WO1998028978A1

WO1998028978A1 - Structured glycerols and structured phosphatides

Info

Publication number: WO1998028978A1
Application number: PCT/US1997/007897
Authority: WO
Inventors: Luke R. Bucci
Original assignee: Weider Nutrition Group, Inc.
Priority date: 1996-05-08
Filing date: 1997-05-08
Publication date: 1998-07-09
Also published as: AU3120797A

Abstract

The present invention includes two novel classes of compounds, Structured Glycerols and Structured Phosphatides. Structured Glycerols have ester bonds between biologically active Compounds and the hydroxyl groups of glycerol and its monoglyceride or diglyceride derivatives. Structured Phosphatides include biologically active Compouds attached by ester bonds to the hydroxyl or phosphate groups of glycerol phosphatide and its monoglyceride or diglyceride derivatives. Suitable biologically active Compounds include drugs, hormones, amino acids, organic acids, peptides, sugars, nucleotides, vitamins, minerals, mineral chelates, intermediary metabolites, and herbal compounds and fatty acids.

Description

STRUCTURED GLYCEROLS AND STRUCTURED PHOSPHATIDES

I . Background of the Invention A. Field of the Invention.

This invention relates to the field of chemical vehicles for delivering biologically active compounds to humans, mammals and other vertebrates, and methods of using the same. More specifically, this invention relates to chemical delivery vehicles for delivering biologically active compounds using esters of glycerol or glycerol phosphates, and methods of using the same.

B. Description of Related Art. Proper nutrition and diet are important to achieving and maintaining good health. Normal diets are often supplemented with nutritionally beneficial compounds to achieve provide general health improvements as well as to treat specific health problems. Such supplements are often single purified compounds taken for specific conditions or to achieve specific results. For example, the administration of free pyruvate can be taken to inhibit free-radical formation (U.S. Patent No. 5,480,909), treat cardiac conditions (U.S. Patent No. 5,294,641), or reduce insulin resistance in diabetics (U.S. Patent No. 5,283,260). Similarly, free beta-hydroxy-beta- methylbutyric acid (HMB) can be administered to promote nitrogen retention (U.S. Patent No. 5,348,979) or enhance the immune response of mammals (U.S. Patent No. 4,992,470). U.S. Patent No. 4,677,121 discloses a method of preventing muscle breakdown by administering free alpha- ketoisocapropic acid or pharmaceutically acceptable salts thereof to humans .

Fatty acids have been used as carriers to deliver beneficial compounds to humans and other vertebrates. For example, compositions utilizing fatty acids to solubilize drugs or steroids during administration have been developed (See U.S. Patent Nos . 4,148,308 and 4,340,594). U.S. Patent No. 4,528,197 discloses a method of enhancing protein anabolism by administering compositions of lipids, carbohydrates and lipids in an emulsion of triglycerides . Fatty acids by themselves may also provide specific health benefits. As an example, U.S. Patent No. 4,703,062 discloses a composition of medium and long chain triglycerides for administration to patients to treat diseases . Triglycerides in the form of structured lipids have also been developed as delivery vehicles for fatty acids. For example, U.S. Patent No. 4,871,768 discloses structured lipids of omega-3 fatty acids and medium chain fatty acids. U.S. Patent Nos. 4,906,664 and 5,081,105, disclose such compositions for use in cancer treatment. U.S. Patent Nos. 4,607,052 and 4,847,296 disclose other triglyceride compositions of fatty acids. The type and size of the fatty acids in the structured lipid may vary. U.S. Patent No. 5,312,836 discloses a synthetic triglyceride of short and non-short chain fatty acids.

U.S. Patent No. 4,952,606 discloses a composition of fatty acids and triglycerides formed by transesterification. U.S. Patent Nos. 4,703,062 and 4,753,963 disclose nutritional supplements and methods of using such supplements as sources of carbohydrates and amino acids. Structured lipids are administered with these components. Each of the patents referenced above is hereby incorporated by reference in its entirety.

