Compositions containing adenosine triphosphate (ATP) and methods of use

Abstract

The present invention provides a composition comprising adenosine or adenosine triphosphate (ATP) acting as an absorption enhancer when combined with a nutritional material(s) such as nutrients, protein, peptides, vitamins, phytochemicals, minerals, fatty acids, or amino acids or a drug. Methods of administering ATP or adenosine to improve the bioavailability of a nutritional material(s) such as nutrients, protein, peptides, vitamins, phytochemicals, minerals, fatty acids, or amino acids or a drug are described.

Claims

1. A method for increasing the bioavailability of a nutritional material in an animal comprising administering enterally to the animal at least one nutritional material containing at least one amino acid comprising glutamine, asparagine, alanine, arginine, and/or citrulline; and an effective dosage of an absorption enhancer, wherein the absorption enhancer is adenosine triphosphate (ATP) or adenosine.

2. The method of claim 1, wherein the nutritional material contains at least one of protein, peptides, and/or individual amino acids.

3. A method for improving the absorption of a nutritional material in a human, comprising administering enterally to the human an effective dosage of an absorption enhancer, wherein the absorption enhancer is adenosine triphosphate (ATP) or adenosine; and at least one nutritional material containing at least one amino acid comprising glutamine, asparagine, alanine, arginine, and/or citrulline.

4. The method of claim 3, wherein the nutritional material contains at least one of protein, peptides, and/or individual amino acids.

5. The method of claim 4, wherein the nutritional material contains additional amino acids.

6. The method of claim 5, wherein the additional amino acids are essential amino acids.

7. The method of claim 5, wherein the additional amino acids are branched chain amino acids.

8. A method for improving the bioavailability of at least one vitamin in an animal, comprising administering enterally to the animal at least one vitamin and an effective dosage of an absorption enhancer for at least fifteen days, wherein the absorption enhancer is adenosine triphosphate (ATP) or adenosine.

9. The method of claim 8, wherein the improved bioavailability is measured as a greater increase in blood serum levels of the vitamin as compared to administration of the vitamin without the absorption enhancer.

10. The method of claim 8, wherein the vitamin is Vitamin K.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 is a graph showing the absorption of total amino acids

(2) FIG. 2 is a graph showing the absorption of essential amino acids.

(3) FIG. 3 is a graph showing the absorption of branched chain amino acids

(4) FIG. 4 is a graph showing the absorption of leucine.

(5) FIG. 5 is a graph showing the absorption of isoleucine.

(6) FIG. 6 is a graph showing the absorption of valine.

(7) FIG. 7 is a graph showing the absorption of histidine.

(8) FIG. 8 is a graph showing the absorption of lysine.

(9) FIG. 9 is a graph showing the absorption of methionine.

(10) FIG. 10 is a graph showing the absorption of phenylalanine.

(11) FIG. 11 is a graph showing the absorption of threonine.

(12) FIG. 12 is a graph showing the absorption of tryptophan.

(13) FIG. 13 is a graph showing the absorption of alanine.

(14) FIG. 14 is a graph showing the absorption of arginine.

(15) FIG. 15 is a graph showing the absorption of asparagine.

(16) FIG. 16 is a graph showing the absorption of aspartic acid.

(17) FIG. 17 is a graph showing the absorption of citrulline.

(18) FIG. 18 is a graph showing the absorption of cysteine.

(19) FIG. 19 is a graph showing the absorption of glutamic acid.

(20) FIG. 20 is a graph showing the absorption of glutamine.

(21) FIG. 21 is a graph showing the absorption of glycine.

(22) FIG. 22 is a graph showing the absorption of ornithine.

(23) FIG. 23 is a graph showing the absorption of proline.

(24) FIG. 24 is a graph showing the absorption of serine.

(25) FIG. 25 is a graph showing the absorption of tyrosine.

(26) FIG. 26 shows the plasma K2 concentration with and without ATP.

(27) FIG. 27 shows the plasma K2 concentration with and without ATP.

