WO2010027498A2 - Compositions and methods for inducing satiety and treating non-insulin dependent diabetes emillitus, pre-diabetic symptoms, insulin resistance and related disease states and conditions - Google Patents

Abstract

The invention provides methods of treatment that induce satiety in a subject for a period of at least around twenty- four hours by once-daily administration to the subject of a controlled release dosage form, wherein the dosage form is administered while the subject is in the fasted state and at a time of around six to around nine hours prior to the subject's next intended meal, and wherein the dosage form comprises a controlled release composition, which comprises an enterically-coated, ileum hormone-stimulating amount of a nutritional substance and releases the majority of the nutritional substance in vivo upon reaching the subject's ileum. The invention also provides a diagnostic tool for probing the health and disease state of the ileal hormones, excess or deficiencies. The invention provides a safe vehicle for targeted deliveries of chemical, pharmaceuticals, natural substances and nutrition to the ileum. The present invention also provides a method for treating noninsulin dependent diabetes mellitus, pre-diabetic symptoms, and insulin resistance, as well as a number of disease states and conditions including gastrointestinal disorders as otherwise described herein.

Description

COMPOSITIONS AND METHODS FOR INDUCING SATIETYAND TREATING

NON-INSULIN DEPENDENT DIABETES EMLLITUS, PRE-DIABETIC SYMPTOMS, INSULIN RESISTANCE AND RELATED DISEASE STATES AND

CONDITIONS

FIELD OF THE INVENTION

The present invention relates to compositions and methods for inducing satiety. The present invention also relates to nutritional supplements to the human diet, and more specifically to nutritional supplements which contain a combination of naturally occurring substances which are particularly adapted to treating noninsulin dependent diabetes mellitus, pre-diabetic symptoms, insulin resistance and related disease states and conditions of the gastrointestinal tract diagnostic applications and transport of other medicments.

RELATED APPLICATIONS

This application claims the benefit of priority of provisional application no. 61/190,818, filed September 3, 2008filed September 3, 2008, entitled "Compositions and Methods for Inducing Satiety" the entire contents of which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

One of the factors thought to contribute to satiety is glucagon-like peptide- 1 (7- 36) amide (GLP-I), which is processed from proglucagon throughout the small bowel and in the distal small bowel (ileum), and to a lesser extent in the ascending colon, as well as in the central nervous system. GLP-I has powerful actions on the gastrointestinal tract. Infused in physiological amounts, GLP-I potently inhibits pentagastrin-induced as well as meal-induced gastric acid secretion. It also inhibits gastric emptying rate and pancreatic enzyme secretion. Similar inhibitory effects on gastric and pancreatic secretion and motility may be elicited in humans upon perfusion of the ileum with carbohydrate- or lipid-containing solutions. Concomitantly, GLP-I secretion is greatly stimulated, and it has been speculated that GLP-I maybe at least partly responsible for this so-called "ileal- brake" effect.

Within the central nervous system, GLP-I has a satiating effect, since administration of GLP-I into the third cerebral ventricle reduces short-term food intake (and meal size), while administration of GLP-I antagonists have the opposite effect. The administration of graded doses of human GLP-I produced plasma glucagon-like peptide- 1 concentrations within physiological ranges and resulted in the reduction of intake of food in non-obese, healthy male subjects.

GLP-I is formed and secreted in parallel in the intestinal mucosa along with glicentin (corresponding to PG (1 69), with the glucagon sequence occupying residues Nos. 33 61); small amounts of C-terminally glycine-extended but equally bioactive GLP- 1 (7 37), (PG (78 108)); intervening peptide-2 (PG (111 122)amide); and GLP-2 (PG (126 158)). A fraction of glicentin is cleaved further into GRPP (PG (1 30)) and oxyntomodulin (PG (33 69)).

GLP-I is also effective in stimulating insulin secretion in NIDDM patients. Additionally, it potently inhibits glucagon secretion. Because of these actions it has pronounced blood glucose lowering effects, particularly in patients with NIDDM. Byetta® (exenatide) is an incretin mimetic and a GLP-I receptor agonist. Byetta® mimics the actions of GLP-I that occur naturally in the gastrointestinal tract and has emerged as an efficacious type 2 (non-insulin-dependent) diabetes therapy adjunct to one or more oral hypoglycemic agents.

Peptide YY (PYY), a 36-amino-acid peptide, is secreted primarily from L-cells residing in the intestinal mucosa of the ileum and large intestine. PYY, which belongs to a family of peptides including neuropeptide Y (NPY) and pancreatic polypeptide, is released into the circulation as PYY(PYY (1-36) and PYY(PYY (3-36); the latter is the major form of PYY in gut mucosal endocrine cells and throughout the circulation. Plasma PYY levels begin to rise within fifteen minutes after the ingestion of food, plateau within approximately ninety minutes, and remain elevated for up to six hours. Exogenous administration of PYY(PYY (3-36) reduces energy intake and body weight in both humans and animals. Via Y2 receptors, the satiety signal mediated by PYY inhibits NPY neurons and activates proopiomelanocortin neurons within the hypothalamic arcuate nucleus. Peripheral PYY(PYY (3-36) binds Y2 receptors on vagal afferent terminals to transmit the satiety signal to the brain.

Insulin is the principal hormone responsible for the control of glucose metabolism. It is synthesized in the β cells of the islets of Langerhans as the precursor, proinsulin, which is processed to form C-peptide and insulin, and both are secreted in equimolar amounts into the portal circulation.

United States Patent Nos. 5,753,253 and 6,267,988 disclosed that since satiety feedback from the ileum is more intense per amount of sensed nutrient than from proximal bowel (jejunum), timing the release of a satiety-inducing agent to predominate in ileum will also enhance the satiety response per amount of agent ingested. Thus, both the spread and predominant site of delivery (ileum) will maximize the effect, so that a small amount of released nutrient will be sensed as though it were a large amount, creating a high satiating effect. U.S. Patent Nos. 5,753,253 and 6,267,988 disclose administration of a satiety-inducing agent with a meal and at a time of around 4-6 hours before the next scheduled meal.

U.S. Patent No. 7,081,239 discloses manipulating the rate of upper gastrointestinal transit of a substance in a mammal, as well as methods of manipulating satiety and post-prandialpyramidal visceral blood flow. The methods of treatment disclosed in U.S. Patent No. 7,081,239 can be administered up to a period of 24 hours prior to ingestion of the food, nutrient and/or drug, but most preferably are administered between about 60 to 5 minutes before ingestion. U.S. Patent No. 7,081 ,239 notes that in prolonged treatment of postprandial diarrhea or intestinal dumping, there is at least a potential for an adaptive sensory feedback response that can allow treatment to be discontinued for a number of days without a recurrence of the disorders. Despite the aforementioned knowledge regarding the role of ileal hormones in digestion and insulin secretion, the need continues to exist for improved therapies that harness the "ileal-brake" effect and GLP-I -insulin pathway to treat or prevent the onset of obesity and obesity-related disorders. The growing prevalence of obesity and obesity-related disorders makes this need particularly acute.

Type II, or noninsulin-dependent diabetes mellitus (NIDDM) typically develops in adulthood. NIDDM is associated with resistance of glucose-utilizing tissues like adipose tissue, muscle, and liver, to the actions of insulin. Initially, the pancreatic islet beta cells compensate by secreting excess insulin. Eventual islet failure results in decompensation and chronic hyperglycemia. Conversely, moderate islet insufficiency can precede or coincide with peripheral insulin resistance.

There are several classes of drugs that are useful for treatment of NIDDM: 1) insulin releasers, which directly stimulate insulin release, carrying the risk of hypoglycemia; 2) prandial insulin releasers, which potentiate glucose-induced insulin secretion, and must be taken before each meal; 3) biguanides, including metformin, which attenuate hepatic gluconeogenesis (which is paradoxically elevated in diabetes); 4) insulin sensitizers, for example the thiazolidinedione derivatives rosiglitazone and pioglitazone, which improve peripheral responsiveness to insulin, but which have side effects like weight gain, edema, and occasional liver toxicity; 5) insulin injections, which are often necessary in the later stages of NIDDM when the islets have failed under chronic hyperstimulation.

Insulin resistance can also occur without marked hyperglycemia, and is generally associated with atherosclerosis, obesity, hyperlipidemia, and essential hypertension. This cluster of abnormalities constitutes the "metabolic syndrome" or "insulin resistance syndrome". Insulin resistance is also associated with fatty liver, which can progress to chronic inflammation, nonalcoholic steatohepatitis, fibrosis, and cirrhosis. Cumulatively, insulin resistance syndromes, including but not limited to diabetes, underlie many of the major causes of morbidity and death of people over age 40. Despite the existence of various drugs, diabetes remains a major and growing public health problem. What is needed is not necessarily new drug therapies, which often are accompanied by significant side effects, but rather a method of treatment that utilizes a unique combination of natural substances, such as those which have been listed as GRAS (Generally Regarded As Safe), which may be administered as a nutritional supplement, without a prescription. There is a particular need to provide a new orally active therapeutic supplement which effectively addresses the primary defects of insulin resistance and isulin failure without side effects, so that the supplement can be administered to those who are in the pre-diabetic stages, or who exhibit pre-diabetic symptoms, so as to forestall or preclude the onset of diabetes.

When sugar is absorbed from the early portion of the jejunum, the sugar quickly reaches the beta cells of the pancreas and gets in these pancreatic cells via the glut 2 glucose transporter. The amount of sugar in the blood plasma is directly proportional to the sugar being transported into the beta cells. The glucose inside the beta cells is metabolised and oxidized, which produces a stimulation of insulin release that is augmented by the simultaneous stimulation of the gastric inhibitor peptide gip and glucagon-like peptide glpl which occurs due to the oral ingestion of sugar.

When insulin is released into the body, it exerts an effect at the cellular level throughout the entire body, but more specifically in the liver, the muscle tissues, and the fat or adipose tissues. The effects can occur in a "short acting" way that stimulates the glucose uptake in muscles and fat cells, thereby increasing the synthesis of glycogen in muscle and liver, inhibiting glucose secretion in the liver, and increasing amino acid uptake, or in a "long term" way which increases protein synthesis and stimulates certain gene expression in all cells. Insulin works by binding with insulin receptors on a cell surface. Once coupled, kinase enzymes push glut 4, the major glucose transport receptor, to attach to the cell surface for driving the glucose intracellularly.

It is generally known that the surface of muscles and fat cells have other receptors that can drive the glucose intracellularly without insulin. These receptors work with IGFl and IGF2 hormones. There is also believed to be a undefined IRR receptor structurally similar to the receptors working with IGFl and IGF2 hormones located on the cell surface but the correlating hormone has not yet been found. In general, the body should maintain a substantial equilibrium, that is, the amount of insulin secreted should be equal to the amount of insulin needed to keep the blood sugar level steady.

One problem that can be experienced is when insulin is not being adequately produced, typically because the pancreas, and more specifically the beta cells, have been destroyed or are sick as per type one diabetes, where the output of insulin is decreased or absent. A second problem is where insulin interactions, that is between the insulin, the insulin receptors, and the cells, are hindered by a multitude of factors so that the action is not an efficient use of the insulin available, and as a result, much more insulin is needed to achieve the same goal of driving the sugar intracellularly.

This second type of problem is associated with noninsulin dependent diabetes or adult onset diabetics, or a different syndrome of insulin resistance. It is this type of insulin inefficiency that the present method and composition are directed to. Insulin resistance or insulin insensitivity encompasses the majority of the population dealing with diabetes; Type A, a genetic defect of the insulin receptors (i.e., leprechaunism, Rabson Mendhall syndrome, and lipodystrophy); Type B, an autoimmune type with an antibody to the insulin receptors; and Type 3, a post membrane receptor resistance, that includes obesity, hypertension, noninsulin dependent diabetes, aging, and polycystic ovary syndrome.