A disadvantage of the compositions described above is that they do not provide a common delivery system for different types of beneficial compounds. For example, when fatty acids are used as emulsions to deliver beneficial compounds, each of these compounds must be capable of forming an emulsion with the fatty acids. Once emulsified and ingested, each compound may be differentially absorbed; some compounds may be inefficiently absorbed during digestion. Another problem with such emulsions is that some beneficial compounds in free, purified form may irritate the digestive tract.

One attempted solution to such problems is to couple beneficial substances, specifically, amino acids or peptides, to fats. U.S. Patent No. 5,583,198 discloses a composition of such beneficial substances linked to fats, including ethanolamine and tromethamine . This patent is incorporated by reference in its entirety. A disadvantage of such compositions is that the beneficial substances may not be readily cleaved from the fat carrier molecule. None of the patents discussed above disclose incorporating a composition for reversibly incorporating beneficial, biologically active compounds into chemical delivery vehicles to aid in the assimilation of those substances by human, other mammals and other vertebrates. There is a need for such delivery vehicles due to the inefficient absorption of many beneficial compounds during digestion. Additionally, many beneficial compounds are exhibit poor gastrointestinal tolerance. Beneficial substances also may be labile, such that they degrade before absorption.

II. Summary and Objects of the Invention

This invention relates to novel delivery vehicles for use in humans, mammals and other vertebrates to deliver biologically active compounds, including drugs, hormones, amino acids, organic acids, peptides, sugars, nucleotides, vitamins, minerals, mineral chelates, intermediary metabolites, and herbal compounds, hereafter described in generic terms in this application as Compounds. (The uncapitalized word compound is still used generically. ) The composition of this invention includes esters of the above-named Compounds to glycerol or glycerol phosphatides, or their monoglyceride or diglyceride forms, to create a class of novel compounds called Structured Glycerols or Structured Phosphatides, respectively. The resultant structured forms are physically distinct from their components .

The rationale for the formation of Structured Glycerols and Phosphatides is to provide an alternate delivery method for biologically active Compounds. Applications of physiologically or therapeutically useful doses after oral administration of these Compounds in a non-esterified form is often limited by gastrointestinal tolerance or poor bioavailability. Structured Glycerols/Phosphatides ameliorate gastrointestinal side effects associated with oral administration of high doses of Compounds, improve uptake of Compounds into the lymphatic and portal systems (especially of lipid-soluble or insoluble Compounds) , improve solubility of Compounds otherwise insoluble, improve tolerability of oral administration of Compounds, provide a time-release or sustained release form of administration of Compounds, and provide improved stability of inherently labile Compounds, such as creatine, S-adenosyl-L-methionine (SAMe) , nicotinamide dinucleotide (NADH) , or L-glutamine. The invention thus described may be used for therapeutic purposes or enhancement of cellular processes in humans, other mammals and other vertebrates. It is an object of the invention to provide novel chemical vehicles, Structured Glycerols and Structured Phosphatides, for delivering biologically active Compounds to humans, mammals and other vertebrates . An advantage of the present invention is that Structured Glycerols provide alternate oral or injectable delivery methods for biologically active Compounds over the administration of non-esterified (free) Compounds. An additional advantage of such Structured

Glycerols is that they provide improved gastrointestinal tolerance, which increases the bioavailability of these compounds. Such improved bioavailability can sustain or prolonged the period of uptake. Another significant advantage is that Structured Glycerols can provide improved stability of Compounds which would otherwise be labile to water, during digestion or during uptake. Another object of the invented Structured Glycerols is to provide a delivery vehicle for specifically tailoring doses of desired Compounds to match clinical needs or storage requirements. An advantage of this invention is that high doses of single biologically active Compounds may be delivered to humans, mammals or other vertebrates. Another advantage is that controlled stoichiometric amounts of up to three different biologically active Compounds may be delivered to humans, mammals or other vertebrates.

