Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1998-04-02
2002-04-16
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S472000, C424S477000, C424S479000, C424S480000, C424S482000
Reexamination Certificate
active
06372254
ABSTRACT:
FIELD OF THE INVENTION
The present invention pertains to a drug delivery system suitable for oral administration that facilitates a pulsatile release of the active agent. A key aspect of the present invention is the discovery that a tablet with an immediate-release compartment, which contains a compressed blend of an active agent and one or more polymers, substantially enveloped by an extended-release compartment, which contains a compressed blend of the active agent and hydrophilic and hydrophobic polymers, can provide a substantially first order delivery of the active agent, interrupted by a timed, pulsed delivery of a preferably increased amount of the active agent. With respect to drugs subject to “first pass” clearance, sustained drug delivery can be achieved through the present invention via an optional instant-release compartment, which provides a dose sufficient to exceed the liver's metabolic capacity and to maintain therapeutic levels, preferably throughout a 24-hour period.
BACKGROUND OF THE INVENTION
Drug efficacy generally depends upon the ability of the drug to reach its target in sufficient quantity to maintain therapeutic levels for the desired time period. The pulsatile release of an active agent is desirable when treating diseases that require drug delivery in a manner to maintain therapeutic levels notwithstanding circadian rhythms. Diseases that benefit from pulsatile drug delivery include angina, for example, which occurs with repeatable regularity at the end of the night and in the early morning hours while the patient is still asleep, and rheumatic diseases such as rheumatoid arthritis, the symptoms of which manifest during the night and into the beginning of the next day.
With traditional extended-release dosage formulations, which exhibit first order release rates, the efficacy of the active agent diminishes at the end of the night and the beginning of the next day. Therefore, a bolus or burst delivery of the active agent during this waning period can improve drug efficacy.
In addition, orally administered drugs must overcome several obstacles to reach their desired targets. Before orally administered drugs enter the general circulation of the human body, they are absorbed into the capillaries and veins of the upper gastrointestinal tract and are transported by the portal vein to the liver. The pH and enzymatic activities found in gastrointestinal fluids may inactivate the drug or cause the drug to dissolve poorly. Following their absorption in the intestine, certain orally administered drugs can be subject to a “first pass” clearance by the liver and excreted into bile or converted into pharmacologically inactive metabolites. Decreased bioavailability of orally administered drugs can be a consequence of this first pass effect.
Orally administered drugs subject to the first pass effect generally exhibit non-linear pharmacokinetics. Until the liver's metabolic capacity has been exceeded, the amount of such drugs in the bloodstream is significantly lower than the amount administered. This metabolic elimination of the given dose results in reduced bioavailability. However, once the administered dose exceeds the liver's metabolic capacity, a significant increase in the drug concentration in the bloodstream may be obtained. The first pass phenomenon presents particular difficulties in the maintenance of therapeutic levels of an orally administered drug over an extended period such as 12 or 24 hours.
Drug delivery systems that have evolved with respect to orally administered drugs subject to the first pass effect include formulations capable of immediate drug release that are suitable for administration from 3-4 times daily, and formulations capable of immediate and sustained drug release that are suitable for once-daily administration. The second type of formulation is preferred because patient compliance with prescribed drug regimens involving once-daily administration is substantially higher than those involving multiple administrations. A sustained release formulation, however, may subject the patient to toxic drug levels over part of the dosing period and sub-therapeutic drug levels over other portions of the dosing period, if the drug release does not occur at appropriate time intervals. The maintenance of therapeutic levels of an orally administered drug over an extended period thus depends upon a drug delivery system capable of providing an appropriate release pattern.
A valuable contribution to the art therefore would be the development of a drug delivery system in a single tablet formulation suitable for oral administration that facilitates a substantially first order delivery of the active agent, interrupted by a timed, pulsed delivery of a preferably increased amount of the active agent, and where the active agent is subject to “first pass” clearance, can provide sustained drug delivery, preferably over a 24-hour period, by a dose sufficient to exceed the liver's metabolic capacity and to maintain therapeutic levels.
SUMMARY OF THE INVENTION
Accordingly, an objective of the present invention is a single orally administrable tablet that can provide a substantially first order delivery of the active agent, interrupted by a timed, pulsed delivery of an increased amount of the active agent. A second objective of the present invention is a single orally administrable tablet that can overcome the “first pass” effect by providing an instant-release dosage sufficient to exceed the liver's metabolic capacity, and then continue to maintain therapeutic drug. levels, preferably-over a 24-hour period. A further objective of the present invention is a method for preparing of a single orally administrable tablet that can provide a substantially first order delivery of the active agent, interrupted by a timed, pulsed delivery of a preferably increased amount of the active agent.
In a preferred embodiment of the invention, these and other objectives can be accomplished through a drug delivery system suitable for oral administration with an immediate-release compartment, which contains a compressed blend of an active agent and one or more polymers, substantially enveloped by an extended-release compartment, which contains a compressed blend of the active agent and hydrophilic and hydrophobic polymers, and substantially enveloped by an optional instant-release compartment, which provides a dose sufficient to exceed the liver's metabolic capacity and to maintain therapeutic levels, preferably throughout a 24-hour period.
In a preferred embodiment of the present invention, the active agent in the extended-release compartment can diffuse out first, resulting in a first order release rate. As the active agent and soluble polymers in the extended-release compartment disintegrate, water will penetrate through the extended-release compartment and cause the immediate-release compartment to expand, creating a bursting effect that further disrupts any remaining integrity of the extended-release compartment. Where an optional inert core (i.e., a core containing one or more polymers without active agent) is present, its swelling in response to the water influx described above can also contribute to a bursting effect. The respective time periods for the dissolution of the active agent, and the bursting effect, can be regulated by varying the composition and relative amounts of the polymers in the compartments.
The extended-release compartment preferably comprises a combination of hydrophilic and hydrophobic polymers. In this embodiment, once administered, the hydrophilic polymer dissolves away to weaken the structure of the extended-release compartment, and the hydrophobic polymer retards the water penetration and helps to maintain the shape of the drug delivery system. The immediate-release compartment preferably comprises a compressed blend of active agent and one or more polymers with disintegration characteristics, which upon exposure to the aqueous medium, would burst to further break apart the already weakened extended-release compartment an
Hsiao Charles
Ting Richard
Arent Fox Kintner Plotkin & Kahn
Impax Pharmaceuticals Inc.
Tran S.
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