# Patent

## Title
Composition and method for the treatment and prevention of endothelial dysfunction

## Abstract

This invention involves compositions and method of using of therapeutic agents for pain relief for the treatment and prevention of disorders associated with endothelial dysfunction, the cause of inflammation, atherosclerosis, cardiovascular disease, diabetes, hypertension, asthma and stroke in mammals comprising anti-inflammatory agents, epinephrine, insulin, anti-viral agents and dietary supplements.

## Background
This application is a continuation-in-part of Ser. No. 09/947,674 filed Sep. 7, 2001, now U.S. Pat. No. 6,567,708, and a continuation of Ser. No. 10/436,528 filed on May 14, 2003, now U.S. Pat. No. 6,930,099, and a continuation of Ser. No. 11/057,671 filed on Feb. 15, 2005, now U.S. Pat. No. 7,846,914, and a continuation of Ser. No. 11/978,505 filed on Oct. 30, 2007, now U.S. Pat. No. 8,017,657, and a continuation of Ser. No. 13,199,805 filed on Sep. 10, 2011


FIELD OF INVENTION
This invention involves compositions of therapeutic agents for pain relief and the treatment and prevention of disorders associated with endothelial dysfunction comprising anti-inflammatory agents, epinephrine, insulin, anti-viral agents and dietary supplements.
BACKGROUND OF THE INVENTION
Endothelial cells are mesodermally derived, simple squamous epithelial cells that line the heart, blood and lymph vessels, line any closed cavity (peritoneal, pleural, pericardial, synovial) and line the intestinal tract. Endothelial cells of blood vessels have both mechanical and functional properties. They provide a barrier effect to the penetration of blood components into the vessel wall and have endocrine functions.
Vascular endothelium is a multi-functional barrier separating blood from interstitium. It plays a role in coagulation, inflammation, angiogenesis and has vasomotor functions. Endothelial dysfunction can be considered as an initial stage of atherosclerosis. Malik J, Melenovsky V, Wichterle D, Function and dysfunction of the endothelium, Cas Lek Cesk 2000 Apr. 12; 139(7):197-202. Endothelium dysfunction is recognized as an early event in the pathogenesis of cardiovascular disease, and linked to hypertension, diabetes mellitus and oxidative stress. Pepine C J, Clinical implications of endothelial dysfunction, Clin Cardiol 1998 November; 21(11):795-9.
Endothelial dysfunction is characterized by a loss of barrier function and an infiltration of cellular material into the vascular wall and loss of physiological vascular tone. There is a loss of nitric oxide mediated physiological vasodilation, increased endothelial adhesion and migration of leucocytes and macrophages into the subendothelial vascular wall. Hypoxia, shear forces and oxidative stress trigger events for endothelial dysfunction. Disorders associated with endothelial dysfunction may occur in any endothelial cells and include; hypertension, atherosclerosis, diabetes, immune system dysfunction, infections, inflammations, macular degeneration, cardiovascular disease and stroke.
SUMMARY OF THE INVENTION
This invention relates to a method and compositions for pain relief and the treatment and prevention of disorders associated with endothelial dysfunction comprising anti-inflammatory agents, epinephrine, insulin anti-viral agents and dietary supplements.


