Solid, orally administrable pharmaceutical composition

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.

Skip to: Description  ·  Claims  ·  References Cited  · Patent History  ·  Patent History
Description
CROSS-REFERENCE TO RELATED APPLIATIONS

This application is the continuation of U.S. application Ser. No. 10/580,711, filed May 18, 2007, which is hereby incorporated herein by reference in its entirety, and which is the national stage application (under 35 U.S.C. §371) of PCT/EP2004/012897 filed Nov. 13, 2004, which claims benefit of German application 10355461.0 filed Nov. 27, 2003.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable.

THE NAMES OF THE PARTIES TO JOINT RESEARCH AGREEMENT

Not Applicable.

INCORPORATED BY REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC OR AS A TEXT FILE VIA THE OFFICE ELECTRONIC FILING SYSYTEM (EFS-WEB).

Not Applicable.

STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINT INVENTOR

Not Applicable.

BACKGROUND OF THE INVENTION

1. Field of the Invention

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-oxanzolidin-5-yl}-methyl)-2-thiophenecarboxamide in hydrophilized form, and its use for the prophylaxis and/or treatment of diseases.

2. Description of Related Art Including Information Disclosed Under 37 CFR 1.97 and 1.98.

5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-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.

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.

To increase the oral bioavailability, various concepts have been described in the past:

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.

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° C.), since an undesirably high proportion of breakdown components is formed during the preparation.

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.

BRIEF SUMMARY OF THE INVETNION

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.

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

  • (a) first granules comprising the active compound (I) in hydrophilized form are prepared by moist granulation
  • (b) and the granules are then converted into the pharmaceutical composition, if appropriate with addition of pharmaceutically suitable additives.

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.

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).

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRWAING(S)

Not applicable.

 DETAILED DESCRIPTION OF THE INVENTION

In a preferred embodiment of the present invention, the active compound (I) is employed in crystalline form.

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 X50 of less than 10 μm, in particular between 1 and 8 μm, and X90 (90% proportion) of less than 20 μm, in particular of less than 15 μm.

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.

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.

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.

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® VA64, BASF), gelatine, guar gum, partially hydrolysed starch, alginates or xanthan are employed here. Particularly preferably, HPMC is employed as a hydrophilic binding agent.

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%.

The optionally present wetting agents employed for the granulating liquid are pharmaceutically suitable wetting agents (surfactants). The following may be mentioned, for example:

  • 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®) or ethoxylated triglycerides. Preferably, sodium lauryl sulphate is employed as a wetting agent.

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%.

In the pre-mixture (original mixture) of the moist granulation, further pharmaceutically suitable additives are present. The following may be mentioned, for example:

    • fillers and dry binding agents such as cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose or maltodextrins
    • disintegration promoters (disintegrants) such as carboxymethylcellulose, croscarmellose (crosslinked carboxymethylcellulose), crospovidone (crosslinked polyvinylpyrrolidone), L-HPC (low-substituted hydroxypropylcellulose), sodium carboxymethyl starch, sodium glycolate of potato starch, partially hydrolysed starch, wheat starch, maize starch, rice starch or potato starch

In the case of tablet formulations having modified (delayed) release of active compound, instead of the disintegration promoter (disintegrant) substances can be present which influence the release rate. The following may be mentioned, for example: hydroxypropylcellulose, hydroxypropyl-methylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, galactomannan, xanthan, glycerides, waxes, acrylic and/or methacrylic acid ester copolymers with trimethylammonium methylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, ethyl acrylate-methyl methacrylate copolymers or methacrylic acid-methyl acrylate copolymers.

The granules obtained in process step (a) are subsequently converted into the pharmaceutical composition according to the invention in process step (b).

Process step (b) comprises, for example, tabletting, filling into capsules, preferably hard gelatine capsules, or filling as sachets, in each case according to customary methods familiar to the person skilled in the art, if appropriate with addition of further pharmaceutically suitable additives.

Pharmaceutically suitable additives which may be mentioned are, for example:

    • lubricants, glidants, flow regulating agents such as fumaric acid, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, higher molecular weight fatty alcohols, polyethylene glycols, starch (wheat, rice, maize or potato starch), talc, highly disperse (colloidal) silica, magnesium oxide, magnesium carbonate or calcium silicate
    • disintegration promoters (disintegrants) such as carboxymethylcellulose, croscarmellose (crosslinked carboxymethylcellulose), crospovidone (crosslinked polyvinylpyrrolidone), L-HPC (low-substituted hydroxypropylcellulose), sodium carboxymethyl starch, partially hydrolysed starch, wheat starch, maize starch, rice starch or potato starch

The present invention further relates to 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 (I) in hydrophilized form.

The solid, orally administrable pharmaceutical composition according to the invention by way of example and preferably comprises granules, hard gelatine capsules or sachets filled with granules, and tablets releasing the active compound (I) rapidly or in a modified (delayed) manner. Tablets are preferred, in particular tablets rapidly releasing the active compound (I). In the context of the present invention, rapid-release tablets are in particular those which, according to the USP release method using apparatus 2 (paddle), such as described in the experimental section in chapter 5.2.2., have a Q value (30 minutes) of 75%.

The active compound (I) can be present in the pharmaceutical composition according to the invention in a concentration of 0.1 to 60%, preferably in a concentration of 1 to 40%, based on the total mass of the formulation. Here, the dose of the active compound (I) is preferably 1 to 100 mg.

If appropriate, the granules of tablets according to the invention are coated in a further step under customary conditions familiar to the person skilled in the art. The coating is carried out with addition of customary coating and film-forming agents familiar to the person skilled in the art, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinyl-pyrrolidone, vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon® VA64, BASF), shellac, acrylic and/or methacrylic acid ester copolymers with trimethylammonium methylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, ethyl acrylate-methyl methacrylate copolymers, methacrylic acid-methyl acrylate copolymers, propylene glycol, polyethylene glycol, glycerol triacetate, triethyl citrate and/or colour additives/pigments such as, for example, titanium dioxide, iron oxide, indigotin or suitable colour lakes.

The present invention further relates to the use of the pharmaceutical composition according to the invention for the prophylaxis and/or treatment of diseases, in particular of thromboembolic diseases such as cardiac infarct, angina pectoris (including unstable angina), reocclusions and restenoses after an angioplasty or aortocoronary bypass, cerebral infarct, transitory ischemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses.

The invention is illustrated in greater detail below by means of preferred exemplary embodiments, to which, however, it is not restricted. If not stated otherwise, all quantitative data below relate to percentages by weight.

Experimental Section

1. Tablet Preparation Using Granules Comprising the Active Compound (I) in Hydrophilized Form/Fluidized Bed Granulation Process

1.1 Tablet Composition (in mg/Tablet)

Active compound (I), micronized 20.0 mg Microcrystalline cellulose 35.0 mg Lactose monohydrate 22.9 mg Croscarmellose (Ac-Di-Sol ®, FMC) 3.0 mg Hydroxypropylmethylcellulose, 5 cp 3.0 mg Sodium lauryl sulphate 0.5 mg Magnesium stearate 0.6 mg Hydroxypropylmethylcellulose, 15 cp 1.5 mg Polyethylene glycol 3.350 0.5 mg Titanium dioxide 0.5 mg 87.5 mg

1.2 Preparation

Hydroxypropylmethylcellulose (5 cp) and sodium lauryl sulphate are dissolved in water. The micronized active compound (I) is suspended in this solution. The suspension thus prepared is sprayed onto the original mixture of microcrystalline cellulose, lactose monohydrate and croscarmellose as a granulating liquid in the course of a fluidized bed granulation. After drying and sieving (0.8 mm mesh width) the resulting granules, magnesium stearate is added and mixed. The press-ready mixture thus obtained is compressed to give tablets having a 6 mm diameter and a fracture resistance of 50-100 N. The subsequent coating of the tablets is carried out using titanium dioxide, which is suspended in an aqueous solution of hydroxypropylmethylcellulose (15 cp) and polyethylene glycol.