The commonly accepted theory for these two types of insulin resistant afflictions is that the sugars are not being transported into the cells due to an autoimmune antibody (Type B) or some sort of post receptor resistance (Type 3). As a result, sugars outside of the cells build up. The pancreas, attempting to equilibrate the level of sugar and insulin, causes insulin production to increase. Even though more insulin is being produced, sugars are not being transported into the cells. Initially, the increase in insulin is capable of overcoming the insulin resistance but this requires a much higher level of insulin production. This stage is considered the pre-diabetic stage where insulin is high but glucose is normal. Ultimately, the pancreas becomes exhausted and it is not capable of keeping up with the high insulin production rate that is required, thereafter causing the sugar levels to spike, with the person eventually becoming a full diabetic. The common non-invasive treatment for diabetics is to start and maintain a proper diet and exercise routine. Second, doctors may prescribe medication such as (i) sulphonyureas to stimulate over secretion of insulin, which can speed up the exhaustion of the pancreas; (ii) metformin prescribed to improve the efficiency of insulin action and also improve on the clearance of glucose in peripheral tissues, therefore decreasing the level of sugar and insulin as well; and (iii) IGFl injection to decrease the level of insulin as well as blood sugar by activating the kinase via its own receptors.

While pre-diabetics have been treated at times with the same medications, the side effects of the medications made it difficult for the patient to improve their health since the foregoing treatments were designed for full diabetics.

SUMMARY OF THE INVENTION

The inventors have discovered that the once-daily administration, preferably once-daily of an ileum-targeting, delayed and/or controlled release dosage form containing a nutritional substance to a fasting subject - at a time of around four and one- half to around ten to twelve hours, preferably around six to around nine hours prior to the subject's next intended meal (most preferably at bedtime) )or in AM- induces satiety in the subject for a period of around twelve hours and preferably twenty-four hours or more (effect can be cumulative depending on the duration of taking the dosage). Alternatively, a dosage may be administered at least twice daily, preferably once before bedtime and once within the first two hours (preferably first hour) of waking. Alternatively three dosages may be administered- once in the morning, once in the afternoon and once before bedtime. While not wishing to be bound by any theory, the inventor believes that the nutritional substance stimulates the "ileal-brake" effect at a particularly advantageous point during a subject's feeding cycle and thereby induces satiety for an extended period of time (for at least about three hours, at least about six hours, at least about twelve hours or as long as twenty- four hours or longer). Compositions and methods of treatment of the invention therefore also prove particularly useful in the treatment or prevention of overweight, overeating, obesity and obesity-related disorders, as well as the treatment of noninsulin dependent diabetes mellitus, pre-diabetic symptoms, metabolic syndrome and insulin resistance, as well as disease states and conditions which occur secondary to diabetes, pre-diabetes, metabolic syndrome and insulin resistance, as well as polycystic (fibrous) ovaries, arteriosclerosis and fatty liver, as well as cirrhosis. The present methods also may be used to increase muscle mass and decrease fat in a subject.

Notably, compositions and methods of treatment of the invention modulate ileum ileal hormone and blood insulin and sugar levels relatively consistently in a variety of tested human subjects and can therefore be used to diagnose the presence of new or established disorders related to absolute or relative deficiency or excessive secretions of one or more hormones of the ileal break, and relative response to the stimuli in the overweight or obese, or in obese related disorders or likely onset of obesity or obesity- related disorders. Compositions according to the present invention may also be used to increase blood concentrations of insulin-like growth factor I and II (IGFl and IGF2) as well as leptin in a subject.

Accordingly, in one embodiment, the invention provides a method of treatment comprising inducing satiety in a subject for a period of at least around twenty-four hours by once-daily administration to the subject of a delayed and/or controlled release dosage form. The dosage form is administered while the subject is in the fasted state and at a time of around six to around nine hours prior to the subject's next intended meal. The dosage form comprises an enterically-coated, ileum hormone-stimulating amount of a nutritional substance and releases the majority of the nutritional substance in vivo upon reaching the subject's ileum.

In some embodiments, satiety is induced in a subject who is overweight, or suffers from obesity or an obesity-related disorder, as determined by the BMI of the subject or patient.

In another embodiment, the invention provides a method of treatment comprising reducing and/or stabilizing a subject's blood sugar and insulin levels, decreasing insulin resistance, for a period of at least around twenty- four hours by once-daily administration to the subject of a delayed and/or controlled release oral dosage form. The dosage form is administered while the subject is in the fasted state and at a time of around six to around nine hours prior to the subject's next intended meal. The dosage form comprises an enterically-coated, ileum hormone-stimulating amount of a nutritional substance and releases the majority of the nutritional substance in vivo upon reaching the subject's ileum.

In still another embodiment, the invention provides a method of treating a subject suffering from a gastrointestinal disorder by administering to the subject a delayed and/or controlled release oral dosage form comprising an enterically-coated, ileum hormone- stimulating amount of a nutritional substance. The dosage form is administered while the subject is in the fasted state and at a time of around four and one-half to ten hours, more preferably around six to around nine hours prior to the subject's next intended meal. The dosage form comprises an enterically-coated, ileum hormone-stimulating amount of a nutritional substance and releases the majority of the nutritional substance in vivo upon reaching the subject's ileum.

In still other embodiments, the invention provides methods of inducing satiety, stabilizing blood sugar and insulin levels, and treating gastrointestinal disorders comprising once-daily administration to a subject in need thereof of an delayed and/or controlled release composition which may comprise an emulsion or a microemulsion containing an ileum hormone-stimulating amount of a nutritional substance. The composition is administered while the subject is in the fasted state and at a time of around four to ten, preferably around six to around nine hours prior to the subject's next intended meal. The composition releases the majority of the nutritional substance in vivo upon reaching the subject's ileum.

In preferred embodiments of the aforementioned methods of treatment of the invention, the dosage form is administered once-daily at bedtime, or in AM. By administering the dosage form to a subject in the fasted state at around four to ten, around six to around nine hours prior to the subject's next intended meal, and delivering substantially all of the nutritional substance to the ileum, methods and compositions of the invention achieve improved levels of plasma gastrointestinal hormones and prove useful in the treatment or prevention of one or more of obesity, obesity-related disorders, and gastrointestinal disorders, as well as metabolic syndrome and/or type II diabetes mellitus.. The benefit of obtaining at least twenty- four hour appetite suppression or feeling of satiety and improved blood sugar and insulin levels from a single oral dosage of an inexpensive nutritional substance increases the likelihood that the subject will adhere to the methods of treatment for an extended time, thereby achieving a maximum health benefit. Further, compositions and methods of the invention utilize nutritional substances that are free of the safety and cost concerns associated with pharmacological and surgical intervention, and can induce long-term satiety with no or a minimal caloric intake.

In another embodiment, the invention provides a delayed and/or controlled release oral dosage form comprising an effective amount of a nutritional substance, preferably D- glucose or dextrose in an amount effective when released in the ileum to stimulate or inhibit the release of hormones in that portion of the small intestine of a subject or patient. This dosage form is administered in accordance with, and achieves the advantages of, the aforementioned methods of treatment of the invention, hi addition, the present invention provides a method for diagnosing metabolic syndrome (glucose intolerance) and/or type II diabetes in a patient or subject.

Thus, the present method provides a means of stimulating or inhibiting the hormones (depending on the hormone) of the ileum in an easy and reproducible or standardized way which did not exist prior to the present method. Pursuant to the present application, the testing on a large scale of the ileal release to study and classify the variation or pathology of the hormone releases as such release relates to satiety and related pathological states and conditions, and the effect these hormones have on the rest of the metabolic and hormonal status of the body is another aspect of the invention. Thus, the present method allows the introduction of one or more dosages in oral dosage form to the ileum of the patient which can be standardized sufficiently to allow the creation of a normal reference range for the hormonal stimulation. It has been discovered that the present invention can be used to probe different diseases stemming from the relative or absolute increase or decrease of the ileal hormones, not only in treating the overweight/obesity metabolic syndrome axis but a number of other gastrointestinal diseases as otherwise described herein.

The present method also can be used to diagnose and treat a number of gastrointestinal disorders and/or conditions which may occur as a consequence of infection, medical treatment or diseases of atrophy, including atrophic gastritis, post chemotherapy disorder, intestinal motility disorder (gut dismotility), mild reflux, chronic pancreatitis, malnutrition, malabsorption, voluntary or involuntary long term starvation, post infectious syndrome, short bowel syndrome, irritable bowel, malabsorption, diarrheal states, post chemotherapy gastrointestinal disorder, post infectious syndrome, radiation enteritis, chronic pancreatitis, celiac disease, fatty liver disease, cirrhosis, radiation, inflammatory bowel disease and Crohn's disease, among others.

In another embodiment, the invention may be used to improve the health of the liver, improve the pancreas health, as well as the health of the intestine, and to decrease/ameliorate fatty liver, to increase the size of pancreatic beta cells (hyperplasia) in the pancreas as well as increase the size of the absorptive villae of the small bowel.

hi another embodiment, the method of preparation of the pills can be used in combination with traditional bioactive agents (medication) delivery by itself or together with the core to deliver the content specifically to the ileum for targeted therapy avoiding absorption, side effects and increasing the yield of the therapy, such as specialized antibiotics, antispasmodic agents, non-specific chelating agents, antibacterial agents, antidiabetes agents, laxatives among numerous others, including natural plant oils such as olive oil, vegetable and animals oils, fats, such as animal fats, butter and vegetable fat, oils and fats from seeds and nuts, stimulants including caffeine, herbs, teas, ingredients that increase post receptor activities at the cellular level, selected extracts or food products and chemicals, natural or otherwise, including metabolites.

In another embodiment, the invention provides a method for diagnosing metabolic syndrome (glucose intolerance) and/or type II diabetes in a patient the present invention approaches the problem of satiety in a natural physiological manner by stimulating hormones in the ileum which act synergistically to provide satiety for a period of at least about 12 hours and preferably at least about 24 hours. It does this most preferably using natural nutritional components in healthful, pleasant compositions which are preferably coated using a polymeric, preferably aqueous pH-sensitive (dissolution/release of contents of formulation occurs at a pH of the ileum, or a pH of approximately 7-8, preferably 7.2-8.0, about 7.4-8.0, about 7.5-8.0) shellac nutrateric coating to effect a natural physiological response within the subject's ileum with favorable results. The present invention represents a change in the nature of inducing satiety in a subject to a more wholesome, natural physiological process, completely distinguishable over pharmaceutical or synthetic approaches.

In other particular embodiments, orally administering a nutritional supplement composition containing an effective amount, more particularly, an ileal hormone stimulating effective amount of a sugar such as dextrose or other nutritional substance as otherwise described herein, optionally combined with one or more of other advantageous substances such as alfalfa leaf, chlorella algae, chlorophyllin and barley grass juice concentrate, and further formulated with a delayed release base adapted to release the composition in the lower gut, in particular the ileum, has been shown to result in normalized blood sugar and insulin levels. In particular, in subjects where there previously was shown to be an absence of elevated blood sugar but the subjects exhibited high insulin levels, that is, pre-diabetic symptoms, administering the supplement caused a decrease in insulin levels back to a normal range while glucose levels remained normal (reduced and/or stabilized). In other words, the body system achieved substantial equilibrium, with substantially no side effects reported. The result was similar to what can be achieved administering drugs such as Metformin and IGF-I, but with a drug free natural food supplement, with relatively few, if any, side effects.

Without being limited by way of theory, it is believed that by stimulating the ileal hormones contained in the lower gut, the inventive nutritional supplement drives the sugar intercelluarly by either (i) stimulating the production or increasing the level of IGf- 1 and/or IGF-2 and/or leptin that will act on their own receptors, (ii) direct action on IGF- 1 and/or IGF-2 and/or leptin receptors, or (iii) stimulating one or more intestinal hormones, including a new intestinal hormone that will act on its own receptors as per the IRR receptors.

