Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-01-26
2002-11-05
Pryor, Alton (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S102000, C514S106000, C514S109000
Reexamination Certificate
active
06476006
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to gastric retention systems and to pharmaceutical dosage forms that use them to release a drug in a patient's stomach or duodenum. More particularly, the invention relates to gastric retention systems suitable for use with bis-phosphonates such as alendronic acid and its pharmaceutically acceptable salts and hydrates thereof, to release these drugs in a controlled manner.
BACKGROUND OF THE INVENTION
After discovery of a new drug for treatment of a human disease further investigation must be undertaken to determine whether it is most effective to administer the drug to a patient intravenously, transdermally, subcutaneously or orally. Orally administered drugs are easy to administer and therefore are often favored whenever an oral route is feasible. However, compliance problems sometimes occur with orally administered drugs when the dosage form is inconvenient to take or must be taken frequently or at inconvenient times. Orally administered drugs are often presented to a patient in such dosage forms as tablets, pills, lozenges and capsules. Most orally administered drugs are absorbed into the bloodstream from the patient's gastrointestinal tract, excepting inhalants which are absorbed by the lungs and sinuses.
Orally-administered drug may be absorbed more readily by the gastrointestinal (“GI”) tract through either the stomach wall or the intestine wall. Few drugs are efficiently absorbed by the colon. Tablets that are designed to carry drugs that are more readily absorbed through the intestine wall are sometimes covered with a coating that is resistant to the acidic conditions of the stomach but which decomposes under the basic conditions of the intestine. This enteric coating allows the tablet to transit the stomach without releasing the active ingredient until it reaches the portion of the GI tract where it is most readily absorbed. This enteric-coating strategy is also effective when the drug is caustic to the lining of the stomach or decomposes under acidic conditions.
It is sometimes desirable that a drug be released in a patient's stomach rather than in the intestine. One such instance is when it is therapeutically advantageous to release the drug over several hours. The average residence time of solid food in the small intestine is about three hours. A controlled release pharmaceutical dosage form may pass through the stomach and intestine and into the colon before the active ingredient has been completely released. However, if the dosage form is retained in the stomach, complete release occurs upstream of the small intestine and the active ingredient will enter the intestine in an unbound state in which it can be readily absorbed before reaching the colon.
It is also desirable to release a drug in the stomach when it is unstable to the basic conditions of the intestine. A composition that is formulated to dissolve upon contact with any aqueous solution will at least partially dissolve in the stomach because it reaches the stomach before it reaches the intestine. However, the average residence time of food in the stomach is only about 1 to 3 hours. Unless the drug is very rapidly absorbed, or the residence time is increased, some of the drug will pass to the intestine. An unstable drug will at least partially decompose to a product compound that either is not absorbed or, if absorbed, may not exert the desired therapeutic effect. Accordingly, decomposition of a base sensitive drug that passes into the intestine reduces the effectiveness of the dosage and, as well, introduces an uncontrollable factor that is detrimental to accurate dosing.
For the foregoing reasons, formulation chemists have developed strategies to increase the retention time of oral dosages in the stomach. One of the general strategies, involves using an intragastric expanding dosage form that swells upon contact with stomach juices, preventing its passage through the pylorus. Intragastric expanding dosage forms use hydrogels which expand upon contact with water to expand the dosage form to sufficient size to prevent its passage through the pylorus. An example of such a dosage form is described in U.S. Pat. No. 4,434,153. The '153 patent discloses a device for executing a therapeutic program after oral ingestion, the device having a matrix formed of a non-hydrated hydrogel and a plurality of tiny pills containing a drug dispersed throughout the matrix.
As reviewed by Hwang, S. et al. “Gastric Retentive Drug-Delivery Systems,”
Critical Reviews in Therapeutic Drug Carrier Systems,
1998, 15, 243-284, one of the major problems with intragastric expanding hydrogels is that it can take several hours for the hydrogel to become fully hydrated and to swell to sufficient size to obstruct passage through the pylorus. Since food remains in the stomach on average from about 1 to 3 hours, there is a high probability that known expanding dosage forms like that of the '153 patent will pass through the pylorus before attaining a sufficient size to obstruct passage.
The rate-limiting factor in the expansion of ordinary hydrogels is the rate of delivery of water to non-surfacial hydrogel material in the dosage form. Conventional non-hydrated hydrogels are not very porous when dry and ingress of water into the hydrogel is slowed further by the formation of a low permeability gelatinous layer on the surface after initial contact with water. One approach to solving this problem uses so-called superporous hydrogels. Superporous hydrogels have networks of pores of 100 &mgr; diameter or more. Pores of that diameter are capable of efficient water transport by capillary action. Water reaches the non-surfacial hydrogel material quickly resulting in a rapid expansion of the superporous hydrogel to its full extent. However, there are also shortcomings attendant to the use of superporous hydrogels. They tend to be structurally weak and some are unable to withstand the mechanical stresses of the natural contractions that propel food out of the stomach and into the intestine. The superporous hydrogels tend to break up into particles too small to be retained.
Non-superporous hydrogels do not suffer from mechanical strength problems to as great an extent as superporous hydrogels. An additional advantage of using conventional hydrogels is that their degradation/erosion rates are well studied. The blended composition of the present invention should be compared with the superporous hydrogels described in Chen, J. and Park, K.
Journal of Controlled Release
2000, 65, 73-82, wherein the mechanical strength of superporous hydrogels is improved by the polymerization of precursor hydrogel monomers in the presence of several superdisintegrants. The result of the polymerization described by Chen and Park is a new substance having interconnecting cross-linking networks of polyacrylate and, e.g. cross-linked carboxymethyl cellulose sodium. Such interconnecting networks are not expected to have the same degradation rates as conventional hydrogels made from the same precursor hydrogel monomers.
Many disease therapies can benefit from improvements in controlled gastric release technology, such as osteoporosis and Paget's disease. Bis-phosphonates such as alendronate, residronate, etidronate and teludronate are commonly prescribed drugs for treatment of these diseases. Despite their benefits, bis-phosphonates suffer from very poor oral bioavailability (Gert, B. J.; Holland, S. D.; Kline, W. F.; Matuszewski, B. K.; Freeman, A.; Quan, H.; Lasseter, K. C.; Mucklow, J. C.; Porras, A. G.; Studies of the oral bioavailablity of alendronate,
Clinical Pharmacology & Therapeutics
(1995) 58, 288-298), serious interference of absorption by foods and beverages other than water (ibid.), and side effects that consist of irritation of the upper gastrointestinal mucosa (Liberman, U. A.; Hirsch, L. J.; Esophagitis and alendronate,
N. Engl. J. Med.
(1996) 335, 1069-70) with the potential for this irritation leading to more serious conditions (
Physicians' Desk Reference,
Fosama
Dahan Mazal
Flashner-Barak Moshe
Lerner Yitzhak
Rosenberger Vered
Kenyon & Kenyon
Pryor Alton
Teva Pharmaceutical Industries Ltd.
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