Yet another object of the invention is to provide a delivery vehicle for biologically active Compounds which are difficult to esterify to carbon hydroxyl groups. Biologically active Compounds may also be esterified to the phosphate groups of glycerol phosphate (s) to form

Structured Phosphatides. In addition to the advantages discussed above for Structured Glycerols, these Structured Phosphatides facilitate delivering a broader spectrum of biologically active Compounds to humans, mammals and other vertebrates.

These and other objects, features and advantages of the invention will be clear to a person of ordinary skill in the art upon reading this specification.

III. Detailed Description of the Prefer Embodiment

The present invention includes two novel classes of compounds, Structured Glycerols and Structured Phosphatides. Structured Glycerols have ester bonds between biologically active Compounds and the hydroxyl groups of glycerol and its monoglyceride or diglyceride derivatives. Structured Phosphatides include biologically active Compounds attached by ester bonds to the hydroxyl or phosphate groups of glycerol phosphatide and its monoglyceride or diglyceride derivatives. The biologically active Compounds within the scope of the present invention include, but are not limited to, drugs, hormones, amino acids, organic acids, peptides, sugars, nucleotides, vitamins, minerals, mineral chelates, intermediary metabolites, and herbal Compounds. Suitable drugs may include acetylsalicylate and acetaminophen. Suitable hormones may include melatonin and serotonin. Suitable amino acids may include the nineteen standard L- amino acids, proline, and non-standard amino acids such as hydroxyproline, selenomethionine, phosphoserine, L- carnithine and phospholeucine, as well as D-amino acids. Suitable organic acids may include pyruvate, lactate, alpha-keto-isocaproic acid and beta-hydroxy-beta- methylbutyric acid (HMB) . Nucleotides with the scope of the invention may include ribo- and deoxyribnucleotides, and phosphoadenosine phosphosulfate . Vitamins within the scope of the invention include vitamin A, niacin, other members of the vitamin B family, vitamins C, D, E, K, and cofactors including riboflavin, pantethine, pantetheine, pantothenic acid, pyridoxal (including phosphate forms) , biotin, thioredoxin, folates, and lipoic acid. Suitable sugars may include glucosamine. Minerals within the scope of the invention include copper, cobalt, iron, manganese, magnesium, selenium, and zinc. Suitable mineral chelates can include chelates of the minerals mentioned above as well as the copper salt of L-lysinate, the ferrous salt of glycinate, the zinc salt of L carnosinate and chromium picolinate salts. Suitable intermediary metabolites may include creatine, ornithine alpha-ketoglutarate, S- adenosyl-L-methionine, phosphoserine, phosphocholine, phosphoinositol, and phosphoethanolamine . Herbal components may include curcumin, ephedrine, caffeine, fumaric acid, cayenne, proanthocyanidin (s) , chlorophyll, and phylloquinone (s) . These biologically active Compounds are only exemplary, as will be appreciated by those of skill in the art. Pharmaceutically acceptable salts of these Compounds are also within the scope of the present invention. Similarly, other biologically active Compounds which may be attached to glycerol or glycerol phosphate as an ester are also intended to be within the scope of the present invention.

Glycerol is a ubiquitous molecule well-known as being the backbone of triglycerides, phospholipids, and other related compounds. Glycerol consists of a three carbon chain with a hydroxyl (alcohol) group on each carbon, and all other bonds being occupied with hydrogen (C₃H₈0₃) . The combination of an acid with a glycerol hydroxyl group results in an ester bond by the elimination of water (H₂0) from the two precursor compounds. Similarly, acid groups can be esterified as a phosphate ester to the phosphate group on glycerol phosphatides.

In nature, esters of glycerol and fatty acids are ever-present, and are termed glycerides (fats or oils) . Such glycerides may include mono-, di- and tri-glycerides . Phospholipid formation involves the substitution of a fatty acid on one end of the glycerol backbone with phosphoric acid (phosphate), forming a phosphatide. Other compounds can be esterified to the phosphate group, and commonly choline, serine, ethanolamine, and inositol are esterified to the phosphate to form the four known phospholipids. The other two hydroxyl sites on the phospholipid glycerol molecule are usually occupied by fatty acids or hydrogen atoms.