Accordingly, in another embodiment, the invention provides a method of treating noninsulin dependent diabetes mellitus, pre-diabetic symptoms, metabolic syndrome, increasing glucose tolerance and/or decreasing insulin resistance by reducing insulin levels in the bloodstream comprising administering a nutritional supplement composition containing an effective amount of a sugar, such as dextrose or other nutritional substance as otherwise defined herein, optionally and preferably combined with one or more of alfalfa leaf, chlorella algae, chlorophyllin and barley grass juice concentrate or sodium alginate, alone or in combination with the other ingredients and further formulated with a delayed release base adapted to release the composition in the lower gut (ileum), that is, in a delayed and/or controlled release dosage form. The dosage form may comprise the nutritional supplement in a unit or partial dose form and have an enteric coating, including a nutrateric coating (e.g., containing shellac as a polymeric material, hypromellose, as an emulsifier, thickener and suspending agent and triacetin as an emulsifier). Alternatively, the nutritional substance (preferably D-glucose or dextrose) and optionally, one ore more of alfalfa leaf, chlorella algae, chlorophyllin and barley grass juice concentrate may be combined with binders, diluents, additives and other pharmaceutical additives such as one or more of a filler, compressibility enhancer (e.g., corn starch or lactose), lubricant (stearic acid), extrusion agent (magnesium stearate), silicon dioxide (dispersing agent), and enteric coated or nutrateric coated with a coating which dissolves at the pH of the ileum and includes one more polymeric components as otherwise described herein.

In another embodiment, the invention provides a method which comprises equilibrating a subject's insulin level to compliment a blood sugar level, preferably by once-daily administration to the subject of a delayed and/or controlled release oral dosage form of the invention.

In still another embodiment, the invention provides a method of treating a subject exhibiting pre-diabetic symptoms comprising administering a nutritional supplement composition containing an effective amount (generally, at least in part, to reduce insulin) of a sugar such as dextrose (glucose) or other nutritional substance as otherwise described here, either alone, or preferably in combination with one or more of alfalfa leaf, chlorella algae, chlorophyllin and barley grass juice concentrate, in a delayed and/or controlled release dosage form, adapted to release the composition in the lower gut, the combination providing an insulin reducing effect so as to equilibrate the amount of insulin produced to correspond to the amount of blood sugar. The dosage form may comprise the nutritional supplement in a unit or partial dose form and having an enteric coating.

By administering the nutritional supplement to a person who exhibits noninsulin dependent diabetes mellitus, pre-diabetic symptoms, and/or insulin resistance, reduced levels of insulin are produced so as to avoid the "over- working" of the pancreas, thereby reducing stress on the pancreas which may forestall, for example, in someone exhibiting pre-diabetes symptoms, the onset of full blown diabetes. Thus, the present invention also has the advantage of reducing the likelihood that a patient or subject with metabolic syndrome or noninsulin dependent diabetes mellitus (type II diabetes) will see these conditions advance to insulin dependent diabetes mellitus (type I diabetes). One benefit of the present invention is that this result can be achieved by administering a relatively inexpensive nutritional supplement, formulated using GRAS ingredients to assure safety, which substantially diminishes cost and avoids as well the side effects associated with drug therapies.

Other aspects of the invention relate to compositions which comprise an effective amount of a nutritional substance as otherwise described herein, preferably glucose or dextrose which is formulated in delayed and/or controlled release dosage form in order to release an effective amount of nutritional substance in the ileum of the patient or subject to whom compositions according to the present invention are administered, generally, at least about 50% of the total amount of the nutritional substance present, and preferably at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, and at least about 95% or more of the nutritional substance present in the composition, hi the case of D-glucose or dextrose as the nutritional substance, it is preferred that at least about 2.5 grams, at least about 7.5 grams and more preferably about 10-12.5 grams or more of glucose be released in the patient's or subject's ileum in order to stimulate ileal hormone release. Compositions according to the present invention comprise effective amounts of a nutritional substance, preferably D-glucose or dextrose, which may be combined with at least one delayed or controlled release component such as a delayed/controlled release polymer or compound such as a cellulosic material, including, for example, ethyl cellulose, methyl cellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, cellulose acetate trimellitiate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), shellac, copolymers of methacrylic acid and ethyl acrylate, copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerization, a mixture of amylose-butan-1-ol complex (glassy amylose) with Ethocel® aqueous dispersion, a coating formulation comprising an inner coating of glassy amylose and an outer coating of cellulose or acrylic polymer material, pectins (of various types), including calcium pectinate, carageenins, aligns, chondroitin sulphate, dextran hydrogels, guar gum, including modified guar gum such as borax modified guar gum, beta.-cyclodextrin, saccharide containing polymers, e.g., a polymeric construct comprising a synthetic oligosaccharide-containing biopolymer including methacrylic polymers covalently coupled to oligosaccharides such as cellobiose, lactulose, raffinose and stachyose, or saccharide-containing, natural polymers including modified mucopolysaccharides such as cross-linked pectate; methacrylate- galactomannan, pH-sensitive hydrogels and resistant starches, e.g., glassy amylose. Other materials include methylmethacrylates or copolymers of methacrylic acid and methylmethacrylate having a pH dissolution profile that delays release in vivo of the majority of the nutritional substance until the dosage form reaches the ileum may also be used. Such materials are available as Eudragit® polymers (Rohm Pharma, Darmstadt, Germany). For example, Eudragit® LlOO and Eudragit® SlOO can be used, either alone or in combination. Eudragit® LlOO dissolves at pH 6 and upwards and comprises 48.3% methacrylic acid units per g dry substance; Eudragit® SlOO dissolves at pH 7 and upwards and comprises 29.2% methacrylic acid units per g dry substance. Generally, the encapsulating polymer has a polymeric backbone and acid or other solubilizing functional groups. Polymers which have been found suitable for purposes of the present invention include polyacrylates, cyclic acrylate polymer, polyacrylic acids and polyacrylamides. A particularly preferred group of encapsulating polymers are the polyacrylic acids Eudragit® L and Eudragit® S which optionally may be combined with Eudragit® RL or RS. These modified acrylic acids are useful since they can be made soluble at a pH of 6 or 7.5, depending on the particular Eudragit chosen, and on the proportion of Eudragit® S to Eudragit® L, RS, and RL used in the formulation. By combining one or both of Eudragit® L and Eudragit® S with Eudragit® RL and RS (5- 25%), it is possible to obtain a stronger capsule wall and still retain the capsule's pH- dependent solubility.

A delayed and/or controlled release oral dosage form used in the invention can comprise a core containing an ileum hormonal-stimulating amount of a nutritional substance along with carriers, additives and excipients that is coated by an enteric coating. In some embodiments, the coating comprises Eudragit® LlOO and shellac, or food glaze Eudragit® SlOO in the range of 100 parts LlOOrO parts SlOO to 20 parts Ll 00:80 parts SlOO, more preferably 70 parts Ll 00:30 parts SlOO to 80 parts Ll 00:20 parts SlOO. In preferred alternatives, the preferred coating is a nutrateric coating which dissolves at the pH of the ileum (about 7-8, about 7.2-8.0, about 7.4-8.0, about 7.5-8.0) comprising a shellac, and emulsifiers such as triacetone and hypromellose, among others. Alternative nutrateric coatings include ethyl cellulose, ammonium hydroxide, medium chain triglycerides, oleic acid, stearic acid. As the pH at which the coating begins to dissolve increases, the thickness necessary to achieve ileum-specific delivery decreases. For formulations where the ratio of Eudragit® L100:S 100 is high, a coat thickness of the order 150-200 μm can be used. For coatings where the ratio Eudragit® L100:S100 is low, a coat thickness of the order 80-120 μm can be used in the present invention.

These and other aspects of the invention are explained further in the following detailed description of the invention.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is a scatter plot of blood levels (ng/ml) (CONFIRM UNITS) of GLP-I, GLP-2, C-peptide, GLP-I (total) (determined by radioimmunoassay (riaRIA)), PYY, blood sugar (bsBS), GLP-I (total) (with plasma), and insulin for five subjects tested in the experiment described in Example 1.

Figure 2 illustrates four-month weight loss of the subject described in the experiment of example 2. Significant weight loss using the presently claimed compositions was evidenced. Further data (not presented) also evidenced consistent significant reduction/stabilization in glucose levels pursuant to the ingestion of a composition according to the present invention within about a 4 hour to 10 hour period.

Figures 3 A and B show the total stimulation above the baseline as a consequence of administration as a function of time to subjects. 2 A is the total stimulation above the baseline for Casel . 2B is the total stimulation above the baseline for Case 2.

Figure 4 discloses a table A containing the statistical correlations undertaken in connection with the experiments of example 3.

Figures 5A-J discloses twelve-hour values of blood levels above baseline of GLP-I (pM), GLP-I (with patient I as outlier and removed from graph), Glucose (blood sugar, mg/dl), C-peptide (ng/ml), Insulin (μlu/ml), GLP-I (total) (ria), PYY (3-36, pg/ml), Leptin (ng/ml), Glucogon (pg/ml), IGF-I (ng/ml) and IGF-II (ng/ml) for subjects F, G, H, I and J tested in the experiment described in Example 3. The IGF and other parameters were measured to try to explain the decrease of insulin resistance seen as well as the simultaneous decrease in both the insulin and glucose showing a significant potential for treating diabetes as well as prediabetes and an increase in muscle mass and reduction in fat mass.

Figures 6A-F shows the results of GLPl response to a formulation according to the present invention for five patients tested. The graphs presented represent the total GLPl (pM) stimulation per hours comparing prior art levels in response to a mixed meal (triangles) and the results obtained from the use of the present invention in 5 patients. Note that the stimulation of the hormones by the present invention occurs between approximately hours 4 and 10 or more (after ingestion). Figure 6F represents outlier results for patient I.

Figures 7A-E shows the results of PYY response in individuals following the ingestion of a formulation according to the present invention. As can be seen from the results presented in these figures, PYY stimulation (pg/ml) is the same pattern as other hormones of the ileal break with a maximum intensity between about 4 to 10 hours, even though the cephalic phase is more prominent than is GLPl (pM). The overall stimulus is consistent with the stimulation by the formulation of the present invention.

Figures 8A-E shows the results of glucose , insulin and C-peptide response in five groups of individuals following the ingestion of a formulation according to the present invention. 8 A shows the results of glucose (mg/dl), insulin (μlu/ml) and C-peptide (ng/ml) response in individuals with normal glucose and mild elevation of insulin; 8B shows the results of glucose, insulin and C-peptide response in individuals with elevated glucose and normal to reduced/low levels of insulin; 8C shows the results of glucose, insulin and C-peptide response in individuals with elevated levels of glucose and insulin; 8D shows the results of glucose, insulin and C-peptide response in individuals with normal glucose and elevated fasting insulin and 8E shows the results of glucose, insulin and C-peptide response in individuals with normal glucose and mild insulin increase.

Figure 9 is a chart showing the change in levels of various blood components during testing, with Table 1 showing the data, for the following subject: white male, 35 years old with a BMI of 29 (overweight). Note that the following is applicable, where relevant for figures 9-28: GLP-I (pM, ria), GLP-2 (ng/ml), Glucose (mg/dl), c-peptide (ng/ml), Insulin (μlu/ml), GLP-I (total) (ria), PYY (3-36, pg/ml), Leptin (ng/ml), Glucogon (ρg/ml), IGF-I (ng/ml) and IGF-II (ng/ml).

