Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-01-05
2001-06-19
Robinson, Allen J. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S468000, C424S470000, C424S472000, C424S473000, C424S474000, C424S475000, C424S476000, C424S479000, C424S480000, C424S482000, C424S484000, C424S486000, C424S488000, C514S534000
Reexamination Certificate
active
06248359
ABSTRACT:
FIELD OF THE INVENTION
This invention pertains to a multi-tablet system for the treatment of urinary incontinence. More particularly, it pertains to a multi-tablet system wherein oxybutynin is released from two tablets at different times to provide a combined sustained delivery of oxybutynin for about a one day period.
BACKGROUND OF THE INVENTION
Oxybutynin is widely known for the treatment of urinary incontinence. Ditropan™ tablets are commercially available tablets that provide a rapid release of oxybutynin in the stomach and upper intestinal tract. Rapid release tablets are typically administered at a rate of about 3-4 tablets per day to treat urinary incontinence. Rapid release tablets, however, typically have undesirable side-effects associated with them due to the high plasma oxybutynin concentrations they provide. These tablets also have a short duration of action due to the short half-life (t
½
≈2 hr) of oxybutynin in plasma.
In order to overcome these disadvantages, controlled release tablets of oxybutynin have been developed. In general, known controlled release tablets provide a sustained delivery of oxybutynin for a period of up to 8-30 hours after administration depending upon the formulation used. Sequential administration (2-3 times per day) of oxybutynin tablets having the same release profile is known.
U.S. Pat. No. 5,399,359 to Baichwal, the entire disclose of which is hereby incorporated by reference, discloses many different controlled release tablet formulations which provide a controlled release of oxybutynin for periods of up to 8, 12, 16, 18, 24 or 30 hours.
U.S. Pat. Nos. 5,912,268, 5,840,754 and 5,674,895 to Guittard, the entire disclosures of which are hereby incorporated by reference, disclose osmotic device formulations which deliver oxybutnin at a controlled rate for a period of about 24 hours.
Appell et al. (“Clinical Evaluation of a Sustained Release Form of Oxybutynin,
Urodynamics Society Symposium Abstracts
(1990), pg. 228), the entire disclosure of which is hereby incorporated by reference, discloses a controlled release tablet Ditropan™ SR, which provides a controlled delivery of oxybutynin for about 8-12 hours.
Sirkiä et al. (“Use of hydrophilic polymers to control drug release from press-coated oxybutynin hydrochloride tablets”,
S. T. P. Pharmacia Sci.
(1993), 3(6), pg. 453-458), the entire disclosure of which is hereby incorporated by reference, discloses a controlled release tablet formulation which provides a controlled delivery of oxybutynin for about 8-12 hours.
Japanese Patent Applications Serial No. 9,388 and No. 163,901 to Enomoto et al., the entire disclosures of which are hereby incorporated by reference, disclose controlled release tablet formulations which deliver oxybutynin at a controlled rate for a period of about 12 hours for once or twice-a day administration.
Osmotic devices and other tablet formulations are known for their ability to provide controlled release of a wide range of drugs. Such osmotic devices and other tablet formulations are disclosed in U.S. Pat. No. 4,014,334 to Theeuwes et al., U.S. Pat. No. 4,576,604 to Guittard et al., Argentina Patent No. 234,493, U.S. Pat. No. 4,673,405 to Guittard et al., U.S. Pat. No. 5,558,879 to Chen et al., U.S. Pat. No. 4,810,502 to Ayer et al., U.S. Pat. No. 4,801,461 to Hamel et al., U.S. Pat. No. 5,681,584 to Savastano et al., U.S. Pat. No. 3,845,770 and Argentina Patent No. 199,301, the entire disclosures of which are hereby incorporated by reference.
It is well known that eating habits have an effect upon the observed plasma oxybutynin concentration in humans. (Lukkari et al., “Effect of food on the bioavailability of oxybutynin from a controlled release tablet”,
Eur. J. Clin. Pharmacol.
, (1996), 50(3), pg. 221-223). Specifically, eating breakfast was shown to reduce the mean retention time of oxybutynin in the plasma. Moreover, patient age and health also have an effect upon the observed plasma oxybutynin concentration in humans (Hughes et al. “Measurement of oxybutynin and its N-desethyl metabolite in plasma, and its application to pharmacokinetic studies in young, elderly and frail elderly patients”,
Xenobiotica
(1992), 22(7), pg. 859-869). Specifically, a trend of increasing peak plasma levels and bioavailability was observed with increasing patient age and frailty, with the differences being more apparent between the active elderly and frail elderly groups than between the active elderly and the young volunteers. Currently available controlled release oxybutynin formulations are not able to compensate for the observed patient to patient variability in oxybutynin therapy.
Thus, a need remains for an adaptable system of treating urinary incontinence which provides a controlled delivery of oxybutynin and maintains safe and therapeutically effective levels of oxybutynin in patients while accounting for their age or health. None of the single tablet prior art systems can fulfill this need.
Moreover, while the prior art discloses a wide variety of tablet formulations that individually provided a rapid or controlled release of oxybutynin, none of the art discloses a system for treating urinary incontinence comprising two tablet dosage forms having different release profiles which together provide a sustained delivery of oxybutynin for a period of about one day.
The present system is capable of providing a broader range of overall release profiles for oxybutynin due to the combination of two or more tablets having different release profiles. Further, the present system provides greater control over the delivery of oxybutynin in treating urinary incontinence and is therefore adaptable from patient to patient.
SUMMARY OF THE INVENTION
The present invention provides a two-tablet system for the treatment of urinary incontinence, wherein the tablets together provide a sustained delivery of oxybutynin for about one day or a period of about 18-26 hours, and preferably about 24 hours. In one embodiment, the present system comprises:
a first tablet which releases oxybutynin after at least about one second after administration of the first tablet; and
a second tablet which releases oxybutynin after at least about three hours after administration of the second tablet;
wherein the first and second tablets together provide a sustained delivery of oxybutynin for a total period of about 18-26 hours.
In another embodiment, the present system comprises:
a first tablet having a first release profile for the release of oxybutynin; and
a second tablet having a different second release profile for the release of oxybutynin, wherein the first and second tablets together provide a sustained delivery of oxybutynin for a period of about 18-30 hours.
According to various preferred embodiments, (a) the first and second tablets are administered concurrently; (b) the first and second tablets are administered sequentially; (c) the first and second tablets maintain a therapeutic level of oxybutynin in the plasma of the mammal for a period of about 24 hours; (d) the first tablet is a rapid release dosage form and the second tablet is a controlled release dosage form; (e) the first tablet releases all of its oxybutynin within about three hours after administration of the first tablet, and the second tablet begins to release its oxybutynin within about five hours after administration of the first tablet and completes its release of oxybutynin within about 24 hours after administration of the first tablet; (1) the first tablet releases all of its oxybutynin less than two hours after administration of the first tablet, and the second tablet begins to release its oxybutynin within about four hours after administration of the first tablet and completes its release of oxybutynin within about 23 hours after administration of the first tablet; (g) the first tablet is a controlled release tablet and the second tablet is a controlled release tablet, the tablets having different release profiles (h) the first tablet maintains therapeutic levels of oxybutynin for a period of up to about 3 hours after
Innovar L.L.C.
Laboratorios Phoenix U.S.A., Inc.
Matos Rick
Robinson Allen J.
LandOfFree
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