HK1099518B - Method for the production of a solid, orally applicable pharmaceutical composition - Google Patents

Description

Process for preparing solid pharmaceutical compositions for oral administration

The present invention relates to a process for the preparation of solid pharmaceutical compositions for oral administration comprising a hydrophilic form of 5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl } -methyl) -2-thiophenecarboxamide and their use for the prevention and/or treatment of diseases.

5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl } -methyl) -2-thiophenecarboxamide (I) is an orally administrable, low molecular weight inhibitor of coagulation factor Xa, which can be used for the prophylaxis and/or treatment of various thromboembolic disorders (see, for example, WO-A01/47919, the disclosure of which is incorporated by reference). If active substance (I) is mentioned below, all variants and various hydrates of 5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl } -methyl) -2-thiophenecarboxamide (I) are included.

The active substance (I) has poor water solubility (about 7 mg/L). Thus resulting in difficulties in oral bioavailability and increased biological variability in absorption rate.

Various concepts have been described in the past for improving oral bioavailability:

solutions of the active substance are generally used, which can be filled, for example, into soft gelatin capsules. Since the active substance (I) is difficult to dissolve in a suitable solvent for this purpose, this option is not feasible in this case, since the necessary dosage concentration therein would lead to capsule sizes which are no longer swallowable.

An alternative approach proposes to amorphize the active substance. This solution has also proved problematic here, since the active substance (I) is also poorly soluble in pharmaceutically acceptable solvents, such as ethanol or acetone. Also because of the high melting point of the active substance (about 230 ℃), amorphization of the active substance by the melt process is disadvantageous because of the undesirably high content of decomposition components in the preparation.

Furthermore, methods for hydrophilizing Hydrophobic active substances are described, for example, In cyclohexarbital and phenytoin (Lerk, Lagas, Fell, Nauta, Journal of Pharmaceutical Sciences Vol.67, No. 7, p.7 1978, p.935-939: "Effect of Hydrophilization on Hydropholic Drugs on Release random reactors"; Lerk, Lagas, Lie-A-Huen, Broersma, Zuurman, Journal of Pharmaceutical Sciences Vol.68, No. 7, p.5 1979, p.634: "Vitro and In Vivo Availability of Hydrophilized proteins"). In this case, the active substance particles are mixed with the methylcellulose or hydroxyethylcellulose solution in a mixer under conditions which substantially eliminate an agglomeration step and are subsequently dried. The active substance thus obtained is subsequently filled without further processing into hard gelatin capsules.

Surprisingly, it has now been found that the specific treatment of the surface of the active substance (I) during the wet granulation phase serves to improve the absorption properties. The use of the hydrophilic form of the active substance (I) in the preparation of an orally administrable solid pharmaceutical composition leads to a significantly improved bioavailability of the formulations thus obtained.

The subject of the present invention is a process for the preparation of an orally administrable solid pharmaceutical composition containing 5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl } -methyl) -2-thiophenecarboxamide in hydrophilic form, wherein,

(a) granules containing the active substance (I) in hydrophilic form are first prepared by wet granulation,

(b) the particles are then transferred to a pharmaceutical composition, if necessary with the addition of additives suitable for the drug.

The wet granulation in process step (a) can be carried out in a mixer (hybrid granulation) or in a fluidized bed (fluidized bed granulation), preferably fluidized bed granulation.

In wet granulation, the active substance (I) can be added as a solid substance to the premix (stock solution) or suspended in the granulation liquid. The active substance (I) suspended in the granulation liquid is preferably introduced into wet granulation (suspension process).

In a preferred embodiment of the invention, the active substance (I) is used in crystalline form.

In a particularly preferred embodiment of the present invention, the crystalline active substance (I) is used in micronized form. Wherein the active substance (I) preferably has an average particle size X of less than 10 μm, particularly preferably from 1 to 8 μm₅₀And X of less than 20 μm, in particular less than 15 μm₉₀(ratio of 90%).

The granulation liquid used in the present invention contains a solvent, a hydrophilic binder and optionally a wetting agent. Wherein the hydrophilic binder is dispersed or preferably dissolved in the granulation liquid.

