Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2002-03-15
2003-09-23
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
Reexamination Certificate
active
06623755
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel pharmaceutical tablets. These tablets have improved surface properties which can aid esophageal transit, thereby reducing the potential for adverse gastrointestinal effects. These compositions are useful for administering pharmaceutical active ingredients, such as bisphosphonates.
BACKGROUND OF THE INVENTION
The pharmaceutical industry employs various methods for compounding pharmaceutical agents into oral tablet formulations. Standard methods for tablet formulation of bisphosphonic acids, however, suffer serious difficulties.
In particular, bisphosphonic acids which bear a basic nitrogen-containing functionality may interact with the lactose of standard formulations resulting in discoloration, instability and potency loss. This degradation of the active ingredient is particularly pronounced in the presence of water and/or elevated temperatures. It is speculated that this incompatibility is specifically due to the Maillard (or “browning”) reaction in which the free amino group of the bisphosphonic acid reacts with the “glycosidic” hydroxyl group of a sugar (such as lactose) ultimately resulting in the formation of brown pigmented degradates. Although this problem may be avoided by the elimination if lactose, the use of lactose as an inert diluent is generally desirable.
The present invention solves this problem by providing a tablet formulation and process therefore that avoids such interaction between the bisphosphonic acid and the lactose in the formulation. In addition the present invention provides a processing advantage since it requires only blending of the ingredients without granulation or addition of water prior to compression.
In addition to compounding problems, bisphosphonates are poorly absorbed from the gastrointestinal tract. See B. J. Gertz et al.,
Clinical Pharmacology of Alendronate Sodium, Osteoporosis Int
., Suppl. 3: S13-16 (1993) and B. J. Gertz et al.,
Studies of the oral bioavailability of alendronate, Clinical Pharmacology
&
Therapeutics
, vol. 58, number 3, pp. 288-298 (Sep. 1995), which are incorporated by reference herein in their entirety. Intravenous administration has been used to overcome this bioavailability problem. However, intravenous administration is costly and inconvenient, especially when the patient must be given an intravenous infusion lasting several hours on repeated occasions. If oral administration of the bisphosphonate is desired, relatively high doses must be administered to compensate for the low bioavailability from the gastrointestinal tract. To offset this low bioavailability, it is generally recommended that the patient take the bisphosphonate on an empty stomach and fast for at least 30 minutes afterwards. However, many patients find the need for such fasting on a daily basis to be inconvenient.
Moreover, oral administration of bisphosphonates has been associated with adverse gastrointestinal effects, especially those relating to the esophagus. See H. Fleisch,
Bisphosphonates in Bone Disease, from the laboratory to the patient
, third edition, 1997. Such oral administration of bisphosphonates sometimes results in patient complaints shortly after dosing; said complaints are usually characterized by the patients as heartburn, esophageal burning, pain and/or difficulty upon swallowing, and/or pain existing behind and/or mid-sternum. It is believed that these complaints originate from esophagitis or esophageal irritation caused by the erosion, ulceration, or other like irritation or the epithelial and mucosal tissues, resulting in the topical irritation thereof. If the dosage form adheres in the esophagus, the active ingredient slowly dissolves and creates a high drug concentration on the mucosal surface of the esophagus.
These unfavorable effects are exacerbated by the presence of refluxed gastric acid. For example, the bisphosphonate, pamidronate has been associated with esophageal ulcers. See E. G. Lufkin et al.,
Pamidronate: An Unrecognized Problem in Gastrointestinal Tolerability, Osteoporosis International,
4: 320-322 (1994), which is incorporated by reference herein in its entirety. Although not as common, the use of alendronate has been associated with esophagitis and/or esophageal ulcers. See P. C. De Groen, et al.,
Esophagitis Associated With The Use Of Alendronate, New England Journal of Medicine
, vol. 335, no. 124, pp. 1016-1021 (1996), D. O. Castell,
Pill Esophagitis—The Case of Alendronate, New England Journal of Medicine
, vol. 335, no. 124, pp. 1058-1059 (1996), and U. A. Liberman et al.,
Esophagitis and Alendronate, New England Journal of Medicine
, vol. 335, no. 124, pp. 1069-1070 (1996), which are incorporated by reference herein in their entirety. The degree of adverse gastrointestinal effects of bisphosphonates has been shown to increase with increasing dose. See C. H. Chestnut et al.,
Alendronate Treatment of the Postmenopausal Osteoporotic Woman: Effect of Multiple Dosages on Bone Mass and Bone Remodeling, The American Journal of Medicine
, vol. 99, pp. 144-152, (August 1995), which is incorporated by reference herein in its entirety. Also, these adverse esophageal effects appear to be more prevalent in patients who do not take the bisphosphonate with an adequate amount of liquid or who lie down shortly after dosing, thereby increasing the chance for esophageal reflux.
What is needed in the art is an oral bisphosphonate dosage form that minimizes the adverse side effects enumerated above. Such a dosage form should prevent and/or lessen the degree of patient discomfort while maximizing the treatment by maintaining the bioavailability of the bisphosphonate.
However, dosage forms of bisphosphonates that are presently being used are problematic. For example, rough, unpolished tablets are useful in order to maintain the bioavailability of the active ingredient. Despite this benefit, the rough texture provides for poor esophageal transit which causes the bisphosphonate to be released too early in the upper gastrointestinal tract, causing the patient discomfort.
To combat the premature release of active ingredient in the upper gastrointestinal tract, dosage forms have been developed to delay the release of the active ingredients after passage through the upper gastrointestinal tract and in some cases through the stomach, i.e., enteric coated tablets. However, enteric and completely coated tablets have disadvantages because in certain instances its undesirable or unnecessary for a medicament to be in a delayed release dosage form. Additionally, enteric and completely coated tablets reduce the bioavailability of the active ingredient.
What is desired in the art are dosage forms that facilitate rapid esophageal transit, minimize or avoid the release of an active ingredient in the upper gastrointestinal tract, deliver the active ingredient to the stomach, and maintain the bioavailability of the active ingredient.
The present invention solves this problem by providing a tablet formulation and process therefor that both facilitates esophageal transit and maintains the bioavailability of the active ingredient. The discontinuous wax polish of the present invention has surprisingly been found to be useful for administering active agents such as bisphosphonates. These tablets with a discontinuous wax polish have the advantage of providing rapid transit through the esophagus to minimize the occurrence of adverse effects. The discontinuous wax coating or polishing also has the advantage over enteric coated tablets of not interfering with the bioavailability of the active ingredient. Thus, the current invention provides a dosage form that eases and/or eliminates patient discomfort after dosing while maintaining the bioavailability of the active ingredient.
It is an object of the invention to provide a pharmaceutical composition, preferably a tablet comprising: an active ingredient, said active ingredient being a bisphosphonic acid or a pharmaceutically acceptable salt or ester thereof; excipients, said excipients comprising a diluent, a binder, a disi
Chen Tzyy-Show H.
Katdare Ashok V.
Nyairo Thomas G.
Daniel Mark R.
Fubara Blessing
Hunter, Jr. James M.
Merck & Co. , Inc.
Page Thurman K.
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