CKD And ESRD.

FIELD OF THE INVENTION.

The present invention introduces novel composition in granules form to be used for enteric dialysis to eliminate toxins and other metabolic waste products, this composition consists of oral Ispaghula seed/husk in granules form coated with three types of polyclonal antibodies that adsorb uremic toxins and their precursors within the gastrointestinal tract, allowing them to be excreted in the feces preventing any progression of CKD.

BACKGROUND OF THE INVENTION

10% of the population worldwide is affected by chronic kidney disease (CKD), and millions die each year because they do not have access to affordable treatment. According the 2010 Global Burden of Disease study, chronic kidney disease was ranked 27 ^th in the list of causes of total number of deaths worldwide in 1990, but rose to 18 ^th in 2010. This degree of movement up the list was second only to that for HIV and AIDs. Over 3 million people worldwide currently receive treatment with dialysis or a kidney transplant to stay alive, yet this number may only represent 10% of people who actually need treatment to live of the 2 million people who receive treatment for kidney failure, the majority are treated in only five countries - the United States, Japan, Germany, Brazil, and Italy. These five countries represent only 13% of the world population. Only 25% are treated in about 100 developing countries that make up over 50% of the world population More than 80% of all patients who receive treatment for kidney failure are in affluent countries with universal access to health care and large elderly populations. It is estimated that number of cases of kidney failure will increase disproportionately in developing countries, such as China and India, where the number of elderly people is increasing. In middle-income countries, treatment with dialysis or kidney transplantation creates a huge financial burden for the majority of the people who need it. In another 112 countries, many people cannot afford treatment at all, resulting in the death of over 2 million people annually from untreated kidney failure. In the US, treatment of chronic kidney disease is likely to exceed $55 billion per year. Treatment for kidney failure consumes 7.1% of the total Medicare budget to care for less than 2% of the covered population. In people aged 60 through 75 worldwide, it is estimated that one in five men, and one in four women, have CKD. Chronic kidney disease is a worldwide health crisis. For example, in the year 2005, there were approximately 60 million deaths worldwide, with 37 million attributed to chronic disease; according to the World Health Organization. Chronic kidney disease can be treated. With early diagnosis and treatment, it's possible to slow or stop the progression of kidney disease. “Treatments are urgently needed to reduce the risk of progression to kidney failure and improve the lives of patients with kidney di seases.

A number of treatment attempts have been based on the use of the intestinal tract as a substitute for kidney function. During a normal digestive process, the gastrointestinal tract delivers nutrients and water to the bloodstream and eliminates some waste products and undigested materials through the bowel. The intestinal wall regulates absorption of nutrients, electrolytes, water and certain digestive aiding Substances Such as bile acids. The intestinal wall also acts as a Semi-permeable membrane allowing Small molecules to pass from the intestinal tract into the bloodstream and preventing larger molecules from entering the circulation.

Nitrogenous wastes such as urea, creatinine and uric acid, along with several other Small and medium molecular weight compounds, flow into the Small intestine and equilibrate across the Small intestine epithelium. Several Studies of intestinal dialysis have shown a daily flow of 70-74 grams of urea, 2.5-1.9 grams of creatinine, 2.3-3.0 grams of uric acid into the intestinal fluid Various invasive and noninvasive attempts including external gut fistula, intestinal dialysis, induced diarrhea, and administration of oral Sorbents and/or encapsulated urease enzyme have been made to extract uremic waste from the gastrointestinal tract

The gut is one of the main sources of uremic toxins resulting from the digestion of proteins that are transformed by the intestinal wall to the blood stream [Urea, creatinine and uric acid] are considered the most formed toxic nitrogenous protein.

Urea and ammonia are the end products of Nitrogen metabolism that derived from dietary protein intake.

Creatinine is a waste product from protein in the diet and from the muscles of the body. Creatinine is removed from the body by the kidneys; as kidney disease progresses, the level of creatinine in the blood increases.

