MXPA97008628A - Treatment of type ii diabetes with high doses of picolinato cróm - Google Patents

Abstract

A method to stabilize blood glucose levels and reduce associated hyperglycemia with type II diabetes. Synthetic chromic tripicolinate is administered, orally or parenterally, to a human who needs it, at a dosage between 1,000 and 10,000 micrograms per day.

Description

TREATMENT OF TYPE II DIABETES WITH HIGH DOSES OF CHROMIC PICOLINATE Field of the Invention The present invention relates to the treatment of non-insulin dependent diabetes mellitus (NIDDM) that attacks adults. More specifically, the invention relates to the treatment of this form of diabetes by the administration of high doses of chromium in the form of chromic picolinate. Background It is known that diabetes affects at least 10 million Americans and millions more may not know they have the disease. In the form of this disease known as Type II diabetes, not dependent on insulin, or that attacks adults (as opposed to juvenile diabetes), the pancreas often continues to secrete normal amounts of insulin. However, this insulin is not effective in preventing the symptoms of diabetes, which include hyperglycemia, impaired carbohydrate metabolism, glycosuria and decreased sensitivity to insulin. These symptoms, if left untreated, often lead to severe complications. Chromium is a nutritionally essential trace element. The essential form of chromium in the diet was established in 1959 by Schwartz, as cited in Present Knowledge in Nutrition, page 571, fifth edition (1984, The Nutrition Foundation, Washington, D.C.). The exhaustion of chromium is characterized by the alteration of the metabolism of glucose, lipids and proteins and by a diminished duration of life. Chromium is essential for the optimal activity of insulin in all known insulin-dependent systems (Boyle et al., Southern Med. J., 70: 1449-1452, 1977). The insufficiency of chromium in the diet has been linked to both the diabetes that attacks in mature age and to cardiovascular diseases. The main sources of energy for the body are glucose and fatty acids. Chromium depletion results in biologically ineffective insulin and compromised glucose metabolism. Under these conditions, the body must rely primarily on lipid metabolism to meet its energy requirements, which results in the production of excessive amounts of acetyl-CoA and ketone bodies. Some of the accumulated acetyl-CoA are diverted to increased cholesterol biosynthesis, which results in hypercholesterolemia. Diabetes mellitus is characterized, in large part, by glucosuria, hypercholesterolemia and often ketoacidosis. The accelerated atherosclerotic process observed in diabetes is associated with hypercholesterolemia (Boyle et al., Supra).

Current drugs used to manage type II diabetes are found in two classes of compounds: bioguanides and sulfonylureas. Bioguanides, for example Metformin, have been approved for use in the United States of America, due to the induction of lactic acidosis. Sulfonylureas, for example tol-butamide and glyburide, decrease plasma glucose, primarily by stimulating insulin secretion and increasing the effects of insulin in some target tissues and by inhibiting hepatic glucose synthesis. Chromium supplementation to normal individuals has been reported to lead to improvements in glucose tolerance, serum lipid concentrations, which include high density lipoprotein cholesterol, insulin and insulin ligation (Anderson, Clin. Phisiol, Biochem ., 4: 31-41, 1986). The supplement of chromium in the trivalent form, for example chromic chloride, is associated with the improvement of the risk factors associated with diabetes that attacks adults and cardiovascular diseases. Chromium is known to function as an insulin co-factor. It binds to insulin and increases the potency of many, perhaps all, of its functions (Boyle et al., Supra). These functions include, but are not limited to, the regulation of carbohydrate and lipid metabolism (Present Knowledge in Nutri tion, supra, on pages 573-577). The introduction of inorganic chromium compounds per se in individuals is not particularly beneficial. Chromium must be converted endogenously into an organic complex or must be consumed as a biologically active molecule. Only about 0.5% of the ingested organic chromium is assimilated into the body (Recommended Daily Allowances, Ninth Revised Edition, The National Academy of Sciences, page 160, 1860). Only 1.2% of most chromium compounds are assimilated into the body. U.S. Patent No. 4,316,927 discloses the discovery that when the selected essential metals are administered to mammals as coordination complexes, exogenously synthesized, of picolinic acid, they are available directly for absorption in the system without competition from others. metals This patent describes a composition and method for selectively supplementing the essential metals in the human diet and for facilitating the absorption of these metals by the intestinal cells. These complexes are safe, cheap, biocompatible and easy to produce. These coordination complexes of essential metals, synthesized exogenously, of picolinic acid (pyridine-2-carboxylic acid), have the following structural formula: where M represents the metallic cation and n is equal to the valence of the cation. For example, when M is Cr and n = 3, then the compound is chromic tripicolinate. Other chromium picolinates can include M = Cr + 2 and n = 2 (chromic dipicolinate) or n = 1 (chromium monopicolinate). The recommended daily allowance (Recommended Daily Allowance or RDA) in the United States of America for chromium is 50-200 micrograms. The U.A. Patent No. 5,087,623 describes the administration of chromic tripicolinate for the treatment of diabetes which attacks adults in doses ranging from 50 to 500 micrograms. The administration of 200 micrograms of chromium in the form of chromic tripicolinate results in a small but statistically significant decrease in glycosylated hemoglobin compared to controls, a long-term blood glucose control index and an accurate indicator of blood glucose levels.

