Biomedically active and delivery site specific capsule-in-capsule liver supplement apparatus and method of use thereof

The invention comprises a biomedically active/delivery site specific capsule-in-capsule liver supplement and method of use thereof. A first set of constituents, of an outer capsule, of a capsule-in-capsule liver supplement, comprises one or more of choline and phosphatidylcholine; a second set of constituents, of an inner capsule, comprise one or more of methionine, glycyrrhetinic acid, silymarin, and phosphatidylcholine; and either capsule optionally contains one or more liver aiding/regulating natural products, where the outer capsule dissolves in the stomach and the inner capsule dissolves in the small intestine. Thus, the dual dissolution process in controlled environments results in complementary and synergistic delivery of liver regulating molecules in a bioavailable form ready for transport through the wall of the small intestine. Further, constituents of the capsule-in-capsule liver supplement include multiple inputs into the methionine cycle, which facilitates/synergistically aids the body's use of the methionine cycle, such as in liver regulation.

BACKGROUND OF THE INVENTION

Field of the Invention

The invention relates to a biomedically active and site specific, capsule-in-capsule liver supplement delivery system.

Discussion of the Prior Art

The human body utilizes interlinked biochemical pathways to maintain system health. Hence, a restriction in one metabolic pathway often affects multiple linked pathways. Similarly, facilitating a pathway often benefits related/linked body systems. One critical pathway is the methionine cycle. In the methionine cycle, S-adenosyl methionine circulates in the blood and functions as a methyl donor. Donating a methyl group to other molecules can accelerate or preserve reactions in the body as a form of metabolic maintenance. Thus, the body benefits from an adequate supply of S-adenosyl methionine in the bloodstream.

A lack of adequate intake of methionine is associated with development of fatty liver disease. What is needed is a system for delivering bioactive methionine to the body.

SUMMARY OF THE INVENTION

A biomedically active and site specific, capsule-in-capsule liver supplement delivery system is described.

Elements and steps in the figures are illustrated for simplicity and clarity and have not necessarily been rendered according to any particular sequence. For example, steps that are performed concurrently or in different order are illustrated in the figures to help improve understanding of embodiments of the present invention.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

The invention comprises a biomedically active/delivery site specific capsule-in-capsule liver supplement and method of use thereof. Generally, a first set of constituents, of an outer capsule, of the capsule-in-capsule liver supplement comprises one or more of choline and phosphatidylcholine; a second set of constituents, of an inner capsule, comprise one or more of methionine, glycyrrhetinic acid, Silymarin, and phosphatidylcholine; and either capsule optionally contains one or more liver aiding/regulating natural products. Thus, the constituents of the capsule-in-capsule liver supplement include multiple inputs into the methionine cycle, which facilitates/synergistically aids the body's use of the methionine cycle, such as in liver regulation.

Referring now toFIG. 1, a simplified version of the methionine cycle100is illustrated. In the methionine cycle100, methionine110is converted to homocysteine120and eventually cysteine130, by way of S-adenosyl methionine140(SAMe) and S-adenosyl homocysteine150(SAH). Other relevant components of the methionine cycle100include adenosine triphosphate162(ATP), water164, choline166, and vitamin B12168. More particularly, ATP162is added to methionine110to form S-adenosyl methionine140, which provides a methyl group to a methyl acceptor142to form S-adenosyl homocysteine150and through addition of water forms homocysteine120. Homocysteine120is either converted back to methionine110through the methylation of choline166, or homocysteine120enters the transsulfuration pathway to form other sulfur-containing amino acids. It has been estimated that 60% of homocysteine120is metabolized by transsulfuration in the liver.

Some people with liver disease, alcoholic liver cirrhosis, and/or liver failure cannot synthesize S-adenosyl methionine or have a diminished ability to synthesize S-adenosyl methionine. As studies in mice show that S-adenosyl methionine protects against and reverses liver damage, S-adenosyl methionine may help normalize levels of liver enzymes in people with liver disease.

