WO2009129913A1

WO2009129913A1 - Solid pharmaceutical preparation comprising 1-[(4-chloro-phenyl)-amide]-2-{[4-(3-oxo-morpholine-4-yl)-phenyl]-amide}-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid

Info

Publication number: WO2009129913A1
Application number: PCT/EP2009/002233
Authority: WO
Inventors: Loannis Chartomatsidis; Thomas T. Frank; Anette Partheil; Friederike Von Burkersroda
Original assignee: Merck Patent Gmbh
Priority date: 2008-04-22
Filing date: 2009-03-26
Publication date: 2009-10-29
Also published as: DE102008020053A1

Abstract

The invention relates to a solid pharmaceutical preparation comprising 1-[(4-chloro-phenyl)-amide]-2-{[4-(3-oxo-morpholine-4-yl)-phenyl]-amide}-4- hydroxy-pyrrolidine-1,2-dicarboxylic acid as an active ingredient and manufacture of the solid pharmaceutical preparation. The preparation exhibits an improved active ingredient release behavior and can be used to combat and prevent thromboembolic illnesses.

Description

Solid pharmaceutical preparation containing 1 - [(4-chloro-phenyl) -amide] -2- {[4- (3-oxomorpholin-4-yl) -phenyl] -amide} -4-hydroxy-pyrrolidine-1, 2-dicarboxylic acid

The present invention relates to a solid pharmaceutical preparation containing 1 - [(4-chloro-phenyl) -amide] -2 - {[4- (3-oxomorpholin-4-yl) -phenyl] -amide-4-hydroxy -pyrrolidine-1, 2-dicarboxylic acid as active ingredient and the preparation of the solid pharmaceutical preparation.

1 - [(4-chloro-phenyl) -amide] -2 - {[4- (3-oxomorpholin-4-yl) -phenyl] -amide} -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid an inhibitor of

Blood coagulation factor Xa, which can be used, for example, for the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.

1 - [(4-chloro-phenyl) -amide] -2 - {[4- (3-oxomorpholin-4-yl) -phenyl] -amide} -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid two chiral centers and thus can form four enantiomers, resulting in the (2R, 4R) -, (2R, 4S) - (2S, 4R) - and the (2S, 4S) -enantiomer. The individual pure enantiomers and all mixtures of two, three or four enantiomers in all proportions can be used therapeutically. Preference is given to pure (2R, 4R) -1 - [(4-chlorophenyl) amide] -2 - {[4- (3-oxomorpholin-4-yl) phenyl] amide} -4- hydroxy-pyrrolidine-1, 2-dicarboxylic acid having the following chemical formula

and hereinafter also referred to as drug A.

The clinical development and subsequent commercialization of this drug requires an easily administered, preferably a solid, orally administered pharmaceutical preparation. However, investigations showed a very low water solubility of the active ingredient, at

Application of the Guidelines for Industry (Waiver of in vivo bioavailability and bioequivalence studies for biopharmaceutics Classification System (August 2000)) revealed a maximum concentration in aqueous buffer media pH 1-7.4 (c _max ) of 0.24 mg / ml. At a designated

Dosage of 100 mg is therefore drug A qualify as sparingly soluble. Since active ingredients must first be brought into solution before their absorption in the gastrointestinal tract when administered orally, a poor oral bioavailability and an increased variability of the absorption rate are to be expected for active ingredient A.

To increase the drug release rate and bioavailability of poorly soluble drugs different measures can be taken. One possibility is the reduction of the particle size of the active ingredient. In this way, the surface of the active ingredient and thus the dissolution rate of the active ingredient can be increased. However, methods used to reduce the particle size, such as milling, lead to undesired effects such as physical stress or increased heat generation, which can lead to active ingredient degradation. Other processes such as recrystallization require the implementation of extensive processes and steps such as solvent extraction, which are associated with other problems such. As elevated residues of toxicologically undesirable organic solvents are afflicted. Experiments with milled (micronized) active ingredient also show that particle size reduction of 1 - [(4-chlorophenyl) amide] -2 - {[4- (3-oxo)] morpholin-4-yl) -phenyl] -amide} -4-hydroxy-pyrrolidine-1, 2-dicarboxylic acid not increased to its dissolution rate.

