WO2009032591A1 - Effet d'aliment dans le traitement de diabètes par des sels de vanadium - Google Patents

Effet d'aliment dans le traitement de diabètes par des sels de vanadium Download PDF

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Publication number
WO2009032591A1
WO2009032591A1 PCT/US2008/074196 US2008074196W WO2009032591A1 WO 2009032591 A1 WO2009032591 A1 WO 2009032591A1 US 2008074196 W US2008074196 W US 2008074196W WO 2009032591 A1 WO2009032591 A1 WO 2009032591A1
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Prior art keywords
vanadium
human
beov
administered
chelated
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PCT/US2008/074196
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English (en)
Inventor
Jay B. Lichter
Christopher Ross E. Orvig
Michael C. Scaife
Katherine H. Thompson
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Akesis Pharmaceuticals Inc.
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Publication of WO2009032591A1 publication Critical patent/WO2009032591A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals

Definitions

  • the invention relates to methods for increasing the oral bioavailability of drug products containing vanadium.
  • 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.
  • said vanadium source is selected from the group consisting of BEOV, BMOV, BIOV, VO(DMM) 2 , VO(DEM) 2 , VO(acac) 2 , VO(salen-SO 3 ), VO(gamma-pga), BFOV, BQOV, VOL and vanadyl sulfate.
  • said vanadium source is BEOV.
  • 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.
  • 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.
  • 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.
  • 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 ma ⁇ ) 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.
  • C max maximum concentration
  • AUC absorption of vanadium
  • the ratio of C max following administration without food to C ma ⁇ 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.
  • the ratio of C ma ⁇ following administration without food to C ma ⁇ 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.
  • 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.
  • 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.
  • 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.
  • the human further (c) ingests a minimal caloric intake for at least 8 hours before administering the chelated vanadium complex.
  • the minimal caloric intake is limited to water.
  • the method further comprises administering an agent selected from an analgesic, an anti-emetic, an anti-spasmodic, or a carminative.
  • the systemic bioavailability of vanadium is at least about 20%.
  • 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.
  • the method further comprises administering an agent selected from an analgesic, an anti-emetic, an anti-spasmodic, or a carminative.
  • the systemic bioavailability of vanadium is at least about 20%.
  • the C ma ⁇ of vanadium in the plasma or blood of the human is at least about 200 ng/niL.
  • the C ma ⁇ of vanadium in the plasma or blood of the human is at least about 100 ng/mL.
  • the C max of vanadium in the plasma or blood of the human is at least about 50 ng/mL.
  • the C max of vanadium in the plasma or blood of the human is at least about 25 ng/mL.
  • the T ma ⁇ of vanadium in the plasma or blood of the human is less than about 2 hours.
  • a chelated vanadium compound in the manufacture of a medicament for the treatment of diabetes in a subject in a fasted state.
  • 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-SO 3 ), VO(gamma-pga), BFOV, BQOV, VOL and vanadyl sulfate.
  • the chelated vanadium compound is BEOV.
  • the medicament is administered in a solid oral dosage form.
  • the fasted state is minimal caloric intake for at least 4 hours before and at least 2 hours after administering the medicament
  • 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.
  • 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.
  • 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.
  • 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
  • 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-SO 3 ), VO(gamma-pga), BFOV, BQOV, VOL and vanadyl sulfate, hi certain embodiments, the chelated vanadium compound is BEOV.
  • the pharmaceutical formulation is administered in a solid oral dosage form.
  • the fasted state is minimal caloric intake for at least 4 hours before and at least 2 hours after administering the medicament.
  • 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.
  • 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.
  • 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.
  • the chelated vanadium compound is in a solid oral dosage form.
  • 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-SO 3 ), V0(gamma- pga), BFOV, BQOV, VOL and vanadyl sulfate.
  • the chelated vanadium compound is BEOV.
  • 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.
  • 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.
  • 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.
  • 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.
  • the chelated vanadium compound is in a solid oral dosage form.
  • 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-SO 3 ), V0(gamma- pga), BFOV, BQOV, VOL and vanadyl sulfate.
  • the chelated vanadium compound is BEOV.
  • 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.
  • 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.
  • 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.
  • 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.
  • the chelated vanadium compound is in a solid oral dosage form.
  • 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-SO 3 ), VO(gamma-pga), BFOV, BQOV, VOL and vanadyl sulfate.
  • the chelated vanadium compound is BEOV.
  • 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.
  • 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.
  • 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.
  • 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.
  • the label further instructs the user to ingest a minimal caloric intake for at least 8 hours before administration of the chelated vanadium complex.
  • additional written instructions for use are provided with the container.
  • 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.
  • 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
  • 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.
  • 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.
  • 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 ma ⁇ ) in plasma or whole blood and the extent of absorption of vanadium (AUC) as compared to the administration of vanadium under fed 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 ma ⁇ ) 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.
  • a source of vanadium e.g., containing about 20, 15, 10, or 5 mg of elemental vanadium
  • the resulting maximum concentration (C ma ⁇ ) 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.
  • the vanadium source e.g., BMOV or BEOV
  • bioavailability generally means the rate and extent to which an active ingredient is absorbed from a drug product and becomes available systemically.
  • 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.
  • 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.
  • 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.
  • 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.
  • treating diabetes means controlling or alleviating the symptoms associated with diabetes, as well controlling or alleviating diabetes itself.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • the present invention is directed to the use of a 3-hydroxy-4- pyrone oxovanadium(IV) salt.
  • the present invention is directed to the use of a vanadyl complex with bidentate maltol-type ligands.
  • 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-SO 3 )), poly(gamma-glutamic acid)oxovanadium(IV) complex (VO(gamma-pga)), Bis(al
  • the present invention is directed to the use of BMOV or BEOV as a source of vanadium.
  • BMOV is described in U.S. Pat. 5,300,496, incorporated herein by reference.
  • the chemical structures of BMOV and BEOV are shown below.
  • 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.
  • the effective amount of BEOV is between about 1 mg to about 90 mg total daily dose.
  • 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.
  • 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.
  • the therapeutically effective amount is about 2 mg total daily dose, which may be given in a single dose or multiple doses.
  • the vanadium source is given once a week or twice a week.
  • the dosing may be more or less frequent.
  • the methods encompass any dosing regimen that is efficacious in treating diabetes.
  • 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.
  • 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.
  • a patient may be administered a short-term satiety factor during fasting periods.
  • satiety factors 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.
  • 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).
  • 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.
  • the prior treatment regimen or a new treatment regimen is optionally re- initiated.
  • 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.
  • "x" is 3 days, 7 days, 10 days, 14 days, 17 days, 21 days, 24 days, 28 days, or 31 days
  • "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.
  • 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.
  • 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 ⁇ -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.
  • 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.
  • 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.
  • 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.
  • 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.
  • adjuvants 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.
  • the formulation 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.
  • 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.
  • the label further instructs the user to ingest a minimal caloric intake for at least 8 hours before administration of the chelated vanadium complex.
  • additional written instructions for use e.g., instructional guidelines for minimal caloric intake
  • 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.
  • 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] tota i; and (3) compare the bioavailability of a well-tolerated dose of BEOV and an equivalent molar dose of oral VOSO 4 .
  • Human volunteers (n 40) were healthy and non-diabetic between the ages of 18 and 45.
  • C max mean maximum vanadium concentration
  • 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 ma ⁇ 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.
  • the food effect influences the observed plasma elimination half life of orally administered BEOV.
  • 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.
  • 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-inf ⁇ nity) and C max .
  • 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 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-inf ⁇ nity) 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-inf ⁇ nity) for BEOV with food is generally greater than about 4.0 up to about 20.0.
  • 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 (Ae 11 ) and AUC: (Ae 11 / AUC) x 100.
  • Vanadium from VOSO 4 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 Vanadium from VOSO 4 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.
  • 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).
  • HbAIc hemoglobin AIc
  • Figure 3 shows fasting glucose levels in a diabetic study volunteer after administration of either placebo or 20 mg BEOV.
  • 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
  • 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.
  • OGTT a standardized meal
  • HbAIc glycosylated hemoglobin
  • Tables IV-XIII HbAIc values and oral glucose tolerance test data in study volunteers at times 0.5, I, 1.5 and 2 hours.