Figure 10 is a chart showing the change in levels of various blood components during testing, with Table 2 showing the data, for the following subject: white male, 33 years old with a BMI of 23 (normal);

Figure 11 is a chart showing the change in levels of various blood components during testing, with Table 3 showing the data, for the following subject: white male, 46 years old with a BMI of 29 (overweight);

Figure 12 is a chart showing the change in levels of various blood components during testing, with Table 4 showing the data, for the following subject: white female, 50 years old with a BMI of 26 (overweight);

Figure 13 is a chart showing the change in levels of various blood components during testing, with Table 5 showing the data, for the following subject: white male, 23 years old with a BMI of 40 (obese);

Figure 14 is a chart showing the change in levels of various blood components during testing, with Table 6 showing the data, for the following subject: white male, 33 years old with a BMI of 32 (obese); Figure 15 is a chart showing the change in levels of various blood components during testing, with Table 8 showing the data, for the following subject: white male, 61 years old with a BMI of 34 (obese);

Figure 16 is a chart showing the change in levels of various blood components during testing, with Table 9 showing the data, for the following subject: white male, 29 years old with a BMI of 26 (overweight);

Figure 17 is a chart showing the change in levels of various blood components during testing, with Table 10 showing the data, for the following subject: black female,

44 years old with a BMI of 37 (obese);

Figure 18 is a chart showing the change in levels of various blood components during testing, with Table 11 showing the data, for the following subject: black male, 18 years old with a BMI of 29 (overweight);

Figure 19 is a chart showing the change in levels of various blood components during testing, with Table 12 showing the data, for the following subject: white female, 58 years old with a BMI of 22 (normal);

Figure 20 is a chart showing the change in levels of various blood components during testing, with Table 13 showing the data, for the following subject: white female,

45 years old with a BMI of 30 (obese);

Figure 21 is a chart showing the change in levels of various blood components during testing, with Table 14 showing the data, for the following subject: white male, 68 years old with a BMI of 29 (overweight);

Figure 22 is a chart showing the change in levels of various blood components during testing, with Table 15 showing the data, for the subject tested; Figure 23 is a chart showing the change in levels of various blood components during testing, with Table 16 showing the data, for the subject tested;

Figure 24 is a chart showing the change in levels of various blood components during testing, with Table 1 showing the data, for the following subject: black female, 24 years old with a BMI of 44 (obese);

Figure 25 is a chart showing the change in levels of various blood components during testing, with Table 18 showing the data, for the tested subject;

Figure 26 is a chart showing the change in levels of various blood components during testing, with Table 19 showing the data, for the following subject: white male, 48 years old with a BMI of 26 (overweight);

Figure 27 is a chart showing the change in levels of various blood components during testing, with Table 20 showing the data, for the following subject: Hispanic female, 47 years old with a BMI of 22 (normal);

Figure 28 is a chart showing the change in levels of various blood components during testing, with Table 21 showing the data, for the following subject: white female, 57 years old with a BMI of 37 (obese).

DETAILED DESCRIPTION OF THE INVENTION

The present invention approaches the problem of insulin resistance in a natural physiological manner by stimulating hormones in the lower gut, that is, the ileum which act synergistically to reduce insulin production, so as to promote a substantial equilibrium between the amount of insulin produced and the amount of blood sugar. It does this using natural nutritional components in healthful, pleasant compositions which are preferably coated using a polymeric, preferably nutrateric coating to release effective nutritional substances within the ileum of a patient or subject and effect a natural physiological response within the subject's ileum with favorable results. The present invention represents a change in the nature of treating an insulin imbalance in a subject, using a more wholesome, natural physiological process, completely distinguishable over pharmaceutical or synthetic approaches. The present invention may also be used treat noninsulin dependent diabetes mellitus, pre-diabetes syndrome, metabolic syndrome, glucose intolerance and insulin resistance as well as a number of gastrointestinal tract disorders or conditions as otherwise described herein. The following definitions are used to describe the present invention and apply unless otherwise indicated.

The term "patient" or "subject" is used throughout the specification within context to describe an animal, generally a mammal and preferably a human, to whom treatment, including prophylactic treatment, with the compositions and/or methods according to the present invention is provided. For treatment of a particular condition or disease state which is specific for a specific animal such as a human patient, the term patient refers to that specific animal.

The term "effective" is used herein, unless otherwise indicated, to describe an amount of a compound, composition or component and for an appropriate period of time which, in context, is used to produce or effect an intended result, whether that result relates to the treatment of a disorder or condition associated with the present invention or alternatively, is used to produce another compound, agent or composition. This term subsumes all other effective amount or effective concentration terms which are otherwise described in the present application.

The term "nutritional substance" refers to the substance which produces the intended effect in the ileum of a patient or subject pursuant to the present invention. A "nutritional substance" includes, but is not limited to, proteins and associated amino acids, fats including saturated fats, monosaturated fats, polyunsaturated fats, essential fatty acids, Omega-3 and Omega-6 fatty acids, trans fatty acids, cholesterol, fat substitutes, carbohydrates such as dietary fiber (both soluble and insoluble fiber), starch, sugars (including monosaccharidesmonosaccharide, fructose, galactose, glucose, disacharidesdisaccharides, lactose, maltose, sucrose, and alcohol), polymeric sugars including inulin and polydextrose, natural sugar substitutes (including brazzein. Curculin, erythritol, fructose, glycyrrhizin, glycyrrhizin, glycerol, hydrogenated starch hydrosylates, isomalt, lactitol, mabinlin, maltitol, mannitol, miraculin, monellin, pentadin, sorbitol, stevia, tagatose, thaumatin, and xylitol), sahlep, and halwa root extract. D-glucose (dextrose) is a preferred nutritional substance. Nutritional substances include all compositions that yield the aforementioned nutrients upon digestion or that contain such nutrients, including polymeric forms of these nutrients.

Additional nutritional components which may be included in compositions according to the present invention include, barley grass, known to be a rich source of highly metabolizable vitamins and minerals such as vitamins A, Bl, B2, B6, and C, potassium, magnesium, and zinc, hi addition, barley grass also has a high concentration of the enzyme superoxide dismutase (SOD), which has been shown to have high levels of antioxidant activity. Barley grass is believed to be an important nutrient in the regulation of the digestive process because the micronutrients, enzymes (e.g., SOD), and fiber contained in barley grass are believed to improve intestinal function.

Alfalfa fresh or dried leaf tea is also usable in the invention, to promote appetite, and as a good source of chlorophyll and fiber. Alfalfa contains biotin, calcium, choline, inositol, iron, magnesium, PABA, phosphorus, potassium, protein, sodium, sulfur, tryptophan (amino acid), and vitamins A, B complex, C, D, E, K, P, and U. Alfalfa supplements are recommended for treating poor digestion, and were shown to lower cholesterol levels in animal studies. Alfalfa is categorized as Generally Regarded as Safe (GRAS) by the FDA. Dosages can range from 25-1500 mg, preferably 500-1000 mg dried leaf per day.

Chlorella is yet another substance usable in the invention in combination with the nutritional substance (preferably D-glucose or dextrose), being a genus of unicellular green algae, grown and harvested in tanks, purified, processed and dried to form a powder. Chlorella is rich in chlorophyll, carotenes, and contains the full vitamin B complex, vitamins E and C, and has a wide range of minerals, including magnesium, potassium, iron and calcium. Chlorella also provides dietary fiber, nucleic acids, amino acids, enzymes, CGF (Chlorella Growth Factor) and other substances. Dosages can range from 300-1500 mg/day.

Chlorophyllin is yet another nutritional substance, being a known food additive and has been used as an alternative medicine. Chlorophyllin is a water-soluble, semisynthetic sodium/copper derivative of chlorophyll, and the active ingredient in a number of internally- taken preparations intended to reduce odors associated with incontinence, colostomies and similar procedures, as well as body odor in general. It is also available as a topical preparation, purportedly useful for treatment and odor control of wounds, injuries, and other skin conditions, such as for radiation burns.

Sodium alginate may also be used as a nutritional substance, preferably in combination with D-glucose of dextrose.

The term "ileum" is used to describe the third (of three) portion of the small intestine just before the small intestine becomes the large intestine in the gastrointestinal tract. The ileum is the final section of the small intestine in most higher vertebrates, including mammals. The ileum follows the duodenum and jejunum in the small intestine, and is separated from the "Cecum" by the ileocecal valve (ICV). In humans, the ileum is about 2-4 meters long, and the pH usually ranges between 7 and 8 (neutral or slightly alkaline). The function of the ileum is mainly to absorb vitamin B12 bile salts and whatever products of digestion were not absorbed by the jejunum. The wall itself is made up of folds, each of which has many tiny finger-like projections known as "villi" on its surface. In turn, the epithelial cells which line these villi possess even larger numbers of microvilli. Therefore, the ileum has an extremely large surface area both for the adsorption of enzyme molecules and for the absorption of products of digestion. The DNES (diffuse neuroendocrine system) cells that line the ileum contain less amounts of the protease and carbohydrase enzymes (gastrin, secretin, cholecystokinin) responsible for the final stages of protein and carbohydrate digestion. These enzymes are present in the cytoplasm of the epithelial cells.

The term "Delays the release in vivo of the majority of the nutritional substance until the dosage form reaches the subject's ileum" means: (1) that not less than around 50% by weight, not less than around 70% by weight, more preferably not less than around 80% by weight, and more preferably not less than around 90%, of the nutritional substance remains unreleased in vivo prior to the dosage form's arrival at a subject's ileum; and (2) that not less than around 50%, not less than around 70% by weight, more preferably not less than around 80% by weight, and more preferably not less than around 90%, of the nutritional substance is remains unreleased in vivo by the time when the dosage form enters the subject's ileum. In preferred aspects of the invention this amount is at least about 1 gram, at least about 2.5 grams, at least about 3 grams, at least about 5 grams, at least about 7.5 grams, preferably about 10 grams to about 12-12.5 grams or more (about 12.5 to about 20 grams, especially of polymeric materials such as polydextrose or those compounds of higher molecular weight) of the nutritional substance and in particular, glucose, is released within the small intestine in the ileum in order to stimulate ileum hormones and related hormones and effect the intended result associated with inducing satiety and/or influencing one or more of insulin resistance (decrease resistance), blood sugar (decrease in/stabilize glucose levels), leptin (increase), glucagon secretion (decrease), insulin release (decrease and/or stabilize release and/or levels), ileum hormone release (increase) or other hormone release, in particular, one or more of GLP-I, glicentin, C-terminally glycine-extended GLP-I (7 37), (PG (78 108)); C-peptide, intervening peptide-2 (PG (111 122) amide); GLP-2 (PG (126 158), GRPP (PG (1 30)), oxyntomodulin (PG (33 69), and other peptide fractions to be isolated, PYY (1-36), PYY (3-36), cholecystokinin (CCK), gastrin, enteroglucagon, secretin, as well as leptin, IGF-I and IGF-2, and preferably, one or more, two or more, three or more, four or more, five or more, six or more, seven or more, or all of GLPl, GLP2, C-peptide, PYY (1-36 and/or 3-36), glucagon, leptin, IGF-I and IGF-2.

The term "ileum hormones" includes all hormones that are associated with intraluminal food substances stimulating the release of said hormones, could be associated with satiety feedback from the ileum or ileum-related stimulation of insulin secretion or inhibition of glucagon secretion. "Ileum hormones" therefore include, but are not limited to, GLP-I, glicentin, C-terminally glycine-extended GLP-I (7 37), (PG (78 108)); intervening peρtide-2 (PG (111 122) amide); GLP-2 (PG (126 158), GRPP (PG (1 30)), oxyntomodulin (PG (33 69), and other peptide fractions to be isolated, PYY (PYY 1-36) and (PYY 3-36), cholecystokinin (CCK), gastrin, enteroglucagon and secretin.

The term "ileum hormone-stimulating amount of a nutritional substance" means any amount of a nutritional substance that is effective to induce measurable hormone release in the ileum, and induce satiety feedback from the ileum or ileum-related stimulation of insulin secretion or inhibition of glucagon secretion, or other effect such as shutting down or decreasing insulin .resistance and increasing glucose tolerance. Consequently, an "ileum hormone-stimulating amount of a nutritional substance" can vary widely in dosage depending upon factors such as the specific nutrient at issue, the desired effect of administration, the desired goal of minimizing caloric intake, and the characteristics of the subject to whom the nutritional substance is administered. For example, at least about 500 mg of D-glucose is used, and a particularly preferred ileum hormonal-stimulating amount of D-glucose includes between about 7.5-8 g to about 12- 12.5 g (mostre preferably around 10 g).

The term "gastrointestinal disorder" includes diarrheal states, malabsorption in the lower gut (i.e., chronic pancreatitis, celiac disease), fatty liver, atrophic gastritis, short bowel syndrome, radiation enteritis, irritable bowel disease, Chron's disease, post infectious syndrome, mild reflux, certain gut dismotility, post chemotherapy disorder, malnutrition, malabsorption, and voluntary or involuntary long term starvation. The present invention may be used to treat each of these conditions, alone or secondary to the treatment or resolution of symptoms associated with noninsulin dependent diabetes mellitus, pre-diabetic symptoms, metabolic syndrome and insulin resistance.

