Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Patent
1998-06-22
2000-12-12
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
424494, 424490, 424489, 424451, 424456, 424457, 424458, 424459, A61K 954, A61K 31485, A61K 962
Patent
active
061595012
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to an oral pharmaceutical modified release multiple-units dosage composition for the administration of an analgesically effective amount of an opioid to obtain both a relatively fast onset of the analgesic effect and the maintenance of an analgesically active plasma concentration for a relatively long period of time. The modified release multiple-units dosage composition comprises at least two fractions wherein individual units containing an opioid are coated with a sustained release coating designed to release the active ingredient in such a manner that both a relatively fast onset of the analgesic effect and the maintenance of an analgesically active plasma concentration for a relatively long period of time are obtained, the composition thereby being adapted to once- or twice-a-day administration.
TECHNICAL BACKGROUND
Drug levels can be maintained above the lower level of the therapeutic plasma concentration for longer periods of time by giving larger doses of conventionally formulated dosage forms. However, it is not a suitable approach to increase dosage as such doses may produce toxic and undesired high drug levels. Alternatively, another approach is to administer a drug at certain intervals of time, resulting in oscillating drug levels, the so-called peak and valley effect. This approach is generally associated with several potential problems, such as a large peak (toxic effect) and valley (non-active drug level) effect, and a lack of patient compliance leading to drug therapy inefficiency or failure. If, however, the plasma concentration is kept constant over the therapeutic level using conventional tablets, an unacceptably high daily dosage is required if the opioid is not administered very frequently.
Controlled release preparations are known which are designed to rapidly release a fraction of a total drug dose. This loading dose is an amount of a drug which will provide a desired pharmacological response as promptly as possible according to the biopharmaceutical properties of the drug. Such formulations which initially release a burst of a therapeutic agent and then release the agent at an essentially constant rate are described in WO 95/14460 published on Jun. 1, 1995. The composition described therein relates to a sustained release opioid formulation comprising a plurality of substrates comprising the active ingredient in a sustained release matrix or coated with a sustained release coating comprising a retardant material. The sustained release beads are then coated with an opioid in immediate release form or, in the case the composition is in the form of a gelatine capsule, the plain opioid is incorporated into the gelatin capsule via inclusion of the sufficient amount of immediate release opioid as a powder or granulated within the capsule. In a further alternative, the gelatine capsule itself is coated with an immediate release layer of the opioid.
A major disadvantage of the above formulation is that the incorporation of the plain opioid in gelatine capsules without a protecting coating on the opioid may easily result in lack of control of the exact dosage, especially if the capsule leaks or the patient breaks the capsule. In addition it is not possible to modify the release in relation to the sustained release fraction, and the only possibility of avoiding toxic plasma concentrations, or controlling the peak plasma concentration, is to decrease the exact amount of opioid of the immediate release portion.
The above-mentioned controlled release preparations are long-acting and release the drug in a sustained manner. However, these types of formulations may result in an undesirable decreased bioavailability, probably because the active ingredient is not released in due time.
Multiple-units formulation techniques according to the invention aim at a modified release of active substance in a predetermined pattern to reduce and delay the peak plasma concentration without affecting the extent of drug availability. The frequency of undesirable side effects may be re
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Corless Peter F.
Nycomed Danmark A/S
Page Thurman K.
Seidleck Brian K.
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