DETAILED DESCRIPTION OF THE INVENTION
Each year 1.5 million Americans suffer heart attacks (myocardial infarction) and 500,000 die of that first attack, with 48% being females. Most of the 500,000 deaths occur within 2 hours after chest pain or other symptoms. In Britain half of all heart attack patients die within two hours of symptom onset and two-thirds of the deaths occur before admission to the hospital. Rawles J, Pre-Hospital Immediate Care 1997; 1:12-18. During this critical 120 minute period, coronary thrombosis could be eliminated and the heart attack prevented if the thrombus could be averted. While the nation's death rate from heart attacks peaked in the 1960s, when the death rate from heart disease was 307.4 per 100,000 people, the rate has plummeted to 134.6 in 1996, but myocardial infarction still ranks as the nation's leading killer. Coronary artery disease (CAD) affects 13.5 million Americans, a million have survived heart attacks, 7 million have angina (myocardial ischemia), 600,000 have undergone coronary bypass surgery and 2,000 have had heart transplants. The economic burden is estimated at $150 billion annually. Tindall W N, Business & Health February 1998.
The vascular endothelium modulates blood vessel tone by secreting a variety of dilating and constricting substances. Dilating agents include nitric oxide (NO), prostacyclin, bradykinin, and endothelium-derived relaxing factor (EDRF) and heparinoids; constricting agents include endothelin, superoxide anion, endothelium-derived constricting factor, locally produced antiotensin II, and thromboxane. These agents not only control and alter vascular tone, but also can affect platelet adhesion and aggregation, influence thrombogenicity of the blood, and participate in cell proliferation and the development and progression of atherosclerosis.
Injury to endothelial cell function, primarily resulting from increased oxidant stress within the endothelium, leads to a cascade of events beginning with activation of vascular cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) and proceeding to expression of adhesion molecules on the cell surface that include vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and endothelial-leucocyte adhesion molecule (ELAM), which attracts monocytes and other leucocytes to adhere to the endothelial surface. Adherence is followed by infiltration of mononuclear cells into the vascular wall, together with activation of monocyte chemoattractant protein-1 (MCP-1), leads to scavenging of oxidized low-density lipoproteins (LDL), formation of lipid-laden foam cells, and development or progression of atherosclerotic plaque. Activation of prothrombogenic stimuli and inactivation of fibrinolytic factors with endothelial dysfunction predisposes these blood vessels to thrombosis. Quyyumi A A, Am J of Med 1998; 105(1A):32S-39S.
Vascular injury triggers thrombosis and a proliferative response. By the release of tissue factor and exposure of subendothelial matrix, the coagulation and platelet pathways are activated and a thrombus is formed, either on a micro or macroendoluminal level. Additionally, platelet activation leads to a variety of mitogens, growth-promoting factors, and cytokines. Potent mitogens, such as platelet-derived growth factor and fibroblast growth factor, cause smooth muscle cells, fibroblasts, inflammatory cells, and endothelial cells to participate in reendothelialization. Smooth muscle cell and fibroblast proliferation and migration result from signal transduction pathways initiated by factors biding to their specific cell-surface receptor. Smooth muscle cells and fibroblasts migrate from the media to the intimal surface. Smooth muscle cells are phenotypically transformed to the synthetic subtype and secrete an extracellular matrix consisting of proteoglycans. Ward S R, Topol E J, Resident & Staff Physician 1995; 41(3):11-18.
British scientists have reported a well-established link between inflammation and cardiovascular events mediated by inflammation-induced dysfunction of the arterial endothelium. Even mild systemic inflammatory responses are associated with significant alteration in endothelial function which lead to increased cardiovascular risk. Hingorani A D, et al., Circulation 2000; 102:994-999.
Thrombus formation is the proximate cause of myocardial infarction, but atherosclerosis, the chief underlying cause, is a chronic disease that progresses over decades of life. Inflammation has a role in both the initiation and the progression of atherosclerosis, and anti-inflammatory agents have a role in the prevention of cardiovascular disease.
Atherosclerosis may be considered as an aberrant form of would-healing in arteries. Repeated minor trauma, leading to subendothelial hemorrhage, may well account for the tendency of atherosclerosis to occur mostly at major blood vessel flexion sites and at sites of mechanical stress, such as the carotid sinus or the bifurcation of the carotid artery. The positive injury potential resulting from petechial hemorrhages in the vascular intima will attract negatively charged platelets and leucocytes and will lead to a layered thrombus formation. Gaps between the endothelial cells of the intima will allow the insinuation of monocytes beneath the endothelium, where it seems they can become transformed into macrophages and engulf oxidized LDL to become foam cells and lead to the formation of the atherosclerotic plaque.
C-reactive protein (CRP) is a natural substance that results from an inflammatory response to injury of infection by mobilizing white blood cells. CRP is an acute-phase reactant that is a biomarker for underlying systemic inflammation, reported in patients with acute ischemia or myocardial ischemia and found to predict recurrent ischemia in those with unstable angina. Base-line levels of CRP in apparently healthy men can predict the risk of the first myocardial infarction and ischemic stroke. Previous infection with Chlamydia pneumonia, Heliobacter pylori, herpes simplex virus, or cytomegalo-virus may be the source of the chronic inflammation detected by CRP. An elevated CRP level is related to inflammation, and increased inflammation is noted for many diseases, such as cancer, cardiovascular disease, infection, connective tissue diseases and injuries. Elevated CRP reflects an increased production of proinflammatory cytokines such as interleukin-6, which may be contributing to the pathophysiology of disease either directly or indirectly through their relationship to other important components of inflammation, thrombosis, or fibrinolysis. Kuller L H, Tracy R P, Arteriosclerosis, Thrombosis, and Vascular Biology 2000; 20(4):901
The Physicians Health Study (PHS) indicates that healthy men with baseline levels of CRP in the highest quartile had a threefold increase in risk of developing future myocardial infarction and twice the risk of developing stroke. These risk estimates were stable over an 8-10 year follow-up period, were not modified by smoking status, and were independent of other cardiovascular risk factors, including total and HDL cholesterol, triglycerides, lipoproteins and fibrinogen. Elevated baseline levels of CRP are also associated with a fourfold increase in the risk of developing clinically severe peripheral arterial disease, again independent of usual risk factors. Plasma levels of ICAM-1 are elevated many years in advance of a first-ever myocardial infarction and that levels of ICAM-1 correlate with CRP. Cellular adhesion molecules, such as ICAM-1, are critical in the adhesion of circulating leucocytes to the endothelial cell and subsequent endothelial transmigration, and provide evidence that cellular mediators of inflammation have a critical role in atherogenesis. CRP levels increase with increasing prevalence of exposure to Heliobactor pylori, the bacteria responsible for gastric ulcers. Ridker P M, Circulation 1998; 97:1671-1674.
Chronic subclinical infection with Chlamydia pneumoniae, Helicbacter pylori, chronic bronchitis, and chronic dental sepsis have been associated with raised values of CRP and have been implicated as risk factors for coronary heart disease. Mendall M A, BMJ 1998; 316:953-954. During acute unstable angina, which if believed to be an immune system-mediated inflammatory disorder, patients had significantly greater levels of CRP and helper T-cells and significantly reduced levels of suppressor T-cells. Caligiuri G, J Am Coll Cardiol 1998; 32:1295-1304.
H pylori is a spiral gram-negative rod that resides beneath the gastric mucus layer adjacent to epithelial cells. It causes a chronic mucosal inflammation and associated with peptic ulcer disease. H pylori is treated with antibiotics and bismuth or bismuth containing compounds such as bismuth subsalicylate. Tierney Jr. L M, McPhee S J, Papadakis M A, Current Medical Diagnosis and Treatment, Appelton & Lange, 3rd ed 1994 p. 490.
Over 50% of those over age 60 and about 20% of those under age 40 are infected with H. pylori. H. pylori eradication may reverse the severity of aspirin-induced gastric injury. Extracts from cranberry, grape seed and blueberry have been shown to inhibit the adhesion of H. pylori to the gastric mucosa and can inhibit H. pylori in vitro. Vattern, D A et al Process Biochemistry 2004. Cranberry juice raises HDL cholesterol levels, inhibits the binding of H. influenza pili to buccal cells and controls gingival and periodontal diseases. Weiss E I, et al J Am Dent Assoc 1998 December; 129(12):1719-23.
H. pylori colonize in the stomach weakening the lining and making the stomach vulnerable to irritation from natural stomach acids. H. pylori causes about nine out of ten duodenal ulcers and more than eight out of ten gastric ulcers.
Probiotics have the potential to minimize gastrointestinal conditions such as diarrhea, irritable bowel syndrome (IBS) and inflammatory bowel disease. Children who were treated for H. pylori with an antibiotic cocktail with probiotic (Lactobacillus reuteri) had less intestinal distress. IBS has been associated with decreased nonpathogenic colonies and increased Clostridium species. Bifidobacterium infantis have shown promise in treating IBS when used with gut-directed antibiotics.