2. Tablet Preparation Using Granules Comprising the Active Compound (I) in Hydrophilized Form/High-Speed Granulation Process

2.1 Tablet Composition mg/Tablet)

Active compound (I), micronized 5.0 mg Microcrystalline cellulose 40.0 mg Lactose monohydrate 33.9 mg Croscarmellose (Ac-Di-Sol ®, FMC) 3.0 mg Hydroxypropylmethylcellulose, 3 cp 2.0 mg Sodium lauryl sulphate 0.5 mg Magnesium stearate 0.6 mg Hydroxypropylmethylcellulose, 15 cp 1.5 mg Polyethylene glycol 400 0.5 mg Iron yellow 0.1 mg Titanium dioxide 0.4 mg 87.5 mg

2.2 Preparation

The substances cellulose, lactose monohydrate and croscarmellose employed are mixed in a high-speed mixer (original granule mixture), Hydroxypropylmethylcellulose (3 cp) and sodium lauryl sulphate are dissolved in water. The micronized active compound (I) is suspended in this solution. The suspension thus prepared is added to the original granule mixture as a granulating liquid and blended uniformly with the original granule mixture with the aid of the rapidly rotating stirrer. After thorough mixing has been carried out, the moist granules are sieved (4 mm mesh width) and dried in the fluidized bed. After sieving the dried granules (0.8 mm mesh width), magnesium stearate is added and mixed. The press-ready mixture thus obtained is compressed to give tablets having a 6 mm diameter and a fracture resistance of 50-100 N. The subsequent coating of the tablets is carried out using titanium dioxide and iron yellow, the pigments being suspended beforehand in an aqueous solution of hydroxypropylmethylcellulose (15 cp) and polyethylene glycol.

3. Preparation of Granules Comprising the Active Compound (I) in Hydrophilized Form and Filling as Sachets

3.1 Granule Composition (in mg/Sachet)

Active compound (I), micronized 50.0 mg Mannitol 662.0 mg Croscarmellose (Ac-Di-Sol ®, FMC) 15.0 mg Hydroxypropylmethylcellulose, 5 cp 15.0 mg Sodium lauryl sulphate 1.0 mg Highly disperse silica (Aerosil ® 200, Degussa) 2.0 mg Strawberry flavouring, spray-dried 5.0 mg 750.0 mg

3.2 Preparation

Hydroxypropylmethylcellulose (5 cp) and sodium lauryl sulphate are dissolved in water. The micronized active compound (I) is suspended in this solution. The suspension thus prepared is sprayed onto the original mixture of mannitol and croscarmellose as a granulating liquid in the course of a fluidized bed granulation. After drying and sieving (0.8 mm mesh width) the resulting granules, highly disperse silica (Aerosil®) and strawberry flavouring are added and mixed. The mixture thus obtained is filled into sachet pouches to 750 mg with the aid of a sachet filling machine.

4. Preparation of Granules Comprising the Active Compound (I) in Hydrophilized Form and Filling into Hard Gelatine Capsules

4.1 Granule Composition (in mg/Capsule)

Active compound (I), micronized 20.0 mg Microcrystalline cellulose 30.0 mg Lactose monohydrate 79.5 mg Maize starch 25.0 mg Hydroxypropylmethylcellulose, 5 cp 4.5 mg Sodium lauryl sulphate 0.5 mg Highly disperse silica (Aerosil ® 200, Degussa) 0.5 mg 160.0 mg

4.2 Preparation

Hydroxypropylmethylcellulose (5 cp) and sodium lauryl sulphate are dissolved in water. The micronized active compound (I) is suspended In this solution. The suspension thus prepared is sprayed onto the original mixture of microcrystalline cellulose, lactose monohydrate and maize starch as a granulating liquid in the course of a fluidized bed granulation. After drying and sieving (0.8 mm mesh width) the resulting granules, highly disperse silica (Aerosil®) is added and mixed. The mixture obtained is filled to 160 mg in each case into hard gelatine capsules of capsule size 2.

5. Comparison of Tablets with/without Hydrophilized Active Compound (I)

5.1 Tablet Composition, Preparation

In order to investigate the tablet properties and the improved bioavailability of formulations containing hydrophilized active compound (I), uncoated tablets having a 10 mg active compound

content (I) of the following composition are prepared (in mg/tablet):

Active compound (I), micronized 10.0 mg Microcrystalline cellulose 40.0 mg Lactose monohydrate 27.9 mg Croscarmellose (Ac-Di-Sol ®, FMC) 3.0 mg Hydroxypropylmethylcellulose, 5 cp 3.0 mg Sodium lauryl sulphate 0.5 mg Magnesium stearate 0.6 mg 85.0 mg

Tablet-A: prepared by direct tabletting without granulation

Tablet B: prepared by the fluidized bed granulation/suspension process described in 1.2

The mixture for tablet A and the granules for tablet B are in each case pressed to give tablets having a diameter of 6 mm and a fracture strength of about 70-80 N.

5.2 Tablet Properties

5.2.1 Disintegration Time in Water (USP Disintegration Tester, Erweka):

    • Tablet A: about 1.5 minutes
    • Tablet B: about 6.5 minutes
      5.2.2 In-Vitro Release

The amounts of active compound released based on the declared total content of the tablets are shown in Table I below:

TABLE 1 In-vitro release 15 min 30 min 45 min 60 min Tablet A 87% 92% 93% 94% Tablet B 94% 95% 96% 96%

(USP paddle, 900 ml of acetate buffer pH 4.5+0.5% sodium lauryl sulphate, 75 rpm)
5.2.3 Bioavailability

For the investigation of the bioavailability, three dogs were in each case administered three tablets of A or three tablets of B in cross-over fashion. The corresponding pharmacokinetic parameters after oral administration of 3 mg of active compound (I)/kg are listed in Table 2 below:

TABLE 2 Pharmacokinetic parameters of active compound (I) Animal Mean S.D. Mean S.D. 1 2 3 geom. geom. arithm. arithm. Tablet A AUC(0-24) [mg · h/l] 1.39 2.31 3.34 2.21 1.55 2.35 0.974 AUC(0-24)norm [kg · h/l] 0.464 0.770 1.11 0.735 1.55 0.782 0.325 Cmax [mg/l] 0.299 0.398 0.430 0.371 1.21 0.376 0.0684 Cmax, norm [kg/l] 0.0997 0.133 0.143 0.124 1.21 0.125 0.0228 C(24)/Cmax [%] 12.2 2.99 55.1 12.6 4.29 23.4 27.8 tmax [h] 1.00 1.50 0.750 1.04 1.42 1.08 0.382 Tablet B AUC(0-24) [mg · h/l] 2.82 3.03 3.73 3.17 1.16 3.19 0.476 AUC(0-24)norm [kg · h/l] 0.938 1.01 1.24 1.06 1.16 1.06 0.159 Cmax [mg/l] 0.478 0.513 0.321 0.428 1.29 0.437 0.102 Cmax, norm [kg/l] 0.159 0.171 0.107 0.143 1.29 0.146 0.0341 C(24)/Cmax [%] 26.4 1.17 93.4 14.2 9.53 40.3 47.7 tmax [h] 1.00 1.50 0.750 1.04 1.42 1.08 0.382

Result: In spite of slower disintegration (see 5.2.1) and very similar in-vitro release (see 5.2.2) of tablet B in comparison to tablet A, tablet B has marked advantages in absorption and thus a bioavailability increased by about 35%. At the same time, a marked decrease in the variability is to be noted. The only difference between tablet A and tablet B is the hydrophilization of the active compound (I) in tablet B with the aid of the suspension process in the course of the moist granulation.

Claims

1. A process for the preparation of a solid, orally administrable pharmaceutical composition comprising an active compound (I) that is 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide in hydrophilized form, comprising the following steps:

(a) first preparing granules comprising the active compound (I) in hydrophilized form using fluidized bed granulation for moist granulation;
(b) and converting the granules into the pharmaceutical composition, if appropriate with addition of pharmaceutically suitable additives.

