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(12) Patent Application Publication (10) Pub. No.: US 2005/0147668A1 Bertelsen Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2005/0147668A1 Bertelsen Et Al US 2005O147668A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0147668A1 Bertelsen et al. (43) Pub. Date: Jul. 7, 2005 (54) QUICK RELEASE PHARMACEUTICAL (52) U.S. Cl. .............................................................. 424/464 COMPOSITIONS OF DRUG SUBSTANCES (57) ABSTRACT (75) Inventors: Poul Egon Bertelsen, Vanlose (DK); Niels Gjorlov Hansen, Fredericksberg The present invention relates to an oral modified release (DK); Hermann Ruckendorfer, pharmaceutical composition for the administration of a Reichenthal (AT); Shigeru Itai, therapeutically and/or prophylactically effective amount of Ageo-shi (JP) an active Substance (a drug Substance) to obtain a relatively fast or quick onset of the therapeutic and/or prophylactic Correspondence Address: effect The drug Substances contained in a modified release EDWARDS & ANGELL, LLP pharmaceutical composition according to the invention are P.O. BOX 55874 Suitably a drug Substance which has a very low Solubitity BOSTON, MA 02205 (US) under acidic conditions, i.e. under conditions similar to those present in the Stomach and/or drug Substances which (73) Assignee: Nycomed Danmark A/S have a pK value below about 5.5 Such as in a range of from about 4 to about 5. The composition is based on a powder (21) Appl. No.: 10/758,233 comprising a therapeutically and/or prophylactically active 1-1. Substance and has Such a particle Size that when the powder (22) Filed: Jan. 13, 2004 is subjected to a sieve analysis, then at least about 90% w/w Related U.S. Application Data of the particles passes through sieves 180 um and the powder is contacted with an aqueous medium to form a particulate (63) Continuation of application No. 09/786,864, filed on composition, which has Such a particle Size that when the Jul. 10, 2001, now Pat. No. 6,713,089, filed as 371 of particulate composition is Subjected to a Sieve analysis, then international application No. PCT/DK99/00480, filed at least about 50% w/w of the particles passes through sieve on Sep. 10, 1999. 180 um. Furthermore, the composition, when tested in accordance with the dissolution method (1) defined herein Publication Classification employing 0.07 N hydrochloric acid as dissolution medium, releases at least about 50% w/w of the active Substance (51) Int. Cl. .................................................. A61K 9/20 within the first 20 min of the test Patent Application Publication Jul. 7, 2005 Sheet 1 of 3 US 2005/0147668A1 Means and 95.0 Percent LSD Intervals 11 25 30 60 128 CaFPO4 (um) Fig. 1 Patent Application Publication Jul. 7, 2005 Sheet 2 of 3 US 2005/0147668A1 Means and 95.0 Percent LSD Intervals NaHCO3 (um) Patent Application Publication Jul. 7, 2005 Sheet 3 of 3 US 2005/0147668A1 Means and 95.0 Percent LSD Intervals US 2005/0147668A1 Jul. 7, 2005 QUICK RELEASE PHARMACEUTICAL integration time but not necessarily a Suitable fast dissolu COMPOSITIONS OF DRUG SUBSTANCES tion rate of the drug Substance under acidic conditions, i.e. a plain tablet will rapidly disintegrates into granules but the 0001. The present invention relates to an oral modified dissolution of the drug Substance from the composition release pharmaceutical composition for the administration and/or the disintegrated composition under acidic conditions of a therapeutically and/or prophylactically effective amount may be unsuitable low due to the solubility properties of the of an active Substance (a drug Substance) to obtain a rela drug Substance itself. The availability of a drug Substance tively fast or quick onset of the therapeutic and/or prophy with respect to absorption, i.e. entrance into the circulatory lactic effect. The drug Substances contained in a modified System, is dependant on the presence of the drug Substance release pharmaceutical composition according to the inven on dissolved form as it is generally accepted that only tion are Suitably a drug Substance which has a very low dissolved Substances are capable of passing the mucous Solubility under acidic conditions, i.e. under conditions membranes in the gastrointestinal tract. Therefore, it is Similar to those present in the Stomach and/or drug Sub important that the dissolution of the drug Substance is stances which have a pK value below about 5.5 such as in a range of from about 4 to about 5. The compositions have Suitably fast even under acidic conditions in order to enable been designed in Such a manner that two important require a fast and initial absorption So that a true fast or immediate ments are obtained, namely i) that the pharmaceutical com therapeutic response is obtainable. position releases the drug Substance very fast under acidic 0005 For drug substances which are weak