Methyl Donation

Methionine110is an essential amino acid containing sulfur. As methionine110is an essential amino acid, which cannot be synthesized internally by humans, it must be ingested, typically through dietary proteins. Methionine110is essential for the synthesis of proteins and many other biomolecules. A lack of adequate intake of methionine110is associated with development of fatty liver disease, which is countered and/or mediated by methionine supplements.

S-adenosyl methionine140is the amino acid methionine100bound to a molecule of ATP162. Referring now toFIG. 2, a non-ATP bound structure of S-adenosyl methionine140is illustrated. Referring again toFIG. 1, S-adenosyl methionine140circulates in the blood naturally and acts as a methyl donor to the methyl acceptor142. Donating a methyl group to other molecules can accelerate or preserve reactions in the body as a form of metabolic maintenance. Thus, the body benefits from an adequate supply of S-adenosyl methionine140in the bloodstream.

As further described infra, the inventor provides a capsule-in-capsule, also referred to as a dual capsule, liver supplement that releases supplemental methionine110and/or methionine110in a bioavailable form, such as S-adenosyl methionine140, in the small intestine after being protected from stomach acids. Further, the capsule-in-capsule liver supplement includes constituents facilitating uptake and use of methionine110and/or S-adenosyl methionine140, again as further described infra. Generally, the capsule-in-capsule liver supplement delivers nutrients to the body in a bioactive form in a region of the body that can absorb the bioactive form, which provides the body the necessary elements of the methionine cycle for self-regulation.

Referring now toFIG. 3, a capsule-in-capsule liver supplement method of generation and use300is described. Liver treatment capsule-in-capsule fabrication310involves placing an inner capsule into an outer capsule, where constituents of the inner capsule and the outer capsule are further described infra. The inventor has determined that use of a phosphatidyl choline suspension of constituents in either capsule to yield a liposome delivery system is enhanced with the addition of de-ionized water, an oil, and/or a fluidization step using a change of temperature. Delivery of the supplement320is through ingestion of the dual capsule. Breakdown of the outer capsule is dominantly in a first gastric breakdown delivery stage330using acids, enzymes, and/or motions of the stomach and a subsequent breakdown of the inner capsule is dominantly in a second intestinal breakdown delivery stage340with uptake through walls of the intestine. Initial breakdown of the outer capsule optionally occurs in the oral cavity. Similarly, initial breakdown of the inner capsule optionally occurs in the stomach.

Referring now toFIG. 4, the capsule-in-capsule delivery system320is further described. Generally, a capsule-in-capsule or dual capsule, such as a capsule-in-capsule liver supplement400, comprises a first capsule or outer capsule410that fully encases and/or circumferentially surrounds a second capsule or an inner capsule420. Herein, a capsule-in-capsule liver supplement400is described, where constituents of the outer capsule420and the inner capsule410are activated, primed, and/or are bioavailable at specific release sites, such as a first digestive track site432and a second digestive track site442, respectively, of a human. For example, the outer capsule410is designed to breakdown in the stomach and the inner capsule420is designed to fully break down in the intestine. The capsule-in-capsule delivery system320facilitates: (1) delivery of a first set of constituents412, contained in the outer capsule410, in an acidic environment, such as a human stomach, and (2) delivery of a second set of constituents422, contained in the inner capsule420, in the small intestine after passing through the acidic environment of the stomach. The synergistic release of constituents of the dual capsule and/or the release of constituents in respective cavities of the digestive track is further described, infra.

Still referring toFIG. 4, the constituents of the capsule-in-capsule liver supplement400are further described. Generally, the first set of constituents412, of the outer capsule410, of the capsule-in-capsule liver supplement400comprises one or more of choline166and phosphatidylcholine. Generally, the second set of constituents422, of the inner capsule420, comprise one or more of: methionine110, glycyrrhetinic acid, Silymarin, and phosphatidylcholine. Either capsule of the capsule-in-capsule liver supplement400optionally contain any vitamin and/or natural product identified as beneficial to liver regulation and/or for liver treatment, such as vitamin B12168; folate, such as folic acid and vitamin B9, Rosa laevigata; Houttuynia cordata; Gardenia jasminoides; Polygoni multiflora; Lycium barbarum; Ginsenoside re; andIxeris dentata.