2. The process according to claim 1, wherein the active compound (I) is employed in crystalline form.

3. The process according to claim 2, wherein the active compound (I) is employed in micronized form.

4. The process according to claim 1, wherein the active compound (I) suspended in the granulating liquid is introduced into the moist granulation.

5. The process according to claim 1, wherein the resulting pharmaceutical composition is a tablet rapidly releasing the active compound (I).

6. A solid, orally administrable pharmaceutical composition comprising an active compound (I) that is 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide in hydrophilized form prepared by a process comprising the following steps:

(a) first preparing granules comprising the active compound (I) in hydrophilized form using fluidized bed granulation for moist granulation;
(b) and converting the granules into the pharmaceutical composition, if appropriate with addition of pharmaceutically suitable additives.

7. The pharmaceutical composition according to claim 6, comprising the active compound (I) in crystalline form.

8. The pharmaceutical composition according to claim 7, comprising the active compound (I) in micronized form.

9. The pharmaceutical composition according to claim 6, wherein the active compound (I) is present in a concentration of 1 to 60% based on the total mass of the composition.

10. The pharmaceutical composition according to claim 6, further comprising sodium lauryl sulphate as a wetting agent.

11. The pharmaceutical composition according to claim 10, wherein said sodium lauryl sulphate is present in a concentration of 0.1 to 5%, based on the total mass.

12. The pharmaceutical composition according to claim 6, further comprising hydroxypropylmethylcellulose as a hydrophilic binding agent.

13. The pharmaceutical composition according to claim 12, wherein said hydroxypropylmethylcellulose is present in a concentration of 1 to 15%, based on the total mass.

14. The pharmaceutical composition according to claim 6 that is in the form of a tablet.

15. The pharmaceutical composition according to claim 14 that is in the form of a rapid-release tablet.

16. The pharmaceutical composition according to claim 15, characterized in that the tablet is covered with a coating.

17. A method for the prophylaxis and/or treatment of thromboembolic diseases comprising administering an effective amount of the pharmaceutical composition of claim 6 to a patient in need thereof.

