WO2017218235A1 - Haptocorrin (r-binder; transcobalamin i) substrates for the oral delivery of vitamins or minerals - Google Patents

Haptocorrin (r-binder; transcobalamin i) substrates for the oral delivery of vitamins or minerals Download PDF

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Publication number
WO2017218235A1
WO2017218235A1 PCT/US2017/036095 US2017036095W WO2017218235A1 WO 2017218235 A1 WO2017218235 A1 WO 2017218235A1 US 2017036095 W US2017036095 W US 2017036095W WO 2017218235 A1 WO2017218235 A1 WO 2017218235A1
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Prior art keywords
haptocorrin
substrate
target compound
zinc
mineral
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PCT/US2017/036095
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French (fr)
Inventor
Robert Doyle
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Robert Doyle
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the haptocorrin 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.
  • FIG. 1 is a schematic of a vitamin or mineral delivery compound according to the present invention.
  • FIG. 2 is a schematic of an exemplary haptocorrin substrate according to the present invention.
  • FIG. 3 is a schematic of another exemplary haptocorrin substrate according to the present invention.
  • FIG. 4 is a schematic of a further exemplary haptocorrin substrate according to the present invention.
  • FIG. 5 is a schematic of a haptocorrin substrate having a zinc binding domain according to the present invention.
  • FIG. 6 is a schematic of the synthesis of a haptocorrin substrate having a zinc binding domain according to the present invention.
  • FIG. 7 is schematic of the synthesis of a haptocorrin substrate having a zinc binding domain chelated to zinc according to the present invention.
  • 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
  • haptocorrin substrate 12 may comprise one or more molecular structure components derived from cobalamin (Bi 2 ), cyanocobalamin,
  • dicyanocobinamide dicyanocobinamide, hydroxocobalamin, methylcobalamin, and adenosylcobalamin to retain the binding domains involved in the interaction with haptocorrin.
  • the corrin ring with B and C ring ethyl- or propionamides may be used.
  • Exemplary haptocorrin substrates 12 are seen in FIGS. 2-4.
  • FIG. 2 shows Bi 2 used as haptocorrin substrate 12
  • FIG. 3 shows dicyanocobinamide as haptocorrin substrate 12
  • FIG. 4 shows a ring modification of the dicyanocobinamide of FIG. 3.
  • the target mineral or vitamin may be chelated to the haptocorrin substrate using conventional chelating processes.
  • 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.
  • a zinc source such as zinc chloride
  • TPEN N,N,N , ,N-Tektrakis(2-pyridylmethyl)-ethylenediamine
  • (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.
  • linker can be substantially irreversible, such as that seen in FIG 5, or reversible by binding via an ester.
  • FIG. 6 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

A complex formed from the chelation of the target mineral or vitamin to a haptocorrin substrate. A haptocorrin substrate, such as B12, can increase bioavailability of the vitamin or mineral increased by allowing the vitamin or mineral to be transported into the intestine by available haptocorrin. Once in the intestine, the haptocorrin substrate will be naturally degraded by pancreatic proteases, thereby releasing the mineral or vitamin chelate for absorption. For example, zinc may be chelated to a haptocorrin substrate for more improved transportation into the intestine. Once in the intestine, the haptocorrin substrate will be degraded by naturally occurring pancreatic proteases, thus releasing the zinc chelate.

Description

TITLE
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 (Bi2), 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 (Bi2), 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 Bi2 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.

Claims

WHAT IS CLAIMED IS:
1. A system for oral delivery of a target compound, comprising:
a haptocorrin substrate; and
a target compound chelated to the haptocorrin substrate.
2. The system of claim 1, wherein the chelated haptocorrin substrate and target compound are characterized by bioavailability of the target compound in the intestine of a subject administered with the chelated haptocorrin substrate and target compound.
3. The system of claim 1, wherein the target compound is a vitamin.
4. The system of claim 1, wherein the target compound is a mineral.
5. The system of claim 3, wherein mineral is zinc.
6. The system of claim 1, wherein the haptocorrin substrate is selected from the group consisting of cobinamide, cyanocobalamin (Bi2), dicyanocobinamide,
aqua/hydroxocobalamin, methylcobalamin, adenosylcobalamin, and combinations thereof.
7. The system of claim 1, wherein the haptocorrin substrate includes a haptocorrin binding domain derived from cobalamin (Bi2), cyanocobalamin,
dicyanocobinamide, hydroxocobalamin, methylcobalamin, or adenosylcobalamin.
8. The system of claim 7, wherein the binding domain is a corrin ring.
9. A method of alleviating a deficiency in a subject, comprising the step of orally administering an amount of a haptocorrin substrate that is chelated to a target compound associated with the deficiency.
10. The method of claim 9, wherein the chelated haptocorrin substrate and target compound are characterized by bioavailability of the target compound in the intestine of the subject.
11. The method of claim 10, wherein the target compound is a vitamin.
12. The method of claim 10, wherein the target compound is a mineral.
13. The method of claim 12, wherein mineral is zinc.
14. The method of claim 9, wherein the haptocorrin substrate is selected from the group consisting of cobinamide, cyanocobalamin (Bi2), dicyanocobinamide,
aqua/hydroxocobalamin, methylcobalamin, adenosylcobalamin, and combinations thereof.
15. The method of claim 9, wherein the haptocorrin substrate includes a haptocorrin binding domain derived from cobalamin (Bi2), cyanocobalamin,
dicyanocobinamide, hydroxocobalamin, methylcobalamin, or adenosylcobalamin.
16. The method of claim 15, wherein the binding domain is a corrin ring.
PCT/US2017/036095 2016-06-15 2017-06-06 Haptocorrin (r-binder; transcobalamin i) substrates for the oral delivery of vitamins or minerals WO2017218235A1 (en)

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US62/350,353 2016-06-15

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160083451A1 (en) * 2013-05-15 2016-03-24 Syracuse University Methods and systems for zinc delivery using intrinsic factor or haptocorrin

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160083451A1 (en) * 2013-05-15 2016-03-24 Syracuse University Methods and systems for zinc delivery using intrinsic factor or haptocorrin

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MARQUES ET AL.: "Kinetics and Activation Parameters of the Reaction of Cyanide with Free Aquocobalamin and Aquocobalamin Bound to a Haptocorrin from Chicken Serum", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 26, no. 25, 5 September 1988 (1988-09-05), pages 12378 - 12383, XP055449141 *

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