As solvent for the granulation liquid, an organic solvent, such as ethanol or acetone, or water or a mixture thereof may be used. Water is preferably used as the solvent.

As hydrophilic binder of the granulation liquid, a hydrophilic additive suitable for the drug is used, preferably an additive which is itself dissolved in the solvent of the granulation liquid.

Preferably, hydrophilic polymers such as 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 salts thereof, vinylpyrrolidone-vinyl acetate copolymers (e.g., HPMC), HPMC, HPC-HPC, HPC-vinyl acetate copolymers, etc. are used thereinVA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginates or xanthan gum. HPMC is particularly preferably used as hydrophilic binderA mixture.

Wherein the concentration of the hydrophilic binder (based on the total mass of the pharmaceutical composition) may be 1-15%, preferably 1-8%.

As wetting agents for the granulation liquid optionally present, wetting agents (surfactants) suitable for the pharmaceutical can be used. Mention may be made, by way of example, of:

sodium salts of fatty alcohol sulfates such as sodium lauryl sulfate, sulfosuccinates such as sodium dioctyl sulfosuccinate, fatty acid partial esters of polyhydric alcohols such as glycerol monostearate, fatty acid partial esters of sorbitan such as sorbitan monolaurate, fatty acid partial esters of polyhydroxyethylene sorbitan such as polyethylene glycol-sorbitan monolaurate, polyethylene glycol-sorbitan monostearate or polyethylene glycol-sorbitan monooleate, polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acid esters, ethylene oxide-propylene oxide block copolymers (poly- (ethylene oxide-co-propylene oxide) ((co-) esters) Or ethoxylated triglycerides. Sodium lauryl sulfate is preferably used as a wetting agent.

The wetting agent is optionally used in a concentration of 0.1 to 5%, preferably 0.1 to 2%, based on the total mass of the pharmaceutical composition.

Other pharmaceutically suitable additives are contained in the wet granulated premix (stock solution). Mention may be made, by way of example, of:

fillers and dry binders 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, e.g. monohydrate), dextrose, maltose, sucrose, glucose, fructose or maltodextrin.

Disintegration promoters (disintegrants) such as carboxymethylcellulose, croscarmellose (cross-linked carboxymethylcellulose), crospovidone (cross-linked polyvinylpyrrolidone), L-HPC (low-substituted hydroxypropylcellulose), sodium carboxymethyl starch, sodium glycolate of potato starch, partially hydrolyzed starch, wheat starch, corn starch, rice starch or potato starch.

In the case of tablet formulations with modified (delayed) active substance release, substances which influence the release rate can be contained without disintegration-promoting agents (disintegrants). Mention may be made, by way of example, of: hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, carboxymethylcellulose, galactomannan, xanthan gum, glycerol esters, waxes, copolymers of acrylic and/or methacrylic esters with trimethylammonium methacrylate, copolymers of dimethylamino methacrylic acid and neutral methacrylic esters, polymers of methacrylic acid or methacrylic esters, ethyl acrylate-methyl methacrylate copolymers or methacrylic acid-methyl acrylate copolymers.

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

Process step (b) comprises, for example, tableting, filling into capsules (preferably hard gelatin capsules) or filling as sachets, all according to conventional methods familiar to the person skilled in the art, optionally with the addition of further pharmaceutically suitable additives.

As pharmaceutically suitable additives there may be mentioned by way of example:

lubricants, glidants, flow regulators, e.g. fumaric acid, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, high molecular weight fatty alcohols, polyethylene glycols, starches (wheat starch, rice starch, corn starch or potato starch), talc, highly dispersible (colloidal) silicon dioxide, magnesium oxide, magnesium carbonate or calcium silicate

Disintegration promoters (disintegrants), for example carboxymethylcellulose, crosslinked carboxymethylcellulose (crosslinked carboxymethylcellulose), crospovidone (crosslinked polyvinylpyrrolidone), L-HPC (low-substituted hydroxypropylcellulose), sodium carboxymethyl starch, partially hydrolyzed starch, wheat starch, corn starch, rice starch or potato starch

Another subject of the invention is a solid pharmaceutical composition comprising a hydrophilic form of 5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl } -methyl) -2-thiophenecarboxamide (I) for oral administration.