Uric acid is a major endogenous antioxidant and peroxynitrite scavenger. Xanthine oxidase oxidizes oxypurines such as xanthine and hypoxanthine to uric acid. In humans and higher primates, uric acid is the final oxidation product of purine catabolism.

DETAILED DESCRIPTION OF THE INVENTION

Our invention depends on catching these three formed toxic peptides.

IgG polyclonal antibodies to urea, creatinine and uric acid are a sheep antibody generated to capture urea, creatinine and uric acid during the passage of these toxic materials from blood stream to intestinal wall.

Anti-Creatinine antibody is a sheep polyclonal antibody tightly connect to the surface of Ispaghula seed granules, designed specifically to capture the creatinine protein only not other similar one, 5 gm of the granules has polyclonal antibodies sufficient to collect from 1.2 to 1.6 gm of creatinine /day through the intestinal passage. Anti-uric antibody is a sheep polyclonal antibody tightly connect to the surface of Ispaghula seed granules, designed specifically to capture the uric acid protein, 5 gm of the granules has polyclonal antibodies sufficient to collect from 1.5 to 1.8 gm of uric /day through the intestinal passage.

Anti-urea antibody is a sheep polyclonal antibody tightly connect to the surface of Ispaghula seed granules, designed specifically to capture the urea protein only not other similar one, 5 gm of the granules has polyclonal antibodies sufficient to collect from 40.0 to 45.5 gm of creatinine /day through the intestinal passage.

The present invention provides a composition and method for enteric dialysis.

SUMMARY OF THE INVENTION.

The present invention provides a method of reducing urea, creatinine and uric acid concentrations through the attachment of IgG polyclonal antibody specific to each of those three formed metabolites forming a complex in the bowel, thus reduces the urea, creatinine and uric acid concentrations in a host suffering from elevated uremic toxins

The purpose of the present invention is to provide a composition for enteric dialysis comprising an Ispaghula seed/husk (Indian flea seeds, Indian flea seeds husks) which has an influence on the motility of the large intestine (stimulation of peristaltic contractions and inhibition of local contractions) resulting in accelerated colonic transit and - due to reduced contact time - in reduced fluid absorption. In addition, water and electrolytes are secreted by stimulation of the active chloride secretion. Which reduces the urea concentration when ingested by a host? DETAILED DESCRIPTION OF THE INVENTION.

In kidney failure there is a decrease in the glomerular filtration rate and the kidneys are unable to maintain homeostasis of the blood. Homeostatic balance of water, body electrolytes [ Sodium, potassium, calcium and other Salts] is no longer possible and nitrogenous wastes are not excreted. Retention of water causes edema and as the concentration of hydrogen ions increases, acidosis develops.

Nitrogenous wastes accumulate and a condition referred to as uremia develops in the blood and tissue. Uremic toxins can be defined as Solutes that: (I) am normally excreted by healthy kidneys, (ii) accumulate progressively during the development of renal failure So that their concentration increases, and (iii) inhibit various physiologic and biochemical functions, as a whole, they contribute to a complex Set of clinical Symptoms that comprise the Uremic Syndrome. Examples of uremic toxins include, but are not limited to, ammonia, urea, creatinine, phenols, indoles, and middle molecular weight molecules. More specifically, in uremia, the concentration of Serum creatinine, blood urea nitrogen (BUN), uric acid is significantly altered with accompanying abnormalities in acid-base equilibrium, electrolytes and water retention. In addition, there are several known and unknown Substances of low and middle molecular weight which have been identified as uremic toxins which also accumulate. If untreated the acidosis and uremia can cause coma and eventually death. The introduction of renal dialysis has contributed to rapid progress in the clinical treatment of renal failure and elucidation of uremia. When a patient has mild kidney failure where the serum creatinine level is less than 400 mmol/L, the patient does not require renal replacement therapy Such as dialysis or renal transplant. However, in general, when the Serum creatinine level rises to 900 umol/ L, the patient needs routine dialysis or a kidney transplant to Survive.