Dosage forms used in methods of the invention can be in a form suitable for oral use, for example, as tablets, troches, lozenges, suspensions, microsuspensionsmicro suspensions, dispersible powders or granules, emulsions, microemulsionsmicro emulsions, hard or soft capsules. Useful dosage forms include osmotic delivery systems as described in U.S. Patent Nos. 4,256,108; 5,650,170 and 5,681,584, multiparticulate systems as disclosed in U.S. Patent No. 4,193,985; systems in which the nutritional substance is coated with a mixed film of a hydrophobic organic compound-enteric polymer as disclosed in U.S. Patent No. 6,638,534; systems such as those described in U.S. Patent Nos. 7,081,239; 5,900,252; 5,603,953; and 5,573,779; enteric-coated dry emulsion formulations (e.g., Journal of Controlled Release, vol. 107, issue 1 20 September 2005, Pages 91-96), and emulsions such as the emulsion system of Olibra® and those disclosed in U.S. Patent No. 5,885,590. Those of ordinary skill in the prior art know how to formulate these various dosage forms such that they release the majority of their nutritional substance in a subject's ileum as otherwise described herein.

Exemplary dosage forms that will release the majority of the nutritional substance in vivo upon reaching the ileum include oral dosage forms such as tablets, troches, lozenges, dispersible powders or granules, or a hard or soft capsules which are formed by coating the nutritional substance with an enteric coating (e.g., an enteric cellulose derivative, an enteric acrylic copolymer, an enteric maleic copolymer, an enteric polyvinyl derivative, or shellac). Preferred enteric coatings have a pH dissolution profile that delays the release in vivo of the majority of the nutritional substance until the dosage form reaches the ileum. Enteric coatings can consist of a single composition, or can comprise two or more compositions, e.g., two or more polymers or hydrophobic organic compound-enteric polymer compositions as described in U.S. Patent No. 6,638,534).

A "material having a pH dissolution profile that delays release in vivo of the majority of the nutritional substance until the dosage form reaches the ileum" includes but is not limited to cellulose acetate trimellitiate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), shellac, copolymers of methacrylic acid and ethyl acrylate, copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerization, a mixture of amylose-butan-1-ol complex (glassy amylose) with Ethocel® aqueous dispersion (Milojevic et al.., Proc. Int. Symp. Contr. ReI. Bioact. Mater. 20, 288, 1993), a coating formulation comprising an inner coating of glassy amylose and an outer coating of cellulose or acrylic polymer material (Allwood et al. GB 9025373.3), calcium pectinate (Rubenstein et al., Pharm. Res., 10, 258, 1993) pectin, chondroitin sulphate (Rubenstein et al. Pharm. Res. 9, 276, 1992), resistant starches (PCT WO 89/11269), dextran hydrogelshydro gels (Hovgaard, et al., 3rd Eur. Symp. Control. Drug Del., Abstract Book, 1994, 87) modified guar gum such as borax modified guar gum, (Rubenstein and Gliko-Kabir, S. T. P. Pharma Sciences 5, 41-46, 1995), beta.- cyclodextrin (Sidke et al., Eu. J. Pharm. Biopharm. 40 (suppl), 335, 1994), saccharide containing polymers, e.g., a polymeric construct comprising a synthetic oligosaccharide- containing biopolymer including methacrylic polymers covalently coupled to oligosaccharides such as cellobiose, lactulose, rafflnose and stachyose, or saccharide- containing, natural polymers including modified mucopolysaccharides such as cross- linked pectate (Sintov and Rubenstein PCTAJS 91/03014); methacrylate-galactomannan (Lehmann and Dreher, Proc. Int. Symp. Control. ReI. Bioact. Mater. 18, 331, 1991) and pH-sensitive hydrogels (Kopecek et al., J. Control. ReI. 19, 121, 1992), and resistant starches, e.g., glassy amylose.

Methylmethacrylates or copolymers of methacrylic acid and methylmethacrylate are preferred materials having a pH dissolution profile that delays release in vivo of the majority of the nutritional substance until the dosage form reaches the ileum. Such materials are available as Eudragit® polymers (Rohm Pharma, Darmstadt, Germany). For example, Eudragit® LlOO and Eudragit® SlOO can be used, either alone or in combination. Eudragit® LlOO dissolves at pH 6 and upwards and comprises 48.3% methacrylic acid units per g dry substance; Eudragit® SlOO dissolves at pH 7 and upwards and comprises 29.2% methacrylic acid units per g dry substance. Generally, the encapsulating polymer has a polymeric backbone and acid or other solubilizing functional groups. Polymers which have been found suitable for purposes of the present invention include polyacrylates, cyclic acrylate polymer, polyacrylic acids and polyacrylamides. Another preferred group of encapsulating polymers are the polyacrylic acids Eudragit® L and Eudragit® S which optionally may be combined with Eudragit® RL or RS. These modified acrylic acids are useful since they can be made soluble at a pH of 6 or 7.5, depending on the particular Eudragit chosen, and on the proportion of Eudragit® S to Eudragit® L, RS, and RL used in the formulation. By combining one or both of Eudragit® L and Eudragit® S with Eudragit® RL and RS (5-25%), it is possible to obtain a stronger capsule wall and still retain the capsule's pH-dependent solubility. In additional preferred aspects of the invention, a coating of shellac (which also includes one or more emulsifiers such as hypromellose and/or triacetin) which is chosen to have a suitable pH-dependent dissolution profile for release the contents of a dosage form such as a tablet within the ileum of a patient or subject may be used. This type of coating provides a nutrateric approach to delayed and/or controlled release using naturally occuring, non-synthetic components.

A delayed and/or controlled release oral dosage form used in the invention can comprise a core containing an ileum hormonal-stimulating amount of a nutritional substance that is coated by an enteric coating. In some embodiments, the coating comprises Eudragit® LlOO and shallac, or food glaze Eudragit® SlOO in the range of 100 parts L100:0 parts SlOO to 20 parts L100:80 parts SlOO, more preferably 70 parts Ll 00:30 parts SlOO to 80 parts Ll 00:20 parts SlOO. As the pH at which the coating begins to dissolve increases, the thickness necessary to achieve ileum-specific delivery decreases. For formulations where the ratio of Eudragit® L100:S100 is high, a coat thickness of the order 150-200 μm can be used. For coatings where the ratio Eudragit® L100:S100 is low, a coat thickness of the order 80-120 μm can be used.used. Dosage forms used in methods of the invention can include one or more pharmaceutically acceptable carriers, additives, or excipients. The term "pharmaceutically acceptable" refers to a carrier, additive or excipient which is not unacceptably toxic to the subject to which it is administered. Pharmaceutically acceptable excipients are described at length by E.W. Martin, in "Remington's Pharmaceutical Sciences", among others well-known in the art. pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

Emulsions and microemulsions may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

Suspensions, in addition to the nutritional substance, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Techniques for formulating the aforementioned useful dosage forms are either disclosed in the references cited above or are well-known to those of ordinary skill in the art. is a particularly preferred dosage form that is useful in the methods of treatment of the invention.

The term "satiety" encompasses a lack of appetite for food or a cessation of food- seeking or food-ingesting behavior. Thus, satiety is a desirable state in conditions in which food intake is preferably curtailed, such as obesity. Alternatively, it can be desirable to suppress a state of satiety in conditions of anorexia or cachexia resulting from causes including illness, starvation, or chemotherapy.

"Stabilizing a subject's blood sugar and insulin levels" means lowering the subject's blood sugar and insulin levels to healthy levels within normal or close to normal ranges.

The terms "obesity" and "overweight" are generally defined by body mass index (BMI), which is correlated with total body fat and estimates the relative risk of disease. BMI is calculated by weight in kilograms divided by height in meters squared (kg/m2). Normal BMI is defined as a BMI of about 18.5 to 24.9 kg/m2. Overweight is typically defined as a BMI of 25- 29.9 kg/m2, and obesity is typically defined as a BMI of at least 30 kg/m2. See, e.g., National Heart, Lung, and Blood Institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, D. C: U.S. Department of Health and Human Services, NIH publication no. 98-4083 (1998). Obesity and its associated disorders are common and very serious public health problems in the United States and throughout the world. Upper body obesity is the strongest risk factor known for type 2 diabetes mellitus and is a strong risk factor for cardiovascular disease. Obesity is a recognized risk factor for hypertension, atherosclerosis, congestive heart failure, stroke, gallbladder disease, osteoarthritis, sleep apnea, reproductive disorders such as polycystic ovarian syndrome, cancers of the breast, prostate, and colon, and increased incidence of complications of general anesthesia. Obesity reduces life-span and carries a serious risk of the comorbidities listed above, as well as disorders such as infections, varicose veins, acanthosis nigricans, eczema, exercise intolerance, insulin resistance, hypertension hypercholesterolemia, cholelithiasis, orthopedic injury, and thromboembolic disease (Rissanen et al., Br. Med. J. 301: 835-7 (1990)). Obesity is also a risk factor for the group of conditions called insulin resistance syndrome, or "Syndrome X" and metabolic syndrome. The present compositions are useful for treating obesity, and favorably impact the conditions which often occur secondary to obesity.

"Obesity-related disorder" includes all of the diseases and disorders mentioned in the preceding definition of "obesity".

"Once-daily administration to the subject of a delayed and/or controlled release dosage form" includes self-administration of the dosage form by the subject.

The invention is described further in the following examples, which are illustrative and are not limiting.

Example 1

Healthy Human Volunteer Study

Formulation 1

600 mg/capsule glucose

100 mg capsule

10% Eudragit coating

Plasticizer (propylene glycol, triethyl acetate and water)

Magnesium stearate

Silicone Dioxide

A single formulation as described for formuatlion 1 above was administered to five healthy adult human volunteers fasting in the morningat bedtime. Each of the volunteers was in the fasted state (i.e., none had eaten within two hours of the formulation administration). Blood levels (ng/ml) of GLP-I, GLP-2, C-peptide, GLP-I (total) (determined by radioimmunoassay (ria)), PYY, blood sugar (bs), GLP-I (total) (with plasma), and insulin for each of the volunteers were measured just prior to administration of the above formulation and every four hours after administration until the eleventh hour after administration of the formulation.

Based on the data obtained for the five individuals tested as above, it was concluded that for all subjects except for one, that blood levels of GLP-I (total) (ria), GLP-I (total) (with plasma), GLP-2, PYY, insulin, C-peptide, and blood sugar peaked at around 6-10 hours after administration of formulation 1. The peak levels of GLP-I (total) (riaRIA), GLP-I (total) (with plasma), GLP-2, and PYY correlated with the peak levels of insulin, C-peptide, and blood sugar, especially for subjects D and E. This suggests that there is an inverted correlation between these two groups and therefore the stimulation of the first grouping causing a reduction of levels of the second grouping. Further, blood sugar and insulin levels dropped as the result of the stimulation of GLP-I, GLP-2, C-peptide, PYY, and insulin.

After the experiment described in this example, some patients continued to take formulation 1 above for an extended period of time and experienced a satiety which ultimately led to weight loss and as well as in one patient significant control of blood sugar and insulin levels.

Levels of blood sugar ileal hormones and their response to food stimulation could be assessed and abnormalities in the response could be evaluated (GLP1,GLP2,PYY,) as well as their levels and stimulation was (bs) and insulin proved relatively consistent for each of the five volunteers, which indicates that methods of the invention can be used to diagnose whether a subject suffers from a disorder associated with an abnormality in their ileal break hormones to respond to food, blood sugar or insulinlevels. For example, a standard dosage form comprising an enterically-coated, ileum hormone-stimulating amount of a nutritional substance could be administered to a subject, the subject's levels of ileal hormones blood sugar and insuline as well as ileal hormones including GLPl, GLP2, PYY, and IGF-I, IGF-2 and leptin could be measured at regular intervals subsequent to administration of the nutritional substance, and measured levels of the ileal hormones (e.g, GLP1,GLP2, PYY, IGF-I, IGF-2, leptin), as well as blood sugar and insulin could be compared to healthy levels of ileal hormones, blood sugar and insulin determined by administering an equivalent enterically-coated, ileum hormone-stimulating amount of a nutritional substance to a control subject.