An orally administrable solid pharmaceutical composition according to the invention illustratively and preferably comprises: granules, hard gelatin capsules or sachets filled with granules and tablets with rapid or modified (delayed) release of active substance (I). Tablets, in particular tablets which release the active substance (I) rapidly, are preferred. Within the scope of the present invention, fast-release tablets are in particular those having a Q value of 75% (30 minutes) according to the USP release method with an apparatus 2 (paddle) such as described in the experimental section under chapter 5.2.2.

The active substance (I) in the pharmaceutical composition of the invention may be present in a concentration of 0.1 to 60%, preferably 1 to 40%, based on the total mass of the formulation. The dosage of active substance (I) here is preferably from 1 to 100 mg.

Granules or tablets according to the invention are optionally coated in a further step under conventional conditions familiar to the person skilled in the art. The coating is carried out with the addition of conventional coating media and film-forming agents familiar to those skilled in the art, such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer (e.g., hydroxypropyl methylcellulose, ethyl cellulose, polyvinylpyrrolidone-vinyl acetate copolymer), and the likeVA64, BASF), shellac, copolymers of acrylic and/or methacrylic esters and trimethylammonium methacrylate, copolymers of dimethylamino methacrylic acid and neutral methacrylic esters, polymerization of methacrylic acid or methacrylic estersEthyl acrylate-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, propylene glycol, polyethylene glycol, triacetin, triethyl citrate and/or dye additives/pigments such as titanium dioxide, iron oxide, indigo or suitable lakes.

Another subject of the invention is the use of the pharmaceutical composition according to the invention for the prevention and/or treatment of diseases, in particular thromboembolic diseases such as myocardial infarction, angina pectoris (including irregular angina), reocclusion and restenosis after angioplasty or aortic coronary bypass, cerebral infarction, transient ischemic attacks, peripheral arterial occlusive disorders, pulmonary embolism or deep vein thrombosis.

The invention is further illustrated below by means of preferred examples, but the invention is not limited to these examples. All amounts given below are in weight percent unless otherwise indicated.

Experimental part

1. Use of granules containing an active ingredient (I) in hydrophilic form for the preparation of tablets/fluid bed forms Granulation process

1.1 tablet composition (mg/tablet)

Active ingredient (I), micronized 20.0mg

Microcrystalline cellulose 35.0mg

Lactose monohydrate 22.9mg

Crosslinked carboxymethylcellulose (A)FMC) 3.0mg

Hydroxypropyl methylcellulose, 5cp 3.0mg

Sodium lauryl sulfate 0.5mg

Magnesium stearate 0.6mg

Hydroxypropyl methylcellulose, 15cp 1.5mg

Polyethylene glycol 3.3500.5 mg

Titanium dioxide0.5mg

87.5mg

1.2 preparation

Hydroxypropyl methylcellulose (5cp) and sodium lauryl sulfate were dissolved in water. The micronized active substance (I) is suspended into this solution. The suspension thus prepared is sprayed as a granulation liquid onto a stock solution consisting of microcrystalline cellulose, lactose monohydrate and croscarmellose in the fluidized bed granulation stage. Magnesium stearate was added and mixed after drying and sieving (mesh width of 0.8 mm) the resulting granules. The thus obtained ready-to-press mixture is compressed into tablets of 6mm diameter and 50-100N breaking strength. The tablets were then coated with titanium dioxide suspended in an aqueous solution consisting of hydroxypropyl methylcellulose (15cp) and polyethylene glycol.