DETAILED DESCRIPTION OF THE INVENTION

(28) It has been surprisingly and unexpectedly discovered that ATP acts as an absorption enhancer to increase the bioavailability of nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids, and/or drugs. The present invention comprises a composition of ATP combined with nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids, and/or drugs.

(29) This combination can be used on all age groups seeking improved bioavailability of nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids, and/or drugs.

(30) In view of the above, in one embodiment the present invention provides a composition comprising an absorption enhancer, typically ATP, included with nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids, and/or drugs. The inclusion of ATP with nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids, and/or drugs provides elevated C.sub.max, T.sub.max and/or AUC levels as compared to nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids and/or drugs administered without ATP. Inclusion of ATP as an absorption enhancer with nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids, and/or drugs is effective to promote the bioavailability of the nutrients, protein, peptides, amino acids, phytochemicals, minerals, fatty acids, and/or drugs. Co-administration of ATP and nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids, and/or drugs causes an increase in the AUC of the nutrients, protein, peptides, vitamins, amino acids, and/or drugs as compared with administration of nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids, and/or drugs without ATP. Administration of ATP with nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids, and/or drugs results in an improved pharmokinetic profile as compared to administration of nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids, and/or drugs without ATP.

(31) Improved bioavailability may also improve the efficacy of the substance exhibiting improved bioavailability. Enhancing the absorption of nutrients, protein, peptides, vitamins, amino acids, and/or drugs provides improves the availability of these substances to tissues and thus provides a more rapid and efficient method to get these substances to the tissues.

(32) As used herein, the term “bioavailability” generally means the rate and extent to which the nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids, and/or drugs are absorbed and become available at the site of action. For oral dosage forms, bioavailability relates to the processes by which the active ingredient (i.e., nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids, and/or drugs) is released from the oral dosage form and moves to the site of action. In general, bioavailability is the amount of nutrients, protein, peptides, vitamins, amino acids, and/or drugs systemically (i.e., blood/plasma levels) available over time.

(33) As used herein, T.sub.max is the time to maximum concentration and C.sub.max is the observed maximum concentration. Area under the curve (AUC) refers to the mean area under the plasma concentration-time curve and is considered to be a direct measurement of the bioavailability of the nutrients, protein, peptides, vitamins, amino acids, and/or drugs.

(34) As used herein, “absorption enhancer” shall mean any substance which is effective to increase the absorption of an agent such as nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids and/or drugs through the mucosa relative to absorption without such agent.

(35) ATP or adenosine acts as an enhancer for the absorption of macromolecules, including, nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids, and/or drugs into the body. Adenine nucleotides or adenosine and inorganic phosphate are including the scope of this invention, including adenosine 5′-monophosphate, adenosine 5′-diphosphate, adenosine 5′-triphosphate and mixtures thereof, pharmaceutically acceptable salts thereof or chelate thereof, or metal complex thereof or liposome thereof.

(36) Adenosine-5′-triphosphate (ATP)

(37) Oral administration of ATP is usually in the form of Adenosine-5′-Triphospate Disodium. In the present invention, Adenosine-5′-Triphosphate Disodium or any form of ATP or adenosine suitable for oral administration may be combined with any of the known coatings suitable for imparting enteric properties in granular form.

(38) One of skill in the art recognizes that ATP may be incorporated into the delivery and/or administration form in a fashion so as to result in a typical dosage range of about 10 mg to about 80 grams, though more or less may be desirable depending on the application and other ingredients.

(39) The composition of ATP and nutrients, protein, peptides, vitamins, amino acids, and/or drugs is administered to an animal in any suitable manner. Acceptable forms include, but are not limited to, solids, such as tablets or capsules, and liquids, such as enteral solutions. Also, the composition can be administered utilizing any pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and examples of such carriers include various starches and saline solutions. In the preferred embodiment, the composition is administered in an edible form. In addition, an effective dosage range may be administered in divided dosages, such as two to three times per day.