The constituents of the capsule-in-capsule liver supplement400include multiple inputs into the methionine cycle100, which synergistically aid the body's use of the methionine cycle100.

Outer Capsule

Still referring toFIG. 4, the outer capsule410is designed to dissolve in an acidic environment of the stomach, aided by gastric motion and/or enzymes, while the second set of constituents422of the inner capsule420are shielded/protected.

The first set of constituents412, in the outer capsule410, optionally and preferably contains choline166. One requirement/burden placed of the human liver is to make choline. Choline is a water soluble essential nutrient. More particularly, choline comprises quaternary ammonium salts containing the trimethylethanolammonium cation and a counter anion, which is stable in stomach acids. The trimethylethanolammonium cation is optionally present in the head group of a phosphatidylcholine, a phospholipid, which is a major component of biological membranes, such as a cell wall, and aids in transport into/through cell membranes through forces related to hydrophilic/hydrophobic areas of the molecule. Thus, the first set of constituents412, in the outer capsule410, optionally and preferably contains phosphatidylcholine, which by containing choline, facilitates subsequent transport, such as through a wall of the small intestine, in blood, or into/through a cell wall.

Recent studies have shown that choline deficiency may have adverse effects. While it is not medically certain whether supplemental choline is beneficial to humans, the inventor notes that site-specific delivery of choline along with other constituents of the methionine cycle has not been addressed. Yet, possible benefits include reducing the risk of fatty liver disease. Hence, choline166, an input to the methionine cycle100, is co-introduced into the body with other elements of the capsule-in-capsule liver supplement400to facilitate the methionine cycle100, allowing the body to regulate/drive related systems, such as liver function.

Like S-adenosyl methionine140, choline166is a methyl donor, which has benefits described below. However, due to the selectivity of some reactions, such as steric and/or localized charge, in some instances choline166donates methyl groups where S-adenosyl methionine140does not and vise-versa. Hence, choline166and S-adenosyl methionine140are synergistic constituents of the capsule-in-capsule liver supplement400.

To aid biotransport, timing of delivery, and to reduce stress on the body, the outer capsule410optionally and preferably contains the first set of constituents412in a phosphatidylcholine suspension.

The term phosphatidylcholine is sometimes used interchangeably with lecithin; however, choline is a component of phosphatidylcholine, which is a component of lecithin.

Inner Capsule

Still referring toFIG. 4, the inner capsule420of the capsule-in-capsule liver supplement400is designed to dissolve in the small intestine after partial or total protection in the acidic environment of the stomach. More particularly, the inner capsule420is enteric coated, which prevents dissolution in the gastric environment. Still more particularly, the enteric coating is stable at a stomach pH, such as about a pH of 3±1, and breaks down at a higher pH present in the small intestine, such as a pH of 7-9 or greater than a pH of 6. Thus, the second set of constituents422of the inner capsule420are shielded/protected from the low pH stomach environment and released in the small intestine in a formulated bioactive form ready for uptake through the walls of the small intestine into the bloodstream.

Methionine

The second set of constituents422, in the inner capsule420, optionally and preferably contains methionine110. Methionine110is sulfur-containing amino acid, typically ingested in the form of dietary proteins. Here, the dietary protein is supplemented with methionine110. Methionine110is used in the methionine cycle100to form homocysteine120and eventually cysteine130after activation with ATP162to form S-adenosyl methionine140. More particularly, the methyl group of methionine is activated by the addition of adenosine to the sulfur of methionine, adjacent the methyl group, via use of energy from the adenosine triphosphate.