2. Preparation of tablets/flash mixers using granules containing active ingredient (I) in hydrophilic form Granulation method

2.1 tablet composition (mg/tablet)

Active ingredient (I), micronised 5.0mg

Microcrystalline cellulose 40.0mg

Lactose monohydrate 33.9mg

Crosslinked carboxymethylcellulose (A)FMC) 3.0mg

Hydroxypropyl methylcellulose, 3cp 2.0mg

Sodium lauryl sulfate 0.5mg

Magnesium stearate 0.6mg

Hydroxypropyl methylcellulose, 15cp 1.5mg

Polyethylene glycol 4000.5 mg

Iron oxide yellow 0.1mg

Titanium dioxide0.4mg

87.5mg

2.2 preparation

The ingredients microcrystalline cellulose, lactose monohydrate and croscarmellose (granulation stock solution) were mixed in a flash mixer. Hydroxypropyl methylcellulose (3cp) and sodium lauryl sulfate were dissolved in water. Suspending the micronised active ingredient (I) in this solution. The suspension thus prepared is added as granulation liquid to the granulation stock and mixed homogeneously with the granulation stock by means of rapidly rotating stirring tools. After the homogeneous mixing carried out, the wet granulate is sieved (mesh width of 4 mm) and dried in a fluidized bed. After sieving the dried granules (mesh width of 0.8 mm) magnesium stearate was added and mixed. The thus obtained ready-to-press mixture is compressed into tablets of 6mm diameter and 50-100N breaking strength. Subsequent tablet coating was performed with titanium dioxide and iron oxide yellow, wherein the pigment was previously suspended in an aqueous solution consisting of hydroxypropyl methylcellulose (15cp) and polyethylene glycol.

3.Preparing granules containing active substance (I) in hydrophilic form and filling as sachets

3.1 granule composition (mg/sachet)

Active ingredient (I), 50.0mg micronised

Mannitol 662.0mg

Crosslinked carboxymethylcellulose (A)FMC) 15.0mg

Hydroxypropyl methylcellulose, 5cp 15.0mg

Sodium lauryl sulfate 1.0mg

Highly dispersible silica (C)Degussa) 2.0mg

Strawberry flavor by spray drying 5.0mg

750.0mg

3.2 preparation

Hydroxypropyl methylcellulose (5cp) and sodium lauryl sulfate were dissolved in water. Suspending the micronised active substance (I) in this solution. The suspension thus prepared is sprayed as a granular liquid onto a stock solution consisting of mannitol and crosslinked carboxymethylcellulose in the fluid bed granulation stage. After drying and sieving (mesh width of 0.8 mm) the resulting granules, highly dispersible silica was added and mixedAnd strawberry flavor. The mixture thus obtained was filled into sachet bags by means of a sachet filling machine at 775.0mg per serving.

4.Preparing granules containing the active substance (I) in hydrophilic form and filling into hard gelatin In the capsule

4.1 granule composition (mg/capsule)

Active ingredient (I), micronized 20.0mg

Microcrystalline cellulose 30.0mg

Lactose monohydrate 79.5mg

Corn starch 25.0mg

Hydroxypropyl methylcellulose, 5cp 4.5mg

Sodium lauryl sulfate 0.5mg

Highly dispersible silica (C)Degussa) 0.5mg

160.0mg

4.2 preparation

Hydroxypropyl methylcellulose (5cp) and sodium lauryl sulfate were dissolved in water. Suspending the micronised active substance (I) in this solution. The suspension thus prepared is sprayed as a granular liquid onto a stock solution consisting of microcrystalline cellulose, lactose monohydrate and corn starch in the fluid bed granulation stage. After drying and sieving (mesh width of 0.8 mm) the resulting granules, highly dispersible silica was added and mixedThe mixture thus obtained was filled in hard gelatin capsules of size 2 capsules at 160mg per serving.

5. Comparison of tablets with and without hydrophilicized active substance (I)

5.1 tablet composition, tablet preparation

In order to investigate the tablet properties and the improved bioavailability of formulations with hydrophilic active substance (I), uncoated tablets with a content of 10mg of active substance (I) were prepared with the following composition (mg/tablet):

active ingredient (I), 10.0mg micronised

Microcrystalline cellulose 40.0mg

Lactose monohydrate 27.9mg

Crosslinked carboxymethylcellulose (A)FMC) 3.0mg

Hydroxypropyl methylcellulose, 5cp 3.0mg

Sodium lauryl sulfate 0.5mg

Magnesium stearate0.6mg

85.0mg

Tablet A:prepared directly from tablets without granulation

Tablet B:preparation by the fluid bed granulation/suspension method described in 1.2

Both the blend for tablet A and the granulate for tablet B were compressed into tablets of 6mm diameter and a breaking strength of about 70-80N.

