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Process for the preparation of a solid, orally administrable pharmaceutical compositionProcess for the preparation of a solid, orally administrable pharmaceutical composition description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080026057, Process for the preparation of a solid, orally administrable pharmaceutical composition. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001]The present invention relates to a process for the preparation of a solid, orally administrable pharmaceutical composition, comprising 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin- -5-yl}-methyl)-2-thiophenecarboxamide in hydrophilized form, and its use for the prophylaxis and/or treatment of diseases. [0002]5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]1,3-oxazol- idin-5-yl}-methyl)-2-thiophenecarboxamide (I) is a low molecular weight, orally administrable inhibitor of blood clotting factor Xa, which can be employed for the prophylaxis and/or treatment of various thromboembolic diseases (for this see WO-A 01/47919, whose disclosure is hereby included by way of reference). If, below, the discussion is of the active compound (I), all modifications of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin- -5-yl}-methyl)-2-thiophenecarboxamide (I), and the respective hydrates are additionally included. [0003]The active compound (I) has a relatively poor water solubility (about 7 mg/l). As a result of this, difficulties with the oral bioavailability and an increased biological variability of the absorption rate can result. [0004]To increase the oral bioavailability, various concepts have been described in the past: [0005]Thus, solutions of active compounds are frequently used which can be filled, for example, into soft gelatine capsules. On account of the poor solubility of the active compound (I) in the solvents used for this purpose, this option is not applicable, however, in the present case, since, in the necessary dose strength, capsule sizes would result which are no longer swallowable. [0006]An alternative process is the amorphization of the active compound. Here, the solution method proves problematical, since the active compound (I) is also poorly soluble in pharmaceutically acceptable solvents such as ethanol or acetone. Amorphization of the active compound by means of the fusion method is also disadvantageous because of the high melting point of the active compound (about 230.degree. C.), since an undesirably high proportion of breakdown components is formed during the preparation. [0007]Furthermore, a process for the hydrophilization of hydrophobic active compounds as exemplified by hexobarbital and phenytoin has been described (Lerk, Lagas, Fell, Nauta, Journal of Pharmaceutical Sciences Vol. 67, No. 7, July 1978, 935-939: "Effect of Hydrophilization of Hydrophobic Drugs on Release Rate from Capsules"; Lerk, Lagas, Lie-A-Huen, Broersma, Zuurman, Journal of Pharmaceutical Sciences Vol. 68, No. 5, May 1979, 634-638: "In Vitro and In Vivo Availability of Hydrophilized Phenytoin from Capsules"). The active compound particles are blended here in a mixer with a methyl- or hydroxyethylcellulose solution with extensive avoidance of an agglomeration step and then dried. The active compound thus obtained is subsequently filled into hard gelatine capsules without further treatment. [0008]Surprisingly, it has now been found that a special treatment of the surface of the active compound (I) in the course of the moist granulation brings about improved absorption behaviour. The use of the active compound (I) in hydrophilized form in the preparation of solid, orally administrable pharmaceutical compositions leads to a significant increase in the bioavailability of the formulation thus obtained. [0009]The present invention relates to a process for the preparation of a solid, orally administrable pharmaceutical composition comprising 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin- -5-yl}-methyl)-2-thiophenecarboxamide in hydrophilized form, in which [0010](a) first granules comprising the active compound (I) in hydrophilized form are prepared by moist granulation [0011](b) and the granules are then converted into the pharmaceutical composition, if appropriate with addition of pharmaceutically suitable additives. [0012]The moist granulation in process step (a) can be carried out in a mixer (=mixer granulation) or in a fluidized bed (=fluidized bed granulation); fluidized bed granulation is preferred. [0013]In the moist granulation, the active compound (I) can either be introduced into the pre-mixture (original mixture) as a solid or it is suspended in the granulating liquid. Preferably, the active compound (I) suspended in the granulating liquid is introduced into the moist granulation (suspension process). [0014]In a preferred embodiment of the present invention, the active compound (I) is employed in crystalline form. [0015]In a particularly preferred embodiment of the present invention, the crystalline active compound (I) is employed in micronized form. The active compound (I) in this case preferably has an average particle size X.sub.50 of less than 10 .mu.m, in particular between 1 and 8 .mu.m, and X.sub.90 (90% proportion) of less than 20 .mu.m, in particular of less than 15 .mu.m. [0016]The granulating liquid used according to the invention contains a solvent, a hydrophilic binding agent and, if appropriate, a wetting agent. The hydrophilic binding agent is in this case dispersed in the granulating liquid or preferably dissolved therein. [0017]The solvents used for the granulating liquid can be organic solvents, such as, for example, ethanol or acetone, or water or mixtures thereof. Preferably, water is used as a solvent. [0018]The hydrophilic binding agents employed for the granulating liquid are pharmaceutically suitable hydrophilic additives, preferably those which dissolve in the solvent of the granulating liquid. [0019]Preferably, hydrophilic polymers such as, for example, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone, polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon.RTM. VA64, BASF), gelatine, guar gum, partially hydrolysed starch, alginates or xanthan are employed here. Particularly preferably, HPMC is employed as a hydrophilic binding agent. [0020]The hydrophilic binding agent can be present here in a concentration of 1 to 15% (based on the total mass of the pharmaceutical composition), preferably of 1 to 8%. [0021]The optionally present wetting agents employed for the granulating liquid are pharmaceutically suitable wetting agents (surfactants). The following may be mentioned, for example: [0022]sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate, sulphosuccinates such as sodium dioctyl sulphosuccinate, partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, partial fatty acid esters of sorbitan such as sorbitan monolaurate, partial fatty acid esters of polyhydroxyethylenesorbitan such as polyethylene glycol sorbitan monolaurate, monostearate or monooleate, polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acid esters, ethylene oxide-propylene oxide block copolymers (Pluronic.RTM.) or ethoxylated triglycerides. Preferably, sodium lauryl sulphate is employed as a wetting agent. [0023]If required, the wetting agent is employed in a concentration of 0.1 to 5% (based on the total mass of the pharmaceutical composition), preferably of 0.1 to 2%. [0024]In the pre-mixture (original mixture) of the moist granulation, further pharmaceutically suitable additives are present. 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