Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2002-02-14
2004-08-24
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S464000, C424S489000
Reexamination Certificate
active
06780437
ABSTRACT:
BACKGROUND
This invention generally provides coated potassium chloride granules that may be used to make extended release potassium chloride tablets. Specifically, the present invention provides ethylcellulose-coated crystals of potassium chloride that may be orally administered to a patient requiring potassium supplementation. The coated potassium chloride granules provide extended release of the potassium chloride in the gastrointestinal tract that results in substantially less irritation to the gastric mucosa.
The administration of many diuretics, commonly used to treat patients having hypertension, increases the excretion of both sodium and potassium. The acute administration of such diuretics to a patient normally causes no problems. However, chronic administration of diuretics to some patients can result in the depletion of potassium from the patient, a condition known as hypokalemia. Potassium depletion may be accompanied by a reduced tolerance to carbohydrates and a deficiency in glycogen deposition. Further, vasopressin-resistant polyuria is another complication. A deficit of potassium also appears to increase the renal synthesis of prostaglandins, which in turn can decrease the permeability to water of the distal nephron and produce a diabetes insipidus-like syndrome.
In order to avoid these complications, supplemental potassium administration is typically needed. When potassium is taken along with a normal diet it is slowly absorbed from the intestinal tract. Following potassium distribution and uptake by the cells, the kidneys excrete an appropriate amount to maintain a proper balance. As a consequence of a large volume of distribution and a rapid response of the kidney, the extracellular and intracellular concentrations of potassium are normally maintained within relatively narrow limits.
When potassium is administrated as a drug, the factors that govern the rate and extent of its distribution are of major importance. It is not possible to increase the total cellular content of potassium significantly above normal. However, it is very easy to raise the extracellular concentration excessively. It is the concentration of potassium in the extracellular fluid that determines life-threatening toxicity.
It is well known that large doses of potassium chloride taken orally can cause gastrointestinal irritation, purging, weakness and circulatory disturbances. Since potassium depletion can cause problems for the patient, a controlled or extended release formulation of potassium chloride that replenishes potassium in an acceptable manner without undesirable side effects is desired.
In an attempt to meet the need for suitable formulations that may be used as a potassium supplement, a number of different dosage formulations have been developed. U.S. Pat. No. 4,352,791 reports a composition of potassium and a therapeutically acceptable salicylate salt of salicylic acid. U.S. Pat. No. 4,340,582 reports an enteric coated tablet that may include potassium chloride. U.S. Pat. No. 4,259,323 reports a potassium chloride emulsion. U.S. Pat. No. 4,259,315 reports a controlled release potassium dosage from gelatin capsules that contain a mixture of ethylcellulose-encapsulated potassium chloride and a hydrophilic surfactant. Film-coated tablets containing potassium chloride in a wax matrix (non-enteric coated) are marketed as a slowly available potassium source. U.S. Pat. No. 4,235,870 reports a slow release pharmaceutical composition of a combination of higher aliphatic alcohols and hydrated hydroxyalkyl cellulose. U.S. Pat. No. 4,863,743 reports a controlled release potassium chloride tablet made of potassium chloride crystals coated with higher molecular weight (measured viscosity greater than 40 cP in toluene/ethanol) ethylcellulose and hydroxypropylcellulose. U.S. Pat. No. 5,397,574 reports controlled release potassium chloride micropellets coated with lower molecular weight (measured viscosity less than 10 cP in toluene/ethanol) ethylcellulose and a plasticizer.
SUMMARY OF THE INVENTION
This invention provides a potassium chloride granule that contains both crystals of potassium chloride and a thermoplastic cellulose ether that forms a coating on the crystals. No other agents, additives, surfactants, or coating and processing aids are used or included in the granule. In one embodiment of the invention the potassium chloride crystals have a size of about 20-60 mesh. In another embodiment the thermoplastic cellulose ether is ethylcellulose having a measured viscosity of about 20 cP.
This invention also includes an extended release tablet made of a plurality of the ethylcellulose-coated potassium chloride granules. The potassium chloride granules that are in the tablet are essentially free of surfactants or other processing additives and agents. The term “essentially free” indicates the absence of surfactants, additives, agents or coating and processing aids during the processing of the granules.
The invention also includes dosage units having different potencies, including 10 milliequivalents (mEq) potassium per unit, 15 mEq potassium per unit, and 20 mEq potassium per unit.
Further, the invention includes a process to produce ethylcellulose-coated potassium chloride granules comprising the steps of i) forming a fluidized bed of potassium chloride crystals at a dew point of about 10-20° C., ii) spraying the fluidized crystals with a mixture of only ethylcellulose, alcohol and water sufficient to coat the crystals, and iii) drying the coated crystals to remove the alcohol and water to provide ethylcellulose-coated potassium chloride granules.
The invention also provides a process for producing ethylcellulose-coated granules in which no additives are required during the spray-coating step for the control of static buildup in the fluid bed processor. The process comprises the steps of i) forming a fluidized bed of potassium chloride crystals, ii) spraying the fluidized crystals with a mixture consisting of ethylcellulose, alcohol, and sufficient water to control the buildup of static charge to enable substantially complete coating of the crystals, and iii) drying the coated crystals to remove the alcohol and water to provide ethylcellulose-coated potassium chloride granules.
Also provided by the present invention is a method for customizing a patient's supplemental potassium dosage regimen. The method comprises providing dosage units (such as, e.g., tablets) having different potencies, and then administering to the patient a suitable combination of dosage units to meet the patient's supplemental potassium requirements.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an extended release potassium chloride tablet that includes ethylcellulose-coated potassium chloride crystals. No other surfactants or processing additives and agents are used in, or are part of, the coating.
In the practice of the present invention, one suitable method for coating potassium chloride is by fluid-bed processing. Static buildup is typically controlled in ordinary fluid-bed processing methods by means of a processing additive. One undesirable consequence of excessive static buildup is that particulate material may stick to the walls of the processing chamber, which can result in reduced yield or efficiency. The material sticking to the walls will be incompletely coated and may not be included with the final product, leading to decreased yield. Material clinging to the chamber walls also complicates cleanup between processing runs. An additional consequence of the presence of excessive static is an increased risk of explosion. An explosion can be triggered by static discharge in the fluid bed environment, due to the large amounts of fine dust present and, in some cases, the presence of organic solvent vapors.
Some common additives that are used to control static buildup include magnesium stearate, titanium dioxide, and talc as well as commercially available products sold under the trade names STAT-LES by Walter G. Legge Company, Inc., Peekskill, N.Y., and LAROSTAT by PPG/Mazer Che
Christenson Bradley L.
Pieloch Mark J.
Faegre & Benson LLP
Page Thurman K.
Upsher-Smith Laboratories, Inc.
Young Micah-Paul
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