Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-05-15
2004-03-16
Lankford, Jr., Leon B. (Department: 1651)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S725000, C424S780000, C424S234100
Reexamination Certificate
active
06706287
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to pharmaceutical compositions and methods of using these compositions to treat renal, hepatic and gastrointestinal diseases by eliminating toxins and other metabolic waste products and reducing or retarding undesirable bacterial over growth. In one embodiment, the pharmaceutical composition comprises a prebiotic, a probiotic, an ammoniaphilic bacteria, and sorbents, all of which are microencapsulated and/or enteric coated. Alternatively, the probiotic, prebiotic and ammoniaphilic bacteria are administered together in a microencapsulated gelatin capsule, while the sorbents, if needed, are administered separately in a microencapsulated and/or enteric coated formulation. These pharmaceutical compositions are useful in treating renal and hepatic diseases and bacterial overgrowth in the gastrointestinal tract.
BACKGROUND OF THE INVENTION
Kidney disease is ranked fourth among the major diseases in the United States afflicting over 20 million Americans. More than 90,000 patients die each year because of kidney diseases. In recent years the number of chronic kidney failure patients has increased about 11 percent annually. About 80,000 Americans on dialysis die of various complications each year and more than 27,000 are on waiting lists for kidney transplants each year with only about 11,000 of these patients receiving transplants. Further, nearly 250,000 Americans suffer from end stage renal disease (ESRD), which is the final stage in chronic renal failure.
In normal, healthy humans, metabolic waste nitrogen is primarily excreted via the kidneys as urea in the urine. However, in individuals with kidney disease, as well as a number of other diseases such as inborn errors in urea cycle enzyme deficit, waste nitrogen accumulates in the body thereby manifesting toxic symptoms. Hyperammonium can lead to mental retardation and, in severe cases, coma.
Currently hemo- or peritoneal-dialysis and renal transplant are the only treatment modalities. However, the economic costs of these treatment modalities are extremely high. For example, in 1996 in the United States alone, the annual cost of ESRD treatment was over 14 billion dollars. In developing and underdeveloped countries with low health care budgets, ESRD patients are deprived access to such treatments due to their high costs. Accordingly, there is a need for alternative modalities of treatment for uremia.
A number of treatment attempts have been based on the use of the bowel as a substitute for kidney function. During a normal digestive process the gastrointestinal tract delivers nutrients and water to the bloodstream and eliminates 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. Studies of intestinal dialysis have shown a daily flow of 71 grams of urea, 2.9 grams of creatinine, 2.5 grams of uric acid and 2.0 grams of phosphate into the intestinal fluid (Sparks, R. E. Kidney Int. Suppl. 1975 Suppl 3, 7:373-376). Accordingly, 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 (Twiss, E. E. and Kolff, W. J. JAMA 1951 146:1019-1022; Clark et al. Trans. Am. Soc. Artif. Intrn. Organs 1962 8:246-251; Pateras et al. Trans. Am. Soc. Artif. Intrn. Organs 1965 11:292-295; Shimizu et al. Chemical Abstracts 1955 103:129004; Kjellstrand et al. Trans. Am. Soc. Artif. Intern. Organs 198127:24-29; and Kolff, W. J. Kidney Int. 1976 10:S211-S214).
Activated charcoal was the first oral sorbent studied for treatment of uremia. Activated charcoal is a highly porous material with large surface area obtained by carbonization of organic materials such as wood, petroleum, coal, peat, and coconut shell followed by activation with steam, carbon dioxide or chemicals such as zinc chloride. Solute adsorption by activated charcoal depends on a number of factors including concentration of the solute in bulk phase, chemical nature of the solute, temperature, and pH. In general, however, activated charcoal binds more avidly to non-polar solutes than polar solutes. In in vivo studies, 190 grams of activated charcoal was required to remove 450 mg of creatinine (Goldenhersh et al. Kidney Int. 1976 10:8251-8253). This reduced efficacy is believed to be due to adsorption of other lipophilic compounds such as cholesterol and related bile acids (Kolff, W. J. Kidney Int. 1976 10:8211-8214; Goldenhersh et al. Kidney Int. 1976 10:8251-8253). Microencapsulation of activated charcoal has been shown to reduce the amount of charcoal needed to 50 grams (Goldenhersh et al. Kidney Int. 1976 10:8251-8253).
AST-120, a proprietary and specially prepared, coated material of porous carbon of 0.2 to 0.4 mm, has been demonstrated to be a more effective charcoal based adsorbent. A dose of 3.2 to 7.2 grams to uremic patients has been disclosed to delay the rise in serum level of creatinine and delay the onset of renal dysfunction in nephrectomized rats as well as 27 uremic patients (Owadu, A. and Shiigai, T. Am. J. Nephrol. 1996 16(2):
124-7
; and Okada, K. and Takahashi, S. Nephrol. Dial. Transplant. 1995 10 (5):
671-6
). AST-120 as an oral adsorbent also delays the progression of renal failure (Miyazaki, T. et al. Nephrol Dial Transplant November 2000; 15(11):
1773-81
).
Several studies have shown that ingestion of dialdehyde starch, also referred to as oxystarch, results in increased excretion of non-protein nitrogen (Giordano et al. Bull. Soc. Ital. Biol. Sper. 1968 44:2232-2234; Giordano et al. Kidney Int. 1976 10:S266-8268: Friedman et al. Proc. Clin. Dia. Trans. Forum 1977 7:183-184). Unlike activated charcoal where adsorption of the uremic solute is a physical process easily reversible, dialdehyde starch binds urea and ammonia via chemisorption involving covalent binding to the two-aldehyde groups. However, like activated charcoal, ingestion of very large amounts of about 30-50 grams of oxystarch only removed 1.5 grams of urea. Additional studies wherein dialdehyde starch and activated charcoal were both ingested demonstrated some improvement in uremic waste removal (Friedman et al. Proc. Clin. Dia. Trans. Forum 1977 7:183-184). Further, coating of dialdehyde starch with gelatin and albumin resulted in 6-fold better sorbency as compared to uncoated dialdehyde starch (Shimizu et al. Chemical Abstracts 1982 97:222903). More recently, retardation of progression of chronic renal failure has been shown following administration of chitosan coated oxycellulose or cellulose dialdehyde (Nagano al. Medline Abstract UI 96058336 1995).
Locust bean gum, a naturally available carbohydrate based polymeric oral sorbent, when administered at 25 grams/day in cottonseed oil to uremic patients, was also demonstrated to remove significant amounts of urea, creatinine and phosphate. Further, locust bean gum adsorbs about 10 times its own weight in water (Yatzidis et al. Clinical Nephrology 197911:105-106). Dietary supplementation with gum arabic fiber has also been demonstrated to increase fecal nitrogen excretion and lower serum nitrogen concentration in chronic renal failure patients on low protein diets (Bliss et al. Am. J. Clin. Nutr.
1996 63:392-98
).
Encapsulated urease enzyme has also been investigated as a non-absorbable oral sorbent for binding ammonia. In early studies zirconium phosphate and encapsulated urease enzyme were used as a non-absorbable oral sorbent for binding ammonia (Kjellstrand et al. T
Dickstein Jack
Mehta Raj
Ranganathan Nataragan
Davis Ruth A.
Kibow Biotech Inc.
Lankford , Jr. Leon B.
Licata & Tyrrell P.C.
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