Another possibility for increasing the bioavailability is the complexation of the poorly soluble active ingredient. For complexation are preferably used well water-soluble cyclodextrin derivatives, which go home with the poorly soluble drug inclusion compounds and so can increase their solubility. However, the available cyclodextrin derivatives have only a limited uptake capacity and complicate the processability of the complex to oral dosage forms. Furthermore, they are not uncontroversial from a toxicological point of view.

Another way to increase the bioavailability of poorly soluble drugs is the use of surfactants, so-called surfactants such. For example, sodium lauryl sulfate. Such surfactants are not safe from a toxicological point of view and should therefore be avoided whenever possible.

It was an object of the present invention for active ingredient A to provide a solid orally administrable dosage form which ensures good release and dissolution of the active ingredient and thereby results in improved bioavailability of the active ingredient. The solid

Dosage form should not contain any toxicologically questionable excipients, be simple in design and producible.

Surprisingly, a preparation corresponding to these requirements could be made available if, in addition to the active substance, it contains one or more sugar alcohols and / or one or more

Contains sugar as filler / s. The present invention therefore relates to a solid pharmaceutical preparation containing 1 - [(4-chlorophenyl) -amide] -2 - {[4- (3-oxomorpholin-4-yl) -phenyl] -amide} -4 -hydroxy-pyrrolidine-1, 2-dicarboxylic acid as an active ingredient and at least one sugar and / or sugar alcohol as a filler. 1 - [(4-chloro-phenyl) -amide] -2 - {[4- (3-oxomorpholin-4-yl) -phenyl] -amide} -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid in the pharmaceutical preparation as a free base or in the form of one of its acid addition salts such. As hydrobromide, hydrochloride, dihydrochloride, acetate, aspartate, benzoate, citrate, fumarate, glutamate, maleate, methanesulfonate or tartrate. Preference is given to 1 - [(4-chloro-phenyl) -amide] -2 - {[4- (3-oxomorpholin-4-yl) -phenyl] -amide} -4-hydroxy-pyrrolidine-1, 2 dicarboxylic acid as the free base or hydrochloride salt. Particularly preferred is the free base. As sugar can be used monosaccharides such. B. hexoses or

Pentoses and disaccharides, which consist of two simple glycosylated monosaccharides linked by a glycolysis. The preparation according to the invention preferably contains glucose, fructose or mannose as monosaccharides and lactose, sucrose or maltose as disaccharides. Particularly preferred is lactose.

By sugar alcohols are meant monosaccharides whose reactive carbonyl group is reduced to the alcohol group, such as. Hexitol or Pentite. Preferably, the solid preparation according to the invention contains as sugar alcohol / e hexitols such. Mannitol, lactitol, maltitol, xylitol or sorbitol. Particularly preferred are mannitol and / or maltitol, most preferably mannitol is included.

The solid pharmaceutical preparation may be in the form of powder, granules, pellets, capsule or tablet. While capsules and tablets provide the amount of active ingredient intended for ingestion in each case as a clearly defined single dose, by means of powders, pellets and

Granules the required amount of active ingredient are easily adjusted.

Granules are free-flowing granular aggregates of powders which can be produced by granulation. Pellets are solid small spherical drug forms such. Granules or microtablets, which preferably have a narrow particle size range. Granules and pellets are an independent dosage form, but can also serve as an intermediate for the production of tablets. If predetermined amounts of active substance by means of powders, granules or pellets can be administered to ensure sufficient

Metering accuracy can also be provided as a separate powder / granules or bottled in capsules. The pharmaceutical preparation according to the invention is preferably present as granules, capsule or tablet, particularly preferably as capsule or tablet, very particularly preferably as tablet.

Depending on the dosage form, the solid preparation according to the invention may contain different adjuvants such as. As binders, additional fillers, disintegrants, flow regulators or lubricants.

Binders are used in particular as auxiliaries for the production of granules and capsules and tablets produced from granules and are u. a. responsible for the cohesion of the powder particles in the granules. Applicable binders are, for example, polymers such as polyvinylpyrrolidone or polyvinyl acetate, starch pastes such. B. corn starch paste, cellulose derivatives such. As hydroxypropylmethylcellulose or hydroxypropylcellulose. The solid preparation according to the invention preferably contains cellulose derivatives as binder, with hydroxypropylmethylcellulose being particularly preferred. Depending on the nature of the binder, this may be contained in the solid preparation according to the invention in a proportion of 0.1 to 80 wt .-%. The solid according to the invention preferably contains

Preparation 1 to 5 wt .-%, particularly preferably 1, 5 to 3 wt .-% binder.