Probiotics not only inhibit H. Pylori but also help prevent ulcers caused by the use of NSAIDs. Probiotics that may be combined with or used with aspirin include but are not limited to Bifidobacterium lactis, Lactobacillus rhamnosus, Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus paracasei, Bifidobacterium, Streptococcus thermophilus, Saccharomyces boulardii, and others. Prebiotics are nondigestible substances that, when consumed, provide a beneficial physiological effect on the host by selectively stimulating the favorable growth or activity of a limited number of indigenous bacteria. Prebiotics may also be incorporated into a fast dissolving tablet to prevent H. pylori infections.
CRP concentrations were increased in about 75% of patients within 24 hours after ischemic stroke, and higher values were significantly associated with large infarct size. Di Napoli M, BMJ 2001; 322:1605. In 1950, the stroke death rate per 100,000 was 88.8. In 1996, it was 26.5. Stroke is the third leading cause of death (after heart disease and cancer). Americans suffer about 500,000 strokes each year and 150,000 stroke deaths. Cerebral thrombosis and cerebral embolism, known as ischemic stroke, account for about 80% of strokes. Cerebral thrombosis often occurs at night or first thing in the morning when blood pressure is normally low. About one-third of those who experience a transient ischemic attack (TIA) have a stroke within five years. Half of the post-TIA strokes occur within a year, 20% within one month. TIAs double the risk of heart attack. Those on ASA had 42% fewer strokes. It has been reported that immediate use of ASA be considered in all patients with acute ischemic stroke. Sandercock P A G, Lancet 1997; 349:1563-1565, 1569-1581.
Many of the current studies point to an inflammatory etiology for cardiovascular and cerebrovascular disorders. Anti-inflammatory agents have shown benefits for the treatment and prevention of these endothelial dysfunction diseases. This invention provides a composition to overcome the obstacles inherent in the prior approaches.
Acetylsalicylic acid (ASA) has been known to treat and prevent cardiovascular disease by reducing thrombosis, but the real effect is as an anti-inflammatory agent. ASA inhibits cyclo-oxygenase in both platelets and endothelial cells. At low doses ASA inhibits the formation of thromboxane A2 (TXA2), a potent vasoconstrictor and platelet agonist formed via cyclo-oxygenase-dependent pathway in platelets. At higher doses, ASA has been shown to block the formation of prostacyclin (PGI2), a vasodilator and inhibitor of platelet aggregation, in endothelial cells.
The use of ASA for the primary prevention of CAD was examined in the PHS in which 22,000 US male physicians were observed for about 5 years. Those who took 325 mg of ASA every other day had a 44% reduction in the incidence of first myocardial infarction, and a 25% reduction in the incidence of subsequent myocardial infarction, stroke, and death from cardiovascular causes. Milani R V, Lavie C J, Postgraduate Medicine 1996; 99(2):109-120. The rates of myocardial infarction were lower for those on acetylsalicylic acid (ASA) for all levels of CRP. Ridker P M, et al, NEJM 336(14):973-979.
NSAIDs fall into seven major classes: proprionic acid derivatives, indole derivatives, fenamates, pyrrolealkanoic acids, pyrazolone derivatives, oxicams and salicylic acids. NSAIDs for purposes of this invention are selected from, but not limited to acetylsalicylic acid, ibuprofen, naproxen and ketoprofen. Most develop some erosions in the stomach after each dose. The number of NSAID users presenting with serious GI complications is low (1-2%), but the high usage of NSAIDs means the number affected is large. The annual death rate amongst patients with rheumatoid and osteoarthritis due to serious adverse consequences of GI ulceration (perforation and hemorrhage) has been estimated at 16,500 in the US alone.
High gastric acidity contributes to NSAID injury to the stomach and duodenal bulb. Most NSAIDs are weak acids (pKa values 3.5 to 6) existing in a non-ionized form at low pH, and are lipid soluble. They readily diffuse into surface cells and become trapped at the higher intracellular pH. This accumulation causes local toxicity. Gastric acid and possibly pepsin, appears to deepen some of the superficial lesions that occur with NSAIDs. Most superficial lesions repair within 1-2 hours, but some patches of damaged tissues do not repair in time to prevent deeper tissue destruction The GI tract protects itself from damaging mechanical and other stresses by producing and secreting onto epithelial surfaces a layer of lubricating mucus. Most GI pathology is probably related to the decreased production of mucus or breaking in the mucus layer. Mucus secretion and successful resealing occur simultaneously, and both require that external calcium be present during a plasma membrane disruption.
The incidence of acute peptic ulcer bleeding can be reduced by the addition of agents that suppress gastric acid formation, that include by not limited to proton pump inhibitors, acid pump inhibitors, H2-receptor antagonists, misoprostol and magnesium. Proton pump inhibitors have been shown to be effective to possible NSAID gastric injury. Leontiadis G I, et al The Cochrane Library Issue 4, 2004, John Wiley & Sons. The use of a proton pump inhibitor (heartburn pill) was also shown to prevent recurrent ulcer bleeding when ASA was combined with esomeprazole (Nexium) as opposed to using clopidogrel (Plavix). Chan F K L, et al NEJM; 2005; 352(3):238-244. Many investigators believe that the active agent in esomeprazole and omeprazole (Prilosec) is magnesium, which also has buffering properties.
The critical factor is how fast ASA is absorbed to reduce thrombosis within the 20 minute time frame. Myocardium (heart muscle) begins to undergo irreversible injury within 20 minutes of ishchemia and a wavefront of death sweeps from the inner to the outer layers of myocardium during a 3 to 6 hour period. The repair process requires two months to complete. Enteric-coated ASA takes about 60 minutes to reach peak blood levels; regular ASA reaches peak blood levels in 30 minutes; but chewing an ASA tablet reaches blood levels and inhibits platelet activity in 5 minutes. Undissolved tablets and large particles that adhere to the gastric mucosa result in lesions. Micropulverized ASA particles, 100-600 μm, cause fewer lesions because they diffuse readily reducing contact with the gastric mucosa. In a fast dissolving tablet, (16-35%) ASA is absorbed by the buccal mucosa and only small particles are swallowed into the esophagus.
Aspirin reduces cardiac vegetations that evolve in experimental Staph aureus endocarditis. It is postulated that aspirin's antipltelet aggregation is combining with its antibacterial effect. Kupferwisser L I, et al Circulation 1999 June 199; 21:2791-7. The dosage of ASA for the present invention consists of 80-120 mg in a fast dissolving tablet which may be repeated when mixed with the amino sugar and zinc compound.
A number of patents disclose the use of ASA, primarily as analgesics both systemically and topically. Cotty et al, U.S. Pat. No. 4,049,803, discloses a composition of acetaminophen, ASA and caffeine. Patel, U.S. Pat. No. 4,867,984, discloses beads of ASA or acetaminophen coated with PVP. Frisbee, U.S. Pat. No. 4,970,081, discloses a formulation for a controlled release aspirin tablet. Bru et al, U.S. Pat. No. 5,437,874, discloses a composition of ASA or carbasalate calcium, metoclopramide, a hydrophilic polymer, anhydrous magnesium citrate and lactose. Eickhoff et al, U.S. Pat. No. 5,518,738, discloses NSAID particles coated with PVP. Liversidge et al, U.S. Pat. No. 5,552,160, discloses surface modified NSAID nanoparticles. Moshyedi, U.S. Pat. No. 5,770,215, discloses a vitamin supplement with ASA. Medford et al, U.S. Pat. No. 5,846,959, discloses a method for treating CVD with PUFA and CV drugs. Riley et al, U.S. Pat. No. 5,948,443, discloses a method for treating nutritional losses and heart disease with ASA, multivitamins and minerals. Noack et al, U.S. Pat. No. 5,973,011, discloses a method of treating endothelial dysfunction with PETN and active compounds to treat CVD. Weissman et al, U.S. Pat. No. 6,121,249, discloses a method for treating CVD with ASA, antioxidants and vitamins. Calanchi et al, U.S. Pat. No. 6,261,602 B1, discloses a microencapsulated mixture of thickening agents, disintegrating agents and pharmaceutically active substances.
NSAIDs inhibit prostaglandin (PG) synthesis by blocking the action of cyclooxygenase (COX), which exists in two forms. COX-1 is present in virtually all tissues and synthesizes PG which provides GI mucosal protection. COX-2 is activated in response to cytokines and other inflammatory factors. NSAIDs currently available inhibit both COX-1 and COX-2 to varying degrees. Selective COX-2 inhibitors, Vioxx (rofecoxib) and Celebrex (celecoxib) were promoted to provide pain relief and avoid GI complications. However, all NSAIDs, including COX-2 inhibitors, can cause GI adverse events, including life-threatening perforations, ulcers or bleeds. One study comparing Vioxx to naproxen detected a four fold risk of myocardial infarction. Nissen S E, et al, JAMA 2001; 286:954-959. Vioxx has now been withdrawn from the market. COX-2 isoenzymes are necessary for maintaining renal blood flow. COX-2 inhibitors have been reported too cause acute renal failure.
Platelets play an important role in the development of atherosclerosis. COX-2 inhibitors reduce the levels of prostacyclin (PGI2), a cyclooxygenase product that inhibits platelet activation and may accelerate atherosclerosis. Nonselective NSAIDs suppress both thromboxane and prostacyclin and retard atherogenesis. Pratico D, Proc Natl Acad Sci USA 2001; 98:3358-3363. The cardioprotective effects of ASA are not seen with COX-2 inhibitors, which do not inhibit TXA2 production by platelets. Hart C, Modern Drug Discovery May/June 1999.
