Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-08-25
2002-12-03
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C424S602000
Reexamination Certificate
active
06489361
ABSTRACT:
BACKGROUND OF THE INVENTION
Phosphorus retention plays a major role in chronic renal failure in the development of both secondary hyperparathyroidism and osteodystrophy. Bricker, N., S. et al.,
Archives of Internal Medicine
123:543-553 (1969); Rubini, M. E. et al.,
Archives of Internal Medicine
124:663-669 (1969); Slatopolsky, E., et al.,
Journal of Clinical Investigation
50:492-499 (1971); Bricker, N. S.,
New England Journal of Medicine
286:1093-1099 (1972); Slatopolsky, E. S., et al.,
Kidney Int
. 2:147-151 (1972).
Antacids are often used to bind dietary phosphorus to prevent phosphorus retention and prevent its absorption. This process is referred to as phosphorus binding and appears to be a chemical reaction between dietary phosphorus and the cation present in the binder compound, which is usually albumin or calcium. The binding results in the formation of insoluble and unabsorbable phosphate compounds, adsorption of phosphorus ions on the surface of binder particles, or a combination of both.
Presently-used antacids are inefficient at binding phosphorus in vivo. For example, a recent study by Ramirez, et al., noted that even though aluminum-containing or calcium-containing antacids were administered in large excess, they bound only 19-35 percent of dietary phosphorus. Ramirez, J. A., et al.,
Kidney Int
. 30:753-759 (1986). Similar conclusions can be derived from data presented in earlier studies. Kirsner, J. B.,
Journal of Clinical Investigation
, 22:47-52 (1943); Clarkson, E. M., et al.,
Clinical Science
43:519-531 (1972); Cam, J. M., et al.,
Clinical Science and Molecular Medicine
51:407-414 (1976); Man, N. K. et al.,
Proceedings of the European Dialysis and Transplantation Association
12:245-55 (1975).
Antacids are used widely, often in large quantities, for indigestion, heartburn or peptic ulcer disease. Despite their consumption in large amounts and often over long periods of time, phosphorus depletion is uncommon in these settings. This fact is additional evidence of the inefficiency of antacids as phosphorus binding agents.
The inefficiency of commonly used phosphorus binders creates a clinical dilemma. The dose of the binder must be increased to control hyperphosphatemia, but increased risk of toxicity of the binder results from the increased dose. This toxicity includes bone disease and aluminum dementia from aluminum-containing antacids and hypercalcemia and soft tissue calcification from calcium-containing antacids. These risks are particularly problematic in patients with chronic renal disease.
It would be very useful to have a phosphorus binder available which does not have the risks associated with ingestion of presently available binders. The binder should be more efficient in binding phosphorus and, thus, would not have to be consumed in the large quantities necessary, for example, when calcium carbonate-containing compositions are used. Such a phosphorus binder would be particularly valuable for administration to individuals with chronic renal failure, in whom phosphorus retention is a serious concern and the risk of toxicity from consumption of presently-available binders is greater than in individuals in whom kidney function is normal.
U.S. Pat. No. 4,870,105 addresses these concerns by disclosing a calcium acetate phosphorus binder. However, it would be advantageous to find a binder with a smaller anion and, hence, a smaller effective dose.
SUMMARY OF THE INVENTION
The present invention relates to a method of binding phosphorus in the gastrointestinal tract and, thus, reducing phosphorus absorption from the intestine. It also relates to a method of reducing serum phosphate levels because phosphorus bound in the gastrointestinal tract results in lower phosphorus absorption than would otherwise occur. It is particularly useful in the treatment and prevention of hyperphosphatemia in individuals with renal disease or other disease in which the ability to excrete phosphorus from the body (e.g., in the urine) is impaired.
The method of the present invention comprises orally administering to an individual a composition which includes calcium formate in sufficient quantity to effectively bind phosphorus, preferably present in food and beverages consumed by the individual, and prevent its absorption in the intestine. In an advantageous form of the invention, the calcium formate is administered at a dose of between 0.5 and 10.0 grams.
The present invention is also a pharmaceutical composition comprising calcium formate in combination with a pharmaceutically acceptable carrier. In a preferred embodiment, the composition comprises 0.5 grams of calcium formate per capsule or tablet. In another preferred embodiment, the composition comprises calcium formate and at least one additional therapeutic ingredient. In a most preferred embodiment, this therapeutic ingredient is a vitamin D compound, typically cholecalciferol.
It is a feature of the present invention that the amount of calcium-containing compound sufficient to inhibit gastrointestinal phosphorus absorption is 10% lighter than therapeutically equivalent amounts of previously known calcium acetate compounds.
Other objects, features and advantages of the present invention will become apparent to one of skill in the art after review of the specification and claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a calcium formate composition for oral administration to an individual. The composition is useful in reducing phosphorus absorption in the gastrointestinal tract. Calcium formate is shown below to be effective in inhibiting phosphorus absorption when administered orally in in vivo tests and has been shown to prevent the absorption of ingested phosphorus at a lower dose than other calcium-containing binders. As a result of these discoveries, calcium formate, alone or in combination with other materials, can be used to bind phosphorus in the gastrointestinal tract, thus reducing the percentage of an amount of phosphorus consumed (i.e., of a given “dose” of phosphorus) which is absorbed. Preferably, this dose would be 0.5-10.0 grams when adjusted to doses intended for human patients.
The present invention also relates to a method of inhibiting gastrointestinal phosphorus absorption. The method of the present invention is based on the demonstration that calcium formate is an effective binder of phosphorus when administered orally to an individual. The method comprises orally administering a quantity of calcium formate sufficient to bind with phosphorus in the gastrointestinal tract. Preferably, this dose is between 10-200 milliequivalents of calcium and is preferably present in either tablet or gelatin capsule form. In a most preferable form of the present invention, the oral dose is ingested at mealtimes.
As a result of the present invention it is possible to administer calcium formate to reduce absorption of dietary phosphorus, which has the net effect of reducing the risks of adverse effects (e.g., bone disease and secondary hyperparathyroidism) observed in individuals (e.g., chronic renal patients) in whom the ability to excrete phosphorus in the urine is impaired.
As used herein, the term “phosphorus” includes phosphorus and phosphate in its various forms (e.g. HPO
4
−
, PO
4
−3
, etc.).
According to the method of the present invention, calcium formate is administered, alone or in combination with other substances (e.g., in a hard gelatin capsule; along with materials necessary to form a tablet or caplet as a delivery vehicle for the calcium formate; or along with a second phosphorus binder or other pharmaceutically useful substance) in sufficient quantities to reduce phosphorus absorption in the gastrointestinal tract. The calcium formate is administered orally, preferably close in time to food and beverage consumption. By “at mealtimes” we mean within 30 minutes of a meal.
In one embodiment, 0.5-10.0 grams of anhydrous calcium formate (11-44 milliequivalents calcium) is taken prior to food consumption (e.g., meal time) and a second dose of 0.5-10.0
Criares Theodore J.
Kim Jennifer
Quarles & Brady LLP
Wisconsin Alumni Research Foundation
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