HK1032541A - Chromium/biotin treatment of type ii diabetes - Google Patents

Description

Treatment of type II diabetes with chromium/biotin

Technical Field

The present invention relates to the treatment of adult-onset non-insulin dependent (type II) diabetes. More particularly, the present invention relates to the treatment of type II diabetes by administration of chromium picolinate and biotin.

Background

At least one million Americans are known to have diabetes, and many suffer from this disease and have not yet been diagnosed. In this disease, termed type II, non-insulin dependent or adult onset (as opposed to juvenile or type I diabetes), the pancreas typically continues to secrete normal amounts of insulin. However, this insulin is ineffective in preventing the symptoms of diabetes, including hyperglycemia, carbohydrate insufficiency, diabetes, and decreased insulin sensitivity. If these symptoms are not treated, serious complications are often caused.

Common drugs used to control type II diabetes fall into two categories: biguanides and sulfonylureas. Biguanides such as metformin are believed to prevent excessive hepatic gluconeogenesis. Sulfonylureas, such as tolbutamide and glibenclamide, lower blood glucose primarily by stimulating insulin secretion, by increasing insulin action in certain targeted tissues, and by inhibiting hepatic glucose synthesis.

Us patent 4315927 discloses that when selected essential metals are administered to mammals in the form of coordination complexes of exogenously synthesized picolinic acid, they are directly absorbed without competing with other metals. These complexes are safe, inexpensive, biologically tolerable and easy to prepare.

Us patent 5087623 describes the administration of chromium tripicolinate for the treatment of type II diabetes at a dose of 50 to 500 μ g of chromium. The recommended allowable daily dose of chromium in the United states is 50-200. mu.g. Although glycosylated hemoglobin is slightly reduced, the accurate indication of blood glucose levels observed is 10.4% after chromium tripicolinate treatment, which is still in the range of diabetes.

International patent application PCT/US96/06493 describes the administration of high ("over-nutrition") doses of chromium (1000 to 10000. mu.g/day) to individuals with type II diabetes. Glycosylated hemoglobin of subjects receiving 1000 μ g of chromium daily in the form of chromium tripicolinate showed a 30% reduction, similar to the level of glucose concentration reduction after fasting and feeding.

Biotin is a prosthetic group of some carboxylation reactions, most notably pyruvate carboxylase, which is involved in gluconeogenesis and in the supplementation of the citric acid cycle, and acetyl CoA carboxylase, which plays a role in fatty acid biosynthesis. A safe and appropriate recommended daily biotin intake of 100-300. mu.g, although no side effects or toxicity were found in clinical studies with daily oral biotin over 200mg (Mock et al, Present Knowledge in Nutrition, 7 th edition, Ziegler, edited by E. et al, ILSI Press, Washington, DC, 1996, pp. 200-235). The super-nutrient dose of biotin has no therapeutic effect on diabetes. High-dose oral or parenteral administration of biotin has been shown to improve oral glucose tolerance in diabetic KK mice (Reddi et al, Life Sci., 42: 1323. sup. 1330, 1988), mice developed diabetes by injection of the chain levostar (Zhang et al, 16 th International Nutrition conference, Montreal, 1997, Abstract, page 264), and to improve tolerance in pre-diabetic Ottsuka Long-Evans Tokushima Fatty mice (Zhang et al, J.Nutr.Sci.Vitamino.42: 517. sup. 526, 1996).

In clinical studies Coggeshall et al (Ann.N.Y.Acad.Sci., 447: 387-one 392, 1985) indicated that oral administration of biotin 16mg per day reduced fasting blood glucose levels in type I diabetic patients whose insulin injections had been temporarily discontinued. This is confirmed by the fact that Maebashi et al (J.Clin.biochem.Nutr.14: 211-218, 1993) teach that the oral administration of 3mg biotin to type II diabetes patients who are difficult to control three times a day results in improved beta cell function, but fasting insulin levels in subjects receiving biotin treatment do not decrease despite a sharp decrease in blood glucose levels.

There is an ongoing need for effective treatment of type II diabetes. The present invention meets this need by providing safe, inexpensive, drug-free therapeutic agents.

Summary of The Invention

One embodiment of the invention is a method for reducing hyperglycemia and stabilizing blood glucose concentrations, the method comprising administering to an individual in need thereof about 50 to 1000 micrograms per day of chromium in the form of synthetic chromium tripicolinate in combination with about 25 μ g to 200mg per day of biotin, the amounts of chromium tripicolinate and biotin together being selected to provide a greater than additive effect. Preferably, the amount of chromium applied as synthetic chromium tripicolinate per day is in the range of 500 to 1000 micrograms. The amount of biotin administered per day is advantageously between about 1mg and 100 mg. In one aspect of this preferred embodiment, the chromium tripicolinate is present in a pharmaceutically acceptable carrier. In another aspect of this preferred embodiment, the biotin is present in a pharmaceutically acceptable carrier. Oral administration of biotin is preferred. Chromium tripicolinate is advantageously administered orally. Preferably, the chromium tripicolinate is administered parenterally. In another aspect of this preferred embodiment, the biotin is preferably administered parenterally.

The invention also provides pharmaceutical compositions comprising chromium in the form of synthetic chromium tripicolinate and biotin, wherein the ratio of chromium to biotin is from about 2: 1 to 1: 200(w/w), and the amounts of chromium tripicolinate and biotin together provide a greater than additive effect.