In normal individuals, the level of glycosylated hemoglobin is less than 6%; however, this value increases to 9-12% in diabetics. Thus, although a small decrease was observed, the value of 10.4% obtained after treatment with chromium is still within the range of diabetics. Thus, the level of blood sugar reduction can not be considered therapeutically relevant. Thus, there is a need for a safe, effective, inexpensive composition capable of significantly lowering blood sugar levels to an acceptable value. The present invention satisfies this need. SUMMARY OF THE INVENTION We have discovered, unexpectedly, that chromic tripicolinate, administered in doses of the order of magnitude greater than that of the RDA, can drastically decrease glucose levels in individuals with diabetes that attacks adults. The present invention provides a method for reducing hyperglycemia and stabilizing the level of serum glucose in humans, which comprises administering between 1,000 and 10,000 micrograms per day of chromium as a synthetic chromic tripicolinate to a human in need thereof. Preferably, the amount of chromium administered is between 1,000 to 5,000 micrograms per day, such as a synthetic chromic tripicolinate. Chromic tripicolinate is advantageously supplied in a pharmaceutically acceptable carrier. According to one aspect of the preferred embodiment, the chromic tripicolate is administered orally. Alternatively, chromic tripicolinate is administered parenterally. Detailed Description of the Invention The present invention relates to the discovery that doses of chromium, administered in the form of chromic tripicolinate, of about one magnitude greater than that of the US RDA, promote a significant reduction in blood glucose levels. , in individuals with Type II diabetes. This reduction is markedly greater than that seen after the administration of doses of chromium found within the RDA and indicate that high doses of chromic picolinate are effective in stabilizing the levels of glucose in the blood. Because chromium is a co-factor that provides insulin's power of action, it would be expected that individuals receiving a dose of chromium at the upper end of the RDA range would bind to all available insulin, which would result in a maximum reduction in blood glucose levels. In view of this, the administration of chromium doses significantly greater than those of the RDA would be expected to exert a blood glucose lowering effect beyond that observed in the upper limit of the RDA range, due to the saturation of the Chromium link sites in all available insulin. Unexpectedly, a daily dose of 1,000 micrograms of chromium, administered as chromium tripicolinate, five times the upper limit of the proposed recommended daily administration (120 μg per day of chromium), significantly reduce blood glucose levels, as assessed by a reduction in glycosylated hemoglobin. Conversely, administration of 200 micrograms of chromium, such as chromic tripicolinate, did not show an effect above the levels obtained with a placebo (Example 1). Similarly, a clinical trial conducted at the University of Texas, San Antonio, did not show a glucose-lowering effect after the administration of 200 micrograms of chromium, such as chromium tripicolinate (Lee et al., Diabetes Care (USA) 17 (12): 1448-1452). The therapeutic benefit of chromium tripicolinate is thus clearly dose-dependent, and doses within the so-called "nutritional range" are unlikely to have a significant therapeutic benefit in the treatment of Type II diabetes. The synthesis of chromic picolinate is described in the patent of E. U. A., No. 5,087,623. In order to reduce the requirement of insulin and / or diabetic drugs and reduce several important risk factors associated with Type II diabetes, it is anticipated that the dose range of chromium administered to a patient, in terms of chromic tripicolinate, between about 1,000 and 10,000 micrograms per day. In a preferred embodiment, this amount is between 1,000 and 5,000 micrograms per day. Although the administration of chromic tripicolinate for the treatment of Type II diabetes is described herein, the administration of chromic monopicolinate and chromic dipicolinate to a patient in need thereof is also within the scope of the invention. For oral administration, chromic picolinatos can be supplied as a tablet, an aqueous or oil suspension, powder or dispersible granules, emulsion, hard or soft capsules, syrup or elixir. The compositions intended for oral use can be prepared according to any method known in the art of manufacturing pharmaceutical compositions and such compositions can contain one or more of the following agents: flavor or sweetening agents, color agents and preservatives . These sweetening and flavoring agents will increase the acceptability of the preparation. Tablets containing chromic tripicolinate in admixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable.

These excipients include the inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulation and disintegration 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 coated by known techniques, to delay disintegration and absorption in the gastro-intestinal tract and thus provide a sustained action for a longer period of time. For example, a material that delays the absorption time of the material, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax, can be employed. Formulations for oral use can also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules, in that the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. The aqueous suspensions may contain the chromic tripicolinate complex of the invention in admixture with excipients suitable for the manufacture of aqueous suspensions. These excipients include suspending agents, dispersing or soaking agents, one or more preservatives, one or more color agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. The oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those noted above, and flavoring agents can be added to provide an acceptable oral preparation. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid. Dispersible powders and granules of the invention, suitable for the preparation of an aqueous suspension by the addition of water, supply the active ingredient in admixture with a dispersing or soaking agent, a suspending agent and one or more preservatives, Additional excipients, For example, sweetening, taste and color agents may also be present. The syrups and elixirs can be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may contain an emollient, a preservative, a flavoring agent or a coloring agent.

