Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-07-10
2004-03-30
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S490000, C424S464000, C424S474000
Reexamination Certificate
active
06713089
ABSTRACT:
The present invention relates to an oral modified release pharmaceutical composition for the administration of a therapeutically and/or prophylactically effective amount of an active substance (a drug substance) to obtain a relatively fast or quick onset of the therapeutic and/or prophylactic effect. The drug substances contained in a modified release pharmaceutical composition according to the invention are suitably a drug substance which has a very low solubility under acidic conditions, i.e. under conditions similar to those present in the stomach and/or drug substances which have a pK
a
value below about 5.5 such as in a range of from about 4 to about 5. The compositions have been designed in such a manner that two important requirements are obtained, namely i) that the pharmaceutical composition releases the drug substance very fast under acidic conditions whereby the drug substance will become dissolved and, accordingly, available for absorption already almost immediately upon entrance into the stomach, and ii) that the mechanical strength of a composition according to the invention is sufficiently high to withstand normal handling of a pharmaceutical composition and to enable the composition to be coated using traditional coating equipment well known by a person skilled in the art. A composition according to the invention is suitable for use in those cases in which a fast onset of a therapeutic and/or prophylactic effect is desired, e.g. in connection with acute pain or mild to moderate pain. Accordingly, suitable therapeutically and/or propylactically active substances may inter alia be found in the class of drug substances denoted non-steroid anti-inflammatory drug substances (abbreviated in the following: NSAID substances or NSAIDs).
DESCRIPTION OF THE INVENTION
Pharmaceutical compositions designed to immediate release of a drug substance is known in the art.
Generally, however, the rationale which lies behind the kind of compositions which have been described to enable an immediate release of a drug substance is to employ a traditional formulation approach (such as, e.g., i) plain tablets which have a disintegration time in water of at the most about 30 min, ii) a traditionally formulated granulate or iii) loose powder of the drug substance itself. 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 development of the so-called SplashDose®, FlashDose® and Flashtabs® are examples of pharmaceutical compositions wherein the focus has been to obtain a very fast disintegration time. Such formulations are suitable for use for drug substances which are readily soluble in the gastrointestinal tract, but basically they do not solve the problems related to drug substances which have poor solubility characteristics.
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 fast dissolution rate of the drug substance under acidic conditions, i.e. a plain tablet will rapidly disintegrates 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 a fast and initial absorption so that a true fast or immediate therapeutic response is obtainable.
For drug substances which are weak acids it is very important to ensure a proper bioavailability of the drug substance already under acid 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 effect do not seem to take all 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. To this end, we have especially focused on compositions comprising a drug substance belonging to the class of drug substances normally denoted NSAIDs, but other drug substances having a low solubility in acidic medium and/or a pK
a
below about 5.5 may as well be suitable for use in a composition according to the invention.
Moreover, patients suffering from acute pain, mild to moderate pain and/or inflammatory conditions and/or related conditions very often require a dosage and a formulation which enable a fast onset of the therapeutic effect of the NSAID substances. The release from the dosage form must be safe, predictable and reliable. Furthermore, from a technical point of view, the release rate and the release pattern of the active drug substance from the composition should not significantly change during the shelf-life of the composition. A change in the release rate and/or release pattern may have a significant impact on the in vivo performance of the composition.
When testing prior art compositions intended for rapid release of the active drug substance (see e.g. Japanese patent No. 33491/90) the present inventors have revealed problems with respect to the release rate obtained and the robustness of the tablets. Thus, the development of a pharmaceutical composition which is suitable for rapid release of the active substance seems surprisingly to be a balance of on the one hand to obtain a composition which is sufficient robust to withstand normal handling (i.e. to have a sufficient mechanical strength) and on the other hand to enable a fast release and dissolution of the active drug substance in an acidic aqueous medium.
Thus, the purpose of the present invention is to provide a pharmaceutical composition for oral use which is useful for a fast delivery of an active drug substance to the circulatory system upon administration.
In one aspect, the invention relates to a quick release pharmaceutical composition for oral administration comprising a therapeutically and/or prophylactically active substance which has a solubility of at the most about 0.1% w/v in 0.1 N hydrochloric acid at room temperature,
the composition being based on a powder comprising the therapeutically and/or prophylactically active substance and having such a particle size that—when the powder is subjected to a sieve analysis—then at least about 90% w/w such as, e.g. at least about 92% w/w, at least about 94% w/w, at least about 95% w/w, at least about 96% w/w, at least about 97% w/w, at least about 97% w/w, at least about 98% w/w or at least about 99% w/w of the particles passes through sieve 180 &mgr;m, the powder being contacted with an aqueous medium to form a particulate composition, which has such a particle size that—when the particulate composition is subjected to a sieve analysis—then at least about 50% w/w such as, e.g., at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w or at least about 95% w/w of the particles passes through sieve 180 &mgr;m, and
the composition—when tested in accordance with the dissolution method I defined herein employing 0.07 N hydrochloric acid as dissolution medium—releases at least about 50% w/w of the active substance within the first 20 min of the
Bertelsen Poul
Hansen Niels Gjørløv
Itai Shigeru
Ruckendorfer Hermann
Corless Peter F.
Edwards & Angell LLP
Nycomed Danmark A/S
O'Day Christine C.
Page Thurman K.
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