The human body possesses extensive abilities to remove (hydrolyze) Compounds esterified to glycerol. As a normal part of digestion, triglycerides are solubilized by bile salts and digested by lipases to yield two fatty acids and one monoglyceride. These components are rapidly absorbed into intestinal enterocytes, reassembled into triglycerides, and delivered to the thoracic duct for transport into systemic circulation. Likewise, phospholipids are digested similarly into lysophosphatides , and reassembled for transport inside gut enterocytes. Short- and medium-chain triglycerides can be transported directly to the liver by the portal route after intestinal absorption.

Non-specific esterases (NSEs) present in intestinal lining cells, the liver, and all cells are capable of digesting any possible combination of esters found on glycerol backbones. Likewise, the ubiquitous presence of high levels of phosphatases (both alkaline and acid phosphatases) in the intestinal lining and all cells is capable of hydrolyzing the bond between a Compound and the phosphate group of a Structured Phosphatide. Thus, there are at least three well-known enzymatic means for digestion, hydrolysis and uptake into the body of Compounds esterified to glycerol or glycerol phosphatides in the form of Structured Glycerol/Phosphatides .

These digestive processes offer advantages of better tolerability, solubility, and capacity over absorption of many free Compounds which exist as ionically- charged molecules. As an illustrative example, uptake into blood and brain tissue of large amounts (over 1 gram per oral dose) of choline from phosphatidyl choline is greater, better tolerated, and therapeutically more advantageous than uptake from an equivalent amount of choline as choline salts (choline base, choline chloride, choline bitartrate, or choline citrate) . Ingestion of multi-gram amounts of ionically-charged Compounds can irritate gastric or intestinal mucosal linings, resulting in efflux of water into the gut, causing osmotic diarrhea. This response by the body to high loads of ionically-charged Compounds has limited applications of oral administration of Compounds, especially single amino acids. The invention described herein also has the advantage of providing improved uptake and tolerability of insoluble or fat-soluble Compounds, both under conditions of impaired fat digestion and normal gastrointestinal conditions. In one preferred embodiment of the invention, a fatty acid may be esterified to the glycerol backbone . Suitable fatty acids may include oleic acid, eicosapentaenoic acid, alpha linolenic acid and valerenic acid. These acids can help solubilize the Structured Glycerol/Phosphatide and facilitate uptake during digestion. In another preferred embodiment of the invention, all of the Compounds on a Structured Glycerol/Phosphatide may be non-fatty acids. Since these groups are smaller and more hydrophilic than fatty acids on triglycerides, the potential for uptake of Structured Glycerol/Phosphatides in toto exists. Once inside gut enterocytes, hydrolysis by NSEs and phosphatases would release the Compounds attached to the glycerol or glycerol phosphate. The Structured Glycerol/Phosphatides can also act as emulsification agents themselves (similar to phospholipids) , improving concomitant uptake of other fatty components of the diet or of hydrolyzed Structured Glycerol/Phosphatides.

Regardless of the route of uptake, once Compounds formerly bound to Structured Glycerol/Phosphatides are in the bloodstream, they can be rapidly taken up, metabolized, and/or excreted by peripheral tissues, as evidenced by previously reported pharmacokinetics of Compounds after intravenous or oral administration. If intact or partially hydrolyzed Structured Glycerol/Phosphatides happen to be translocated into the blood, the ubiquitous presence of phosphatases in serum and tissues, along with NSE activity in all tissues should hydrolyze the Structured Glycerol/Phosphatides into its molecular components.