An object of the present invention is to provide a composition for enteric dialysis comprising spherical particles of Ispaghula seed/husk coated with three types of polyclonal antibodies to reduce the urea concentration when ingested by a host. Dialysis can serve as a lifetime therapy for ESRD patients. However, dialysis is very expensive, inconvenient, time consuming and may occasionally produce one or more Side effects. With a Successful kidney transplant, a patient can live a more normal life with less long-term expense. However, there are also high costs associated with transplant Surgery, the recovery period and the continuous need for anti-rejection medications. Further, there are often times a shortage of Suitable donors. Accordingly, there is a need for alternative Strategies.

Nitrogenous wastes which accumulate in uremia flow into the gut by diffusion.

The present invention provides a formulation of comprise Ispaghula seed/husk granules, Ispaghula seed is widely used for treatment of constipation due to its mucilaginous components. When it mixed with water it was swelling due to its mucilaginous seed coat which gives bulk and lubrication. Ispaghula seed increases the volume of the feces by absorbing water in the gastrointestinal tract, which stimulates peristalsis. The intraluminal pressure is decreased, colon transit is increased, and the frequency of defecation is increased.

These granules were coated with cryogel as ligand to adsorb the antibodies on the granules surface, the potential use of complexation cryrogel ligand systems coated the granules as an effective antibody oral delivery platform. These cryogel microparticles provide the ability to protect the antibody from the harsh acidic environment of the GI tract and release it in the neutral pH of the small intestine where the antibody can be stay for a long time. Additionally, these particles preserve antibody bioactivity upon release resulting in increased performing their biological function. A Complementary study done to investigate the efficacy of the formulations based on these particles for in vivo protection in a disease model. A three types of IgG polyclonal antibodies to urea, creatinine and uric acid were coated the granules surface and linked with the cryogel ligands, Instillation of Such composition permit reduction in frequency and even elimination of the need for dialysis. PRO ® A granules of the present invention are sheep polyclonal antibodies produced to be able to capture specific toxic proteins in the intestinal cavity. They are beneficial antibodies cabling to reduce the elevated serum level of urea, creatinine and uric acid.

Just administering these granules with cup of water two times daily two hours after a meal intake the granules with its coated antibodies will retain in the intestinal tract for about 6-8 hrs. To receive the penetrating toxic materials (urea, creatinine and uric acid) from blood capillaries to the permeable cell membrane of the intestinal tract, every type of the specific polyclonal antibodies capturing its specific toxic protein on the seed granule surface forming a heavy complex molecules from urea/anti urea abs , creatinine/anti creatinine Abs and uric acid/anti uric acid Abs, Ispaghula seeds also is permeable for water from its surface leads to swelling of the granule particle gave a wide surface area for more complexes formation that prevent the reverse pass way of these large molecules again to the blood stream and influence the motility of the large intestine (stimulation of peristaltic contractions and inhibition of local contractions) resulting in accelerated colonic evacuation.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 (A, B and C) were

A- Ispaghula seed/husk granules.

B- is the cryogel ligand to adsorb the antibodies on the granules surface. C- represent the granules coated with the cryogel ligand. Figure 2 (D, E, F and G) were

D- is IgG polyclonal Abs to urea E- IgG polyclonal ab to uric acid F- IgG polyclonal ab to creatinine

G- is the final form for every granule in our invention, every granule has cryogel ligand catches three types of IgG polyclonal Abs in its outer surface.

Figure 3 (H, I, J, K, L and M) were

H- is the lumen of blood vessel

I- is the toxic small molecules (urea, creatinine and uric acid that passed from the blood vessel to intestinal cavity

J- represent the intestinal epithelial lining

K- were the granules accumulate in the intestinal cavity coated with its three types of Abs,

L- shows the capture of the antibodies to the toxic material passed through the blood vessel to the intestinal cavity

M- is the inability of the large complexes molecules to pass again through the intestinal lining cells to the blood vessel again.

Figure 4 (N and O) were

N- is the formation of urea/Anti urea- creatinine/Anti creatinine-uric/Anti uric acid complexes in coated surface of the granules to be ready to evacuate with the action of seeds peristalsis physiological action

O- represent the waste products excretion via the intestinal bowl