acids it is very conditions whereby the drug Substance will become dis important to ensure a proper bioavailability of the drug Solved and, accordingly, available for absorption already Substance already under acid conditions in order to achieve almost immediately upon entrance into the stomach, and ii) a true rapid therapeutic effect. However, the various that the mechanical Strength of a composition according to approaches disclosed with respect to achievement of a the invention is Sufficiently high to withstand normal han combination of a rapid effect do not seem to take all the dling of a pharmaceutical composition and to enable the above-mentioned factors into account and, hence, there is a composition to be coated using traditional coating equip need for developing compositions which enable a true rapid ment well known by a person skilled in the art. A compo onset of the therapeutic effect. To this end, we have espe Sition according to the invention is Suitable for use in those cially focused on compositions comprising a drug Substance cases in which a fast onset of a therapeutic and/or prophy belonging to the class of drug Substances normally denoted lactic effect is desired, e.g. in connection with acute pain or NSAIDs, but other drug substances having a low solubility mild to moderate pain. Accordingly, suitable therapeutically in acidic medium and/or a pK, below about 5.5 may as well and/or propylactically active Substances may inter alia be be Suitable for use in a composition according to the found in the class of drug Substances denoted non-Steroid invention. anti-inflammatory drug Substances (abbreviated in the fol 0006 Moreover, patients suffering from acute pain, mild lowing: NSAID substances or NSAIDs). to moderate pain and/or inflammatory conditions and/or related conditions very often require a dosage and a formu DESCRIPTION OF THE INVENTION lation which enable a fast onset of the therapeutic effect of 0002 Pharmaceutical compositions designed to immedi the NSAID substances. The release from the dosage form must be safe, predictable and reliable. Furthermore, from a ate release of a drug Substance is known in the art. technical point of View, the release rate and the release 0.003 Generally, however, the rationale which lies behind pattern of the active drug Substance from the composition the kind of compositions which have been described to should not significantly change during the shelf-life of the enable an immediate release of a drug Substance is to employ composition. A change in the release rate and/or release a traditional formulation approach (Such as, e.g., i) plain pattern may have a significant impact on the in Vivo per tablets which have a disintegration time in water of at the formance of the composition. most about 30 min, ii) a traditionally formulated granulate or iii) loose powder of the drug Substance itself. By doing So 0007 When testing prior art compositions intended for the immediate release part of the composition is intended to rapid release of the active drug Substance (see e.g. Japanese release the drug Substance in a manner which corresponds to patent No. 33491190) the present inventors have revealed a plain tablet formulation or the like and the term “imme problems with respect to the release rate obtained and the diate' is in Such a context intended to denote that the release robustness of the tablets. Thus, the development of a phar of the drug Substance is faster than the release from a maceutical composition which is Suitable for rapid release of Sustained release composition. The development of the the active Substance Seems Surprisingly to be a balance of on so-called Splash Dose(R), Flash Dose(R) and Flashtabs(R) are the one hand to obtain a composition which is Sufficient examples of pharmaceutical compositions wherein the focus robust to withstand normal handling (i.e. to have a Sufficient has been to obtain a very fast disintegration time. Such mechanical strength) and on the other hand to enable a fast formulations are Suitable for use for drug Substances which release and dissolution of the active drug Substance in an are readily Soluble in the gastrointestinal tract, but basically acidic aqueous medium. they do not Solve the problems related to drug Substances 0008 Thus, the purpose of the present invention is to which have poor Solubility characteristics. provide a pharmaceutical composition for oral use which is 0004 Especially in those cases where the drug substance useful for a fast delivery of an active drug Substance to the has a low Solubility in an acidic medium having a pH of from circulatory System upon administration. about 1 to about 3, i.e. a pH corresponding to the pH in the 0009. In one aspect, the invention relates to a quick Stomach, the traditional formulation approach will lead to a release pharmaceutical
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