Further, this example and the following examples establish that compositions such as formulation 1 above, among others, when administered while the subject is in the fasted state and at a time of about 3 to 12 hours, preferably about six to about nine hours prior to the subject's next intended meal, provide an ileum hormone-stimulating amount of a nutritional substance that approximates the minimum natural caloric amount of the substance needed to induce satiety. Example 2 Obese Subject Study

Figure 2 illustrates four-month weight loss and blood sugar levels of a subject who took a single capsule according to formulation 1 once-daily in the fasted state at bedtime (about six to about nine hours prior to the subject's next intended meal) for a period of about four months. As illustrated in Figure 2, the subject achieved a significant decrease in weight (about 24 pounds) at the end of about four months. The subject's blood sugar levels also improved significantly over the course of formulation 1 administration. Over the course of the four month period, the subject experienced periods of satiety that lasted as long as 12 hours or longer, and enjoyed a substantial overall caloric intake reduction. By the end of the four month period, the subject would no longer be diagnosed as obese and had blood sugar levels that were well within acceptable ranges.

Example 3

Formulation II

Blend : Amount Range Alfalfa Leaf 3.00 1-10+

Chlorella Algae 3.00 1-10+

Chlorophyllin 3.00 1-10+

Barley Grass Juice Concentrate 3.00 1-10+

Dextrose 1429.00 500-3000+

Other Tablet Ingredients:

Aqueous Shellac 388.40 125-750+

Corn Starch NF 80.00 25-160+

Hypromellose USP 32.40 10-65+

Stearic Acid NF (Vegetable Grade) 19.50 6.5-35+

Triacetin FCC/USP 19.30 6.5-40+

Magnesium Stearate NF/FCC 7.00 2.5-15+

Silicon Dioxide FCC 2.50 0.75-5.0+

Formulation II was provided by mixing the actives with corn starch, stearic acid, magnesium stearate and silicon dioxide and pressing into a tablet, and coating the tablet with the shellac, triacetin and the hypromellose.

Based upon the results in examples 1 and 2, the inventors embarked upon a project to create a vehicle which can be given orally and deliver the nutritional substance to the ileum to stimulate the ileal break. The following data (appearing in attached figures 3-8) reports the results of the experiment conducted on the formulation II composition. A number of formulations of pills with different coatings and structures and at times sub coatings were also used and tested and analyzed such that formulation II resulted. With the initial results, it was apparent that the pill composition and content indicate a logical pattern consistent with the hypothesis of stimulating the ileal hormonal break to induce satiety. The experiments were also performed to answer the issue of consistency of effect and the results obtained suggested that the approach was amenable for standardization and usage as a therapeutic composition, as well as a diagnostic tool in the future, the extra results showed improvement of the blood sugar and on subsequent testing of insulin and C-peptide showed that stimulation of insulin and C-peptide did not foil explain the theory involved in decreasing insulin resistance. Leptin, IGFl and IGF2 were measured and our results evidence that the stimulation of those factors contribute to the stabilization of blood sugar and reduction in insulin resistance observed.

The experiment was performed on volunteers as part of the testing of the different compositions, and structure of the pill in order to determine the best stimulation. The present example reports the results of the five patients that took formulation II as well as the graphs associated with it (Figures 3-8). Informed consent was obtained prior to administering the composition to five fasting volunteers, allowing them water only ad libidum throughout the day. They were given the recommended daily dose of formulation II after being examined by a physician and their vitals deemed appropriate for the test. A base line level blood level was obtained at hour 0 then hourly thereafter till hour 10. The blood was collected by a registered nurse, labeled accordingly and coded by a professional national lab, prepared according to the instruction of another out of state specialized national lab including cold centrifuge immediately upon receipt of the sample. The labeled coded samples were stored in dry ice refrigerated and shipped to 3 different specialty national labs for analysis and measurement of the metabolic and hormonal levels. The data was forwarded as per code numbers to the local national lab and encoded appropriately to match the volunteers for analysis. Analysis was performed and graphs were drawn accordingly. No unusual event occurred; Applicants were surprise with the results of one individual for the extremely high level of gpll that did not follow the same pattern as the others. Even though it was advantageous to maintain that individual within the data to enhance the statistics, Applicants removed that data from the data presented.

Applicants note that the other pill compositions tested showed similar but less significant stimulation and a slight modification in pattern, in accordance with the expected formulation release and stimulation of the pills. The subjects were monitored at all times by a registered nurses and a physician. The results appear in Figures 3-8. Those figures clearly evidence that the compositions of the present invention had a favorable impact on blood glucose, reduced insulin resistance, and had favorable impact on glucagon, GLP 1, blood glucose, C-peptide, insulin, PYY, Leptin, IGF-I and IGF-2. Note that the IGFl and IGF-2 parameters may help explain some of the significant difference in muscle mass preservation observed and reduced fat mass using the present compositions. The results for GLPl (Figure 6) suggest satiety as well as favorable body composition (reduce fat/increased muscle), which matches to a certain extent the levels achieved with bypass surgery without the attendant complications and side effects of such surgery. The results for PYY (Figures 7A-E) follow a similar stimulation pattern with earlier stimulation coupled with sustained stimulation at the level of about 3-8 hours and maximum intensity of 4 to 10 hours after the ingestion of the present composition. The patterns are predictable and amenable to standardization and are indicative of ileal peptide stimulation which contributes to appetite suppression.

Regarding the response of glucose, c-peptide and insulin to the composition of the present invention, that data is summarized in figure 8A-J. Given the wide variation and the response of glucose/insulin interaction, the inventor divided the patients into categories with differerent starting points to determine if there is any difference in the action of the present compositions on the different groups (normal glucose/mild elevation insulin; elevated glucose/normal to low insulin levels; elevated glucose and elevated insulin; normal glucose/elevated fasting insulin and normal glucose/mild insulin increase). The principal effect of the present compositions is homeostasis; regulation of blood sugar and insulin is in a manner consistent with the suppression/reduction of insulin resistance and an increase in glucose tolerance (by upregulating ileal hormones, IGF-I, IGF-2 and leptin). In the first group (normal glucose/mild elevation insulin, figure 8A-B), the insulin levels are suppressed with a slight decrease in glucose levels, consistent with suppression of insulin resistance. The second group (elevated blood sugar/normal to low insulin levels, figure 8C-D) demonstrated that in the absence of insulin stimulation is similar to a typical stimulation of insulin in type 2 diabetes, with the peak of stimulation of insulin stimulation occurring early in the process, but with insulin declining later in the process, evidencing homeostasis and a reduction in insulin resistance and enhanced glucose tolerance over time. The third group (elevated blood sugar and insulin, figure 8E-F) demonstrates the continual seesaw between insulin stimulation and suppression as it relates to suppression of insulin resistance as insulin trended down over time with insulin evidencing bouts of stimulation within a cycle. The fourth group (normal glucose/elevated fasting insulin) evidenced decline in glucose and insulin consistently over time (significant insulin decline with 3-4 hours after administration of composition). In the fourth group (normal glucose/mild insulin increase, figure 81- J), insulin reduction with decrease decrease in blood glucose further evidenced suppression of insulin resistance.

In this set of experiments, the inventor was able to stimulate hormones of the ileal break using a safe, effective oral formulation comprising nutritional supplements with enteric release (delayed/controlled release) to generate a feeling of satiety that occurs naturally after meals, while helping to curb appetite in a natural way without the side effects of prior art methods. The experiments evidenced a coherent pattern of hormone release that can serve as a diagnostic tool for testing the ileal break hormones for insufficiencies, excesses or other abnormalities. Also shown is the fact that the present invention stimulats IGFl and IGF2 and leptin as well as decreasing/suppressing insulin resistance and inhancing glucose tolerance, giving it excellent prospects for treating NIDDM (type II diabetes mellitus), prediabetes, metabolic syndrome and insulin resistance. By stimulating the ileal hormones pursuant to the present invention, the present invention represents an enhancer of well being, muscle mass preservation or production. Futher, the present invention also is able to stimulate glucagon, glucagon- like (enteroglucagon, etc.).

Example 4

An experiment was undertaken using two different formulas (including formula II, above, in order to determine the maximum yield of the pills given to subjects volunteers. The volunteers were divided in groups of 7, and different pills compositions were given to each. The object was to investigate and measure multiple parameters besides blood sugar, such as glucose homeostasis to include insulin cpeptide glucose, igfl, igf2, glucagon, as well as leptin. The composition of the pills was developed in such a way so as to decrease the number of pills from an initial 16 to 7. The pills were given orally while fasting, and the blood work was drawn hourly for all parameters and each tube was coded for both time and patient. The blood product was handled by a professional staff prepared as required by the different tests, and the samples sent to two different national labs that provided results in coded numbers.

Once decoded and analysed for each patient, the results were taken as the average response to the different parameters for the different patients, that is those that started with either an abnormal insulin level, abnormal glucose level or both.

The two pills composition used during this testing were as follows (ingredients per tablet, in mg), Formula II (as above) in Example 3 :

Proprietary Blend: Amount Range

Alfalfa Leaf 3.00 1-10+

Chlorella Algae 3.00 1-10+

Chlorophyllin 3.00 1-10+

Barley Grass Juice Concentrate 3.00 1-10+

Dextrose 1429.00 500-3000+

Other Tablet Ingredients:

Aqueous Shellac 388.40 125-750+

Corn Starch NF 80.00 25-160+

Hypromellose USP 32.40 10-65+

Stearic Acid NF (Vegetable Grade) 19.50 6.5-35+

Triacetin FCC/USP 19.30 6.5-40+

Magnesium Stearate NF/FCC 7.00 2.5-15+

Silicon Dioxide FCC 2.50 0.75-5.0+ Formulation II was provided by mixing the actives with corn starch, stearic acid, magnesium stearate and silicon dioxide into a tablet, and coating the tablet with the shellac, triacetin and the hypromellose.

Formula III utilized a coating composed of 2% clear polyvinyl alcohol (PVA) coating plus 14% of a nutrateric coating. The clear coating was made up of polyvinyl alcohol, talc, polyethylene glycol, polysorbate 80; the nutrateric coating was made up of ethyl cellulose, ammonium hydroxide, medium chain triglycerides, oleic acid, stearic acid. The proprietary blend of active ingredients comprised sodium alginate and dextrose, 1150 gm (85 % by weight of Formula III.

Protocol testing.

All subjects were volunteers that signed an informed consent in regard to the GRAS compliant supplement which was to be administered. Each subject presented fasting, with the last oral intake having occurred the night prior. Baseline lab work was completed, including blood sugar, insulin and, c-peptide, as well as other hormones. Samples were collected by licensed professionals, and handled by professional lab technicians. The sample tubes were labeled according to a preset protocol, for anonymity and shipped in frozen containers as specified by the contracted, licensed labs for testing.

Sampling was done on an hourly basis, before and after the oral ingestion of the supplement. Vitals were taken before each draw. No food or drink was allowed prior or during the test, though water was allowed adlib. The results were compiled in the enclosed Tables, illustrated by the enclosed charts comprising Figures 9-28 and Tables 1-

21.

The subjects selected were part of a much larger group, with only those that were found to have abnormal insulin or abnormal blood sugar or both included. There were no significant changes in levels of insulin, glucose or c-peptide for the rest of the group. As evidenced by the figures and the corresponding tables, generally, blood sugar as well as insulin decreased and/or stabilized, in response to administering the nutritional supplement, which apparently results in a hormonal stimulation. This response appears to be greater the higher the starting value, indicating a significant decrease in insulin resistance. Also it can be noted that the more normal the value of insulin and glucose, the less significant are the changes to their values, indicating that the effect of the pill is self limiting, that is, surprisingly, the nutritional supplement acts favourably to correct abnormal levels but does not pose a danger of decreasing blood sugar below normal, so there is no risk for hypoglycaemia. This makes the nutritional supplement particularly useful in persons who are only exhibit pre-diabetic symptoms, where drug therapy has not yet been indicated or is not preferred given the risk of side effects.