(40) The present invention can be used with enteral feeding tubes that deliver nutrients and medications. Such feeding tubes may be used to deliver nutrients and medications to the stomach, small bowel, and jejunal regions. Feeding tubes may be nasoenteric, inserted through the mouth, or percutaneous. Enteral feeding may be administered by various methods, including continuous, cyclic, bolus and intermittent.

(41) The present invention can be used with oral nutritional products containing nutrients, protein, peptides, vitamins, and/or amino acids, such as Ensure, IsoPure, Boost, Glucerna, Jevity, Osmolite or other supplemental nutritional liquids.

(42) ATP is present in the composition in any form. A range of ATP in the present invention includes ATP in the amount of around 10 milligrams to around 80 grams. In the preferred embodiment, the range of ATP is around 100 milligrams to around 1.6 grams.

(43) When the composition is administered orally in an edible form, the composition is preferably in the form of a dietary supplement, foodstuff or pharmaceutical medium, more preferably in the form of a dietary supplement or foodstuff. Any suitable dietary supplement or foodstuff comprising the composition can be utilized within the context of the present invention. One of ordinary skill in the art will understand that the composition, regardless of the form (such as a dietary supplement, foodstuff or a pharmaceutical medium), may include amino acids, proteins, peptides, carbohydrates, fats, sugars, vitamins, phytochemicals, minerals and/or trace elements.

(44) In order to prepare the composition as a dietary supplement or foodstuff, the composition will normally be combined or mixed in such a way that the composition is substantially uniformly distributed in the dietary supplement or foodstuff. Alternatively, the composition can be dissolved in a liquid, such as water, or emulsified in a liquid.

(45) The composition of the dietary supplement may be a powder, a gel, a liquid or may be tabulated or encapsulated.

(46) Although any suitable pharmaceutical medium comprising the composition can be utilized within the context of the present invention, preferably, the composition is combined with a suitable pharmaceutical carrier, such as dextrose or sucrose.

(47) Methods of calculating the frequency by which the composition is administered are well-known in the art and any suitable frequency of administration can be used within the context of the present invention (e.g., one 6 g dose per day or two 3 g doses per day) and over any suitable time period (e.g., a single dose can be administered over a five minute time period or over a one hour time period, or, alternatively, multiple doses can be administered over an extended time period). The combination of ATP and nutritional materials (including nutrients, protein, peptides, vitamins, phytochemicals, minerals, fatty acids, and amino acids) and/or drugs can be administered over an extended period of time, such as weeks, months or years.

(48) It will be understood by one of ordinary skill in the art that ATP and nutrients, protein, peptides, vitamins, amino acids, and/or drugs do not have to be administered in the same composition to perform the claimed methods. Stated another way, separate capsules, pills, mixtures, liquids etc. of ATP and nutrients, protein, peptides, vitamins, amino acids, phytochemicals, minerals, fatty acids, and/or drugs may be administered to a subject to carry out the claimed methods.

(49) Any suitable dose of ATP can be used within the context of the present invention. Methods of calculating proper doses are well known in the art.

EXPERIMENTAL EXAMPLES

(50) The following examples will illustrate the invention in further detail. It will be readily understood that the composition of the present invention, as generally described and illustrated in the Examples herein, could be synthesized in a variety of formulations and dosage forms. Thus, the following more detailed description of the presently preferred embodiments of the methods, formulations and compositions of the present invention are not intended to limit the scope of the invention, as claimed, but it is merely representative of the presently preferred embodiments of the invention.

Example 1

(51) The purpose of this study was to determine whether oral ATP supplementation would affect the absorption of nutrients from the gastrointestinal (GI) tract following consumption of a mixed protein shake.

(52) Methods

(53) Six young, healthy adults (3 M, 3 F) participated in this study. All were free from GI disease/symptoms and were not taking any medication or supplements known to alter GI function or nutrient absorption.