Referenced Cited
U.S. Patent Documents
2811555 October 1957 Larive et al.
3279880 October 1966 Straley et al.
4128654 December 5, 1978 Fugitt et al.
4250318 February 10, 1981 Dostert et al.
4327725 May 4, 1982 Cortese et al.
4344934 August 17, 1982 Martin et al.
4500519 February 19, 1985 Lormeau et al.
4705779 November 10, 1987 Madi-Szabo et al.
4724141 February 9, 1988 Schmidt et al.
4765989 August 23, 1988 Wong et al.
4948801 August 14, 1990 Carlson et al.
4977173 December 11, 1990 Brittelli et al.
5002937 March 26, 1991 Bosies et al.
5254577 October 19, 1993 Carlson et al.
5349045 September 20, 1994 Jiang
5532255 July 2, 1996 Raddatz et al.
5561148 October 1, 1996 Gante et al.
5565571 October 15, 1996 Barbachyn et al.
5654428 August 5, 1997 Barbachyn et al.
5654435 August 5, 1997 Barbachyn et al.
5688792 November 18, 1997 Barbachyn et al.
5756732 May 26, 1998 Barbachyn et al.
5792765 August 11, 1998 Riedl et al.
5801246 September 1, 1998 Barbachyn et al.
5827857 October 27, 1998 Riedl et al.
5910504 June 8, 1999 Hutchinson et al.
5922708 July 13, 1999 Riedl et al.
5929248 July 27, 1999 Barbachyn et al.
5935724 August 10, 1999 Spillman et al.
5972947 October 26, 1999 Tsaklakidis et al.
5977373 November 2, 1999 Gadwood et al.
5998406 December 7, 1999 Hester et al.
6069160 May 30, 2000 Stolle et al.
6074670 June 13, 2000 Stamm et al.
6159997 December 12, 2000 Tsujita et al.
6218413 April 17, 2001 Hester et al.
6251869 June 26, 2001 Bohanon
6265178 July 24, 2001 Martin, Jr.
6281210 August 28, 2001 Hester, Jr.
6294201 September 25, 2001 Kettelhoit et al.
6303626 October 16, 2001 Abramovici et al.
6514529 February 4, 2003 Yamamoto et al.
6589552 July 8, 2003 Stamm et al.
6805881 October 19, 2004 Kanikanti et al.
6818243 November 16, 2004 Nagashima et al.
7034017 April 25, 2006 Straub et al.
7045631 May 16, 2006 Rosentreter et al.
7078417 July 18, 2006 Rosentreter et al.
7109218 September 19, 2006 Rosentreter et al.
7129255 October 31, 2006 Rosentreter et al.
7157456 January 2, 2007 Straub et al.
20010029351 October 11, 2001 Falotico et al.
20010046987 November 29, 2001 Hester et al.
20030153610 August 14, 2003 Straub et al.
20030161882 August 28, 2003 Waterman
20040162427 August 19, 2004 Rosentreter et al.
20040242660 December 2, 2004 Straub et al.
20050064006 March 24, 2005 Perzborn et al.
20050182055 August 18, 2005 Berwe et al.
20050261502 November 24, 2005 Rosentreter et al.
20060154969 July 13, 2006 Rosentreter et al.
20060258724 November 16, 2006 Straub et al.
20070026065 February 1, 2007 Benke et al.
20070149522 June 28, 2007 Thomas
20080026057 January 31, 2008 Benke
20080090815 April 17, 2008 Straub et al.
20080200674 August 21, 2008 Straub et al.
20100151011 June 17, 2010 Benke
Foreign Patent Documents
744002 February 2002 AU
2836305 March 1979 DE
3417113 November 1984 DE
196 04 223 August 1997 DE
19962924 July 2001 DE
10105989 August 2002 DE
10129725 January 2003 DE
10355461 June 2005 DE
0 127 902 December 1984 EP
0 316 594 May 1989 EP
0 352 781 January 1990 EP
0350002 January 1990 EP
0623615 November 1994 EP
0645376 March 1995 EP
0738726 October 1996 EP
0 785 200 July 1997 EP
0930076 July 1999 EP
0950386 October 1999 EP
2140687 December 1984 GB
WO-93/09103 May 1993 WO
WO-93/23384 November 1993 WO
WO-97/03072 January 1997 WO
WO-97/09328 March 1997 WO
WO-97/10223 March 1997 WO
WO-98/00116 January 1998 WO
WO-98/01446 January 1998 WO
WO-98/54161 December 1998 WO
WO-99/02525 January 1999 WO
WO-99/03846 January 1999 WO
WO-99/21535 May 1999 WO
WO-99/24428 May 1999 WO
WO-99/29688 June 1999 WO
WO-99/31092 June 1999 WO
WO-99/37304 July 1999 WO
WO-99/37630 July 1999 WO
WO-99/37641 July 1999 WO
WO-99/40094 August 1999 WO
WO-99/59616 November 1999 WO
WO-00/16748 March 2000 WO
WO-01/42242 June 2001 WO
WO-01/44212 June 2001 WO
WO-01/46185 June 2001 WO
01/47919 July 2001 WO
WO-01/47919 July 2001 WO
WO-01-47949 July 2001 WO
WO-02/15940 February 2002 WO
WO-0215940 February 2002 WO
WO-02/25210 March 2002 WO
WO-02/38126 May 2002 WO
WO-0238126 May 2002 WO
WO-02/064575 August 2002 WO
WO-02/070484 September 2002 WO
WO-02/070485 September 2002 WO
WO-02/070520 September 2002 WO
WO-02/079195 October 2002 WO
WO-02/079196 October 2002 WO
WO-03/000256 January 2003 WO
WO-03/008384 January 2003 WO
WO-03/035133 May 2003 WO
WO-03/053441 July 2003 WO
WO-2004/060887 July 2004 WO
WO-2005/060940 May 2005 WO
WO-2005/068456 July 2005 WO
WO-2006/072367 July 2006 WO
WO-2006/079474 August 2006 WO
WO-2007/036306 April 2007 WO
WO-2007/039122 April 2007 WO
WO-2007/039132 April 2007 WO
WO-2007/039134 April 2007 WO
WO-2007/042146 April 2007 WO
WO-2008/012002 January 2008 WO
WO-2008/052671 May 2008 WO
Other references
  • Gao et al. International Journal Pharmaceutics. 2002; 237: 1-14.
  • Letter from Bayer Pharma Aktiengesellschaft to European Patent Office (“EPO”) dated Sep. 26, 2011 containing grounds for appeal of Opposition Division's partial revocation of Bayer's EP Patent 1 689 370 B1.
  • Letter from ratiopharm GmbH to the EPO dated Sep. 26, 2011 containing grounds for appeal of Opposition Division's upholding of Bayer's auxiliary request 2 in the Opposition to EP Patent 1 689 370.
  • Letter from ratiopharm GmbH to the EPO dated May 9, 2012 in the appeal of the Opposition Division's decision in EP Patent 1 689 370.
  • Letter from Bayer Pharma Aktiengesellschaft dated May 9, 2012 in the appeal of the Opposition Division's decision in EP Patent 1 689 370.
  • Letter from Bayer Pharma Aktiengesellschaft dated Aug. 31, 2012 in the appeal of the Opposition Division's decision in EP Patent 1 689 370.
  • Parikh, D. M. (editor), “Handbook of Pharmaceutical Granulation Technology”, 1997, vol. 81, pp. 7-9, publisher: Marcel Dekker, Inc., New York.
  • Von Bruchbausen, F., “Hagers Handbuch der pharmazeutischen Praxis”, 5th edition, Heidelberg, 1991, pp. 728-734.
  • Ohm, A., “Critical Manufacturing Variables and In Vitro Dissolution Tests in View of In Vivo Performance”, in Bio-International 2-Bioavailability, Bioequivalence and Pharmacokinetic Studies, Blume H.H. and Midha, K.K. (eds.), mepharm, Stuttgart, 1995, pp. 261-279.
  • Gennaro, A. R. (ed.), “Remington: The Science and Practice of Pharmacy,” 2000, 20th Edition, p. 865.
  • “FIP Guidelines for Dissolution Testing of Solid Oral Products,” Pharm. Ind. 59, No. 9, 1997, pp. 760-766.
  • FDA, Center for Drug Evaluation and Research, Guidance for Industry, “Dissolution Testing of Immediate Release Solid Oral Dosage Forms”, 1997, pp. 1-11.
  • Shah, V. P., “In Vitro Dissolution Profile of Water-Insoluble Drug Dosage Forms in the Presence of Surfactants,” Pharmaceutical Research, 1989, vol. 6, No. 7, pp. 612-618.
  • Klein. S., “The Use of Biorelevant Dissolution Media to Forecast the In Vivo, Performance of a Drug,” The AAPS Journal, 2010, vol. 12, No. 3, pp. 397-406.
  • Bono, F., et al., “Human Umbilical Vein Endothelial Cells Express High Affinity Receptors for Factor Xa”, Journal of Cellular Physiology, 1997, vol. 172, pp. 36-43.
  • Cocks, T. M., et al., “Protease-Activated Receptors: Sentries for Inflammation”, Tips, 2000, vol. 21, pp. 103-108.
  • Ross, R., “Atherosclerosis—An Inflammatory Disease”, New England J. of Medicine, 1999, vol. 340, No. 2, pp. 115-126.