Disintegrants may be included to shorten the disintegration time of tablets so that the active ingredient is rapidly released from the tablets. Examples of disintegrants which can be used according to the invention are microcrystalline cellulose, cross-linked polyvinylpyrrolidone, such as, for example, B. Cross-povidone or cross-linked carboxymethylcellulose. The solid preparation according to the invention particularly preferably contains carboxymethylcellulose, very particularly preferably crosslinked carboxymethylcellulose, as disintegrant. Depending on the nature of the disintegrating agent in the solid preparation according to the invention in a

Be contained by weight of 0.01 to 20 wt .-%. Preferably, the solid preparation according to the invention contains 0.1 to 10 wt .-%, particularly preferably 0.5 to 5 wt .-% of disintegrant.

Flow regulators can be contained in powders or granules and are admixed to increase their flowability.

Likewise flow control agents may be contained in tablets, as far as they are prepared by compression of powders or granules. Also in this case they are added to the powders / granules to increase their flowability, in particular to a uniform filling of the matrices before compression to the tablet and thus a high

To ensure dosing accuracy. For example, finely divided silica (Aerosil) or dried starch can be used as flow regulators. The solid preparation according to the invention preferably contains fumed silica as flow regulator. Flow control agents are preferably contained in the solid preparation according to the invention in a proportion of 0.1 to 5 wt .-%, preferably 0.2 to 3 wt .-%, particularly preferably 0.3 to 2 wt .-%.

As far as the solid preparation according to the invention is a tablet, it may also contain lubricant to reduce the sliding friction of the Tablettierguts and the press die in the die and avoid sticking to the punches during the tableting process. Suitable lubricants are alkaline earth metal salts of fatty acids such as magnesium stearate, higher fatty alcohols or talc. Preferably, the solid preparation of the invention contains magnesium stearate as a lubricant. Lubricants are solid in the invention Preparation preferably contain in a proportion of 0.1 to 10 wt .-%, preferably 0.5 to 5 wt .-%, particularly preferably 1 to 4 wt .-%.

If the solid preparation according to the invention is a tablet, it can be provided with a coating. As a coating are film-forming polymers such. B. those from the group of cellulose derivatives, dextrins,

Strengths, natural gums, such. B. gum arabic, xanthans, alginates, polyvinyl alcohol, polymethacrylates and its derivatives such. B. Eudragite, by means of various pharmaceutical conventional methods, such as. As film coating, as solutions or suspensions can be applied to the tablet. Usually here

Solutions / suspensions used, in addition to the film-forming polymer, other auxiliaries such as hydrophilizers, plasticizers, surfactants, dyes and white pigments, such as. B. titanium dioxide.

The production of the solid preparation according to the invention can be carried out according to the methods known to the person skilled in the art.

The preparation of powders can be carried out, for example, by adding the active compound with the sugar alcohol and optionally with further auxiliaries, such as flow regulators, and then mixing them. The preparation of the granules is carried out by granulation, which can basically be done on a wet or dry way. In wet granulation, for example, a powder mixture comprising the active ingredient together with the sugar alcohol and optionally further suitable auxiliaries, with a granulating liquid, which preferably contains a binder, is added to the aggregates of suitable size

(Granules) and then dried. The active ingredient can also be introduced by suspension in the granulation in the granules. The transfer of the powder mixture into aggregates of suitable size can, for. B. by the so-called build-up granulation, for example in the coating pan, by plate granulation or in the Fluidized bed process, z. B. by the smooth or Wurster method, or by the so-called degradation granulation done in the powder mixture first moistened and processed into a plastically deformable mass and then, for example by extrusion through a sieve with mesh size suitable in the aggregates of desired

Size is transferred. In dry granulation, the powder mixture is compacted, for example, by means of compacting between two counter-rotating compacting rollers to slugs, which are then comminuted into granules. Pellets can be made by granulation and then rounding

(Sphäronisieren), for example by means of plate granulation, or by compression of powders or granules are made into microtablets.

The preparation of the preparation according to the invention in the form of tablets can be effected by compressing powder mixtures (direct tabletting) or by compressing granules. In the simplest case of direct tabletting, the active ingredient is first mixed with the sugar and / or sugar alcohol (in a direct tabletting quality) and, if appropriate, further auxiliaries, and the powder mixture obtained is pressed directly into the solid preparation according to the invention.