The preparations of chromic tripicolinate for parenteral administration may be in the form of a sterile injectable preparation, such as a sterile, aqueous or oleaginous injectable suspension. This suspension can be formulated according to methods well known in the art, which use suitable dispersing or soaking agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Suitable diluents include, for example, water Ringer's solution and isotonic sodium chloride solution. In addition, conventional sterile fixed oils can be employed as a solvent or suspension medium. For this purpose, any soft fixed oil can be employed, which include the synthetic mono- and di-glycerides. In addition, fatty acids, such as oleic acid can similarly be used in obtaining injectable preparations. The pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as a liquid paraffin, or a mixture thereof. Suitable and ultering agents include naturally occurring gums, such as acacia gum and tragacanth gum, naturally occurring phosphatides, such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as mono sorbitan oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsions may also contain sweetening and flavoring agents. The amount of the chromic tripicolinate that can be combined with the carrier material to produce a single dose form will vary depending on the host treated and the particular mode of administration. A clinical trial of the effect of high doses of chromic tripicolinate in Type II diabetes is described in the following example. Example 1 Treatment of High-Dose Chromic Tripicolinate A double-blind, randomized clinical trial of 180 subjects who have Type II diabetes was performed. One third of subjects received an oral daily dose of 1,000 micrograms of chromium, in the form of chromium picolinate (two 500 microgram capsules); Another third received 200 micrograms of chromium; and the remaining third received a placebo. These doses were administered for four months. At the beginning of the study and after two and four months, fasting and table-top glucose levels were measured two hours after performing the glucose tolerance test. The levels of hemoglobin glucosilda were also measured by standard methods. Subjects who received the 1,000 microgram chromium dose, such as chromic tripicolinate, exhibited an average reduction in glycosylated hemoglobin of 30%, and a similar reduction in fasting and table-top glucose levels (28 and 27%, respectively ). A 30% decrease in glycosylated hemoglobin in diabetic individuals corresponds to glycosylated hemoglobin values between 6 and 8, which are below the range of 8 to 12 observed in most diabetics. Conversely, the group that received only 200 micrograms of chromium per day did not exhibit a statistically significant decrease in these parameters compared to the group to which the placebo was administered. The above description of the invention is indicated to help understand the invention. It will be understood that variations of the invention, including all equivalents not known or further developed, are considered to be within the scope of the invention, which is limited only by the following amended claims.

Claims (15)

1. CLAIMS 1. A method to reduce hyperglycemia and stabilize serum glucose level in humans, this method involves administering between 1,000 and 10,000 micrograms per day of chromium, such as synthetic chromic tripicolinate, to a human who needs it .
2. 2. The method of claim 1, which comprises administering between 1,000 and 5,000 micrograms per day of chromium, such as synthetic chromic tripicolinate.
3. 3. The method of claim 1, wherein the tripolyolinate chromium is in a pharmaceutically acceptable carrier.
4. 4. The method of claim 3, wherein the chromic tripicolinate is administered orally.
5. 5. The method of claim 3, wherein the chromic tripicolinate is administered parenterally.
6. 6. Synthetic chromic tripicolinate, in a unit dose form, each dose is between approximately 1,000 and 10,000 micrograms of chromium, for the treatment of hyperglycemia and / or the stabilization of glucose levels in serum in a human being who needs it.
7. 7. The chromic tripicolinate of claim 6, wherein each dose comprises between about 1,000 and 5,000 micrograms of chromium.
8. 8. The chromic tripicolinate of claim 6 or 7, in a form suitable for oral administration.
9. 9. The chromic tripicolinate of claims 6 or 7, in a form suitable for parenteral administration.
10. 10. The chromic tripicolinate of claims 6 or 7, in a pharmaceutically acceptable carrier.
11. 11. The use of synthetic chromic tripicolinate in unit dose form, each dose has between about 1,000 and 10,000 micrograms of chromium, in the preparation of a medicament for the treatment of hyperglycemia and / or the stabilization of serum glucose levels in a human being who needs it.
12. 12. The use according to claim 11, wherein each dose comprises between about 1,000 and 5,000 micrograms of chromium.
13. 13. The use, according to claims 11 or 12, in which the chromium tripolyolinate is in a form suitable for oral administration.
14. 14. The use according to claims 11 or 12, wherein the chromium tripolyolinate is in a form suitable for parenteral administration.
15. 15. The use according to claims 11 or 12, wherein the chromium tripolyolinate is delivered in a pharmaceutically acceptable carrier.