  • Nakata, M., et al., “DX9065a an Xa Inhibitor, Inhibits Prothrombin-Induced A549 Lung Adenocarcinoma Cell Proliferation”, Cancer Letters, 1998, vol. 122, pp. 127-133.
  • Kaiser, B., et al., “A Synthetic Inhibitor of Factor Xa, DX-9065a, Reduces Proliferation of Vascular Smooth Muscle Cells in Vivo in Rats”, Thrombosis Research, 2000, vol. 98, pp. 175-185.
  • Altieri, D. C., et al., “Identification of Effector Cell Protease Receptor-1”, The Journal of Immunology, 1990, vol. 145, No. 1, pp. 246-253.
  • Coughlin, S. R., “Thrombin Signalling and Protease-Activated Receptors”, Nature, 2000, vol. 407, pp. 258-264.
  • Ornstein, D. L., et al., “Cancer, Thrombosis, and Anticoagulants”, Current Opinion in Pulmonary Medicine, 2000, vol. 6, pp. 301-308.
  • Dabbagh, K., et al., “Thrombin Stimulates Smooth Muscle Cell Procollagen Synthesis and mRNA Levels via a PAR-1 Mediated Mechanism”, Thrombasis and Haemostasis, vol. 79, No. 2 1997, pp. 405-409.
  • Herault, J-P., et al., “Activation of Human Vascular Endothelial Cells by Factor Xa: Effect of Specific Inhibitors”, Biochemical Pharmacology, 1999, vol. 57, pp. 603-610.
  • Leveugle, B., et al., “Heparin Oligosaccharides that Pass the Blood- Brain Barrier Inhibit β-Amyloid Precursor Protein Secretion and Heparin Binding to β-Amyloid Peptide”, Journal of Neurochemistry, 1998, vol. 70, No. 2, pp. 736-744.
  • Molino, M., et al., “Differential Expression of Functional Protease-Activated Receptor-2 (PAR-2) in Human Vascular Smooth Muscle Cells”, Arteriosclerosis, Thrombasis, and Vascular Biology, vol. 18, No. 5, 1998, pp. 825-832.
  • Plescia, J., et al., “Activation of MAC-1 (CD11b/CD18)-Bound Factor X by Release Cathepsin G Defines an Alternative Pathway of Leucocyte Initiation of Coagulation”, Biochem. J., 1996, vol. 319, pp. 873-879.
  • Howells, G. L., et al., “Proteinase-Activated Receptor-2: Expression by Human Neutrophils”, Journal of Cell Science, 1997, vol. 110, pp. 881-887.
  • Herbert, J.-M., et al., “Effector Protease Receptor 1 Mediates the Mitogenic Activity of Factor Xa for Vascular Smooth Muscle Cells in Vitro and In Vivo”, J. Clin. Invest., 1998, vol. 101, No. 5, pp. 993-1000.
  • Donnelly, K. M., et al., “Ancylostoma caninum Anticoagulant Peptide Blocks Metastasis In Vivo and Inhibits Factor Xa Binding to Melanoma Cells In Vitro”, Thromb Haemost, 1998, vol. 79, pp. 1041-1047.
  • Ragosta, M., et al., “Specific Factor Xa Inhibition Reduces Restenosis After Balloon Angioplasty of Atherosclerotic Femoral Arteries in Rabbits”, Circulation, 1994, vol. 89, No. 3, pp. 1262-1271.
  • Zhang, Y., et al., “Tissue Factor Controls the Balance of Angiogenic and Antiangiogenic Properties of Tumor Cells in Mice”, J. Clin. Invest., 1994, vol. 94, pp. 1320-1327.
  • Green, D., et al., “Lower Mortality in Cancer Patients Treated with Low-Molecular-Weight Versus Standard Heparin”, The Lancet, 1992, vol. 339, p. 1476.
  • Ko, F. N., et al., “Coagulation Factor Xa Stimulates Platelet-Derived Growth Factor Release and Mitogenesis in Cultured Vascular Smooth Muscle Cells of Rat”, J. Clin. Invest., 1996, vol. 98, No. 6, pp. 1493-1501.
  • Kakkar, A. K., et al., “Antithrombotic Therapy in Cancer”, BMJ, 1999, vol. 3318, pp. 1571-1572.
  • Gasic, G. P., et al., “Coagulation Factors X, Xa, and Protein S as Potent Mitogens of Cultured Aortic Smooth Muscle Cells”, Proc. Natl. Acad. Sci. USA, 1992, vol. 89, pp. 2317-2320.
  • Cirino, G., et al., “Factor Xa as an Interface Between Coagulation and Inflammation: Molecular Mimicry of Factor Xa Association with Effector Cell Protease Receptor-1 Induces Acute Inflammation In Vivo”, J. Clin. Invest., 1997, vol. 99, No. 10, pp. 2446-2451.
  • Senden, N. H. M., et al., “Factor Xa Induces Cytokine Production and Expression of Adhesion Molecules by Human Umbilical Vein Endothelial Cells”, The Journal of Immunology, 1998, vol. 161, pp. 4318-4324.
  • Papapetropoulos, A., et al., “Hypotension and Inflammatory Cytokine Gene Expression Triggered by Factor Xa-Nitric Oxide Signaling”, Proc. Natl. Acad. Sci. USA, 1998, vol. 95, pp. 4738-4742.
  • Camerer, E., et al., “Tissue Factor- and Factor X-dependent Activation of Protease-Activated Receptor 2 by Factor VIIa”, PNAS, 2000, vol. 97, No. 10, pp. 5255-5260.
  • Donovan, F. M., et al., “Thrombin Induces Apoptosis in Cultured Neurons and Astrocytes via a Pathway Requiring Tyrosine Kinase and RhaA Activities”, The Journal of Neuroscience, 1997, vol. 17, No. 14, pp. 5316-5326.
  • Lindner, J. R., et al., “Delayed Onset of Inflammation in Protease-Activated Receptor-2-Deficient Mice”, The Journal of Immunology, 2000, pp. 6504-6510.
  • Bouchard, B. A., et al., “Effector Cell Protease Receptor-1, a Platelet Activation-dependent Membrane Protein, Regulates Prothrombinase-catalyzed Thrombin Generation”, The Journal of Biological Chemistry, 1997, vol. 272, No. 14, pp. 9244-9251.
  • Molino, M., et al., “Endothelial Cell Thrombin Receptors and PAR-2”, The Journal of Biological Chemistry, 1997, vol. 272, No. 17, pp. 11133-11141.
  • Nicholson, A. C., et al., “Effector Cell Protease Receptor-1 Is a Vascular Receptor for Coagulation Factor Xa”, The Journal of Biological Chemistry, 1996, vol. 271, No. 45, pp. 28407-28413.
  • Watson, D. J., et al., “Heparin-Binding Properties of the Amyloidogenic Peptides Aβ and Amylin”, The Journal of Biological Chemistry, 1997, vol. 272, No. 50, pp. 31617-31624.
  • Tuszynski, G. P., et al., “Isolation and Characterization of Antistasin”, The Journal of Biological Chemistry, 1987, vol. 262, No. 20, pp. 9718-9723.
  • Kranzhöfer, R., et al., “Thrombin Potently Stimulates Cytokine Production in Human Vascular Smooth Muscle Cells but Not in Mononuclear Phagocytes”, Circulation Research, 1996, vol. 79, No. 2, pp. 286-294.
  • Schwartz, R. S., et al., “Neointimal Thickening After Severe Coronary Artery Injury is Limited by Short-term Administration of a Factor Xa Inhibitor”, Circulation, 1996, vol. 93, No. 8, pp. 1542-1548.
  • Abendschein, D. R., et al., “Inhibition of Thrombin Attenuates Stenosis After Arterial Injury in Minipigs”, JACC, 1996, vol. 28, No. 7, pp. 1849-1855.
  • Carmeliet, P., et al., “Gene Manipulation and Transfer of the Plasinogen and Coagulation System in Mice”, Seminars in Thrombosis and Hemostasis, 1996, vol. 22, No. 6, pp. 525-542.
  • Stouffer, G. A., et al., “The Role of Secondary Growth Factor Production in Thrombin-Induced Proliferation of Vascular Smooth Muscle Cells”, Seminars in Thrombosis and Hemostasis, 1998, vol. 24, No. 2, pp. 145-150.
  • Bevilacqua, M. P., et al., “Inducible Endothelial Functions in Inflammation and Coagulation”, Seminars in Thrombosis and Hemostasis, 1987, vol. 13, No. 4, pp. 425-433.
  • Riedl, B., et al., “Recent Developments with Oxazolidinone Antibiotics”, Exp. Opin. Ther. Patents, 1999, vol. 9, No. 5, pp. 625-633.
  • Barbachyn, M.R., et al., “Identification of Novel Oxazolidinone (U-100480) with Potent Antimycobacterial Activity”, J. Med. Chem., 1996, vol. 39, pp. 680-685.
  • Tucker, J. A., et al, “Piperazinyl Oxazolidinone Antibacterial Agents Containing a Pyridine, Diazene, or Triazene Heteroaromatic Ring”, J. Med. Chem. 1998, vol. 41, pp. 3727-3735.
