Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-07-17
2003-07-29
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S451000, C424S457000, C424S464000, C424S468000, C424S469000, C424S470000, C424S472000, C424S474000, C424S484000, C424S489000
Reexamination Certificate
active
06599529
ABSTRACT:
This application is a 371 of PCT/DK98/00388 filed Sep. 10 1998,
The present invention relates to an oral pharmaceutical modified release multiple-units composition for the administration of a therapeutically and/or prophylactically effective amount of a non-steroid anti-inflammatory drug substance (in the following abbreviated “an NSAID substance”) to obtain both a relatively fast or quick onset of the therapeutic effect and the maintenance of a therapeutically active plasma concentration for a relatively long period of time. The modified release multiple-units composition comprises at least two fractions of multiple units such as a first and a second fraction. The first fraction comprises individual units which are designed to quickly release the drug substance and the second fraction comprises individual units which are designed to slowly release the drug substance to enable a delayed and extended release of the drug substance. Typically, the second fraction comprises multiple units which are coated with a sustained release coating designed to release the drug substance in such a manner that the maintenance of a therapeutically active plasma concentration for a relatively long period of time are obtained. By suitable adjustment of the release pattern of the at least first and second fraction a composition is obtained which is 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 active substance is not administered very frequently. Controlled release compositions 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 fast as possible according to the biopharmaceutical properties of the drug substance. Generally, such compositions in some more or less sophisticated manner are composed of a sustained release part and a part which either contains a free amount of the drug substance or it releases the drug substance in the same manner as if the drug substance had been formulated as a plain formulation (e.g. in the form of normal tablets or granulates). Such compositions which initially release a burst of a therapeutic agent and then release the agent at an essentially constant rate are described, e.g., in WO 95/14460 (Euroceltique S. A.) 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, an amount of free opioid (i.e. the opioid is included as such and has not been processed into a specific formulation e.g. by means of pharmaceutically acceptable excipients) is incorporated into the gelatin capsule via inclusion of a sufficient amount of opioid within the capsule. In a further alternative, the gelatine capsule itself is coated with an immediate release layer of the opioid.
Generally, the rationale which lies behind the kind of compositions which have been described to enable an immediate release of a drug substance as well as a sustained release of the drug substance is to combine a traditional formulation approach (such as, e.g., i) plain tablets which have a disintegration time in water of at the most about 15 min for uncoated tablets, cf. Ph. Eur. (the requirements for coated tablets or capsules are at the most 30 min), ii) a traditionally formulated granulate or iii) loose powder of the drug substance itself) with a controlled release approach. By doing so the immediate release part of the composition is intended to release the drug substance in a manner which corresponds to a plain tablet formulation or the like and the term “immediate” is in such a context intended to denote that the release of the drug substance is faster than the release from a sustained release composition. The immediate release is in no way intended to be faster than that of a traditional or plain composition.
Especially in those cases where the drug substance has a low solubility in an acidic medium having a pH of from about 1 to about 3, i.e. a pH corresponding to the pH in the stomach, the traditional formulation approach will lead to a pharmaceutical composition which has a suitable fast disintegration time but not necessarily a suitable dissolution rate of the drug substance under acidic conditions, i.e. a plain tablet will rapidly disintegrate into granules but the dissolution of the drug substance from the composition and/or the disintegrated composition under acidic conditions may be unsuitable low due to the solubility properties of the drug substance itself. The availability of a drug substance with respect to absorption, i.e. entrance into the circulatory system, is dependant on the presence of the drug substance on dissolved form as it is generally accepted that only dissolved substances are capable of passing the mucous membranes in the gastro-intestinal tract. Therefore, it is important that the dissolution of the drug substance is suitably fast even under acidic conditions in order to enable an initial absorption already from the stomach so that a true fast or immediate therapeutic response is obtainable. Furthermore, if a drug substance—dependent on pH can exist on un-ionized as well as ionized form (e.g. acetyl salicylic acid which at an acid pH below its pK
a
value predominantly is present on an unloaded, i.e. un-ionized form, whereas at a pH above its pK
a
value predominantly is present on ionized form). For drug substances which are weak acids it is very important to ensure a proper bioavailability of the drug substance already under acidic conditions in order to achieve a true rapid therapeutic effect. However, the various approaches disclosed with respect to achievement of a combination of a rapid and a sustained effect (e.g. in the publications mentioned above) do not seem to take the above-mentioned factors into account and, hence, there is a need for developing compositions which enable a true rapid onset of the therapeutic effect as well as a sustained effect. To this end, we have especially focused on compositions comprising a drug substance suitable for use in situations where a rapid effect is needed but also in situations where an extended effect is desirable in order to develop compositions suitable for administration less frequent than compositions on the market today, more specifically to enable administration on a once or twice daily basis. Examples of suitable drug substances are, e.g., substances which have a pain relief effect. More specifically, interesting drug substances are those belonging to the class of drug substances normally denoted NSAIDs or NSAID substances.
In EP-A-0 438 249A1 (ELAN Corporation P.L.C.) is given another example of a composition which has been designed to release naproxen immediately and sustained. However, as shown in Example 18 herein, the so-called immediate release of naproxen does not take place under acidic conditions, i.e. conditions prevailing in the stomach. Ac
Bertelsen Poul
Skinhøj Annette
Corless Peter F.
Di Nola-Baron Liliana
Edwards & Angell LLP
Nycomed Danmark A/S
O'Day Christine C.
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