Another embodiment of the invention is the use of synthetic chromium tripicolinate at about 50 to 1000 micrograms per day of chromium in combination with biotin at about 25 μ g to 200mg per day to lower hyperglycemia and stabilize blood glucose levels in an individual. Preferably, the synthetic chromium tripicolinate is provided at about 500 to 1000 micrograms chromium per day. Biotin is advantageously present in an amount of about 1mg to 100 mg. In one aspect of this preferred embodiment, the chromium tripicolinate and biotin are present in a pharmaceutically acceptable carrier.

Detailed description of the preferred embodiments

The present invention includes the discovery that administration of chromium as chromium picolinate in combination with low or high doses of biotin results in a significant reduction in and stabilizes blood glucose levels in individuals with type II diabetes from a maximum RDA amount up to five times this amount. This reduction is much greater than would be expected from administration of one of the components alone, thus indicating a synergistic effect.

The synthesis of chromium picolinate is described in US 5087623. Chromium tripicolinate and biotin can be purchased from health food stores, drug stores and other sources. In order to reduce the need for insulin and/or diabetes drugs and to reduce several important risk factors associated with type II diabetes, it is contemplated that the dose of chromium administered to a patient as chromium tripicolinate may range from about 50 to 1000 μ g/day. In a preferred embodiment, this amount is from about 500 to 1000. mu.g/day. In view of the biotin component of the combination therapy, a daily dose of about 25. mu.g to 200mg is preferred. More preferably, the daily dose of biotin is about 1mg to 100 mg.

For oral administration, the chromium picolinate and biotin may be provided as tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions for oral administration may be prepared according to any method known to the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more of the following agents: sweetening agents, flavouring agents, colouring agents and preserving agents. Sweetening and flavoring agents may be added to enhance the palatability of the preparation. Tablets containing chromium tripicolinate and non-toxic pharmaceutical excipients for tablet preparation may be accepted. Pharmaceutically acceptable means that the agent is acceptable from the standpoint of compatibility with the other components of the formulation (and is not injurious to the patient). These excipients include inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid: binding agents such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay substance such as glyceryl monostearate or glyceryl distearate may be applied alone or in combination with a wax.

Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions may contain the chromium tripicolinate complex of the invention and excipients suitable for the preparation of aqueous suspensions. Such excipients include suspending agents, dispersing or wetting agents, one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose and saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water comprise the active ingredient together with a dispersing or wetting agent, suspending agent, and one or more preservatives. Other excipients, for example sweetening, flavoring and coloring agents, may also be present.

Syrups or elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. These preparations may also contain demulcents, preservatives, flavoring or coloring agents.

The chromium tripicolinate formulation for parenteral administration may be a sterile injectable formulation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to methods well known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Suitable diluents include, for example, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may be conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of the injectables.

These pharmaceutical compositions may also be in the form of oil-in-water solutions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, a mineral oil such as liquid paraffin, or mixtures thereof. Suitable emulsifying agents include natural gums such as gum acacia and gum tragacanth, natural phospholipids, such as soya bean phospholipid, esters or partial esters of fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. These emulsions may also contain sweetening and flavoring agents.

The amount of chromium tripicolinate/biotin that may be mixed with the carrier material to produce a single dosage form may vary depending on the subject being treated and the particular mode of administration.

The above description of the invention is only intended for the understanding of the present invention. It should be understood that numerous changes may be made in the invention, including all equivalents now known or later developed, which fall within the scope of the invention, which is limited only by the claims which follow.

Claims (14)

1. A method for reducing hyperglycemia and stabilizing blood glucose levels, the method comprising administering to an individual in need thereof about 50 to 1000 micrograms of chromium per day in the form of synthesized chromium tripicolinate in combination with about 25 μ g to 200mg of biotin per day, wherein the amounts of chromium tripicolinate and biotin that are co-selected provide a greater than additive effect.

2. The method of claim 1 comprising administering about 500 to 1000 micrograms of chromium per day in the form of synthetic chromium tripicolinate.

3. The method of claim 1, comprising administering about 1mg to 100mg of biotin per day.

4. The method of claim 1, wherein the chromium tripicolinate is present in a pharmaceutically acceptable carrier.

5. The method of claim 1, wherein the biotin is present in a pharmaceutically acceptable carrier.

6. The method of claim 1, wherein said chromium tripicolinate is administered orally.

7. The method of claim 1, wherein said biotin is administered orally.

8. The method of claim 1, wherein said chromium tripicolinate is administered parenterally.

9. The method of claim 1, wherein said biotin is administered parenterally.

10. A pharmaceutical composition comprising chromium in the form of synthetic chromium tripicolinate and biotin, wherein the ratio of chromium to biotin is from about 2: 1 to 1: 200(w/w), wherein the amounts of chromium tripicolinate and biotin which are co-selected provide a greater than additive effect.

11. Use of a synthetic chromium tripicolinate in an amount of about 50 to 1000 micrograms chromium per day in combination with biotin in an amount of about 25 to 200mg per day to lower hyperglycemia and stabilize blood glucose levels in an individual.

12. The use of claim 11, wherein the synthetic chromium tripicolinate is provided at about 500 to 1000 micrograms of chromium per day.

13. The use of claim 11, wherein the biotin is present in an amount of about 1mg to 100 mg.

14. The use of claim 11, wherein the chromium tripicolinate and biotin are present in a pharmaceutically acceptable carrier.