  • Brickner, S.J., et al., “Synthesis and Antibacterial Activity of U-100592 and U-100766, Two Oxazolidinone Antibacterial Agents for the Potenial treatment of Multidrug-Resistant Gram-Positive Bacterial Infections” J. Med. Chem., 1996, vol. 39, pp. 673-679.
  • Gregory, W.A., et al., “Antibacterials. Synthesis and Structure-Activity Studies of 3-Aryl-2-oxooxazolidines. 1. The “B” Group”, J. Med. Chem., 1989, vol. 32, No. 8, pp. 1673-1681.
  • Berry, C. N., et al., “Antithrombotic Actions of Argatroban in Rat Models of Venous, ‘Mixed’ and Arterial Thrombosis, and its Effects on the Tail Transection Bleeding Time”, Br. J. Pharmacol., 1994, vol. 113, pp. 1209-1214.
  • Meng, K., et al., “Effect of Acetylsalicyclic Acid of Experimentally Induced Arterial Thrombosis in Rats”, Naunyn-Schmiedeberg's Arch. Pharmacol.,1977, vol. 301, pp. 115-119.
  • Chern, J.W., et al., “Studies on Quinazolines IX:1 Fluorination Versus 1,2-Migration on the Reaction of 1,3-Bifunctionalized Amino-2-Propanol with DAST”, Tetrahedron Lett., 1998, vol. 39, pp. 8483-8486.
  • Shakespeare, W. C., et al., “Palladium-Catalyzed Coupling of Lactams with Bromobenzenes”, Tetrahedron Lett., 1999, vol. 40, pp. 2035*2038.
  • Renger, B., et al., “Direkte N-Arylierung von Amiden: Eine Verbesserung der Goldberg-Reaktion”, Synthesis, 1985, pp. 856-860.
  • Aebischer, E., et al., “Synthesis of N-Arylrolipram Derivatives—Potent and Selective Phosphodiesterase-IV Inhibitors—by Copper Catalyzed Lactam-Aryl Halide Coupling”, Hetercycles, 1998, vol. 48, No. 11 , pp. 2225-2229.
  • Pfeil, E., et al., “β-Aminoäthylierung von Indol und 2-methylindol”, Angew Chem., 1967, vol. 79, No. 4, pp. 188-189.
  • Ziegler, C. B., et al., “Synthesis of Some Novel 7-Substituted Quinolonecarboxylic Acids via Nitroso and Nitrone Cycloadditions”, J. Hetercycl. Chem., 1988, vol. 25, No. 2, pp. 719-723.
  • Bartoli, G., et al, “Electronic and Steric Effects in Nucleophilic Aromatic Substitution. Reaction by Phenoxides as Nucleophiles in Dimethyl Sulfoxide”, J. Org. Chem., 1975, vol. 40, No. 7, pp. 872-874.
  • Reppe, et al., “N-p-Merthoxyphenyl-pyrrolidon”, Justus Liebigs Ann. Chem., 1955 vol. 596, p. 208.
  • Luvalle, J.E., et al., “Oxidation Processes. XXI.1 The Autoxidation of the ρ-Phenylenediamines”, J. Am. Chem. Soc., 1948, vol. 70, pp. 2223-2233.
  • Snyder, H.R., et al., “Imidazo[4,5ƒ]quinolines III: Antibacterial 7-Methyl-9-(substituted Arylamino)imidazo[4,5-ƒ]quinolines”, J. Pharm. Sci., 1977, vol. 66, pp. 1204-1406.
  • Adams, R., et al., “Sulfanilamide Derivatives. I”, J. Am. Chem. Soc. 1939, vol. 61, pp. 2342-2349.
  • Khanna, I.K. , et al., “1,2-Diarylpyrroles as Potent and Selective Inhibitors of Cyclooxygenase-2”, J. Med. Chem., 1997, vol. 40 , pp. 1619-1633.
  • Gutcait, A., et al., “Studies on Quinazolines. 6.1 Asymmetric Synthesis of (S)-(+)- and (R)-(−)-3-[[4-(2-Methoxyphenyl)piperazin-1-yl]methylthio-2,3,-dihydromidazo[1,2-c]quinazolines”, Tetrahedron Asym., 1996, vol. 7, No. 6, pp. 1641-1648.
  • Grell, W., et al., “Repaglinide and Related Hypoglycemic Benzoic Acid Derivatives”, J. Med. Chem., 1998, vol. 41, pp. 5219-5246.
  • Artico, M. et al., “Research on Compounds with Antiblastic Activity”, Farmaco Ed. Sci. 1969, vol. 24, pp. 179-190.
  • Dankwardt, S. M., et al., “Nonpeptide Bradykinin Antagonist Analogs based on a Model of a Sterling-Winthrop Nonpeptide Bradykinin Antagonist Overlapped with Cyclic Hexapeptide Bradykinin Antagonist Peptides”, Bioorg. Med. Chem. Lett., 1997, vol. 7, No. 14, pp. 1921-1926.
  • Reppe, et al., “N-6-Aminohexyl-pyrrolidon”, Justus Liebigs Ann. Chem. 1955, vol. 596, pp. 204.
  • Bouchet, P., et al., “σ Values of N-Substitutes Azoles”, J. Chem. Soc. Perkin Trans., 1974, vol. 2, pp. 449-451.
  • Surrey, A. R., et al., “The Preparation of N-Benzyl-3-Morpholones and N-Benzyl-3-Homomorpholones from N-(Hydroxyalkyl)-chloroacetamides” J. Amer. Chem. Soc., 1955, vol. 77, pp. 633-636.
  • Tong, L.K.J., et al., “The Mechanism of Dye Formation in Color Photography. VII. Intermediate Bases in the Deamination of Quinonediimines” J. Amer. Chem. Soc. 1960, vol. 82, 1988-2001.
  • Delande, S.A., “Heterocycles”, Chemical Abstracts, American Chemical Society, 1979, vol. 90, pp. 663.
  • Bots, M., et al., Coagulation and Fibrinolysis Markers and Risk of Dementia, Haemostasis, vol. 28 (1998); pp. 216-222.
  • Benzakour, O., et al., “Cellular and molecular events in atherogenesis; basis for pharmocological and gene therapy approaches to stenosis,” Cellular Pharmacology, 1996, vol. 3, pp. 7-22.
  • Kanthou, C., et al., “Cellular effects of thrombin and their signalling pathways,” Cellular Pharmacology, vol. 2 (1995); pp. 293-302.
  • Kaiser, B., et al., “Antiproliferation Action of Factor Xa Inhibitors in a Rat Model of Chronic Restenosis,” Abstracts of the XVIIth Congress of the International Society on Thrombosis and Haemostasis, Aug. 1999, p. 144.
  • Tyrrell, D., et al., “Heparin in Inflammation: Potential Therapeutic Applications Beyond Anticoagulation,” Advances in Pharmacology, vol. 46 (1999); pp. 151-208.
  • Smirova, I., et al., “Thrombin Is an Extracellular Signal that Activates Intracellular Death Protease Pathyways Inducing Apoptosis in Model Motor Neurons,” J. Neurobiology, vol. 36 (1998); pp. 64-80.
  • Bono, F., et al., “Factor Xa Activates Endothelial Cells by a Receptor Cascade Between EPR-1 and PAR-2,” Arterioscler Thromb Vasc Biol., Nov. 2000; pp. 1-6.
  • Lala, P. et al, “Role of Nitric Oxide in tumor progression: Lessons Learned from Experimental Tumors,” Cancer and Metastasis Review, vol. 17, pp. 91-106 (1998).
  • Golub, T. et al., Molecular Classification of Cancer Science (1999), vol. 286, 531-537.
  • FDA mulls drug to slow late-stage Alzheimer's [online], [retrieved on Sep. 23, 2003]. Retrieved from the internet, URL:http://www.cnn.com/2003/HEALTH/conditions/09/24/alzheimers.drug.ap/index.html>.
  • Ulllman's Encyclopedia of Industrial Chemistry, Fifth Revised Ed., Editors: Elvers, B., Hawkins, S., VCH Verlagsgesellschaft mbH, Weinheim, 1985-1996, Ch. 5, 488-506.
  • Zhu, B., Scarborough, R., “Recent Advances in Inhibitors of Factor Xa in the Prothrombinase Complex,” Curr. Opinions Card. Pul. Ren. Inv. Drugs, 1:63-87 (1999).
  • Uzan, A., “Antithrombotic Agents,” Emerging Drugs: The Prospect for Improved Medicines, 3: 189-208 (1998).
  • Kaiser, B., “Thrombin and Factor Xa Inhibitors,” Drugs of the Future, 23: 423-426 (1998).
  • Al-Obeidi, F., Ostrem, J., “Factor Xa Inhibitors,” Expert Opin. Therapeutic Patents, 9: 931-953 (1999).
  • Al-Obeidi, F., Ostrem, J., “Factor Xa Inhibitors by Classical and Combinatorial Chemistry,” DDT, 3: 223-231 (May 1998).
  • Hauptmann, J. et al., “Synthetic Inhibitors of Thrombin and Factor Xa: From Bench to Bedside,” Thrombosis Research, 93: 203-241 (1999).
  • Pschyrembel, Klinisches Worterbuch, 257. Auflage, 1994, Walter de Gruyter Verlag, p. 199-200, Stichwort “Blutgerinnung.”
  • Rompp Lexikon Chemie, Ver. 1.5, 1998, Georg Thieme Verlag Stuttgart, Stichwort “Blutgerrinung” Lubert Stryer, Biochemie, Spektrum der Wissenschaft Verlagsgesellschaft mbH Heidelberg, 1990, p. 259.
  • Pschyrembel, Klinisches Worterbuch, 257. Auflage, 1994, Walter de Gruyter Verlag, p. 610, Stichwort “Heparin.”