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 amount of active substance released, based on the total content of the tablets disclosed, is given in table 1 below:

table 1: in vitro release

	15 minutes	30 minutes	45 minutes	60 minutes
					Tablet A	87％	92％	93％	94％
Tablet B	94％	95％	96％	96％

(USP Paddle, 900ml acetate buffer pH 4.5+ 0.5% sodium lauryl sulfate, 75 rpm)

5.2.3 bioavailability

To study bioavailability, three dogs were dosed with three tablets a or three tablets B in a crossover fashion. The corresponding pharmacokinetic parameters after oral administration of 3mg of active ingredient (I)/kg are listed in table 2 below:

table 2: pharmacokinetic parameters of active substance (I)

As a result: despite slower disintegration (see 5.2.1) and very similar in vitro release (see 5.2.2), tablet B has a significant advantage in absorption compared to tablet a and thus an improved bioavailability of about 35%. A significant reduction in variability was also demonstrated. The only difference between tablets a and B is that in the case of tablet B substance (I) is hydrophilized by means of a suspension process in the wet granulation stage.

Claims (19)

1. Process for the preparation of an orally administrable solid pharmaceutical composition containing 5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl } -methyl) -2-thiophenecarboxamide (I) in hydrophilic form, characterized in that,

(a) granules containing active substance (I) are first prepared by wet granulation, in which the active substance (I) is treated with a granulation liquid containing a solvent, a hydrophilic binder and optionally a wetting agent,

(b) the particles are then converted into a pharmaceutical composition with or without the addition of pharmaceutically suitable additives.

2. A process according to claim 1, characterized in that fluid bed granulation is used as the wet granulation process.

3. The process as claimed in claim 1 or 2, characterized in that the active substance (I) is used in crystalline form.

4. A process according to claim 3, characterized in that the active substance (I) is used in micronized form.

5. The process as claimed in claim 1, characterized in that the active substance (I) suspended in the granulation liquid is introduced into a wet granulation process.

6. The method according to claim 1, characterized in that the pharmaceutical composition is a tablet with a rapid release of the active substance (I).

7. An orally administrable solid pharmaceutical composition prepared by the process of claim 1.

8. Solid pharmaceutical composition for oral administration comprising 5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl } -methyl) -2-thiophenecarboxamide (I), wherein the active compound (I) is treated with a granulating liquid comprising a solvent, a hydrophilic binder and optionally a wetting agent.

9. Pharmaceutical compositions according to claim 8, containing the active substance (I) in crystalline form.

10. Pharmaceutical composition according to claim 9, containing the active substance (I) in micronized form.

11. Pharmaceutical composition according to any one of claims 7 to 10, characterized in that the active ingredient (I) is present in an amount of 1 to 60% by mass of the total mass of the formulation.

12. The pharmaceutical composition of claim 7, comprising sodium lauryl sulfate as a wetting agent.

13. The pharmaceutical composition according to claim 12, containing sodium lauryl sulfate in an amount of 0.1-5% by mass.

14. The pharmaceutical composition of claim 7, comprising hydroxypropylmethylcellulose as a hydrophilic binder.

15. The pharmaceutical composition of claim 14, comprising hydroxypropyl methylcellulose in an amount of 1-15% by mass of the total.

16. The pharmaceutical composition of claim 7 in the form of a tablet.

17. The pharmaceutical composition of claim 16 in the form of a fast-release tablet.

18. Pharmaceutical composition according to claim 16 or 17, characterized in that the tablet is covered with a coating.

Use of 5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl } -methyl) -2-thiophenecarboxamide (I) for the preparation of a medicament for the prevention and/or treatment of thromboembolic disorders, wherein the active compound (I) is treated with a granulation liquid comprising a solvent, a hydrophilic binder and optionally a wetting agent.