ASA in addition to its well-appreciated ability to inhibit PG and TX, can also switch on the production of the body's own anti-inflammatory lipid mediators, namely aspirin-triggered lipoxins. ASA acetylates COX-2 and re-directs COX-2's catalytic activity away from generating intermediates of prostaglandins and thromboxanes and towards producing another compound (15R-HETE), which is converted to 15-epi-Lipoxin A4 by 5-lipoxygenase in activated neutrophils and then rapidly released. The new compound is termed aspirin-triggered 15-epi-lipoxin A4 (ATL) is unique to aspirin, as other widely used NSAIDs are unable to generate ATL. Both Lipoxin A4 and ATL act at the low nanomolecular concentration range via interaction with a specific cell surface receptor (denoted the Lipoxin A4 receptor) and possess potent protection in peritonitis, dermal inflammation, reprofusion injury, periodontitis and angiogenesis. ATL formation within the vasculature is relevant in the cardioprotective actions of aspirin. ATL may protect against the initial inflammatory events that could lead to deleterious cardiovascular effects. Chiang N, Serhan C N, Discovery Medicine 2004; 4(24):470-475.
In 2-23% of adults with asthma, and rarely in children with aspirin, aspirin and NSAIDs cause asthma exacerbations. Prompt administration of intramuscular epinephrine is the usual treatment for systemic anaphylaxis and asthma. Epinephrine administered orally is inactivated in the GI tract. Epinephrine delivered by a fast dissolving tablet would be absorbed by the buccal mucosa and pass directly into the systemic circulation avoiding the first-pass effect. In rabbit studies a 2.5 mg sublingual epinephrine tablet reached a peak of effectiveness at 20.8 minutes, while an injection of epinephrine reached peak effectiveness in 15.8 minutes. Gu X, Simons K J, Simons F E. Biopharmaceutics & Drug Disposition 2002; 23:213-216. A fast dissolving tablet with 0.15-50 mg of epinephrine is an alternative method of prevention and treating endothelial dysfunction associated with the inflammation associated with asthma and anaphylactic shock.
Aspirin is contraindicated in patients with influenza because of the alleged association of aspirin and influenza causing Reye syndrome. In many cases it turned out the symptoms attributed to Reye's syndrome were actually manifestations of inborn errors of metabolism, where the body could not make enough of a certain enzyme. There is not one single article that has ever established a causal relationship between Reye's syndrome and the intake of aspirin.
One solution is to combine antiviral drugs with the NSAID, amino sugar and zinc compound. Influenza virus targets the endothelial cells and is linked to hemagglutin, myocarditis and myositis. Feldmann A, et al J Virol 2000 September; 74(17):8018-27. The neuraminidase inhibitors, such as amantadine, rimantadine, zanamivir and oseltamivir, are a new class of antiviral agents that interfere with the replication of influenza A and B. Neuraminadase (NA) is a critical protein of the surface membrane of the influenza virus. The flu virus consists primarily of RNA molecules wrapped in proteins. Once a virus has invaded a cell and multiplied new virus particles emerge from the cell bound together. One viral protein, and enzyme called neuraminidase, is required for the bundle to unglue itself so that individual virus particles can infect other cells. Zanamivir foils the flu by binding to neuraminidase and deactivating it, so that the virus particles stay bundled. Even in young adults, a flu shot is at best 70-90% effective. Among elderly people, whose immune response is weakened, the vaccine is only 30-50% effective. Neuraminidase inhibitors may work against the virus even as flu shots fail because it will still be able to dock to neuraminidase's conserved site. The addition of one or more neuraminidase inhibitors to the composition or other antiviral agents may offer the prevention of endothelial dysfunction from the influenza virus.
Some supplements that may be added to the formulation to reduce flu symptoms include: N-acetyl-cysteine (NAC), zinc, selenium, vitamin D and black elderberry. NAC is a metabolite of the amino acid cysteine, an antioxidant and precursor to glutathione, can reduce flu symptoms. Zinc and selenium are minerals that strengthen the immune system and boost the protective antibody response. Persons with healthy Vitamin D levels were found to get fewer colds and cases of flu. Black elderberry contains flavonoids, including anthocyanins, that can bolster immunity and keep viruses from effectively implanting in mucus membranes.
ASA has also been reported to be effective in reducing the risk of gastric cancer. Zaridze D, Int J Cancer 1999; 82:473-476. ASA has also been reported to be effective against diabetic retinopathy, Alzheimers Disease, colon and rectal cancer, deep vein thrombosis, kidney failure, migraine headaches, cataracts, gallstones, and insect bites. Life-long use of low-dose aspirin prevents inflammatory and endogenous oxidative insults accompanying aging and attempt to increase maximum and mean life span.
Aspirin is an inexpensive, anti-inflammatory, antioxidant compound that effects the immune system and cardiovascular health. Aspirin affects oxidant production, cytokine responses and blocks glycosidation reactions, thus posing as a triple threat against the symptoms of aging. Phillips T, Leeuwenburgh C. Lifelong aspirin supplementation as a means to extending life span. Rejuvenation Research 2004; 7(4):343-252. Long-term use of low dose aspirin may double the chances of individuals living a healthy life into their 90s. Aspirin use may reduce the risk of breast cancer by 20%, lung cancer by 30%, colorectal cancer and prostate cancer by 50%. Aspirin may reduce the risk of Alzheimer's disease, cataract, gallstones, reflux esophagitis, oral gum deterioration and prolong both the quantity and quality of life. Morgan G. A quantitative illustration of the public health potential of aspirin. Medical Hypothesis 2003; 60(6):900-902.
It is one object of this invention to incorporate an NSAID, such as ASA, to provide pain relief and anti-inflammatory and anti-thrombotic benefits to prevent and treat endothelial dysfunction.
One of the gastrointestinal (GI) side-effects of nonsteroidal anti-inflammatory drugs (NSAIDs), is aggravating or initiating colitis type disorders, and explained by the hypothesis that NSAIDs inhibit glucosamine synthetase resulting in a reduction of the glucoaminoglycan (GAG) layer of the GI tract. The GAG layer is mechanical, located in the pre-endothelial and sub-endothelial area in the arterial network, and an electrostatic barrier, due to the negative charges from the highly anionic GAGs. The neutralization of the electrostatic barrier, results in a breakdown of the GAG defense, resulting in an increase in extravasation of body fluids into the intestinal lumen and also the passage of toxins and large foreign molecular weight antigens into the circulation. Russell A L, Medical Hypothesis 1999; 52(4):297-301. There is a close histological and pathophysiological association with endothelial membrane changes in GI disorders and the endothelium of the vasculature. An atheroma occurs due to a defect in GAG function at the inflammation site of the endothelium allowing the defect to be saturated with cholesterol. Aminosugars such as glucosamine, chondroitin and synthetic mucopolysaccharide pentosam sulfate have been shown to replace the GAG layer and improve GI and vascular inflammatory disorders. Rheumatoid arthritis is believed due to increased permeability of the GI tract. Glucosamine, for purposes of this invention, may be regarded as a preventative of endothelium dysfunction.
Amino sugars, for purposes of this invention, consist of but are not limited to; glucosamine, glucosamine sulphate, glucosamine hydrochloride, N-acetylglucosamine and Poly-Nag. Glucosamine, which is formed in the body as glucosamine-6-phosphate (G6-P), is a building block for glycolipids, glycoproteins, glycosaminoglycans, hyaluronate and proteoglycans. It is an essential component of cell membranes and cell surface proteins as well as interstitial structural molecules that hold cells together.
Glucosamine is a small molecule, very soluble in water, and 90% absorbed in the GI tract. Glucosamine sulfate (GS) appears to be linked to its ability to stimulate the synthesis of proteoglycans needed to stabilize cell membranes and increase intracellular ground substance. Since the anti-inflammatory ability of GS is different than that of NSAIDs, it is possible the two might have a synergistic effect in alleviating some types of inflammation. Evidence indicates a combined treatment utilizing glucosamine with an NSAID can decrease the amount of NSAID required to produce an antiexudative result by a factor of 2-2.7 times with preservation of activity. Kelly G S, Alt Med Rev 1998; 3(1):27-39.
The dosage range for glucosamine can vary from 200 mg to 3000 mg per day, in divided doses, for the treatment and prevention of endothelial dysfunction, osteoarthritis and inflammation, depending on body weight and severity of symptoms. The usual dosage is 20-50 mg (5-40%) per fast dissolving tablet based on the amount of ASA used in each dosage. In a rapidly disintegrating tablet the amount of glucosamine to protect the lining of the mouth and gastric mucosa is reduced due to the rapid absorption of the ASA in the oral cavity. Glucosamine administered in a fast disintegrating tablet may prevent endothelial dysfunction and provides mucoadhesion and enhanced drug bioavailability. Dosage of 100-200 mg per tablet based on the amount of fast disintegrating material used is disclosed.
