Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-03-29
2002-01-22
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S468000, C424S488000, C424S486000, C424S487000
Reexamination Certificate
active
06340475
ABSTRACT:
This invention is in the general field of pharmacology, and relates in particular to formulations for drugs that benefit from a prolonged time of controlled release in the stomach and upper gastrointestinal (GI) tract, and from an enhanced opportunity of absorption in the stomach and upper GI tract rather than the lower portions of the GI tract. One goal in this invention is to release highly soluble drugs in a controlled manner over an extended period of time. Another goal is to extend the time of delivery into the stomach of drugs that are preferentially absorbed high in the GI tract, for purposes of achieving a greater and more prolonged therapeutic effect and thus reducing the frequency of administration required; a more efficient use of the drugs; and a more effective treatment of local stomach disorders. Another goal is to minimize both lower-tract inactivation of the drug and drug effects on the lower intestinal flora by confining the delivery and absorption of the drug to the upper GI tract.
BACKGROUND OF THE INVENTION
Drugs that are administered in the form of conventional tablets or capsules become available to body fluids at a rate that is initially very high, followed by a rapid decline. For many drugs, this delivery pattern results in a transient overdose, followed by a long period of underdosing. This is a pattern of limited clinical usefulness. The delivery pattern was improved in the 1970's with the introduction of a variety of controlled delivery systems. By providing relatively constant, controlled drug delivery, these systems avoided the overdose and the underdose effects. These improvements provided effective medication with reduced side effects, and achieved these results with reduced dosing frequency.
Many of these controlled delivery systems utilize hydrophilic, polymeric matrices that provide useful levels of control to the delivery of sparingly soluble drugs. For soluble drugs, however, and particularly for highly soluble drugs, such matrices do not provide adequate control over the drug release rate, instead resulting in a release that approximates first-order kinetics. That is, the rate of release is an inverse function of the square root of the elapsed time. With this pattern of release, most of the drug in the matrix is often released within the first hour in an aqueous medium.
One method of prolonging the release of a highly water-soluble drug is disclosed in International Patent Application Publication No. WO 96/26718, published Sep. 6, 1996 (applicant: Temple University; inventor: Kim). The method of this publication is the incorporation of the drug into a polymeric matrix to form a tablet that is administered orally. The polymer is water-swellable yet erodible in gastric fluids, and the polymer and the proportion of drug to polymer are chosen such that:
(i) the rate at which the polymer swells is equal to the rate at which the polymer erodes, so that the swelling of the polymer is continuously held in check by the erosion, and zero-order release kinetics (constant delivery rate) of the drug from the matrix are maintained;
(ii) the release of drug from the matrix is sustained over the full erosion period of the polymer, the tablet therefore reaching complete solution at the same time that the last of the drug is released; and
(iii) release of the drug from the matrix will be extended over a period of 24 hours.
A key disclosure in WO 96/26718 is that to achieve the release of drug in this manner requires the use of a low molecular weight polymer. If, by contrast, a high molecular weight polymer is used and the swelling rate substantially exceeds the erosion rate, the lack of erosion will prolong even further the delivery of the drug residing close to the center of the tablet and even prevent it from being released. Thus, there is no disclosure in WO 96/26718 that a drug of high water solubility can be released from a high molecular weight polymer in a period of time substantially less than 24 hours, or that any advantage can be obtained by the use of a polymer that does not erode as quickly as it swells. This failure is particularly significant since even swollen tablets will not remain in the stomach beyond the duration of the fed mode, which typically lasts for only 4 to 6 hours.
For drugs of any level of solubility, the retention of the drug in a tablet or other dosage form beyond the duration of the fed mode raises a number of problems that detract from the therapeutic efficacy of the drug. These problems arise from the tendency of the tablet when the patient is no longer in the fed mode to pass from the stomach into the small intestine, and over a period of 2-4 hours to pass through the small intestine, thus reaching the colon with the drug still in the tablet. This loss of effectiveness occurs with drugs that provide their maximum benefit with minimum side effects when absorbed in the stomach and upper GI tract rather than the colon. The reasons are either favorable conditions in the stomach, unfavorable conditions in the colon, or both.
For example, most orally administered antibiotics have a potential of altering the normal flora of the gastrointestinal tract, and particularly the flora of the colon. One result of these alterations is the overgrowth of the organism
Clostridium difficile,
which is a serious adverse event since this organism releases dangerous toxins. These toxins can cause pseudomembranous colitis, a condition that has been reported as a side effect of the use of many antibiotics. In its milder forms, pseudomembranous colitis can cause mild nausea and diarrhea while in its stronger forms, it can be life-threatening or fatal. Examples of highly soluble antibiotics that pose this type of threat are amoxicillin, cefuroxime axetil, and clindamycin. Cefuroxime axetil (i.e., the axetil ester of cefuroxime), for example, becomes active when hydrolyzed to free cefuroxime, but when this occurs prior to absorption, it can be detrimental to essential bacterial flora. Hydrolysis to the active form typically occurs in the tissues into which the ester has been absorbed, but if the ester reaches the lower intestine, enzymes in the lower intestine cause the hydrolysis to occur in the intestine itself, which not only renders the drug unabsorbable but also converts the drug to the active form where its activity alters the flora. Examples of sparingly soluble antibiotics that pose the same type of threat are clarithromycin, azithromycin, ceftazidine, ciprofloxacin, and cefaclor.
A goal of the present invention is to avoid this type of alteration of the lower intestinal flora by delivering antibiotics, regardless of their level of solubility, in a manner that confines their delivery to the stomach and upper small intestine. Slow, continuous delivery from a gastric retentive system assures that both drug delivery and drug absorption are confined to the upper GI tract. More efficient delivery of antibiotics will also avoid transient overdosing which is a major cause of overgrowth of
Clostridium difficile.
Another example is the class of drugs that are susceptible to degradation by exposure to gastric fluid, either by enzymes or low solution pH. The swellable hydrophilic matrix of the present invention protects the yet undelivered drug during the 4 to 6 hour delivery period during which the drug is continuously released while the dosage form is retained in the stomach. One example of such a drug is topiramate, a drug that is used for the treatment of epilepsy. Topiramate is absorbed preferentially high in the GI tract and is hydrolyzed by the acidic environment of the stomach. The dosage form and delivery system of the present invention will confine the delivery of the drug to the stomach and duodenum. As the drug diffuses out of the swollen matrix, it is susceptible to the acidic environment, but the undelivered drug is protected from degradation by the polymer matrix.
Another example is the class of drugs that are known to have an absorption window high in the GI tract, but are incompletely absorbed or have a wide absorption range, i
Louie-Helm Jenny
Markey Micheline
Shell John W.
DepoMed, Inc.
Seidleck Brian K.
Townsend and Townsend / and Crew LLP
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