Controlled Release Potassium Dosage Form

This invention relates to oral administration forms of potassium, and more particularly to controlled release tablets or capsules containing potassium chloride in a form which releases the drug gradually over a prolonged period of time after ingestion to protect the gastrointestinal tract from the irritation and toxicity accompanying high potassium ion concentrations.

Potassium is the principal intracellular cation in mammals. It is present in a concentration of approximately 140 meg/L inside the cell. The intracellular potassium may be lost over a period of time from various stressful and debilitating conditions including diuretic drug treatment. As the intracellular potassium is depleted, various cells, including heart muscle, become dysfunctional, eventually resulting in death. Various means are available for correcting potassium loss, including direct intravenous injection and oral dosage forms.

Ironically, the potassium ion is quite toxic outside the cell. It normally has a concentration of about five meg/L in extracellular fluids. Levels that are much greater stop cell function. If the required therapeutic dose is injected in concentrated form intravenously, it may kill the patient instantly. When it is administered orally as the potassium chloride salt, it may cause irritation, inflammation and erosion of the mucosal lining of the gastrointestinal tract.

A variety of oral dosage forms of potassium have been developed to provide long term potassium supplements that are less harmful to the user.

U.S. Pat. No. 4,863,743 issued Oct. 5, 1989 to Hsiao provides a review of the prior art of oral therapeutic potassium supplements and the problems they present. He discloses a controlled release tablet formed from potassium chloride crystals coated with a coating mixture of ethylcellulose and one member selected from hydroxypropylcellulose and polyethylene glycol and compressed into tablets with microcrystalline cellulose and crosslinked polyvinylpyrrolidone. He found that low viscosity ethylcellulose was not suitable because the particles broke up during compression. He therefor recommended the high viscosity material of 100 cp., and claims are limited to greater than 40 cp.

U.S. Pat. No. 5,035,898 issued Jul. 30, 1991 to Chang et al. discloses potassium chloride crystals coated with a combination of high viscosity ethylcellulose and at least one of hydroxypropylcellulose and polyethyleneglycol as taught by Hsiao along with a magnesium salt.

The present invention is an oral dosage form of potassium chloride comprised of potassium chloride crystals coated with a coating comprised of a low viscosity ethylcellulose in combination with triacetin. Applicant has discovered that low viscosity ethylcellulose (10 cp.) when mixed with triacetin makes a coating which does not break when compressed into tablets. This is opposite to the teaching of Hsiao who had to use high viscosity (greater than 40 cp. ) ethylcellulose in combination with his other ingredients to reduce breakage on compression.

If any of the coated crystals break with their coating, then the drug is immediately in contact with the mucosa in crystal form, which is extremely irritating.

It is accordingly an object of the invention to provide drug crystals having a non-frangible coating so that the mucosa will be exposed initially to crystals with intact coating. The coating should be such that it is permeable to water and dissolved salt, thereby gradually releasing the drug after the tablet or capsule has dissolved and the individual coated crystals have dispersed.

An advantage of Applicant's coating formulation is that it is more efficient in coating by the fluidized bed coating process because the coating solution may be used at a higher concentration than the high viscosity materials of the prior art, as well as providing a stronger coating. The coated crystals or pellets may be compressed into tablets or introduced into gelatin capsules.

Another object of the present invention is to provide a safe method of treating patients suffering from potassium depletion.

These and other objects, advantages and features will become apparent to those skilled in the art upon further study of the detailed description.

Micropellets having potassium chloride cores and a water permeable but insoluble coating are first prepared.

The cores are prepared by passing crystalline potassium chloride through a sieve.

The coating solution is prepared by first dissolving ethylcellulose 10 cp. in alcohol and then dissolving triacetin in the solution.

The cores are then coated by spray coating with the solution in a fluidized bed coater and then dried in the coater to form micropellets with a non-frangible coating suitable for tabletting with appropriate tabletting agents without having the coatings fracture from the pressures associated with the tabletting process.

Because the ethylcellulose is of such a low viscosity, the coating solution may be made up in a much higher concentration for faster and more economical coating.

The plasticizer triacetin has been found to enable use of this low viscosity ethylcellulose while reducing frangibility of the resultant coating.

The finished coated micropellets are then ready for incorporation in capsules such as gelatin capsules by well known capsule filling techniques. The finished coated micropellets are then also ready for forming into tablets in combination with tabletting agents well known in the art such as microcrystalline cellulose, cross linked polyvinylpyrrolidone and myvatex to produce a tablet which readily dissolves in an aqueous environment to release the micropellets. The pellets are readily dispersed throughout the gut by the normal peristaltic activity. The individual pellets are permeable to water which passes through the coating to slowly dissolve the potassium chloride core. The dissolved salt passes out through the coating to the gastrointestinal fluid. The elution process is very slow. Because of the delayed release of the salt and the dispersal of the pellets, there are no areas within the gut mucosa subjected to a high concentration of the dissolved potassium. This eliminates the problems associated in the past with potassium supplements which caused irritation and even erosion of the gastrointestinal mucosa.

The following example describes a typical formulation of the coated micropellets, and methods of manufacture thereof:

The above dissolution data is presented as evidence that the coating of the pellets is so strong that the conversion into tablets has not caused any substantial early release of the salt such as would be harmful to the user.

The triacetin serves as a plasticizer in the coating which makes it more resistant to breakage. Other plasticizers which may be used for this purpose include: propylene glycol; triethyl citrate; tributyl citrate; and diethylphthalate. The coating may contain between 70-90% ethylcellulose.

The ethylcellulose may have a viscosity of less than 15 cp.

The potassium chloride is preferably between 20-50 mesh size.

The above disclosed invention has a number of particular features which should preferably be employed in combination although each is useful separately without departure, from the scope of the invention. While I have shown and described the preferred embodiments of my invention, it will be understood that the invention may be embodied otherwise than as herein specifically illustrated or described, and that certain changes in the form and arrangement of parts and the specific manner of practicing the invention may be made within the underlying idea or principles of the invention within the scope of the appended claims.