Established safe and effective dose ranges in humans for the nutritional supplement of the invention ranges from 500 to 12500 mg/day, preferably within the range of about 7,500mg/day to about 12,000mg/day, preferably about 10,000 mg/day.. While not being limited by way of theory, the product therefore negates/reduces insulin resistance, thereby allowing blood sugar to enter the cells, with insulin at normal levels, as opposed to the abnormally high levels of insulin generated in the test subjects, and therefore decreasing insulin levels to base line. This allows the body to use more energy while decreasing the noxious effect of high insulin that promote obesity as well as the vicious cycle associated with high insulin levels, such as per metabolic syndrome, polycystic ovaries, arteriosclerosis, hypertension, fatty liver, etc.

The insulin production modulation achieved by administering the inventive formulating containing GRAS ingredients is believed to occur through the action of a stimulated hormone within the lower gut, which either acts through igf like receptors or through a different receptor than the receptor for igf or insulin, possibly like receptor IRR. Since the nutritional supplement composition is not absorbed and appears to work through hormone stimulation, a new hormone from the same area could be stimulated as well that acts on a receptor, either its own or through IGF stimulation. Accordingly, pursuant to the presentn invention, it was discovered that a nutritional supplement composed of GRAS compliant ingredients is effective in treating noninsulin dependent diabetes mellitus, pre-diabetic symptoms, and insulin resistance, with no side effects, by acting to suppress insulin resistance, lower/stabilize blood sugar, and therefore could be used in treating all form of insulin resistance as per NIDDM, polycystic ovary as well as type b insulin resistance.

The terms and expressions that have been employed in this application are used as terms of description and not of limitation, and there is no intent in the use of such terms and expressions to exclude any equivalent of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as claimed.

Thus, it will be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

hi addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.

Claims

Claims:

1. A method of treatment comprising inducing satiety in a subject for a period of at least around twelve hours, preferably at least around twenty-four hours by once-daily administration to the subject of a delayed and/or controlled release dosage form, wherein the dosage form is administered while the subject is in the fasted state and at a time of around four and one half to around ten hours, preferably around six hours to around nine hours prior to the subject's next intended meal, and wherein the dosage form comprises an enterically-coated, ileum hormone-stimulating amount of a nutritional substance and releases the majority of the nutritional substance in vivo upon reaching the subject's ileum.

2. The method of claim 1, wherein the dosage form comprises an enterically-coated tablet, troche, lozenge, dispersible powder or granule, a hard or soft capsule, or an emulsion or microemulsionmicro emulsion formulated for releasing the majority of the nutritional substance in vivo upon reaching the subject's ileum.

3. The method of claim 1, wherein the dosage form is made by coating the nutritional substance with a material which has a pHpH dissolution or time delayed profile that delays the release in vivo of the majority of the nutritional substance until the dosage form reaches the subject's ileum.

4. The method of claim 4, wherein the material having a pH dissolution profile that delays the release in vivo of the majority of the nutritional substance until the dosage form reaches the subject's ileum is selected from the group consisting of cellulose acetate trimellitiate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose, ethyl cellulose and mixtures of hydroxypropylmethyl - cellulose and ethyl cellulose each of which contains a subcoating, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), shellac, copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerization.

5. The method of claim 5, wherein the copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerization, are substantially insoluble in gastric fluid and in intestinal fluid at a pH of below around 7.

Also hydroxypopyl methylcellulose, as well as ethyl cellulose ,each with its own subcoating

6. The method of claim 5, wherein the nutritional substance is coated by a shellac Eudragit® Eudragit L, Eudragit S, Eudragit L or S with Eudragit RL, Eudragit L or S with Eudragit RSpolymer or mixtures thereofcoating.

7. The method of claim 1 wherein the dosage form is a capsule that contains multiparticulates, each of which comprise an enterically-coated nutritional substance core.

8. The method of claim 7, wherein the nutritional substance core is coated by a material having a pH dissolution profile that delays release in vivo of the majority of the nutritional substance until the multiparticulate reaches the subject's ileum.

10. The method of claim 1, wherein the nutritional substance is selected from the group consisting of sugars, free fatty acids, lipids, polypeptides, amino acids, and compositions that yield sugars, free fatty acids, polypeptides, or amino acids upon digestion.

11. The method of claims 10, wherein the nutritional substance is glucose.

12. The method of claim 1 , wherein the delayed and/or controlled release dosage form is administered once-daily at bedtime.

13. The method of claim 12, wherein the dosage form is administered nocturnally.

14. The method of claim 1 , further comprising monitoring the subject' s blood levels of one or more of the following: GLP-I, GLP -2, PYY, C-peptide, glucagon, blood sugar, insulin, leptin, IGF-I and IGF-2.

15. The method of claim 14, wherein the subject's blood level of GLP-I, GLP-2, PYY, C-peptide, blood sugar, glucagon, insulin, IGF-I, IGF-2, and/or leptin is monitored before administration of the dosage form and at a time of around six to around nine 10 hours after administration of the dosage form.

16. The method of claim 15, wherein the amount or frequency of administration of the nutritional substance is adjusted depending upon the subject's blood levels of GLP-I, GLP-2, PYY, C-peptide, blood sugar, glucagons, insulin, IGF-I, IGF-2 and/or leptin.

17. A method of treatment comprising stabilizing a subject's blood sugar and insulin levels for a period of at least around twenty- four hours by once-daily administration to the subject of a delayed and/or controlled release oral dosage form, wherein the dosage form is administered while the subject is in the fasted state and at a time of around four to around twelve hours, preferably about six hours to about ten hours, prior to the subject's next intended meal, and wherein the dosage form comprises an enterically-coated, ileum hormone-stimulating amount of a nutritional substance and releases the majority of the nutritional substance in vivo upon reaching the subject's ileum.

18. The method of claim 17, wherein the dosage form comprises an enterically-coated tablet, troche, lozenge, dispersible powder or granule, a hard or soft capsule, or an emulsion or microemulsion formulated for releasing the majority of the nutritional substance in vivo upon reaching the subject's ileum.

19. The method of claim 17, wherein the dosage form is made by coating the nutritional substance with a material which has a pH dissolution or time delay profile that delays the release in vivo of the majority of the nutritional substance until the dosage form reaches the subject's ileum.

20. The method of claim 19, wherein the material having a pH dissolution profile that delays the release in vivo of the majority of the nutritional substance until the dosage form reaches the ileum is selected from the group consisting of cellulose acetate trimellitiate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose, ethyl cellulose or mixtures of hydroxypropylmethyl cellulose and ethyl cellulose containing a subcoating, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), shellac, copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerization.

21. The method of claim 20, wherein the copolymers of methacrylic acid and ethyl to correct for the new coating acrylate, and copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerization, are substantially insoluble in gastric fluid and in intestinal fluid at a pH of below around 7. Also hydroxypopyl methylcellulose, as well as ethyl cellulose ,each with its own subcoating

22. The method of claim 21, wherein the nutritional substance is coated by a Eudragit® polymer coating.

23. The method of claim 17 wherein the dosage form is a capsule that contains multiparticulates, each of which comprise an enterically-coated nutritional substance core.

24. The method of claim 17 wherein the dosage form is a capsule that contains multiparticulates, each of which comprise a nutritional substance which is coated by a material having a pH dissolution profile that delays release in vivo of the majority of the nutritional substance until the multiparticulate reaches the ileum.

25. The method of claims 17, wherein the nutritional substance is selected from the group consisting of sugars, free fatty acids, lipids and root extract polypeptides, amino acids, and foods that yield sugars, free fatty acids, polypeptides, or amino acids upon digestion.

26. The method of claims 17, wherein the nutritional substance is glucose.

27. The method of claim 17, wherein the delayed and/or controlled release dosage form is administered once-daily at bedtime.

28. The method of claim 17, wherein the dosage form is administered nocturnally.

29. The method of claim 17, further comprising monitoring the subject's blood levels of one or more of the following: GLP-I, GLP -2, PYY, C-peptide, blood sugar,sugar and insulin.and other peptides

30. The method of claim 17, wherein the subject's blood level of GLP-I, GLP-2, PYY, C-peptide, blood sugar, or insulin is monitored before administration of the dosage form and at a time of around nine hours after administration of the dosage form.

31. The method of claim 30, wherein the amount or frequency of administration of the nutritional substance is adjusted depending upon the subject's blood levels of GLP-I, GLP-2, PYY, C-peptide, blood sugar, or insulin.

32. A method of treating a subject who suffers from a gastrointestinal disorder comprising once-daily administration to the subject of a delayed and/or controlled release oral dosage form, wherein the dosage form is administered while the subject is in the fasted state and at a time of around six to around nine hours prior to the subject's next intended meal, and wherein the dosage form comprises an enterically-coated, ileum hormone-stimulating amount of a nutritional substance and releases the majority of the nutritional substance in vivo upon reaching the subject's ileum.

33. The method of claim 32, wherein the dosage form comprises an enterically-coated tablet, troche, lozenge, dispersible powder or granule, a hard or soft capsule, or an emulsion or microemulsion formulated for releasing the majority of the nutritional substance in vivo upon reaching the subject's ileum.

34. The method of claim 32, wherein the dosage form is made by coating the nutritional substance with a material which has a pH dissolution profile that delays the release in vivo of the majority of the nutritional substance until the dosage form reaches the subject's ileum.

35. The method of claim 34, wherein the material having a pH dissolution or time delay profile that delays the release in vivo of the majority of the nutritional substance until the dosage form reaches the ileum is selected from the group consisting of cellulose acetate trimellitiate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose, ethyl cellulose or mixtures of hydroxypropylmethyl cellulose and ethyl cellulose containing a subcoatingsub coating, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), shellac, copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerization. Also hydroxypopyl methylcellulose, as well as ethyl cellulose ,eachcellulose, each with its own subcoatingown subcoating

36. The method of claim 35, wherein the copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerization, are substantially insoluble in gastric fluid and in intestinal fluid at a pH of below around 7.

Also hydroxypopyl methylcellulose, as well as ethyl cellulose ,eachcellulose, each with its own own subcoatingsubcoating

37. The method of claim 36, wherein the nutritional substance is coated by a Eudragit polymer coating.

38. The method of claim 36 wherein said Eudragit polymer coating comprises Eudragit L, Eudragit S, Eudragit L or S with Eudragit RL, Eudragit L or S with Eudragit RS or mixtures thereof.

38. The method of claim 32 wherein the dosage form is a capsule that contains multiparticulates, each of which comprise an enterically-coated nutritional substance core.

39. The method of claim 38, wherein the nutritional substance core is coated by a material having a pH dissolution profile that delays release in vivo of the majority of the nutritional substance until the multiparticulate reaches the subject's ileum.

40. The method of claims 32, wherein the nutritional substance is selected from the group consisting of sugars, free fatty acids, polypeptides, amino acids, and compositions that yield sugars, free fatty acids, polypeptides, or amino acids upon digestion.

41. The method of claims 40, wherein the nutritional substance is D-glucose.

42. The method of claim 32, wherein the delayed and/or controlled release dosage form is administered once-daily at bedtime or in the morning (AM).

43. The method of claim 42, wherein the dosage form is administered nocturnally or upon awakening.

44. A method of treatment comprising inducing satiety in a subject for a period of at least around twenty- four hours by once-daily administration to the subject of a delayed and/or controlled release dosage form, wherein the dosage form is administered while the subject is in the fasted state and at a time of around four to around ten hours prior to the subject's next intended meal, and wherein the dosage form comprises an emulsion or microemulsion an ileum hormone-stimulating amount of a nutritional substance and releases the majority of the nutritional substance in vivo upon reaching the subject's ileum.

45. The method of claim 1 wherein the subject is overweight, obese or suffers from an obesity-related disorder.

46. The method of claim 1 wherein the delayed and/or controlled release dosage form is a hard or soft capsule or tablet formed by coating glucose with a Eudragit® polymer coating.

47. The method of claim 1 wherein the delayed and/or controlled release dosage form is a capsule formed by coating glucose with a shellac coating, which optionally includes an emulsifier.

