, an anti-emetic, an anti-spasmodic, or a carminative.

38. The method of claim 34, wherein the systemic bioavailability of vanadium is at least about 20%.

39. The method of claim 34, wherein the C_maχ of vanadium in the plasma or blood of the human is at least about 200 ng/mL.

40. The method of claim 34, wherein the C_maχ of vanadium in the plasma or blood of the human is at least about 100 ng/mL.

41. The method of claim 34, wherein the C_maχ of vanadium in the plasma or blood of the human is at least about 50 ng/mL.

42. The method of claim 34, wherein the C_max of vanadium in the plasma or blood of the human is at least about 25 ng/mL.

43. The method of claim 34, wherein the T_max of vanadium in the plasma or blood of the human is less than about 2 hours.

44. A method for treating diabetes in a human in which the human:

(a) orally administers a therapeutically effective amount of a chelated vanadium compound; and

(b) ingests a minimal caloric intake for at least 4 hours before and at least 4 hours after administering the chelated vanadium complex.

45. The method of claim 44, wherein the human further (c) ingests a minimal caloric intake for at least 8 hours before administering the chelated vanadium complex.

46. The method of claim 44 or 45, wherein the minimal caloric intake is limited to water.

47. The method of claim 44 or 45, further comprising administering an agent selected from an analgesic, an anti-emetic, an anti-spasmodic, or a carminative.

48. The method of claim 44, wherein the systemic bioavailability of vanadium is at least about 20%.

49. The method of claim 44, wherein the C_max of vanadium in the plasma or blood of the human is at least about 200 ng/mL.

50. The method of claim 44, wherein the C_max of vanadium in the plasma or blood of the human is at least about 100 ng/mL.

51. The method of claim 44, wherein the C_maχ of vanadium in the plasma or blood of the human is at least about 50 ng/mL.

52. The method of claim 44, wherein the C_max of vanadium in the plasma or blood of the human is at least about 25 ng/mL.

53. The method of claim 44, wherein the T_max of vanadium in the plasma or blood of the human is less than about 2 hours.

54. Use of a chelated vanadium compound in the manufacture of a medicament for the treatment of diabetes in a subject in a fasted state.

55. The use as in claim 54, wherein the chelated vanadium compound is selected from the group consisting of BEOV, BMOV, BIOV, VO(DMM)₂, VO(DEM)₂, VO(acac)₂, VO(salen-SO₃), VO(gamma-pga), BFOV, BQOV, VOL and vanadyl sulfate.

56. The use as in claim 54, wherein the chelated vanadium compound is BEOV.

57. The use as in claim 54, wherein the medicament is administered in a solid oral dosage form.

58. The use as in claim 54,wherein the fasted state is minimal caloric intake for at least

4 hours before and at least 2 hours after administering the medicament.

59. The use as in claim 54, wherein the medicament is administered in the range of about 0.5 mg to about 90 mg, per dose, and the dose is administered at least twice weekly.

60. The use as in claim 54, wherein the medicament is administered in the range of about 1 mg to about 90 mg, per dose, and the dose is administered at least twice weekly.

61. The use as in claim 54, wherein the medicament is administered in a range of about

1 mg to about 5 mg, per dose, and the dose is administered at least twice weekly.

62. A method for reducing fasting blood sugar in a human patient comprising administering a therapeutically effective amount of a chelated vanadium compound to an individual in a fasted state.

63. The method of claim 62, wherein the chelated vanadium compound is in a solid oral dosage form.

64. The method of claim 62,wherein the chelated vanadium compound is selected from the group consisting of BEOV, BMOV, BIOV, VO(DMM)₂, VO(DEM)₂, VO(acac)₂, VO(salen-SO₃), VO(gamma-pga), BFOV, BQOV, VOL and vanadyl sulfate.

65. The method of claim 62, wherein the chelated vanadium compound is BEOV.

66. The method of claim 65,wherein the therapeutically effective amount of BEOV is in the range of about 0.5 mg to about 90 mg, per dose, and the dose is administered at least twice weekly.

67. The method of claim 65,wherein the therapeutically effective amount BEOV is in the range of about 1 mg to about 90 mg, per dose, and the dose is administered at least twice weekly.

68. The method of claim 65, wherein the therapeutically effective amount of BEOV is in the range of about 1 mg to about 5 mg, per dose, and the dose is administered at least twice weekly.

69. The method of claim 62, wherein the human patient has diabetes.

70. A method for improving the glucose tolerance in a human patient comprising administering a therapeutically effective amount of a chelated vanadium compound to an individual in a fasted state.