The following structure is considered to be one generic form of the inventive concept: H₂C0 - Rl

I HCO - R2

I H₂CO - R3 where Rl, R2 and R3 are independently selected from hydrogen, drugs, hormones, amino acids, organic acids, peptides, sugars, nucleotides, vitamins, minerals, mineral chelates, intermediary metabolites, and herbal compounds. Each of Rl, R2 and R3 are attached to the glycerol backbone through an ester bond. The above formula shows the ester oxygen which is links the glycerol backbone and the R group .

Another structure considered to be a generic form of the inventive concept: H₂CO - Rl

HCO - R2

I H₂C - 0P0₃ - R3 where Rl, R2 and R3 are independently selected from hydrogen, drugs, hormones, amino acids, organic acids, peptides, sugars, nucleotides, vitamins, minerals, mineral chelates, intermediary metabolites, and herbal compounds. Each of Rl, R2 and R3 are attached to the glycerol backbone through an ester bond or a phosphate ester bond. The above formula shows the ester oxygen which is shared between the glycerol (or glycerol phosphate) and the R group.

Many possible combinations of Structured Glycerols or Phosphatides with biologically active Compounds are within the scope of the present invention.

In the simplest example, one or more biologically active Compounds of the same type can be esterified to glycerol or glycerol phosphatide. For example, the same or different amino acids could be esterified to glycerol or glycerol phosphatides. Another possible Structured

Glycerol/Phosphatide compound would include different types of biologically active Compounds. For example, a fatty acid, an amino acid and a drug could be esterified to glycerol or glycerol phosphate . In a more preferred embodiment of the invention, the invented Structured Glycerols/Phosphatides include dietary supplements, since each biologically active substance occurs naturally. For example, one Structured Glycerol/Phosphatide would include an alpha tocopherol molecule attached at one hydroxyl, a fatty acid bound at the middle hydroxyl, and an amino acid bound to the phosphate group on the other end of the glycerol backbone. In another more preferred embodiment, the Structured Glycerol/Phosphatide includes pharmaceuticals or drugs. An example of a pharmaceutical Structured Glycerol/Phosphatide would be a tetracycline antibiotic attached at one position of the glycerol backbone, a fatty acid at the central position, and a phosphoserine at the third position. The identity of biologically active Compounds on Structured Glycerol/Phosphatides can be manipulated to deliver desired Compounds found to be efficacious for repletion or treatment of health conditions .

The invented Structured Glycerols and Phosphatides can also provide improved stability of biologically active Compounds which would otherwise be labile to water, during digestion or during uptake. For example, creatine, S-adenosyl-L-methionine (SAMe) , nicotinamide dinucleotide (NADH) , and L-glutamine are typically labile and unavailable for absorption during digestion. By esterifying these chemicals to the invented Structured Glycerols/Phosphatides, their stability and bioavailability can be markedly increased.

Table One illustrates various embodiments of Structured Glycerols/Phosphatides. Although separate Compounds are listed as attached to different positions on the glycerol backbone, the order may be varied without affecting the Proposed Use. Likewise, a mixture of three different Structured Glycerols/Phosphatides, each containing only one compound could be mixed together in equimolar amounts to achieve the same delivery of Compounds as listed in the Table. Table 1. Partial List of Proposed Uses for Specific Structured Glycerols/Phosphatides

Table 1 . ( cont . )

Compounds Attached to Proposed Use

Positions

Rl , R2, R3

A: Chlorophyll Gastric and duodenal ulcers,

B: L-Carnosinate, Zinc salt ulcerative colitis,

C: L-Glutamine inflammatory bowel diseases

A: Ipriflavone Osteoporosis, bone loss

B: Phylloquinone disorders

C: Cholecalciferol

A: Glucosamine Osteoarthritis, degenerative

B: S-Adenosyl-L-methionine joint diseases, spinal

C: Phosphoadenosine stenosis, chronic low back

Phosphosulfate pain

A: L-Selenomethionine Psoriasis

B: Eicosapentaenoic acid

C: Alpha Linolenic acid

A: Hydergine^® Memory loss, senile

B: Oleic acid dementia, cognitive

C: Phosphoserine or impairment phosphocholine

A: L-Lysinate, copper salt Rheumatoid arthritis,

B: Eicosapentaenoic acid rheumatic diseases,

C: Curcumin bursitis, tendinitis Table 1 (cont . )