The second set of constituents422, in the inner capsule420, optionally and preferably contains S-adenosyl methionine110. S-adenosyl methionine140is the amino acid methionine100bound to a molecule of ATP162. S-adenosyl methionine140circulates in the blood naturally and acts as a methyl donor to the methyl acceptor142. Donating a methyl group to other molecules can accelerate or preserve reactions in the body as a form of metabolic maintenance. Thus, the body benefits from an adequate supply of S-adenosyl methionine140in the bloodstream. S-adenosyl methionine140aids in restoration of liver function in the presence of chronic liver diseases such as alcoholic and non-alcoholic cirrhosis as well as cholestasis. S-adenosyl methionine140functions as a methyl donor in the synthesis and formation of phosphatidylcholine and L-cysteine, which are both necessary for maintaining liver health.

Further, providing S-adenosyl methionine140in the capsule-in-capsule liver supplement400further aids the body as S-adenosyl methionine140is used to synthesize phosphatidyl choline.

For clarity of presentation and without loss of generalization, S-adenosyl methionine140is also referred to herein as S-Adenosyl-L-methionine and/or SAMe.

Subsequent to activation of methionine110to form S-adenosyl methionine140, S-adenosyl methionine140is primed for removal of the methyl group to form S-Adenosyl Homocysteine (SAH)150, which is subsequently converted to homocysteine120through removal of the adenosine molecule. Homocysteine120, in liver cells, enters the transsulfuration pathway, catalyzed by vitamin B6, to produce cysteine130. Thus, by providing S-adenosyl methionine140in the small intestine, optionally with other drivers of the methionine cycle100, the body's ability to regulate the transsulfuration pathway in the liver is enhanced. The body optionally uses the homocysteine120to reform methionine110.

The second set of constituents422, in the inner capsule420, optionally and preferably contains glycyrrhetinic acid or glycyrrhetic acid. Glycyrrhetinic acid is a pentacyclic triterpenoid derivative of the beta-amyrin type. Glycyrrhetinic acid is isolated from licorice plants, such as through hydrolysis of glycyrrhizic acid present in licorice. Glycyrrhetinic acid stimulates pancreatic secretion and mucous secretion in the intestines and markedly increase intestinal motility. Optionally, the capsule-in-capsule liver supplement400includes glycyrrhizin in the outer capsule410and/or in the inner capsule420in place of and/or in conjunction with glycyrrhetinic acid as glycyrrhetinic acid is the major metabolite of glycyrrhizin. However, delivery of bioactive glycyrrhetinic acid is preferred due to the synergistic benefit of simultaneous delivery of the capsule-in-capsule liver supplement400constituents, further described infra.

The second set of constituents422, in the inner capsule420, optionally and preferably contains silymarin or milk thistle. Milk thistle or silymarin is used in a natural treatment for liver disorders, such as cirrhosis, jaundice, and hepatitis. More particularly, silymarin inhibits fibrogenesis in the liver and has an antioxidant activity used to counter chronic liver diseases caused by oxidative stress, such as alcoholic and/or non-alcoholic fatty liver diseases and drug and/or chemical-induced hepatic toxicity.

The second set of constituents422, in the inner capsule420, optionally and preferably contains phosphatidylcholine (PPC). As described, supra, phosphatidylcholine is a phospholipid that aids in transport into/through cell membranes through forces related to hydrophilic/hydrophobic areas of the phosphatidylcholine molecule. Thus, the second set of constituents422, in the inner capsule420, optionally and preferably contains phosphatidylcholine, which facilitates subsequent transport of members of the second set of constituents through a wall of the small intestine, in blood, and/or into/through a cell wall.

The inner capsule420optionally and preferably contains the second set of constituents422in a phosphatidylcholine suspension.

Additional Capsule-in-Capsule Constituents

Either capsule of the capsule-in-capsule liver supplement400optionally and preferably contains any natural product or supplement identified as beneficial to the methionine cycle100, liver regulation, and/or for liver treatment, such as serine, to aid export of methionine cycle; trimethylglycine or betaine; vitamin B12168; vitamin B6; folate, such as folic acid and vitamin B9; Rosa laevigata; Houttuynia cordata; Gardenia jasminoides; Polygoni multiflora; Lycium barbarum; Ginsenoside re; and/orIxeris dentata, which are further described infra.

