HAPTOCORRIN (R-BINDER; TRANSCOBALAMIN I) SUBSTRATES

FOR THE ORAL DELIVERY OF VITAMINS OR MINERALS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.

62/350,353, filed on June 15, 2016.

BACKGROUND OF THE INVENTION

1. FIELD OF THE INVENTION

[0002] The present invention relates to methods and systems for oral delivery of minerals or vitamins and, more specifically, to the use of haptocorrin substrates to enhance oral zinc or magnesium delivery and zinc or magnesium absorption.

2. DESCRIPTION OF THE RELATED ART

[0003] Vitamin and mineral deficiencies are widespread and affect the health and well-being of populations worldwide. As much as 25% of the world's population may have inadequate levels of zinc in their diet, for example, due to a combination of factors including limited access to zinc-rich foods such as animal products, oysters, or shellfish, and the abundance of zinc inhibitors such as phytin that are common in plant-based foods. Thus, even if an individual's zinc intake levels are adequate, the levels of inhibitors in the diet through consumption of foods such as cereals, corn, and rice may mean that inadequate amounts of zinc are absorbed. As a result, zinc deficiency may not necessarily be treated by providing dietary zinc supplements or increasing the amount of zinc rich foods consumed by individuals having diets comprised of foods containing zinc inhibitors.

[0004] A human being with adequate levels of zinc comprises 2-4 grams of the mineral dispersed throughout their body, with major concentrations found in the brain, muscles, and bones. Zinc is utilized by the human body in a wide array of different metabolic processes, including the metabolism of RNA and DNA, signal transduction, gene expression, apoptosis, and, perhaps most importantly, the structure and function of proteins such as enzymes.

[0005] Insufficient levels of zinc in the body, however, can have devastating effects ranging from minor to devastating. Minor side-effects of low zinc levels include diarrhea, acne, and low testosterone, while major issues include cognitive and motor function impairment, chronic renal disease, and the malfunction of processes such as eyesight, memory, and smell, among many others. As a result, zinc deficiency can result in significant reduction of quality of life, leading even to increased mortality rates.

[0006] Other minerals and vitamins are also susceptible to poor bioavailability due to, among other things, acid hydrolysis or absorption problems that arise from the presence of endogenous chelators and/or precipitation of the minerals. Accordingly, there is a need in the art for methods and systems that facilitate vitamin and mineral supplementation in a manner that avoids dietary inhibitors and provides an adequate amount of the vitamins and minerals to be absorbed.

BRIEF SUMMARY OF THE INVENTION

[0007] The present invention involves the chelation of the target mineral or vitamin to a haptocorrin protein substrate. Bioavailability will be significantly increased by allowing the vitamin or mineral to be transported into the intestine where the haptocorrin will be naturally degraded by pancreatic proteases, thus releasing the mineral or vitamin chelate. For example, by chelating zinc to a haptocorrin substrate, bioavailability will be significantly increased as zinc will be protected from acid hydrolysis and more readily transported into and, in part, down through the intestine. Once in the intestine, the haptocorrin will be degraded by naturally occurring pancreatic proteases, thus releasing the zinc chelate, which will then be transported across the intestine.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWF G(S)

[0008] The present invention will be more fully understood and appreciated by reading the following Detailed Description in conjunction with the accompanying drawings, in which:

[0009] FIG. 1 is a schematic of a vitamin or mineral delivery compound according to the present invention;

[0010] FIG. 2 is a schematic of an exemplary haptocorrin substrate according to the present invention;

[0011] FIG. 3 is a schematic of another exemplary haptocorrin substrate according to the present invention;

[0012] FIG. 4 is a schematic of a further exemplary haptocorrin substrate according to the present invention;

[0013] FIG. 5 is a schematic of a haptocorrin substrate having a zinc binding domain according to the present invention;

[0014] FIG. 6 is a schematic of the synthesis of a haptocorrin substrate having a zinc binding domain according to the present invention; and [0015] FIG. 7 is schematic of the synthesis of a haptocorrin substrate having a zinc binding domain chelated to zinc according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0016] Referring to the figures, wherein like numerals refer to like parts throughout, there is seen in FIG. 1 a schematic of a delivery compound 10 comprising a haptocorrin substrate 12 that has been chelated to a target mineral or vitamin 14, such as zinc.

Haptocorrin substrate 12 may comprise cyanocobalamin (Bi ₂ ), dicyanocobinamide or any cobinamide, aqua/hydroxocobalamin, methylcobalamin, adenosylcobalamin, and

combinations thereof. Additionally, haptocorrin substrate 12 may comprise one or more molecular structure components derived from cobalamin (Bi ₂ ), cyanocobalamin,

dicyanocobinamide, hydroxocobalamin, methylcobalamin, and adenosylcobalamin to retain the binding domains involved in the interaction with haptocorrin.

[0017] For example, the corrin ring with B and C ring ethyl- or propionamides may be used. Exemplary haptocorrin substrates 12 are seen in FIGS. 2-4. As examples, FIG. 2 shows Bi ₂ used as haptocorrin substrate 12, FIG. 3 shows dicyanocobinamide as haptocorrin substrate 12, and FIG. 4 shows a ring modification of the dicyanocobinamide of FIG. 3.

[0018] The target mineral or vitamin may be chelated to the haptocorrin substrate using conventional chelating processes. For example, the haptocorrin substrate may be chelated to zinc by mixing a zinc source, such as zinc chloride, with a chelating agent, such as N,N,N ^, ,N-Tektrakis(2-pyridylmethyl)-ethylenediamine (TPEN), dipicolylamine, diethylenetriaminepentaacetic acid, aspartic acid, glutamic acid, n,n,n',n'-tetrakis(2- pyridylmethyl)ethylenediamine, bisquinoline, or bisthiazole.

EXAMPLE

[0019] There is seen in FIG. 5, an exemplary haptocorrin substrate 12

(dicyanocobinamide) that has been modified to include a zinc binding domain covalently attached through a carbamate linker off the /-propionamide of the in the form of the dipyridyl amine. It should be recognized by those of skill in the art that the linker can be substantially irreversible, such as that seen in FIG 5, or reversible by binding via an ester.

[0020] An example process for making the modified haptocorrin substrate 12 is seen in FIG. 6. The process involves removing the dimethybenzimidazole-ribose moiety of di cyanocobalamin by reacting with sodium cyanide in ethanol at 50 °C for 16 hours.

Subsequent reaction of the produced dicyanocobinamide with 1, 1 '~Carhonyl-di-(] ,2,4~ triazole) (CDT) and dipyridylamine in DMSO produces the final structure. [0021] Referring to FIG. 7, the modified haptocorrin substrate 12 may then be chelated to target mineral or vitamin 14, shown using zinc chloride in water or buffer as an example. It should be recognized that known chelatings agent may be selected to target specific vitamins or minerals of interest and that a multiple chelating agent that allows for chelation of multiple molecules of the target vitamin or mineral to a single haptocorrin binding substrate 12 may be used.