71. The method of claim 70, wherein the chelated vanadium compound is in a solid oral dosage form.

72. The method of claim 70, wherein the chelated vanadium compound is selected from the group consisting of BEOV, BMOV, BIOV, VO(DMM)₂, VO(DEM)₂, V0(acac)₂, VO(salen-SO₃), VO(gamma-pga), BFOV, BQOV, VOL and vanadyl sulfate.

73. The method of claim 70, wherein the chelated vanadium compound is BEOV.

74. The method of claim 73, wherein the therapeutically effective amount of BEOV is in the range of about 0.5 mg to about 90 mg, per dose, and the dose is administered at least twice weekly.

75. The method of claim 73, wherein the therapeutically effective amount BEOV is in the range of about 1 mg to about 90 mg, per dose, and the dose is administered at least twice weekly.

76. The method of claim 73, wherein the therapeutically effective amount of BEOV is in the range of about 1 mg to about 5 mg, per dose, and the dose is administered at least twice weekly.

77. The method of claim 70, wherein, the human patient has diabetes.

78. A method for reducing glycosylated hemoglobin in a human patient comprising administering a therapeutically effective amount of a chelated vanadium compound to an individual in a fasted state.

79. The method of claim 78, wherein the chelated vanadium compound is in a solid oral dosage form.

80. The method of claim 78, wherein the chelated vanadium compound is selected from the group consisting of BEOV, BMOV, BIOV, VO(DMM)₂, VO(DEM)₂, VO(acac)₂, VO(salen-SO₃), VO(gamma-pga), BFOV, BQOV, VOL and vanadyl sulfate.

81. The method of claim 78, wherein the chelated vanadium compound is BEOV.

82. The method of claim 81 , wherein the therapeutically effective amount of BEOV is in the range of about 0.5 mg to about 90 mg, per dose, and the dose is administered at least twice weekly.

83. The method of claim 81, wherein therapeutically effective amount BEOV is in the range of about 1 mg to about 90 mg, per dose, and the dose is administered at least twice weekly.

84. The method of claim 81, wherein therapeutically effective amount of BEOV is in the range of about 1 mg to about 5 mg, per dose, and the dose is administered at least twice weekly.

85. The method of claim 78, wherein, the human patient has diabetes.

86. A pharmaceutical formulation comprising a chelated vanadium compound for the treatment of diabetes in a human patient in a fasted state.

87. A pharmaceutical formulation comprising a chelated vanadium compound for the reduction of fasting blood sugar in a human patient.

88. A pharmaceutical formulation comprising a chelated vanadium compound for the improvement of glucose tolerance in a fasted human patient.

89. A pharmaceutical formulation comprising a chelated vanadium compound for the reduction of glycosylated hemoglobin in a fasted human patient.

90. The formulation of any one of claims 86-89, wherein the chelated vanadium compound is selected from the group consisting of BEOV, BMOV, BIOV, VO(DMM)₂, VO(DEM)₂, VO(acac)₂, VO(salen-SO₃), VO(gamma-pga), BFOV, BQOV, VOL and vanadyl sulfate.

91. The formulation of any one of claims 86-89, wherein the chelated vanadium compound is BEOV.

92. The formulation of claim 91 , wherein the formulation is administered in a solid oral dosage form.

93. The formulation of claim 91, wherein the fasted state is minimal caloric intake for at least 4 hours before and at least 2 hours after administering the medicament.

94. The formulation of claim 91, wherein the formulation is administered in the range of about 0.5 mg to about 90 mg, per dose, and the dose is administered at least twice weekly.

95. The formulation of claim 91, wherein the formulation is administered in the range of about 1 mg to about 90 mg, per dose, and the dose is administered at least twice weekly.

96. The formulation of claim 91, wherein the formulation is administered in a range of about 1 mg to about 5 mg, per dose, and the dose is administered at least twice weekly.

97. An article of manufacture comprising a container containing a chelated vanadium compound and a label with the container, wherein the label instructs the user to administer orally the chelated vanadium compound for the treatment of diabetes; and the label further instructs the user to ingest a minimal caloric intake for at least 4 hours before and at least two hours after administration of the chelated vanadium complex.

98. The article of manufacture of claim 97, wherein the label further instructs the user to ingest a minimal caloric intake for at least 8 hours before administration of the chelated vanadium complex.

99. The article of manufacture of claim 97 or 98, wherein additional written instructions for use are provided with the container.