Fruit ofRosa laevigata, an evergreen climbing shrub native to southern China and/or an extract thereof is optionally included in the capsule-in-capsule liver supplement400, functioning as a sterol regulatory element-binding proteins inhibitor, at a mass of at least 0.1, 1, or 5 mg and less than 500 mg.

Houttuynia cordatais one a species in the genusHouttuynia, which is a flowering plant native to Southeast Asia. Optionally,Houttuynia cordataand/or an extract ofHouttuynia cordata, at a mass of at least 0.1, 1, or 5 mg and less than 100, 500, 1000, or 2000 mg, is optionally included in the capsule-in-capsule liver supplement400functioning as a triglyceride and/or cholesterol reducing element in the liver.

Fruit ofGardenia jasminoides, an evergreen flowering plant of the family Rubiaceae from Southeast Asia and/or an extract ofGardenia jasminoides,

at a mass of at least 0.1, 1, or 5 mg and less than 1000 mg, is optionally included in the capsule-in-capsule liver supplement400functioning as fatty acid synthase inhibitor.

The radix, root, ofPolygoni multiflora, a lipid regulator, is optionally included in the capsule-in-capsule liver supplement400with a mass of 1 to 300 mg.

Lycium barbarumis a species of boxthorn in the family Solanaceae from which the goji berry or wolfberry is harvested, whereLycium barbarumdecreases hepatic lipid accumulation. Optionally,Lycium barbarumL. and/or an extract, such as a water and/or ethanol extract, ofLycium barbarumL., at a mass of at least 0.1, 1, or 5 mg and less than 100, 500, 1000, or 2000 mg, is optionally included in the capsule-in-capsule liver supplement400.

Ginsenoside-Re fromPanax ginsengor Koreanginsengroot is optionally included in the capsule-in-capsule liver supplement400, functioning as a glycerol 3-phosphate acyltransferases inhibitor, at a concentration of at least 0.1, 1, or 5 mg and less than 250 mg.

Ixeris dentatais in the dandelion family and is an Asian flowering plant. Optionally,Ixeris dentataand/or an extract ofIxeris dentatal, at a mass of at least 0.1, 1, or 5 mg and/or less than 50, 100, 250, or 500 mg, is optionally included in the capsule-in-capsule liver supplement400functioning as decreasing hepatic accumulation of lipids.

For clarity of presentation and without loss of generality, two examples of the capsule-in-capsule liver supplement400are provided.

Example I

In a first example, the capsule-in-capsule liver supplement400comprises two capsules, the outer capsule410and the inner capsule420. The outer capsule410encases choline, preferably in a phosphatidylcholine suspension, where the outer capsule dissolves in a pH range of the stomach. The inner capsule420is encased in the outer capsule410. The inner capsule420comprises an enteric coating, which dissolves in a pH range higher, more basic, than a stomach pH. For instance, the enteric coating is stable at a stomach pH of 3 and dissolves at a small intestine pH of 7, which results in release of the components of the inner capsule420in the small intestine. The inner capsule410encapsulates methionine, S-adenosyl methionine, glycyrrhetinic acid, and/or silymarin. Optionally and preferably, each of the water soluble methionine, S-adenosyl methionine, glycyrrhetinic acid, and/or silymarin are blended with phosphatidylcholine into a liposomal and/or emulsified form. Thus, the second set of constituents422of the inner capsule maintain a bioactive form after passage through the stomach cavity and dissolution in the small intestine and are already emulsified when delivered into the small intestine. Optionally, the outer capsule410and/or the inner capsule420additionally contain a liver aiding natural product.