Table 1 . (cont . )

The invented Structured Glycerols/Phosphatides may be used for therapeutic purposes or enhancement of cellular processes in humans and mammals for delivery of Compounds by oral or injectable means. As will be appreciated by those of skill in the art, suitable doses of the Structured Glycerols and Phosphatides will vary according to the particular Compounds esterified to that vehicle. The appropriate dosages will be readily determinable by those in the art, according to the composition of the specific Structured Glycerol/Phosphatide.

The invented Structured Glycerols/Phosphatides may be manufactured by numerous methods, as will be appreciated by those of skill in the art. In one preferred embodiment, these delivery vehicles are enzymatically synthesized. For example, Compounds could be attached nonspecific esterases in the presence of a stoichiometric excess of selected Compounds over glycerol or glycerol phosphate or mono- or di- glyceride forms thereof. Similarly, Compounds can be covalently linked to the phosphate moiety of glycerol phosphate using reversible phosphatases .

Structured Glycerols and Phosphatides may be synthesized using chemical means. Such means for chemically forming esters bonds are known in the art. For example, the Kirk-Othmer Encyclopedia of Chemical Technology (4^th ed., 1991) discloses methods for esterification for different types of organic esters. (This reference is incorporated by reference) . Amino acids and other Compounds can be esterified to glycerol or glycerol phosphate under acidic conditions. Suitable acids may include strong acids such as sulfuric, hydrochloric or phosphoric acids and§ Lewis acids. As will be appreciated by those of skill in the art, strong acids are only suitable for Compounds which are stable under strongly acidic conditions. For example, glutamine and asparagine will be labile under strongly acidic conditions. Another method of chemical synthesis includes acid-regenerated cation-exchange resins. Such resins may be periodically charged and regenerated, but are also suitable for use in continuous processes .

Esters of Structured Glycerols and Phosphatides may also be formed using other methods of chemical synthesis. For example, esters between glycerol hydroxyl groups and Components can be formed using acid anhydrides or acid chlorides of the Components. Similarly, amide, nitrile, ether aldehyde, ketone and even alcohol groups of the Compounds or derivatives of the Compounds can be covalently attached to glycerol or glycerol phosphatides under the appropriate conditions to form ester bonds.

Examples of such syntheses are disclosed in the Kirk-Othmer Encyclopedia of Chemical Technology.

Glycerol is commercially available from numerous sources. Glycerols are preferably of food grade quality. Glycerol phosphate is also readily available from commercial sources or may be synthesized using phosphorylating enzymes such as glycerol kinase . Derivatives of glycerol, including mono- and di -glycerides, and glycerol phosphates, such as mono- and di-phosphatides, containing fatty acids are also commercially available from numerous sources, such as Sigma Chemical Company, Aldrich Chemical Company.

Once synthesized, the Structured Glycerol/Phosphatide may be purified using numerous purification schemes, including distillation, reactive extraction, reverse osmosis and chromatography . Heat distillation is preferred for stable Compounds which will not degrade under those conditions . Evaporative distillation may be suitable for volatile Structured Glycerols/Phosphatides. Reverse osmosis is preferred for larger Structured Glycerols and Phosphatides, especially when they are separated from smaller molecular weight, non- esterified Compounds. Similarly, chromatography, particularly bulk column chromatography, HPLC, FPLC and similar methods are suitable for obtaining high quality separations of the Structured Glycerols/Phosphatides from the unreacted Compounds or side reactions formed during the esterification.

While the present invention has been described and illustrated in conjunction with a number of specific embodiments, those skilled in the art will appreciate that variations and modifications may be made without departing from the principles of the invention as herein illustrated, described and claimed.

The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are to be considered in all respects as illustrative, and not restrictive. The scope of the invention, is therefore, indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope .

Claims

Claim 1. A compound of the following formula:

H₂C0 Rl

HCO R2

H₂C0 - R3

wherein Rl, R2 , and R3 are independently selected from hydrogen, drugs, hormones, amino acids, peptides, sugars, nucleotides, vitamins, minerals, mineral chelates, intermediary metabolites, herbal compounds, and fatty acids; wherein Rl, R2 or R3 are not all hydrogen; wherein not more than two of Rl, R2 or R3 are fatty acids and the others of Rl , R2 or R3 are not hydrogen; and wherein if two of Rl, R2 or R3 are fatty acids, the other of Rl, R2 or R3 is not phosphocholine, phosphoserine, phosphoethanolamine, or phosphoinositol .

Claim 2. A compound of the following formula:

H₂C0 Rl

HC - R2

H₂C - 0P0₃ - R3

where Rl , R2 , and R3 are independently selected from hydrogen, drugs, hormones, amino acids, peptides, sugars, nucleotides, vitamins, minerals, mineral chelates, intermediary metabolites, herbal compounds, and fatty acids; wherein Rl, R2 or R3 are not all hydrogen; wherein if both Rl and R2 are fatty acids, R3 is not hydrogen, choline, serine, ethanolamine, or inositol .

Claim 3. The compound of any of the preceding claims, wherein two of Rl, R2 and R3 are independently selected from hydrogen, drugs, hormones, amino acids, peptides, sugars, nucleotides, vitamins, minerals, mineral chelates, intermediary metabolites, and herbal compounds, and the other of Rl, R2 and R3 is a fatty acid.

Claim 4. The compound of any of the preceding claims, wherein Rl or R2 is a fatty acid and R3 and the other of Rl and R2 are independently selected from hydrogen, drugs, hormones, amino acids, peptides, sugars, nucleotides, vitamins, minerals, mineral chelates, intermediary metabolites, and herbal compounds, such that Rl, R2 and R3 are all different.

Claim 5. The compound of any of the preceding claims, wherein Rl, R2, and R3 are independently selected from drugs, hormones, amino acids, peptides, sugars, nucleotides, vitamins, minerals, mineral chelates, intermediary metabolites, and herbal compounds.

Claim 6. The compound of any of the preceding claims, wherein Rl, R2 and R3 are different.

Claim 7. The compound of any of the preceding claims, wherein at least one of Rl, R2 and R3 are dietary supplements .

Claim 8. The compound of any of the preceding claims, wherein at least one of Rl , R2 and R3 are pharmaceuticals .

Claim 9. The compound of any of the preceding claims, wherein at least one of Rl , R2 and R3 is a biologically active drug.

Claim 10. The compound of any of the preceding claims, wherein at least one of Rl , R2 and R3 is an amino acid.

Claim 11. The compound of claim 10, wherein at least one of Rl , R2 and R3 is an L- amino acid.

Claim 12. The compound of any of the preceding claims, wherein at least one of Rl , R2 and R3 is a vitamin.

Claim 13. The compound of any of the preceding claims, wherein at least one of Rl , R2 and R3 is a mineral chelate.

Claim 14. The compound of claim 13 , wherein said mineral chelate comprises chelates of copper, cobalt, iron, manganese, magnesium, selenium, or zinc.

Claim 15. The compound of any of the preceding claims, wherein at least one of Rl, R2 and R3 is a herbal compound .

Claim 16. The compound of claim 15, wherein at least one of Rl , R2 and R3 comprises curcumin, ephedrine, caffeine, fumaric acid, cayenne, proanthocyanidin (s) , chlorophyll, or phylloquinone (s) .

Claim 17. The compound of any of the preceding claims, wherein at least one of Rl , R2 and R3 comprises a vitamin or cofactor.

Claim 18. A method for oral delivery to humans and other vertebrates using the compounds of any of the preceding claims.

Claim 19. A method for injectable delivery to humans and other vertebrates using the compound of any of the preceding claims .