The use of amino sugars, such as glucosamine, is well known in the art. Jacobi, U.S. Pat. No. 3,859,436, discloses a topical composition of glucose, fructose, glucosamine and desoxyribose and ribose. Prudden, U.S. Pat. No. 4,006,224, discloses a method for treating ulcerative colitis with d-glucosamine. Henderson, U.S. Pat. No. 5,364,845, discloses a composition for the repair of connective tissue with glucosamine, chrondroitin sulfate and manganese. Sherman et al, U.S. Pat. No. 6,117,851, discloses a method for treating osteoarthritis.
It is a further object of this invention to incorporate an amino sugar, such as glucosamine, to enhance the GAG defense, anti-inflammatory properties, and synergistic effect with NSAIDs to treat and prevent endothelial dysfunction.
Zinc is known to have gastroprotective effects in both humans and experimental animals. Gastric lesions were induced in rats by the intragastric administration of indomethacin. Mucosal ulcerations were completely prevented by pre-treatment with zinc sulphate. These protective effects result from the inhibition of lipid peroxidation and the preservation of mucosal nitric oxide synthase. Joseph R M, Varela V, Kanji V K, Subramony C, Mihas A A, Aliment Pharmacol Ther 1999 February; 13(2):203-8. Zinc sulphate taken orally was shown to heal gastric ulcers at three times the rate of a placebo. Zinc sulphate taken orally appears to act by the local action of zinc ions on the gastric mucosa. Frommer D J, Med J of Australia 1975; 2:793-796.
Zinc promotes the healing of ulcers and gastric erosions and thickening of the mucous layer, which would buffer excess acid. Zinc inhibits gastric acid secretion within seconds and the effect on parietal cells of the gastric mucosa is prolonged.
Zinc compounds have anti-inflammatory and anti-infective properties. Zinc has an inhibitory effect on the release of histamine from mast cells due to its stabilizing effect of the mast cell membrane. Mast cells isolated from specimens of atherosclerotic plaques contained matrix metalloproteinase type 9, one of the enzymes that can produce collagen degradation. Kovanen Pt, et al. J. Am College of Cardiology 1998; 32:606-612. Zinc can inhibit the growth of Streptococci and Actinomyces bacteria when used as a dentifrice. Zinc compounds have antiseptic, antifungal, antiviral and astringent properties. As an astringent, zinc can be used therapeutically to arrest hemorrhage by coagulating blood, check diarrhea, reduce inflammation of mucus membranes, promote healing, toughen skin and decrease sweating. Zinc's dominant biological action is membrane stabilization. The inhibitory effect of zinc on allergy and immunology make it an excellent enhancement to glucosamine and chondroitin therapy.
Phospholipids, such as phosphatidylcholine (PC), combined with NSAIDs may facilitate absorption of the NSAID and reduce gastric ulceration. Combining PC with the NSAID can vary in dosage from 20 mg to 200 mg based on the delivery vehicle.
One of the side effects of ASA is salicylate inducted hearing loss and tinnitus. The inner ear has the highest concentration of zinc in the body. Studies have suggested that a zinc deficiency can cause a hearing-nerve impairment and tinnitus. Shambaugh G E Jr., Am J Otol 1989 March; 10(2):156-60. Salicylate-induced hearing loss was completely prevented by the simultaneous administration of zinc. Gunther T, Rebentisch E, Vormann J, J Trace Elem Electrolytes Health Dis 1989 March; 3(1):51-3. Zinc was also found to be useful in treating tinnitus. Ochi K, Ohashi T, et al Nippon Jibiinkoka Gakkai Kaiho 1997 September: 100(9):915-9.
In a preferred form of the invention, the composition uses a zinc salt with the dosage range of 5 to 60 mg per day (1-10%) in divided doses, and may be combined with an NSAID such as aspirin or by itself in a fast disintegrating tablet. Zinc salts are selected from a group consisting of, but not limited to: zinc sulfate, zinc chloride, zinc acetate, zinc phenol sulfonate, zinc borate, zinc bromide, zinc nitrate, zinc glycerophosphate, zinc benzoate, zinc carbonate, zinc carnosine, zinc citrate, zinc hexafluorosilicate, zinc diacetate trihydrate, zinc oxide, zinc peroxide, zinc salicylate, zinc silicate, zinc stannate, zinc tannate, zinc titanate, zinc tetrafluoroborate, zinc gluconate, and zinc glycinate.
It is a further object of this invention to incorporate a zinc compound, such as zinc gluconate or sulphate, to reduce inflammation, prevent gastric ulceration, prevent toxic side effects of NSAIDs, and treat and prevent endothelial dysfunction. The amount of a zinc compound is reduced when a rapidly disintegrating tablet is used because the agents are absorbed in the oral cavity.
Diabetes (diabetes mellitus) is a disorder of metabolism where the body cannot use blood sugar as energy causing hyperglycemia, either because it has too little insulin or because it cannot use the insulin it produces. Type-1 diabetes, often diagnosed in children, occurs when the immune system destroys pancreatic cells that make insulin. Type-2 diabetes, accounts for 90-95% of cases, develops later in life, and results from a resistance to insulin or a secretory defect. In the United States, 24 million or 8% of the population have diabetes and 79 million have prediabetes. By 2030, 10% of the world population will have diabetes, growing from 366 million in 2011 to 552 million as reported by the International Diabetes Federation.
Insulin is a hormone secreted by the pancreas that regulates carbohydrates and fat metabolism in the body. Insulin causes cells in the liver, muscle and fat tissue to take up glucose from the blood and store it a glycogen. Insulin, initially stimulates the dilation of terminal arterioles, which increases capillary recruitment without concomitant changes in total limb blood flow. Insulin stimulates the production of nitric oxide (NO) and secretion of endothelelin-1 (ET-1) from endothelial cells. Regulation of endothelial function by insulin results in the production and release of mediators. Activation of endothelial NO synthase (eNOS) increases production of NO. NO reduces the expression of adhesion molecules in endothelium, promotes vasorelaxation, and inhibits proliferation of vascular smooth muscle cells (VSNC) and adhesion, activation, secretion and aggregation of platelets. Potenza M A, et al, Vascular actions of insulin with implications for endothelial dysfunction, Am J Physiol Endocrinol Metab 2009; 297:E568-E577.
Vasodilation is one of the most important vascular effects produced by insulin. Insulin traverses the vascular endothelium via a transcellular, receptor-mediated pathway and may act on endothelium to facilitate its own transendothelial transport. A dysfunctional endothelium tends toward a vasoconstrictor, prothrombotic, and proinflammatory state secondary to the loss of NO bioactivity. Endothelial dysfunction is a key event in the pathogenesis of vascular complications for metabolic disorders, including diabetes, obesity, and the metabolic syndrome. Insulin therapy may directly improve endothelial function because insulin induces eNOS. Rask-Madsen, C, et al, Insulin therapy improves insulin-stimulated endothelial function in patients with type-2 diabetes and ischemic heart disease, Diabetes 2001; 50:2611-2618.
Chronic exposure to high insulin levels, such as occurs with insulin injections, may induce insulin resisitance, and endothelial dysfunction. Endothelial cells have insulin receptors, and insulin stimulates NO release from endothelial cells. Cleland S J, et al, Insulin action is associated with endothelial function in hypertension and type-2 diabetes, Hypertension 2000; 35 (2):5007-511. Sufficient insulin to normalize plasma glucose levels may reduce cardiovascular events and reduce new-onset diabetes (NEJM 2012; 367:319-328).
There are many sources of insulin (bovine, swine, human, etc) and many forms of insulin (fast acting, long acting, zinc and protamine zinc, etc.) but administration is primarily by injection or infusion pump. Delivery options include; dermal, nasal, pulmonary and oral. Oral insulin has focused on protecting insulin from proteolytic degradation in the stomach and upper portion of the small intestine. See Dhawan, S et al, Novel approaches for oral insulin delivery, Pharmaceutical Technology 2009; 33(7) for a full discussion of the many attempts at oral insulin delivery. The applicant is not aware of the delivery of insulin by means of an orally disintegrating tablet.
In the present invention, insulin, either as one form, such as fast acting or as a combination of various forms may be combined with mucoadhesive agents, permeation and penetration enhancers, ascorbic acid, unsaturated fatty acids, transferosomes, drug carriers, sugar based excipients, antioxidants, insulin sensitizers, anti-inflammatory agents, protease enzyme inhibitors and disintegrants. Mucoadhesive agents are natural, such as glucosamine, or synthetic and capable of attaching to mucosal surfaces to prolong the residence time for absorption of the active agent. An overview of mucohesive agents and permeation and penetration enhancers are listed in: Int J of PharmTech Research 2010; 2(1):719-735; Innovative Systems Design and Engineering 2010; 2(3) ISSN 2222-2871 (online); Pharm Tech November 1997: 58-86. The compounds cited in the articles are incorporated by reference.
Drugs having low bioavailability can be enhanced by various classes of transmucosal and transdermal penetration enhancers on the buccal mucosa Ind J Pharm Edu Res 2011; 45(4):370-374. Most oral insulin tablets are swallowed with various-agents to protect the insulin Pharm Tech; 2009; 33(7):16 pgs, or use a spray propellant J Diabetes Sci Technol 2009; 3(3):568-584. None of the techniques for oral insulin use an orally disintegrating tablet.
One preferred composition comprises bovine insulin (27 U/mg), mannitol, sucrose, crospovidone, glucosamine, sodium EDTA, stevia, ascorbic acid, color and flavor agents and magnesium stearate. The amount of insulin can vary depending on the purpose as either a support form of insulin for counteracting hyperglycemia when regular insulin is injected or for routine control of hyperglycemia in prediabetic conditions.