Example II

In a second example, the capsule-in-capsule liver supplement400comprises one or more of choline, S-adenosyl methionine, glycyrrhetinic acid, silymarin, phosphatidylcholine, serine, trimethylglycine, betaine, vitamin B12, vitamin B6, folate, folic acid, and vitamin B9in a range of 0.1 to 2000 mg per individual component and more preferably in a range of 25 or 50 to 100, 250, 500, or 1000 mg per component. In one case, the capsule-in-capsule liver supplement400comprises 50 to 2000 mg of choline; 50 to 1000 mg of S-adenosyl methionine140; 50 to 1000 mg of glycyrrhetinic acid; 10 to 500 mg of silymarin; and/or 50 to 3000 mg of phosphatidylcholine. In a second case, the capsule-in-capsule liver supplement400comprises 500±100 mg of choline166, 500±100 mg of S-adenosyl methionine140, 500±100 mg of glycyrrhetinic acid, 250±50 mg of silymarin, and/or 900±300 mg of phosphatidylcholine. In a third case, the capsule-in-capsule liver supplement400comprises 500±100 mg of choline166in the outer capsule410and 500±100 mg of S-adenosyl methionine140, 500±100 mg of glycyrrhetinic acid and 250±50 mg of silymarin in the inner capsule420, where either capsule contains up to 1000 mg of phosphatidylcholine. In a fourth case, in addition to any of choline166, S-adenosyl methionine140, glycyrrhetinic acid, silymarin, and/or phosphatidylcholine, the outer capsule410and/or the inner capsule420contains at least 0.1, 1, 5, 10, 25, or 50 mg of any one or more of: serine, trimethylglycine, betaine, vitamin B12, vitamin B6, folate, folic acid, vitamin B9, Rosa laevigata, Houttuynia cordata, Gardenia jasminoides, Polygoni multiflora, Lycium barbarum, Ginsenoside re, andIxeris dentata. In any case, the total weight of components of the capsule-in-capsule liver supplement400are contained in 1, 2, 3, 4, or 5 capsules, with the mass of each constituent distributed in any manner between the multiple capsules, such as evenly into three separate capsule in the capsule-in-capsule liver supplement400.

Generally, the inventor has determined, in stark contrast to oral delivery of a liquid, delayed and simultaneous delivery into the small intestine, in a bioactive form, in a phosphatidylcholine suspension, liposome, and/or in an emulsified system, of one or more of choline166, S-adenosyl methionine140, glycyrrhetinic acid, silymarin, phosphatidylcholine, serine, trimethylglycine, betaine, vitamin B12, vitamin B6, folate, folic acid, vitamin B9, Rosa laevigata, Houttuynia cordata, Gardenia jasminoides, Polygoni multiflora, Lycium barbarum, Ginsenoside re, andIxeris dentatafacilitates body regulation of the liver and related metabolic pathways due to the synergistic availability of multiple molecules used in the methionine cycle, liver, and/or liver regulation processes.

Embodiments are described partly in terms of functional components and various assembly and/or operating steps. Such functional components are optionally realized by any number of components configured to perform the specified functions and to achieve the various results. The systems and components described herein merely exemplify applications. Further, embodiments described herein, for clarity and without loss of generality, optionally use any number of conventional techniques for manufacturing, assembling, connecting, and/or operation. Components, systems, and apparatus described herein are optionally used in any combination and/or permutation.

In still yet another embodiment, the invention comprises and combination and/or permutation of any of the elements described herein.

The particular implementations shown and described are illustrative of the invention and its best mode and are not intended to otherwise limit the scope of the present invention in any way. Furthermore, the connecting lines shown in the various figures are intended to represent exemplary functional relationships and/or physical couplings between the various elements. Many alternative or additional functional relationships or physical connections may be present in a practical system.

In the foregoing description, the invention has been described with reference to specific exemplary embodiments; however, it will be appreciated that various modifications and changes may be made without departing from the scope of the present invention as set forth herein. The description and figures are to be regarded in an illustrative manner, rather than a restrictive one and all such modifications are intended to be included within the scope of the present invention. Accordingly, the scope of the invention should be determined by the generic embodiments described herein and their legal equivalents rather than by merely the specific examples described above. For example, the steps recited in any method or process embodiment may be executed in any order and are not limited to the explicit order presented in the specific examples. Additionally, the components and/or elements recited in any apparatus embodiment may be assembled or otherwise operationally configured in a variety of permutations to produce substantially the same result as the present invention and are accordingly not limited to the specific configuration recited in the specific examples.