If the preparation according to the invention is prepared in the form of a tablet by compressing granules, it is possible to use granules which have been prepared by wet or dry granulation. Advantageously, the granules are still pressed with a so-called outer phase containing an excipient or a

Mixture of several excipients, in particular lubricants, flow regulators and / or disintegrating agents, mixed.

According to a preferred embodiment of the invention, the solid preparation is a tablet and contains 0.1 to 50% by weight of 1 - [(4-chlorophenyl) amide] -2 - {[4- (3-oxomorpholine) 4-yl) -phenyl] -amide} -4-hydroxy- pyrrolidine-1,2-dicarboxylic acid, 30 to 99.8% by weight of lactose and / or mannitol and 0.1 to 10% by weight of crosslinked carboxymethylcellulose.

According to a particularly advantageous embodiment, the solid preparation is a tablet and contains 5 to 40% by weight of 1 - [(4-chlorophenyl) amide] -2 - {[4- (3-oxomorpholin-4-yl ) -phenyl] -amide} -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid, 40 to 80% by weight of mannitol and 2 to 7% by weight of crosslinked carboxymethylcellulose.

The subject of the present patent application is further a process for the preparation of a solid pharmaceutical preparation in the form of a tablet, which is characterized in that

Direct tableting or by pressing produced by wet or dry granulation granules and then optionally provided with a coating.

According to a preferred embodiment of the invention, the process for preparing the tablet is characterized in that the active ingredient is mixed with lactose monohydrate and fumed silica, croscarmellose sodium and magnesium stearate and that this mixture is compressed into tablets.

The embodiments, without being limited thereto, explain the

Invention.

example 1

Influence of particle size of drug A on its release behavior

Agent A is micronized with an air jet mill and tested for release behavior in vitro compared to non-micronized drug. The release results are summarized in Table 1.

Tab. 1: Release of micronized (mic) and non-micronised (n-mic) active substance A in a paddle stirrer model (mean values, n = 3, relative standard deviation (RSD)): 100 mg active ingredient A released in 1000 ml 0.1 N HCl + 0.5% sodium lauryl sulfate at 50 revolutions per minute

It turns out that the reduction of the active ingredient particle size does not lead to an increase in the dissolution rate.

Example 2

By trituration of the components in a laboratory mortar for about 10 minutes, binary triturations containing in each case 100 mg of active ingredient A and 50, 100, 200, 400, 800 spray-dried lactose monohydrate granules (LMG) are prepared and tested for in vitro release. The in vitro release results are summarized in Table 2.

Tab. 2: Release of active ingredient from mixtures of 100 mg of active ingredient with different LMG contents (blade stirrer model, mean values, n = 3) in 1000 ml of 0.1N HCl at 50 revolutions per minute

It follows that the dissolution rate of the pure active ingredient increases with increasing lactose content.

The triturate can be administered directly, preferably as a divided powder, to which patients are administered.

Example 3

Containing capsule

Active ingredient A 100 mg

Lactose monohydrate 200 mg

Highly dispersed silica 2 mg

Magnesium stearate 6 mg

The ingredients are mixed together, filled into size 0 hard gelatin capsules and tested for their in vitro release. The results are summarized in Table 3.

Tab. 3: Release of active ingredient from hard gelatine capsules (blade stirrer model, mean values, n = 6) in 1000 ml of 0.1 N HCl at 75 revolutions per minute

Example 4

Containing granules

Active ingredient A 100 mg

Lactose 100 mg

Corn starch 10 mg microcrystalline cellulose 36 mg

Croscarmellose Na 6 mg

Highly dispersed silica 1 mg

Magnesium stearate 2 mg

The active substance is mixed together with the lactose and with a

Corn starch paste granulated in a classic way. The granules can be directly to the

Patients are administered or processed into a tablet.

For further processing to the tablet the granules are the remaining

Ingredients were added, all mixed together, and the mixture then tabletted. Example 5

Containing granules

Active ingredient A 100 mg

Mannitol 116 mg

Hydroxypropylmethlycellulose 5 mg

Croscarmellose Na 2.3 mg

Highly dispersed silica 1, 2 mg

Magnesium stearate 5.8 mg

The active ingredient is mixed together with the mannitol and with a

Hypromellose solution classically granulated. , The granules can be administered directly to the patient or processed into a tablet. For further processing to the tablet, the remaining ingredients are added to the granules, all mixed together, and then the mixture is tabletted.