48. The method of claim 48 wherein the emulsifier is hypromellose, triacetin or a mixture thereof.

49. The method of claim 1 wherein the delayed and/or controlled release dosage form is a capsule formed by coating glucose with ethylcellulose.

50. A method of diagnosing whether a subject suffers from an abnormally responsive ileal hormone release disorder, the method comprising:

(a) administering a dosage form comprising a delayed and/or controlled release ileum hormone-stimulating amount of a nutritional substance to the subject while the subject is in the fasted state and at a time of around four to around ten hours prior to the subject's next intended meal; (b) measuring the subject's levels of blood sugar and insulin at regular intervals over a period subsequent to administration of the nutritional substance; and

(c) comparing measured levels of blood sugar and insulin to healthy (normal) levels of blood sugar and insulin over an identical period that have been determined by administering an equivalent delayed and/or controlled release ileum hormone-stimulating amount of a nutritional substance to a control subject, wherein a level of insulin and/or blood sugar which decreases in said patient compared to said healthy level is evidence of an abnormally responsive ileal hormone release disorder.

50. A method of diagnosing whether a subject suffers from an obesity-related, or abnormally responsive ileal hormone release disorder, the method comprising

(a) measuring one or more of the subject's levels of ileal hormones selected from the group of at least GLP 1 ,GLP2, PYY and enteroglucagon after a period of fasting;

(b) administering a dosage form comprising a controlled release, ileum hormone- stimulating amount of a nutritional substance to the subject while the subject is in the fasted state and at a time of around four hours to around ten hours prior to the subject's next intended meal;

(c) measuring the subject's levels of said hormones and optionally blood sugar and insulin at regular intervals subsequent to administration of the nutritional substance; and

(d) comparing measured levels of said hormones and optional levels of blood sugar and insulin to healthy levels of hormones and blood sugar and insulin that have been determined by administering an equivalent controlled release ileum hormone-stimulating amount of a nutritional substance to a control subject; and

(e) determining based upon said comparing step the likelihood that said tested subject suffers from an obesity-related, or abnormally responsive ileal hormone release disorder.

51. The method according to claim 47 or 48 wherein said nutritional substance is D- glucose in an amount ranging from about 500 mg to about 12.5 grams.

52. A method of treating a gastrointestinal disease or disorder in a patient in need thereof comprising administering to said patient an effective amount of a controlled release composition comprising an ileum hormone stimulating nutritional substance which releases about 50% by weight of said nutritional substance in the ileum of said patient wherein said gastrointestinal disease or disorder selected from the group consisting of atrophic gastritis, post chemotherapy disorder, intestinal motility disorder (gut dismotility), mild reflux, chronic pancreatitis, malnutrition, malabsorption, voluntary or involuntary long term starvation, post infectious syndrome, short bowel syndrome, irritable bowel, malabsorption, diarrheal states, post chemotherapy gastrointestinal disorder, post infectious syndrome, radiation enteritis, celiac disease, fatty liver disease, cirrhosis, radiation, inflammatory bowel disease and Crohn's disease.

53. A method of treating a disease or disorder selected from the group consisting of metabolic syndrome, pre-diabetic symptoms, noninsulin dependent diabetes mellitus, glucose intolerance or insulin resistance or a disease state or condition which occurs secondary to said disease or disorder comprising administering to said patient or subject an effective amount of a nutritional substance and releasing at least about 50% of the nutritional substance in said composition in the ileum of said patient or subject.

54. The method according to claim 53 wherein said secondary disease state is polycystic (fibrous) ovaries, arteriosclerosis, fatty liver or cirrhosis.

55. A method of treating a patient or subject to improve the health of the liver, pancreas and/or intestine of said patient or subject comprising administering to said patient or subject an effective amount of a nutritional substance and delivering at least about 50% of the nutritional substance in said composition in the ileum of said patient or subject.

56. A method of treating a patient or subject to decrease fatty liver, increase the size of beta cells in the pancreas or increase the size of absorptive villae of the small bowel of said patient or subject comprising administering to said patient or subject an effective amount of a nutritional substance and releasing at least about 50% of the nutritional substance in said composition in the ileum of said patient or subject.

57. A method of treating a patient or subject to decrease body fat and/or increase muscle mass comprising administering to said patient or subject an effective amount of a nutritional substance and releasing at least about 50% of said nutritional substance in said composition upon reaching the ileum of said patient of subject.

58. The method according to any of claims 52-56 wherein said nutritional substance is D-glucose.

59. A method of stimulating IGF-I, IGF-2, leptin or mixtures thereof in the gastrointestinial tract of a patient or subject said method comprising administering to said patient or subject an effective amount of a nutritional substance and delivering at least about 50% of the nutritional substance in said composition in the ileum of said patient or subject.

60. A method of treatment comprising administering a nutritional supplement composition containing GRAS ingredients for treating noninsulin dependent diabetes mellitus, pre-diabetic symptoms, and insulin resistance, the nutritional supplement composition containing an effective amount of a nutritional substance, optionally combined with one or more of Alfalfa leaf, chlorella algae, chlorophyllin and barley grass juice concentrate, and further formulated into a delayed release form adapted to release the nutritional supplement in the lower gut or ileum.

61. The method according to claim 60 wherein said nutritional substance is D-glucose

62. The method of claim 59 or 60 wherein the dosage form is administered while the subject is in the fasted state and at a time of around four to around ten hours, preferably around six hours to around nine hours prior to the subject's next intended meal, and wherein the dosage form comprises a controlled release insulin regulating amount of the nutritional substance and releases at least about 50% by weight of the nutritional substance in vivo upon reaching the subject's ileum.

63. The method of claim 60, wherein the dosage form comprises a nutritional substance core and an enterically-coated tablet, troche, lozenge, dispersible powder or granule, a hard or soft capsule, or an emulsion or microemulsion.

64. The method of claim 60, wherein the dosage form is made by coating the nutritional substance with a material which has a pH dissolution or time delayed profile that delays the release in vivo of the majority of the nutritional substance until the dosage form reaches the subject's ileum.

65. The method of claim 64, wherein the material having a pH dissolution profile that delays the release in vivo of the majority of the nutritional substance until the dosage form reaches the subject's ileum is selected from the group consisting of cellulose acetate trimellitiate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose, ethyl cellulose, color con, food glaze and mixtures of hydroxypropylmethyl cellulose and ethyl cellulose each of which contains a subcoating, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), shellac, copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerization.

66. The method of claim 65, wherein the copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerization, are substantially insoluble in gastric fluid and in intestinal fluid at a pH of below around 7.

67. The method of claim 65, wherein the nutritional substance is coated by Eudragit L, Eudragit S, Eudragit L or S with Eudragit RL, Eudragit L or S with Eudragit RS or mixtures thereof.

68. The method of claim 63 wherein said nutritional substance is coated with shellac.

69. The method of claim 63 wherein the dosage form is a capsule that contains multiparticulates, each of which comprise an enterically-coated nutritional substance core.

70. The method of claim 69, wherein the nutritional substance core is coated by a material having a pH dissolution profile that delays release in vivo of the majority of the nutritional substance until the multiparticulate reaches the subject's ileum.

71. The method of claim 60 wherein said nutritional substance is dextrose present at from about 500 to 3000 mg.

72. The method of claim 60, wherein the nutritional substance is selected from the group consisting of sugars, free fatty acids, polypeptides, amino acids, and compositions that yield sugars, free fatty acids, polypeptides, or amino acids upon digestion.

73. The method of claims 72, wherein the nutritional substance is glucose.

74. The method of claim 60, further comprising administering the nutritional supplement once-daily at bedtime.

75. The method of claim 60, further comprising administering the nutritional supplement nocturnally.

76. The method of claim 60, further comprising monitoring the subject's blood levels of one or more of the following: GLP-I, GLP-2, PYY, C-peptide, blood sugar, insulin, leptin, enteroglucagon and glucagon.

77. The method of claim 60, further comprising monitoring the subject's blood levels of one or more of the following: GLP-I, GLP-2, PYY, C-peptide, blood sugar, insulin, leptin and glucagon before administering the dosage form and at a time of around four to around ten hours after administering the dosage form.

78. The method of claim 77, further comprising adjusting an amount or a frequency of administration of the nutritional supplement depending upon the subject's blood levels of GLP-I, GLP-2, PYY, C-peptide, blood sugar, insulin, leptin and glucagon.

79. The method of any of claims 60-78 wherein the nutritional substance comprises Alfalfa Leaf, 3.00mg, Chlorella Algae, 3.00 mg., Chlorophyllin, 3.00 mg, Barley Grass Juice Concentrate, 3.00 mg, and Dextrose, 1429.00 mg..

80. A delayed/controlled release composition comprising an effective amount of a nutritional substance, optionally combined with one or more of Alfalfa leaf, chlorella algae, chlorophyllin and barley grass juice concentrate, and further formulated into a delayed or controlled release form adapted to release at least 50% by weight of the nutritional substance upon reaching the lower gut or ileum.

81. The composition of claim 80, wherein the dosage form comprises a nutritional substance core and an enterically-coated tablet, troche, lozenge, dispersible powder or granule, a hard or soft capsule, or an emulsion or microemulsion.

82. The composition of claim 80 or 81, wherein the dosage form is made by coating the nutritional substance with a material which has a pH dissolution or time delayed profile that delays the release in vivo of the majority of the nutritional substance until the dosage form reaches the subject's ileum.

83. The composition of claim 82, wherein the material having a pH dissolution profile that delays the release in vivo of the majority of the nutritional substance until the dosage form reaches the subject's ileum is selected from the group consisting of cellulose acetate trimellitiate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose, ethyl cellulose, color con, food glaze and mixtures of hydroxypropylmethyl cellulose and ethyl cellulose each of which contains a subcoating, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), shellac, copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid and_ ethyl acrylate to which a monomer of methylacrylate has been added during polymerization.

84. The composition of claim 83, wherein the copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerization or shellac, are substantially insoluble in gastric fluid and in intestinal fluid at a pH of below around 7.

85. The composition of claim 84 wherein the nutritional substance is coated by Eudragit L, Eudragit S, Eudragit L or S with Eudragit RL, Eudragit L or S with Eudragit RS, mixtures thereof or shellac.

86. The composition of claim 85 wherein said nutritional substance is coated with shellac.

87. The composition of claim 80 wherein the dosage form is a capsule that contains multiparticulates, each of which comprises an enterically-coated nutritional substance core.

88. The composition of claim 81, wherein the nutritional substance core is coated by a material having a pH dissolution profile that delays release in vivo of the majority of the nutritional substance until the multiparticulate reaches the subject's ileum.

89. The composition according to claim 88 wherein the material is shellac.

90. The composition according to any of claims 80-89 wherein said nutritional substance is dextrose (D-glucose) present at from 500 to 3000 mg.

91. The composition according to claim 80, wherein the nutritional substance is selected from the group consisting of sugars, free fatty acids, polypeptides, amino acids, and compositions that yield sugars, free fatty acids, polypeptides, or amino acids upon digestion.

92. The composition according to any of claims 80-91 further comprising an effective amount of an antibiotic, antispasmodic agent, non-specific chelating agent, antidiabetes agent, laxative or mixture thereof.

93. A delayed/controlled release composition comprising a core and an enteric coating, said core comprising an effective amount of glucose optionally combined with one or more of alfalfa leaf, chlorella algae, chlorophyllin and barley grass juice concentrate in combination with corn starch, stearic acid, magnesium stearate and silicone dioxide, and said coating comprising shellac, hypromellose and triacetin, wherein said composition is adapted to release at least about 50% by weight of the nutritional substance in the ileum.

94. A delayed/controlled release composition according to formulation II of example 3 hereof.

95. The composition according to any of claims 80-94 further comprising an effective amount of a plant or animal oil, an animal or vegetable fat, a seed or nut oil or fat, a stimulant selected from the group consisting of caffeine, an herb, tea and mixtures thereof, an ingredient that increases post receptor activities at the cellular level, an extract or food product or a natural or synthetic chemical, including a metabolite.