Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1998-08-12
2002-04-02
Dudash, Diana (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S468000, C424S494000, C424S497000
Reexamination Certificate
active
06365182
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the fields of pharmacy and medicine and in particular to dosage forms for the delivery of potassium.
BACKGROUND OF THE INVENTION
Potassium supplementation is used for patients who have hypokalemia without metabolic alkalosis, in digitalis intoxication and in patients with hypokalemic familial periodic paralysis. It is also used for the prevention of hypokalemia in patients at risk therefor. Potassium is a naturally occurring ion required for normal cell function. The K
+
ion can be depleted during therapies with diuretics, frequently used in treating hypertension and congestive heart failure. Oncology patients on highly restrictive diets also frequently need potassium replacement.
The typical potassium replacement patient is over 65 years old. Frequently, the patient is significantly older. Patients in this demographic may have difficulty swallowing large tablets for many reasons including dysphagia, a changed or diminished “gag” reflex. Oncology patients also are prone to swallowing difficulties. This would make swallowing tablets difficult under the best of circumstances. However, the current potassium replacement does not offer the best of circumstances. The tablets tend to be large, chalky, desiccating and difficult to swallow.
One of the leading potassium supplements is a potassium chloride formulation sold under the trademark K-DUR® available from Key Pharmaceuticals, Inc., Galloping Hill Road, Kenilworth, N.J. 07033. The approved label for K-DUR® tablets indicates that each tablet should be taken with a meal and with a full glass of water. Each dose should be taken without crushing, chewing or sucking the tablet. Patients who have difficulty in swallowing whole tablets may break the tablet in half and attempt to take each half separately with a glass of water. For those who still can't swallow the tablet, the label instructs one in how to prepare an aqueous water suspension. However, dispersing K-DUR® in water is inconvenient, can be difficult for older individuals and may require an excess of water to retrieve the entire dose from a glass. This poses a potential threat to patients with significant fluid restriction and an inconvenience to patients with incontinence problems.
The only alternative to the current potassium supplement is potassium given in a liquid form. However, these liquids have an extremely unpleasant metallic taste. The result is patients who are non-compliant. Non-compliance with potassium replacement therapy has been shown to lead to clinically significant health risks such as cardiac arrhythmia and sudden death. Therefore, there is a significant need for finding effective alternative delivery systems for potassium replacement therapy.
SUMMARY OF THE INVENTION
The present invention solves this need by providing an orally disintegrable tablet suitable for use in the delivery of potassium. The tablet contains between about 50 and about 80% coated potassium chloride crystals by weight of the tablet. These coated potassium chloride crystals have a particle size ranging from between about 100 to about 2,000 microns and include between about 10 and about 20% of a coating based on the weight of the coated potassium chloride crystals. The coating is generally an extended release coating. The tablet also includes between about 5 and about 35% of a rapidly dissolvable sugar or sugar alcohol filler. The rapidly dissolvable sugar or sugar alcohol filler has a particle size selected to be complementary to the particle size of the coated potassium chloride crystals and generally ranges between about 300 and about 1,500 microns. The tablet also includes between about 0 and about 15% of a binder, including insoluble filler-binders, between about 1 and about 10% of a disintegrant; and between about 0 and about 15% of an effervescent couple. The sugar or sugar alcohol, binder disintegrant and effervescent couple are all provided in amounts based on the weight of the finished tablet.
In a particularly preferred embodiment, the tablet of the present invention weighs between about 1200 and about 3000 mg and contains between about 5 and about 25 milliequivalents (mEq) of potassium. More preferable, the tablet will weigh between about 1300 and about 2800 mg and contain between about 10 and about 20 mEq of potassium.
The present invention solves the aforementioned problems by using some rather counterintuitive insights. First, the instructions approved by the Food and Drug Administration for use of potassium chloride tablets specifically direct one not to crush, chew or suck on such supplements. However, by employing just such a suckable formulation, it has been unexpectedly found that one is able to obtain an organoleptically pleasing dosage form—one that can enhance compliance. Second, one of the more daunting aspects of current potassium supplements is their relative size, chalkiness and desiccating nature. Particularly for older patients, such tablets present a significant problem. To overcome the problem of a large chalky tablet, one would seek to use either an entirely different dosage form (liquid, etc.), or find a way of reducing the tablet's size and volume. However, it has now been found that by actually increasing the amount of material administered, and to some lesser extent, the size of the resulting tablet, one is nonetheless able to obtain a dosage form which overcomes the difficulties and inabilities of the patients most likely to use same. It is indeed ironic that while one would think of making the potassium containing tablet lighter and/or smaller to overcome compliance issues, the answer was actually found by going in the completely opposite direction.
Third and even more surprisingly, if one were to ignore the instructions of the manufacturer, take a commercially available potassium chloride supplement tablet, and allow it to dissolve in their mouth, two things would happen. First, the tablet which contains upwards of 90% or more coated potassium chloride would take between about 40 seconds and a minute to actually disintegrate. Second, because the tablet contains such a significant quantity of insoluble coated active material, the results of disintegration would the formation of a “sandbox” in the patient's mouth; a most unpleasant sensation to say the least. This would be both unpleasant in the mouth and difficult to swallow.
It has now been found that by decreasing the relative proportion of active ingredients and supplementing with a rapidly water dissolvable filler, by selecting fillers and materials having relatively similar particle size to the coated active, one is actually able to obtain a tablet which is rapidly disintegrable in the mouth without the objectionable organoleptic properties of present formulations. Moreover, despite the fact that the size and volume of the tablet have actually been increased, the disintegration time is maintained and preferably decreased. A commercially available 10 milliequivalent potassium chloride tablet can dissolve in the mouth between 30 seconds and a minute as previously stated. In truth, disintegration times of about 45 seconds or more are to be expected. An otherwise equivalent formulation of the present invention, despite being 50% greater in overall weight nonetheless can substantially disintegrate in under 30 seconds.
The use of organoleptically pleasing ingredients such as a mild level of effervescence to stimulate the production of saliva and accentuate disintegration, and rapidly dissolving filler such as mannitol (mannitol has a negative heat of solution which further adds to the organoleptically pleasing nature of the formation), one obtains a dosage form which rapidly disintegrates and forms a watery slurry which is much more organoleptically pleasing and very easy to swallow.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In accordance with the present invention, “orally disintegrable” means that the tablet will disintegrate substantially into its component parts (e.g. the insoluble coated particles, insoluble disintegrant
Chastain Sara J.
Hontz John
Khankari Rajendra K.
Berman Alysia
Cima Labs Inc.
Lerner David Littenberg Krumholz & Mentlik LLP
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