Example 6

Containing tablet

Active ingredient A 100 mg

Lactose monohydrate 200 mg

Croscarmellose Na 10 mg

Highly dispersed silica 5 mg

Magnesium stearate 5 mg

The tablets are prepared by mixing the active ingredient with lactose monohydrate, croscarmellose Na, fumed silica and magnesium stearate and subsequent compression of this mixture.

The tablets are tested for their in vitro release. The results are summarized in Table 4.

Tab. 4: Release of the tablets (blade stirrer model, mean values, n = 6) in 1000 ml of 0.1 N HCl at 50 revolutions per minute

Studies on the stability of the preparations

The stability of the preparations according to the invention is tested in shelf life studies. For this purpose, the solid preparations are stored at 25 ° C with a relative humidity (r.F.) Of 60% in HDPE (= High Density Polyethylene) bottles, outsourced at certain times and investigated by suitable analytical methods.

The stability data of a preparation according to the invention according to Example 6 are summarized in Table 5.

Tab. 5: Data on the stability of preparations according to Example 6 as a function of the duration of storage (25 ° C., 60% rh)

Example 7

Containing tablet

Active ingredient A 100 mg

Mannitol 270 mg

Croscarmellose-Na 1 \ <2L mmgg

Highly dispersed silica 66 mmgg

Magnesium stearate 1122 mmgg The tablets are prepared by mixing the active ingredient with mannitol, croscarmellose-Na, fumed silica and magnesium stearate and then pressing this mixture.

Analytical test methods:

Identity, content, purity

For quantitative determination of the active ingredient content and the impurities in tablets is a chromatographic

Separation method with UV detection according to Ph Eur 2.2.29 used: Reversed phase HPLC with a LiChroCHART 250 - 4 LiChrospher 60 RP-select B (5μm) column. To calculate the content and the purity, an external standard is used.

In vitro drug release

The method is equivalent to Ph Eur 2.9.3. To determine the drug release rate, a paddle stirrer apparatus is used. Sampling takes place after specified times. The determination of the active ingredient content is via UV.

Claims

claims

1. A solid pharmaceutical preparation containing 1 - [(4-chloro-phenyl) -amide] - 2 - {[4- (3-oxomorpholin-4-yl) -phenyl] -amide} -4-hydroxy-pyrrolidine 1, 2-dicarboxylic acid as active ingredient and at least one sugar and / or

Sugar alcohol as a filler.

2. A solid pharmaceutical preparation according to claim 1, characterized in that (2R, 4R) -1 - [(4-chloro-phenyl) -amide] -2 - {[4- (3-oxomorpholin-4-yl) -phenyl] -amide} -4-hydroxy-pyrrolidine-1, 2-dicarboxylic acid is included.

3. Solid pharmaceutical preparation according to claim 1 and / or 2, characterized in that as sugar glucose, fructose, mannose, lactose, sucrose and / or maltose and / or as sugar alcohol sorbitol, mannitol and / or maltitol is included.

4. Solid pharmaceutical preparation according to claim 3, characterized in that lactose and / or mannitol is included.

5. Solid pharmaceutical preparation according to one or more of claims 1 to 4, characterized in that it is present as granules, capsule or tablet.

6. Solid pharmaceutical preparation according to claim 5, characterized in that it is a tablet.

7. Solid pharmaceutical preparation according to one or more of

Claims 1 to 6, characterized in that this is a disintegrating agent contains.

8. Solid pharmaceutical preparation according to one or more of

Claims 1 to 10, characterized in that it contains 0.1 to 50% by weight of 1 - [(4-chlorophenyl) amide] -2 - {[4- (3-oxomorpholin-4-yl) -phenyl] -amide} -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid, 30 to 99.8% by weight of lactose and / or mannitol and 0.1 to 10% by weight of crosslinked carboxymethylcellulose.

9. A process for preparing a solid pharmaceutical preparation according to one or more of claims 1 to 8, characterized in that it is prepared by direct tabletting or by compression of granules prepared by wet or dry granulation and then optionally provided with a coating.

10. The method according to claim 9, characterized in that this method is a Direkttablettierung