Hypertension contributes to endothelial dysfunction, particularly in coronary vessels. Mild hypertension is defined as a systolic pressure of 140 to 159 mm Hg and a diastolic pressure of 90 to 99 mm Hg. Untreated hypertension increases the incidence of stroke, coronary events, heart and renal failure and shortens life expectancy. Atherosclerosis is much more likely to appear in those parts of the circulatory system subjected to the highest blood pressure. In human hypertension, endothelial dysfunction has been documented in peripheral and coronary macro- and microcirculation and in renal circulation. Taddei S et al, J Cardiovasc Pharmacol 1998; 32 Suppl (3):S41-7.
Dietary supplements are products that people add to their diets and comprise; vitamins, minerals, herbs and other botanicals, amino acids, fatty acids, substances such as enzymes, organ tissues, glandulars and metabolites and other substances meant to improve ones diet. Dietary supplements that have been associated with improving exercise tolerance and recovery, lowering blood pressure and improving endothelial dysfunction and immune dysfunction. Supplements include, but are not limited to; magnesium, potassium, Coenzyme Q10, Vitamin A, B vitamins, Vitamin C, Vitamin D, Vitamin E, Vitamin K2, L-arginine, citrulline, flaxseed and fish oils, taurine, garlic, chromium, citicoline, chromium picolinate, phosphatidylserine. L-glutamine, glutathione, selenium, alpha-lipoic acid, folic acid, hawthorn, licorice extract, pantothenic acid, zinc salts, branched-chain amino acids (leucine, isoleucine, valine, etc), melatonin, resveratrol, C12 peptide, aliphatic alcohols such as policosanol and octacosanol, GABA, DHEA, GPC, alpha GPC, phospholipids, lutein, zeaxanthin, and various herbs, roots and botanicals.
Reversing oxidative stress and the subsequent inhibition of lipid peroxidation should improve endothelial dysfunction. Vitamin E supplements, 600 mg per day, in a double-blind trial showed improvement in endothelial-dependent dilation of the brachial artery. Vitamin C improved vascular dysfunction in diabetics. The combined effects of Vitamin C and E prevented endothelial dysfunction during transient hyperglycemia after oral glucose loading in healthy subjects. Guerci B, et al, Diabetes Metab (Paris) 2001, 27: 436-447.
Vasoprotective supplements such as Vitamins C and E, calcium, omega-3 fatty acids, L-arginine, citrulline, folic acid will improve endothelial function. Supplementation with folic acid and vitamin B12 improved brachial artery endothelium-dependent dilation in patients with CHD and that this action may be mediated through reduced concentrations of free plasma homocysteine. Chambers J C, et al, Circulation 2000; 102:2479-2483. B vitamins (folic acid, vitamin B6, vitamin B12) reduce homocysteine that cause endothelial dysfunction, impair vascular reactivity, promote inflammatory processes leading to age-related macular degeneration (AMD) and atherosclerosis. The combination of folic acid (2.5 mg), vitamin B6 (50 mg) and vitamin B12 (1 mg) reduced the risk of confirmed AMD by 34% and the risk of visually significant AMD by 41% over 7.3 years. Vitamin B12 is best delivered by ODT to be absorbed by the buccal mucosa due to denaturation of vitamin B12 by gastric juices.
Ascorbic acid (Vitamin C) reverses endothelial motor dysfunction in patients with coronary artery disease. Investigators found that long-term ascorbic acid treatment has a sustained beneficial effect on endothelium-derived nitric oxide action. Vita J A, Circulation 1999; 99:3234-3240. Vitamin C was also found to reverse endothelial dysfunction in cardiomyopathy. Figulla H R, et al, Am J Cardio 2001; 88:1001-1005. Doses of 500 mg/day lowered systolic blood pressure by 10% after one month.
Coenzyme Q10 (CoQ), a natural substance produced by the body, belongs to a family of compounds called quinones. CoQ therapy in doses of 50 mg/twice a day can reduce blood pressure and stabilize blood glucose levels. Hodgson J M, Eur J Clin Nutr 2002; 56:1137-1142. Similar results were obtained with calcium salts and alpha-lipoic acid supplementation. Vasdev S, et al, J Hypertens 2000 May; 18(5):567-73.
Magnesium intake of 10 to 40 mmol is associated with reductions in blood pressure. Miller E R, et al, Am J Hypertens 2002; 15:691-696. Oral magnesium and potassium salts contribute to the electrical stability of the heart. Zehender M, et al, J Am Coll Cardiol 1997; 29:1028-1034. Magnesium oral doses range from 10-50 mg but can be reduced with fast dissolving tablets. Potassium supplementation can prevent and treat hypertension, especially in those who are unable to reduce their sodium intake. Whelton P K, Semin Nephrol 1999 September; 19(5):494-9. Modest increases in dietary potassium of 48 to 60 mmol/day lowers blood pressure in elderly hypertensive subjects. Fotherby M D, Int J Clin Pract 1997 June; 51(4):219-22.
The enzyme nitric oxide synthase generates nitric oxide (NO) from the amino acid L-arginine. NO is responsible for vasodilator tone in the coronary arteries and the regulation of blood pressure in the systemic arteries. Arginine supplementation reverses endothelial dysfunction and lowers blood pressure. Siani A, et al, Am J Hypertens 2000 May; 13(5 Pt 1):547-51. Oral dose of L-arginine ranges for 50-5,000 mg.
Citrulline, an amino acid, like arginine can be converted into nitric oxide. Citrulline is transformed in the kidneys to arginine and necessary for endothelial health. Oral doses for citrulline ranges from 50-600 mg.
Taurine reverses endothelial dysfunction, and restored endothelial function in smokers to that of nonsmokers. Taurine has a protective effect on endothelial structure and function and restores nitric oxide synthase protein expression. Fennessy F M et al. Circulation 2003; 107:410-415.
Melatonin inhibits NO production both in vivo and in vitro. It inhibits bradykinin-induced NO production by endothelial cells. Low levels of melatonin are associated with an increased risk of adverse cardiovascular events after myocardial infarction. Melatonin regulates cycles of sleep and wakefulness and has been reported to reduce tinnitus. Dosage can range from 0.5-5.0 mg.
Melatonin is a free radical scavenger and antioxidant and has a high lipid and aqueous solubility allowing it to cross the blood-brain barrier into the circulation and cell organelles. Some of the conditions improved with melatonin use include; sleep disorders, jet lag, glaucoma, cataracts, depression, amyloid aggregation in Alzheimer's disease, septic shock, brain, heart and lung aging, skeletal muscle ischemia, tinnitus, Parkinson's disease and arrhythmias. Recent studies have shown that fluoride in the water systems, monosodium glutamate (MSG) in foods, and aspartame reduce the production of melatonin. Supplemental melatonin ranges from 1 mg to 20 mg per day.
Casein-derived protein hydrolysate (C12 Peptide) has angiotensin-converting enzyme (ACE) inhibiting properties and can also reduce plasma angiotensin II and aldosterone levels. Dosage can range from 25-1,500 mg.
Policosanol is a mixture of higher primary aliphatic alcohols isolated from sugar cane, whose main component is octacosanol, is known to reduce systolic and diastolic blood pressure. This supplement also inhibits platelet aggregation and has cholesterol lowering properties. Mas R, et al, Asia Pac J Clin Nutr 2004; 13(Suppl):S101. Gluni-Berthold I, Berthold H K, Am Heart J 2002 February; 143(2):356-65.
To the mixture may also be added; dyes, flavorings, cranberry extract, grapeseed extract, blueberry extract, sweeteners, pigments, antioxidants, antibacterial agents, anti-inflammatory agents, effervescent salts, probiotics, prebiotics, bismuth compounds, such as those known to persons skilled in the art may be added in amounts sufficient to impart their particular characteristic.
The above-mentioned patents are hereby incorporated by reference.
Orally disintegrating tablet (ODT) technology consists of a solid dosage form containing medicinal substances which rapidly dissolves, usually in less than 60 seconds when placed on the tongue. Since 40% of the population have difficulty swallowing pills, many do not take their medications. The ODT can be made by many techniques, including direct compression, wet granulation and lyophilization. Sugar based excipients such as mannitol, sorbitol, dextrose, fructose and zylitol are blended with disintegrants such as microcrystalline cellulose, effervescent agents, alginic acid and crospovidone.
Absorption of therapeutic agents from the oral cavity provides direct entry into the systemic circulation, thus avoiding the first-pass effect of the liver and degradation in the gastrointestinal tract. It is estimated that the permeability of the buccal mucosa of the oral cavity is 4 to 4000 times greater than that of the skin. ODT provides many advantages over the use of regular pills that must be digested in the GI tract.
The compositions may be in the form of chewable tablets. They may be formulated from compressible carbohydrates comprising mannitol, sorbitol, dextrose, sucrose and mixtures thereof, combined with binders such as cellulose, starch, gums, gelatin, fats and oils. Sweeteners, flavors and color agents may be added to the active agent or drug and compressed into a chewable tablet.
The compositions may be in the form of a powder that is added to water or other liquid for swallowing. Effervescent salts may be added to the composition along with flavor and color agents.
Many variations of the present invention will suggest themselves to those skilled in the art in light of the above-detailed description. All such obvious modifications are within the full intended scope of the appended claims. This invention is further illustrated by the following examples which are to be regarded as illustrative only, and in no way limit the scope of the invention.
Example 1