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Abstract

L'invention porte sur un procédé d'accroissement de la biodisponibilité orale du vanadium par administration d'une quantité thérapeutiquement efficace d'une source de vanadium à un patient à jeun, ladite administration résultant en un accroissement du taux et de l'ampleur d'absorption de ladite source de vanadium par rapport à l'administration dans des conditions où le patient est alimenté. Il a également été suggéré que l'administration conduit à un accroissement de la concentration maximale (Cmax) du plasma ou du sang total et de l'ampleur d'absorption de vanadium (AUC) par rapport à l'administration de la source de vanadium dans des conditions où le patient est alimenté. Le procédé comprend de plus l'administration des composés de vanadium chélatés à des patients diabétiques et/ou d'un agent sélectionné parmi un analgésique, un antiémétique, un antispasmodique ou un carminatif.
PCT/US2008/074196 2007-08-28 2008-08-25 Effet d'aliment dans le traitement de diabètes par des sels de vanadium WO2009032591A1 (fr)

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CN117224690A (zh) * 2023-11-10 2023-12-15 江苏海王健康生物科技有限公司 一种作为助剂的γ-聚谷氨酸混合物、组合物、制备方法
CN117224690B (zh) * 2023-11-10 2024-01-30 江苏海王健康生物科技有限公司 一种作为助剂的γ-聚谷氨酸混合物、组合物、制备方法

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