(54) The study utilized a placebo-controlled, cross-over study design with a balanced treatment order. Trials were separated by 7 days.

(55) Subjects arrived to the laboratory in the morning following an overnight fast. A polyethylene catheter was inserted and a baseline blood sample is drawn.

(56) Participants consumed either 400 mg ATP or a placebo capsule with 4 oz of water.

(57) Ten minutes after consuming the supplement capsule, participants consumed a 10-oz vegan protein shake containing 20 g protein, 1.5 g HMB, and 5 g sucrose.

(58) Blood samples were taken at 15, 30, 45, 60, 75, 90, 120, 150, and 180 minutes after shake ingestion.

(59) Plasma was separated and frozen for analysis of amino acids levels.

(60) Results

(61) In FIG. 1 depicting total amino acids, ATP increased C.sub.max (5%) and AUC (7%). Based on unadjusted t-tests, the change in total amino acids (ΔTAA) is higher with ATP supplementation at all timepoints.

(62) In FIG. 2 depicting essential amino acids, based on unadjusted t-tests, the change in essential amino acids (ΔEAA) is higher at timepoints between 60 and 180 minutes with ATP supplementation.

(63) In FIG. 3 depicting branched chain amino acids, based on unadjusted t-tests, the change in branched chain amino acids (ΔBCAA) is higher with ATP supplementation at 120 minutes.

(64) For the AUC for individual amino acids, ATP increased AUC for Glutamine (10%, p=0.02) (FIG. 20) Citrulline (13%; p=0.06) (FIG. 17) Asparagine (20%; p=0.04) (FIG. 15) Alanine (19%; p=0.07) (FIG. 13)
Individual Amino Acids

(65) Plots of each individual amino acid are depicted in FIGS. 4 through 25. These are expressed as change from baseline (Blue=Placebo, Orange=ATP).

(66) ATP increases total amino acid availability during 3 hours post-prandial to a mixed protein shake. The individual amino acids that demonstrated increased bioavailability include glutamine, asparagine, alanine and citrulline. Without being limited by any particular theory, this may occur due to ATP enhancing uptake of select amino acids from the gut and/or inhibiting the clearance of select amino acids from circulation. ATP may affect the glutamine transporters in the enterocytes causing increased absorption of glutamine, asparagine, alanine and citrulline.

(67) The data demonstrates that ATP acts as an absorption enhancer for certain amino acids, including glutamine, asparagine, arginine, alanine and citrulline. The addition of ATP to any composition administered for the benefits of these amino acids will improve the bioavailability of these amino acids. For example, U.S. Pat. No. 6,031,000 describes administering β-hydroxy-β-methylbutyric acid (HMB) with at least one amino acid, including glutamine, for treating disease-associated wasting (including age associated muscle wasting), decreasing serum-level triglycerides, decreasing the serum viral load, and redistributing fat. Addition of ATP to the compositions and methods of use of the compositions of this patent improves the bioavailability of the amino acids in the compositions. Juven is a product used for wound healing and to build and maintain lean body mass that contains glutamine arginine and HMB. Addition of ATP to this type of amino-acid containing product improves the bioavailability of the amino acids in these products.

(68) Glutamine has been shown to be used in instances of metabolic stress, impaired gastrointestinal function due to severe trauma, diarrhea, inflammatory bowel disease, and surgery, severe burns or injury due to chemotherapy or radiation, instances of malabsorptive conditions (such as Crohn's disease), acute trauma and wound healing. Addition of an absorption enhancer such as ATP to a composition containing glutamine results in the improved bioavailability of glutamine and improved systemic utilization of glutamine

(69) Arginine has been shown to be useful for treating or lessening the effects of pulmonary hypertension in sickle cell disease, wound healing, improving kidney function, maintaining immune and hormone function, dilating and relaxing the arteries, improving blood flow in the arteries of the heart, improving symptoms of clogged arteries, chest pain and coronary artery disease, improving erectile dysfunction, decreasing blood pressure and improving hypertension. Addition of an absorption enhancer such as ATP to a composition containing arginine results in the improved bioavailability of glutamine and improved systemic utilization of arginine.