  • Rompp Lexikon Chemie, Ver. 1.5, 1998, Georg Thieme Verlag Stuttgart, Stichwort “Heparin.”
  • Pschyrembel, Klinisches Worterbuch, 257. Auflage, 1994, Walter de Gruyter Verlag, p. 292, Stichwort “Cumarinderivate.”
  • Becker, M.R., et al., “Synthesis, Sar and in Vivo Activity of Novel Thienopyridine Sulfonamide Pyrrolidininones as Factor Xa Inhibitors,” Bioorganic and Medicinal Chemistry Letters, 9: 2753-2758 (1999).
  • Linder, J., et al., “Delayed Onset of Inflammation in Protease-Activated Receptor-2-Deficient Mice,” J. Immunology, 2000, pp. 6504-6510.
  • Cirino, G. et al. Inflammation-Coagulation Network: Are Serine Protease receptors the knot?; Tips; 200, vol. 21, pp. 170-172.
  • Roehrig, S. et al. Discovery of the Novel Antithrombotic Agent 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (BAY 59-7939): An Oral, Direct Factor Xa Inhibitor. J. Med. Chem. 48, 22. Sep. 2005, pp. 5900-5908.
  • Caira, M. Crystalline Polymorphism of Organic Compounds. Springer Verlag Berlin Heidelberg 198, 1998, pp. 163-208.
  • Hancock, B. et al. Characteristics and Significance of the Amorphous State in Pharmaceutical Systems. Journal of Pharmaceutical Science. 86, 1 (Jan. 1997), pp. 1-12.
  • Chiou, W.L. et al. Pharmaceutical Applications of Solid Dispersion Systems. Journal of Pharmaceutical Sciences 60, (1971). 128-1302.
  • Ford, J.L. The Current Status of Solid Dispersions. Pharm Acta HeIv. 61, (1986)69-88.
  • Rasenack, N. et al. Poorly Water-soluble Drugs for Oral Delivery—A Challenge for Pharmaceutical Development. Pharmazeutische Industrie 67, Nr. 5 (2005), 583-591.
  • Breitenbach, J. Melt extrusion: from process to drug delivery technology. European Journal of Pharmaceutics and Biopharmaceutics 54 (2002) 107-117.
  • Breitenbach, J. Feste Loesungen durch Schmelzextrusion—ein integriertes Herstellkonzept. Pharmazie in unserer Zeit 29 (2000), 46-49.
  • Stroke: Warning Signs and Tips for Prevention [online], retrieved Aug. 20, 2007 from the internet at http://familydoctor.org/online/famdocen/home/common/heartdisease/basics/290.html.
  • Kubitza, et al., Multiple dose escalation study Investigating the pharmacodyanamics, safety, and pharmacokinetics of BAY 59-7939 an oral, direct Factor Xa inhibitor in healthy male subjects, Blood, vol. 102:11:Nov. 16, 2003, p. 811a.
  • Kubitza, et al., Abstract 3010, Single dose escalation study investigating the pharmacodyanamics, safety, and pharmacokinetics of BAY 59-7939 an oral, direct Factor Xa inhibitor in healthy male subjects, Blood, vol. 102:11. Nov. 16, 2003, p. 813a.
  • Reppe, et al., Justus Liebigs Ann. Chem. 596, 1955, p. 209.
  • Wong et al., The Journal of Pharmacology and Experimental Therapeutics, vol. 295, No. 1 (2000) pp. 212-218.
  • Ross, Russell, “Atherosclerosis—An Inflammatory Disease,” The New England Journal of Medicine; vol. 340, No. 2; pp. 115-126 (Jan. 14, 1999).
  • Perzborn, E. et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939-an oral, direct Factor Xa inhibitor. Journal of Thrombosis and Haemostasis 3, 3, Mar. 2005, pp. 514-521.
  • Espinosa, G. et al. Thrombotic microangiopathic haemolytic anaemia and antiphospholipid antibodies. Annals of the Rheumatic Diseases, 63, 6, Jun. 2004, pp. 730-736.
  • Bonomini, V. et al. A New Antithrombotic Agent in the Treatment of Acute Renal Failure Due to Hemolytic-Uremic Syndrome and Thrombotic Thrombocytopenic Purpura. Nephron 37, 1984, 2, 144.
  • Sinha, U. et al. Antithrombotic and hemostatic capacity of factor Xa versus thrombin inhibitors in models of venous and arteriovenous thrombosis. European Journal of Pharmacology 2000, 395, 51-59.
  • Betz, A. Recent advances in Factor Xa inhibitors. Expert Opinion Ther. Patents 2001, 11, 1007-1017.
  • Tan, K.T. et al. Factor X inhibitors. Expert Opinion Investig. Drugs 2003, 12, 799-804.
  • Ruef, J. et al. New antithrombotic drugs on the horizon. Expert Opinion Investig. Drugs 2003, 12, 781-797.
  • Samama, M.L. Synthetic direct and indirect factor Xa inhibitors. Thromobis Research 2002, 106, V267-V273.
  • Quan, M.L. The race to an orally active Factor Xa inhibitor: Recent advances. Current Opinion in Drug Discovery & Development 2004, 7, 460-469.
  • The Ephesus Study, Blood 2000, 96, 490a.
  • The Penthifra Study, Blood 2000, 96, 490a.
  • The Pentamaks Study, Blood 2000, 96, 490a-491a.
  • The Pentathlon 2000 Study, Blood 2000, 96, 491a.
  • Leadley, R.J. Coagulation Factor Xa Inhibition: Biological Background and Rationale. Current Topics in Medical Chemistry 2001, 1, 151-159.
  • Gilligan, D.M. et al. The Management of Atrial Fibrillation. The American Journal of Medicine, vol. 101, (4) 1996, 413-421.
  • Kubitza, D. et al. Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases. Expert Opinion on Investig. Drugs, vol. 15, (8) 2006, pp. 843-855.
  • Williams, E.M. Vaughan. Classificating anti-arrhythimic drugs. In: Cardiac Arrythias—Proceedings of a symposium, sandoe E., soedertaeje: Astra (1970), pp. 449-469.
  • Lieberman et al., “Pharmaceutical Dosage Forms: Tablets”, Marcel Dekker, Inc, 1980, vol. 1., pp. 109-124.
  • European Patent Office Communication of a Notice of Opposition dated Nov. 20, 2008, for EP Patent 1689370 B1.
  • Opposition to EP 1689370 B1 filed Nov. 12, 2008 by ratiopharm GmbH.
  • Reply to the Opposition to EP Patent 1689370 filed Jun. 15, 2009.
  • Reply to Patentee's Statement dated Jun. 15, 2009, filed in European Patent Office on Jan. 8, 2010.
  • Communication dated Mar. 31, 2010 in Opposition to EP 1 689 370B1.
  • Datasheet for Zyvoxid from South African Electronic Package Inserts, May 29, 2001.
  • Aulton, “Pharmaceutics: The Science of Dosage Form Design”, 1998, pp. 136-137 and 154-156.
  • Pfizer, “Gebrauchsinformation: Information Fuer Den Anwender”, Stand der Informationen: Oct. 2008.
  • “About FDA: The Biopharmaceutics Classification System (BCS) Guidance” of the US Food and Drug Administration, Jun. 3, 2009.
  • Pfizer, “Zyvoxid® Linezolid”, Prescribing Information in Israel, Apr. 20, 2006.
  • “British Pharmacopoeia 2009,” vol. I & II, General Notices Part II: Solubility.
  • Provisional Opinion of the Opposition Division of the European Patent Office in Opposition to EP Appl. 04 797 879, dated Jan. 14, 2011 (10 pages).
  • Welshman et al., “Linezolid Absolute Bioavailability and the Effect of Food on Oral Bioavailability”, Biopharmaceutics & Drug Disposition, 2001, vol. 22, pp. 91-97.
  • Jain et al., “Pharmaceutical Product Development Technologies Based on the Biopharmaceutical Classification System”, Pharmazie, 2009, vol. 64, pp. 483-490.
  • Aulton, “Pharmaceutics: The Science of Dosage Form Design”, 2002 (2nd Ed.), pp. xiii, 6-9, 24-27, 113-114, 138, 142, 144, 253 and 273.
  • Bauer, K.H., et al., Lehrbuch der Pharmazeutische Technologie, 2002, pp. 220, 221 and 311, Publisher: Wissenschaftliche Verlagsgesllschaft mbH, Stuttgart.
  • Information from European Patent Office mailed Apr. 12, 2011 in Opposition to EP 1 689 370 rejecting Opposition over amended claims.
  • Kedvessy, G., et al., “Investigations into the absorption of some poorly water-soluble active ingredients from suspensions and tablets,” Pharmazie, 1975, vol. 30, H. 7, pp. 476-478. (In German).