Fast dissolving tablet for aspirin



















Acetylsalicylic acid
81
mg



Mannitol
120
mg



Sorbitol
100
mg



Crospovidone
30
mg



Glucosamine sulfate
25
mg



Aspartame
5
mg



Zinc gluconate
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg










The fast dissolving tablet in Example 1 provides aspirin for rapid absorption by the buccal mucosa.
Example 2










Fast dissolving tablet for aspirin, extra strength



















Acetylsalicylic acid
160
mg



Mannitol
120
mg



Sorbitol
100
mg



Crospovidone
30
mg



Glucosamine sulfate
25
mg



Aspartame
5
mg



Zinc gluconate
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg










The fast dissolving tablet in Example 2 provides an extra strength aspirin for rapid absorption by the buccal mucosa.
Example 3










Fast dissolving tablet for aspirin.



















Acetylsalicylic acid
81
mg



Mannitol
120
mg



Sorbitol
100
mg



Crospovidone
30
mg



Aspartame
5
mg



Zinc gluconate
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg










The fast dissolving tablet in Example 3 provides aspirin for rapid absorption by the buccal mucosa with a zinc salt.
Example 4










Fast dissolving tablet for aspirin



















Acetylsalicylic acid
81
mg



Mannitol
120
mg



Sorbitol
100
mg



Crospovidone
30
mg



Glucosamine sulfate
25
mg



Aspartame
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg










The fast dissolving tablet in Example 4 provides aspirin for rapid absorption by the buccal mucosa with an amino sugar.
Example 5










Fast dissolving tablet for aspirin with an 


agent that suppresses gastric acid formation.



















Acetylsalicylic acid
81
mg



Mannitol
120
mg



Dextrose
100
mg



Crospovidone
30
mg



Glucosamine sulfate
25
mg



Misoprostol
20
mg



Aspartame
5
mg



Zinc gluconate
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg










The fast dissolving tablet in Example 5 provides aspirin and an agent that suppresses gastric acid formation for rapid absorption by the buccal mucosa.
Example 6










Fast dissolving tablet with 


ibuprofen for those with influenza



















Ibuprofen
100
mg



Mannitol
120
mg



Sucrose
100
mg



Crospovidone
30
mg



Glucosamine sulfate
25
mg



Amantadine
25
mg



Aspartame
5
mg



Zinc gluconate
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg









The fast dissolving tablet in Example 6 provides an NSAID for those who may have influenza combined with one or more antivirals to prevent endothelial dysfunction.
Example 7










Fast dissolving tablet with aspirin for lowering blood


pressure and/or providing cardiovascular protection



















Mannitol
120
mg



Sucrose
100
mg



Magnesium taurate
100
mg



Acetylsalicylic acid
81
mg



Potassium citrate
50
mg



Crospovidone
30
mg



Glucosamine sulfate
25
mg



Vitamin E
25
mg



Aspartame
5
mg



Coenzyme Q10
5
mg



Vitamin B3
5
mg



Vitamin B6
5
mg



Zinc gluconate
5
mg



Stearic acid
2
mg



Policosanol
2
mg



Magnesium stearate
2
mg



Folic acid
80
mcg



Vitamin B12
20
mcg









The fast dissolving tablet in Example 7 provides a composition of blood pressure lowering and/or cardiovascular protection with lipid lowering dietary supplements and aspirin.
Example 8










Fast dissolving tablet for lowering blood pressure



















Mannitol
120
mg



Sucrose
100
mg



Magnesium taurate
100
mg



Potassium citrate
50
mg



Crospovidone
30
mg



Glucosamine sulfate
25
mg



Vitamin E
25
mg



Aspartame
5
mg



Coenzyme Q10
5
mg



Vitamin B3
5
mg



Vitamin B6
5
mg



Zinc gluconate
5
mg



Stearic acid
2
mg



Resveratrol
2
mg



Magnesium stearate
2
mg



Policosanol
2
mg



Vitamin K2
20
mcg



Folic acid
80
mcg



Vitamin B12
20
mcg









The fast dissolving tablet in Example 8 provides a composition of blood pressure lowering and/or cardiovascular protection with lipid lowering dietary supplements.
Example 9