Example 2

(70) The purpose of this study was to assess the effects of ATP and K2 supplementation individually and in combination.

(71) Methods

(72) A total of 11 subjects (6 male, 5 female; ages 20-30) completed all study periods. Treatments were administered in a double-blinded, crossover design with a Latin Square sequence design to minimize confounding effects of treatment order. Participants were semi-randomly assigned to treatment sequences; at least one male and one female participant were assigned to each sequence to minimize any confounding effects of sex.

(73) During each study period, participants consumed one of 4 supplements for 15 days: ATP (400 mg/d) K2 (200 μg/d) as menaquinone-7 (NOW® MK-7, containing MenaQ7®) ATP (400 mg/d)+K2 (200 μg/d) placebo

(74) Blood samples were taken before and after each supplementation period for the measurement of serum K2 concentration, carboxylated/undercarboxylated osteocalcin ratio (a marker of K2 function), and clinical chemistry and hematology.

(75) Results

(76) TABLE-US-00001 Participant Characteristics Mean SE Sex (M/F) 6/5 Age (y) 22.8 1.1 Height (cm) 173.6 2.6 Weight (kg) 68.3 3.0 Body Fat (%) 16.8 1.5 BMI (kg/m.sup.2) 22.6 0.8

(77) Supplement compliance was 94±2%. All participants consumed ≥73% of the provided doses for all periods.

(78) Blood samples were analyzed for K2 levels. Average serum K2 levels were 1.08±0.25 ng/mL after 15 days of K2 supplementation and 2.29±0.49 ng/mL after 15 days of K2+ATP supplementation (p<0.05). Two participants did not accumulate K2 in serum during either of the treatment periods. Consuming ATP and K2 together enhances the bioavailability of K2.

(79) For safety analyses, blood samples were also analyzed for clinical chemistry and hematology. Though some small differences were observed, all were small and none were clinically relevant. No adverse effects were observed for any of the supplements.

(80) In FIGS. 26-27, post-supplementation values are presented. In FIG. 26, plasma levels of Vitamin K2 as menaquinone-7 (K2 MK-7) were measured by LC/MS/MS before and after 15 days of supplementation with 200 μg/d K2 MK-7 with or without 400 mg/d ATP (n=9). After 15 days of supplementation, mean plasma K2 MK-7 levels were 113% higher after ATP+K2 supplementation vs. K2 supplementation alone. Data presented as mean+SE *Statistically significant difference (p<0.05) between K2 and ATP+K2.

(81) In FIG. 27, plasma levels of Vitamin K2 as menaquinone-7 (K2 MK-7) were measured by LC/MS/MS before and after 15 days of supplementation with 200 μg/d K2 MK-7 with or without 400 mg/d ATP (n=9, lines represent individual subjects). After 15 days of supplementation, plasma levels of Vitamin K2 as menaquinone-7 (K2 MK-7) were higher in 8/9 subjects after ATP+K2 supplementation vs. K2 supplementation alone.

(82) The combination of ATP+Vitamin K2 improves the bioavailability of K2, as average vitamin K2 levels were nearly twice as high when vitamin K2 supplements were consumed along with 400 mg/d ATP compared to when vitamin K2 supplements were consumed with placebo capsules.

(83) The foregoing description and drawings comprise illustrative embodiments of the present inventions. The foregoing embodiments and the methods described herein may vary based on the ability, experience, and preference of those skilled in the art. Merely listing the steps of the method in a certain order does not constitute any limitation on the order of the steps of the method. The foregoing description and drawings merely explain and illustrate the invention, and the invention is not limited thereto, except insofar as the claims are so limited. Those skilled in the art who have the disclosure before them will be able to make modifications and variations therein without departing from the scope of the invention. The terms subject and animal are used interchangeably throughout this application and are in no way limited to one term or the other.