  • Lerk, C.F., et al., “In Vitro and In Vivo Availability of Hydrophilized Phenytoin from Capsules,” Journal of Pharmaceutical Sciences, May 1979, vol. 68, No. 5, pp. 634-638.
  • Letter from ratiopharm to EPO dated Apr. 4, 2011 in Opposition to EP Patent 1 689 370.
  • Remington Pharmacia, Chapter 83, Preformulación, 1998, pp. 2231-2232.
  • Provisional minutes of the oral proceedings in the Opposition in the European Patent Office to EP 1 689 370 B (May 3, 2011).
  • Decision of the European Patent Office in the Opposition to EP 1 689 370B (May 16, 2011).
  • Lerk, et al., “Effect of Hydrophilization of Hydrophobic Drugs on Release Rate from Capsules,” J. of Pharma. Sciences, 67(7), pp. 935-939 (1978).
  • Greaves, et al., “Novel Approaches to the Preparation of Low-Dose Solid Dosage Forms,” Pharmaceutical Technology, pp. 60-64, Jan. 1995.
  • Eisenführ Speiser, “Einwendungen eines Dritten gemäβ Artikel 115 EPÜ,” which translated is Third Party Observation Pursuant to EPC Article 115, Mar. 17, 2014, submitted by Eisenführ Speiser to the European Patent Office in EP Application No. 1689370. (35 pages).
  • Amendment mailed Jul. 28, 2010, in U.S. Appl. No. 11/317,720.
  • Gandhi et al., “Extrusion and Spheronization in the Development of Oral Controlled-Release Dosage Forms”, PSTT, 1999, vol. 2, No. 4, pp. 160.
  • Hilgers, et al., “Predicting Oral Absorption of Drugs: A case . . . ,” 2003, Pharmaceutical Research, 20(8), pp. 1149-1155.
  • Kubitza et al., “Safety, Pharmacodynamics, and Pharmacokinetics of a Single Doses of BAY 59-7939, an Oral, Direct Factor Xa Inhibitor”, Pharmacodynamics and Drug Action, 2005.
  • Lippold, “Controlled Release Products: Approaches of Pharmaceutical Technology,” Oral Controlled Release Products: Therapeutic and Biopharmaceutic Assessment, editors U. Gundert-Remy and H. Moeller, 1989, pp. 39-57, Stuttgart, Germany.
  • Melia, “Hydrophilic Matrix Sustained Release Systems Based on Polysaccharide Carriers”, Critical Reviews in Therapeutic Drug Carrier Systems, 1991, vol. 8, No. 4, pp. 395-421.
  • Muller, et al., “Emulsion and Nanosuspensions for the Formulation of Poorly Soluble Drugs,” 1997, pp. 20.
  • Opposition of Ratiopharm GmbH to EP Patent 1 830 855 B1 filed Nov. 23, 2010.
  • Opposition of Sandoz GmbH to EP Patent 1 830 855 B1 filed Nov. 24, 2010.
  • Response to Final Office Action mailed Jan. 13, 2011, in U.S. Appl. No. 11/317,720.
  • Santus et al., “Osmotic Drug Delivery: A Review of the Patent Literature”, Journal of Controlled Release, 1995, vol. 35, pp. 1-21.
  • Vazquez et al., “Influence of Technological Variables on Release of Drugs From Hydrophilic Matrices”, Drug Development and Industrial Pharmacy, 1992, vol. 18 No. 11&12, pp. 1355-1375.
  • Verma et al., “Formulation Aspects in the Development of Osmotically Controlled Oral Drug Delivery Systems”, Journal of Controlled Release, 2002, vol. 79, pp. 7-27.
  • Verma et al., “Osmotically Controlled Oral Drug Delivery”, Drug Deveopment and Industrial Pharmacy, 2000, vol. 26, No. 7, pp. 695-708.
  • Advisory Action mailed Jan. 25, 2011, in U.S. Appl. No. 11/317,720.
  • Alderman, “A Review of Cellulose Ethers in Hydrophilic Materices for Oral Controlled-Release Dosage Forms”, Int. J. Pharm. Tech. & Prod. Mfr., 1984, vol. 5, No. 3, pp. 1-9.
  • Verma, et al., “Osmotically controlled oral drug delivery,” 2000, Drug Development and Industrial Pharmacy 26(7), pp. 695-708.
  • Weinz et al., “In vitro metabolism of BAY 59-7939—an oral, direct Factor Xa inhibitor”, Drug Metabolism and Isotope Chemistry.
  • Bayer HealthCare's Reply to the Opposition to EP Patent 1830855 by ratiopharm GmbH, dated Jun. 28, 2011 with first auxiliary claim request (19 pages).
  • Office Action mailed Feb. 11, 2015, in U.S. Appl. No. 14/202,481.
  • Amendment mailed May 11, 2015, in U.S. Appl. No. 14/202,481.
  • Gao et al., “Fluid bed granulation of a poorly water soluble, low density, micronized drug: comparison with high shear granulation,” International Journal of Pharmaceutics 237 (2002), pp. 1-14.
  • Eisenfuhr Speiser, “Einwendungen eines Dritten gemass Artikel 115 EPU,” which translated is Third Party Observation Pursuant to EPC Article 115, dated Jun. 17, 2014, submitted by Eisenfuhr Speiser for client Helm AG to the European Patent Office in EP Application Publication No. EP1689370.
  • Herbert Lieberman and Leon Lachman (eds.), “Pharmaceutical Dosage Forms: Tablets”, 1980, vol. 1, chapter 3 entitled “Compressed Tablets,” pp. 109-124.
  • Dilip Parikh (ed.), “Handbook of Pharmaceutical Granulation Technology,” 1997, pp. 7-9, published by Marcel Dekker, Inc., New York—Basel.
  • Anonymous, “Third Party Observations Under Article 115 EPC,” filed against European Patent EP1689370, Jun. 26, 2014 (with cover letter from EP Board of Appeal forwarding for patentee on Jul. 1, 2014).
  • Weinz et al., “In vitro metabolism of BAY 59-7939—an oral, direct Factor Xa inhibitor”, 7th International Meeting of the International Society for the Study of Xenobiotics; Vancouver, BC, Canada; Aug. 29-Sep. 2, 2004, ISSN: 0360-2532.
  • Bayer HealthCare's Reply to the Opposition to EP Patent 1830855 by ratiopharm GmbH, dated Jun. 28, 2011 with first auxiliary claim request (39 pages).
  • Benke et al., U.S. Appl No. 14/202,481, entitled “Process for the Preparation of a Solid, Orally Administrable Pharmaceutical Composition”.
  • Declaration of Klaus Benke, Oct. 29, 2014, submitted in EPO Opposition to EP Patent 04797879.
  • Bayer Submission in EPO Opposition to EP Patent 04797879; dated Nov. 3, 2014.
  • Voight, R. “Pharmazeutische Technologie,” Publisher: Deutscher Apotheker Verlag Stuttgart, 2000, pp. 166-167.
  • Herzfeldt, C., “Propädeutikum der Arzneiformenlehre, Galenik 1,” Pulisher: Springer-Verlag, Berlin, 1992, pp. 133-135.
  • Minutes of the Oral Proceedings in Appeal of Opposition to EP Patent 04797879 dated Jun. 9, 2015; 6 pgs.
  • Bayer submission in EPO Opposition/Appeal to EP Patent 04797879 dated Apr. 13, 2015; 47 Pgs.
  • Ratiopharm GmbH Response Submission in EPO Opposition/Appeal to EP Patent 04797879, dated May 15, 2015; 33 Pgs.
  • Bayer Reply Submison in EPO Opposition/Appeal to EP Patent 04797879 dated May 29, 2015; 151 pgs.
  • Provisional Opinion in EPO OppositionlAppeal to EP Patent 04797879 dated Jun. 1, 2015; 36 pgs.
  • Bayer Submission in EPO Opposition/Appeal to EP Patent 04797879 dated Jun. 5, 2015; 8 pgs.
  • Minutes of the Oral Proceedings in Appeal of Opposition to EP Patent 04797879 dated Jun. 9, 2015; 3 pgs.
  • Notice of Allowance, U.S. Appl. No. 14/202,481 mailed Jul. 16, 2015.
Patent History
Patent number: 9283228
Type: Grant
Filed: Apr 11, 2014
Date of Patent: Mar 15, 2016
Patent Publication Number: 20140248349
Assignee: BAYER INTELLECTUAL PROPERTY GMBH (Monheim)
Inventor: Klaus Benke (Bergisch Gladbach)
Primary Examiner: Johann R Richter
Assistant Examiner: David Browe
Application Number: 14/250,863
Classifications
Current U.S. Class: Spiro Ring System (514/462)
International Classification: A61K 9/28 (20060101); A61K 31/5377 (20060101); A61K 9/16 (20060101); A61K 9/20 (20060101); A61K 9/48 (20060101);