Fast dissolving tablet for improving exercise recovery



















Mannitol
120
mg



Sucrose
100
mg



Magnesium taurate
100
mg



Potassium citrate
50
mg



Crospovidone
30
mg



Glucosamine sulfate
25
mg



Vitamin E
25
mg



Creatine
25
mg



Sodium chloride
10
mg



Bromelain
5
mg



Aspartame
5
mg



Coenzyme Q10
5
mg



Vitamin B3
5
mg



Vitamin B6
5
mg



Zinc gluconate
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg



Folic acid
80
mcg



Vitamin B12
20
mcg









The fast dissolving tablet in Example 9 provides a composition of supplements to prevent endothelial dysfunction and improve exercise tolerance and recovery.
Example 10










Fast dissolving tablet for improving exercise recovery



















Mannitol
120
mg



Sucrose
100
mg



Potassium citrate 
50
mg



Citrulline
50
mg



Crospovidone
30
mg



Leucine
25
mg



Creatine
25
mg



Isoleucine
15
mg



Valine
15
mg



Sodium chloride
10
mg



Bromelain
5
mg



Aspartame
5
mg



Zinc gluconate
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg



Folic acid
80
mcg



Vitamin B12
20
mcg









The fast dissolving tablet in Example 10 provides a composition of supplements to prevent endothelial dysfunction and improve exercise tolerance and recovery.
Example 11










Fast dissolving tablet for 


asthma or anaphylactic shock



















Mannitol
120
mg



Sucrose
100
mg



Crospovidone
30
mg



Epinephrine
30
mg



Aspartame
5
mg



Epinephrine
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg









The fast dissolving tablet in Example 11 provides a composition to treat asthma and anaphylactic shock.
Example 12










Fast dissolving tablet for a zinc compound



















Mannitol
120
mg



Sucrose
100
mg



Crospovidone
30
mg



Vitamin E
25
mg



Zinc gluconate
10
mg



Aspartame
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg









The fast dissolving tablet in Example 12 provides a composition to treat endothelial dysfunction.
Example 13










Fast dissolving tablet for an amino sugar



















Glucosamine
200
mg



Mannitol
120
mg



Sucrose
100
mg



Crospovidone
30
mg



Vitamin E
25
mg



Aspartame
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg









The fast dissolving tablet in Example 13 provides a composition to treat endothelial dysfunction.
Example 14










Fast dissolving tablet containing melatonin


and prevent endothelial dysfunction.



















Mannitol
120
mg



Sucrose
100
mg



Crospovidone
30
mg



Aspartame
5
mg



Melatonin
1
mg



Stearic acid
2
mg



Magnesium stearate
2
mg









The fast dissolving tablet in Example 14 provides a composition to treat H. pylori infection and endothelial dysfunction.
Example 15










Fast dissolving tablet containing dietary supplements to prevent 


endothelial dysfunction associated with cognitive decline.



















Mannitol
120
mg



Sucrose
100
mg



Crospovidone
30
mg



Aspartame
5
mg



Melatonin
1
mg



Magnesium stearate
2
mg



Coenzyme Q10
2
mg



Vitamin B3
10
mg



Vitamin B12
10
mcg



Vitamin C
20
mg



Vitamin E
2
mg



Alpha-glycerophosphocholine (alpha-GPC)
25
mg



Citicoline
8
mg



Resveratrol
5
mg



Acetyl L-carnitine
10
mg










Example 16










Powder composition for aspirin



















Acetylsalicylic acid
81
mg



Mannitol
50
mg



Sorbitol
50
mg



Crospovidone
30
mg



Glucosamine sulfate
25
mg



Calcium carbonate
10
mg



Aspartame
5
mg



Zinc gluconate
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg









The powder composition in Example 16 is added to a liquid and absorbed by the buccal mucosa and gastrointestinal tract.
Example 17










Chewable tablet for aspirin



















Acetylsalicylic acid
81
mg



Mannitol
120
mg



Sorbitol
100
mg



Microcrystalline cellulose
80
mg



Glucosamine sulfate
25
mg



Hydrolyzed gelatin
10
mg



Aspartame
5
mg



Zinc gluconate
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg









The chewable tablet in Example 17 provides aspirin for those with difficulty swallowing regular tablets and has absorption by the buccal mucosa.
Example 18










Fast dissolving tablet containing probiotics to treat 


H. pylori infections and prevent endothelial dysfunction.



















Mannitol
120
mg



Sorbitol
100
mg



Lactobacillus acidophilus (5 billion units)
100
mg



Crospovidone
30
mg



Aspartame
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg









The fast dissolving tablet of Example 18 provides a composition to treat H. pylori infection and endothelial dysfunction.
Example 19










Fast dissolving tablet containing vitamins, minerals, electrolytes


and supplements to prevent endothelial dysfunction



















Mannitol
120
mg



Sucrose
100
mg



Magnesium taurate
100
mg



Potassium citrate
50
mg



Crospovidone
30
mg



Glucosamine sulfate
25
mg



Vitamin E
25
mg



L-citrulline
15
mg



Ascorbic acid
15
mg



Stevia
5
mg



Coenzyme Q10
5
mg



Vitamin B3
5
mg



Vitamin B6
5
mg



Vitamin D3
5
mg



Zinc gluconate
5
mg



Stearic acid
2
mg



Magnesium stearate
2
mg



Folic acid
80
mcg



Vitamin B12
20
mcg









Fast dissolving tablet containing supplements to treat and prevent endothelial dysfunction
Example 20










Fast dissolving tablet containing insulin 


to treat and prevent endothelial dysfunction.



















Mannitol
220
mg



Sucrose
100
mg



Starch
70
mg



Crospovidone
30
mg



Glucosamine sulfate
20
mg



Ascorbic acid
20
mg



NaEDTA
10
mg



Mango color
7
mg



PeachMango flavor
7
mg



Stevia
5
mg



Insulin
4
mg



Magnesium stearate
2
mg









The fast dissolving tablet of Example 20 provides a composition to deliver insulin to treat and prevent endothelial dysfunction.

## Claims

1. A composition comprising;
amino sugar (0.5-4%)
dietary supplements (25-70%)
mucoadhesive (0.5-20%)
in the form of a rapidly disintegrating tablet,
or optionally in the form of a chewable tablet or powder to accelerate local and systematic absorption.

2. A composition comprising;
insulin (0.5-10%)
mucoadhesive (1-40%)
one or more permeation enhancers (0.1-10%)
in the form of a rapidly disintegrating tablet,
or optionally in the form of a chewable tablet or powder to accelerate local and systematic absorption,
wherein the composition treats and reduces endothelial dysfunction in mammals.

3. The composition of claim 2, wherein the composition further comprises one or more agents selected from a group comprising; flavorings, sweeteners, pigments, antioxidants, immune stimulants, antibacterial agents, effervescent agents, and anti-inflammatory agents.

4. A method for the treatment and reduction of endothelial dysfunction in a mammal, comprising administering to the mammal a composition comprising;
insulin,
mucoadhasive,
one or more permeation or penetration enhancers,
in the form of a rapidly disintegrating tablet,
or optionally in the form of a chewable tablet or powder to accelerate local and systemic absorption.

5. The method of claim 4, wherein the composition further comprises one or more agents selected from a group comprising; flavorings, sweeteners, pigments, antioxidants, immune stimulants, antibacterial agents, effervescent agents, and anti-inflammatory agents.