DE102008020053A1 - Solid pharmaceutical preparation containing 1 - [(4-chloro-phenyl) -amide] -2 - {[4- (3-oxomorpholin-4-yl) -phenyl] -amide} -4-hydroxy-pyrrolidine-1, 2-dicarboxylic acid - Google Patents

Abstract

The 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, as well as the preparation of the solid pharmaceutical preparation. The preparation has improved drug release behavior and can be used to control and prevent thromboembolic disorders.

Description

 The 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 an active ingredient as well as the preparation of solid pharmaceutical Preparation.

1 - [(4-chloro-phenyl) -amide] 2 - {[4- (3-oxo-morpholin-4-yl) -phenyl] -amide} -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid is an inhibitor of the blood coagulation factor Xa, for example to combat and prevent thromboembolic Diseases such as thrombosis, myocardial infarction, arteriosclerosis, Inflammation, apoplexy, angina pectoris, restenosis after Angioplasty and intermittent claudication can be used.

und nachfolgend auch als Wirkstoff A bezeichnet wird.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. Pure (2R, 4R) -1 - [(4-chloro-phenyl) -amide] -2 - {[4- (3-oxomorpholin-4-yl) -phenyl] -amide} -4- is preferably used. 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, studies have shown a very low water solubility of the active substance, when applying the guidelines for the industry ( Guideline for Industry "Waiver of in vivo bioavailability and bioequivanlence studies for immediate release solid oral dosage forms based on biopharmaceutics classification system (August 2000) ) resulted in a maximum concentration (c _max ) of 0.24 mg / ml in aqueous buffer media pH 1-7.4. At a prescribed dosage of 100 mg, active ingredient A is therefore to be classified 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 Increasing the drug release rate and bioavailability poorly soluble drugs can be different Measures are taken. One possibility is the reduction of the particle size of the active ingredient. As a result, the surface of the drug and thus increases the dissolution rate of the drug become. Used to reduce the particle size However, methods such as grinding lead to unwanted Effects such as physical stress or increased heat generation, which can lead to drug degradation. Other procedures like recrystallization require the implementation of more extensive Processes and steps such as solvent extraction, the with other problems such. B. increased residues from toxicological point of view undesirable organic Solvents are afflicted.

tries with milled (micronized) active ingredient also show that particle size reduction of 1 - [(4-chloro-phenyl) -amide] -2 - {[4- (3-oxomorpholin-4-yl) -phenyl] -amide} -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid not increased to the dissolution rate.

A another way to increase bioavailability is the complexation of the poorly soluble active ingredient. For complexing are preferably used readily water-soluble Cyclodextrin derivatives with the poorly soluble active ingredient Inclusion compounds go home and so their solubility can increase. The available However, 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.

A further possibility to increase the bioavailability poorly soluble drugs is the use of surfactants Substances, 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 The object of the present invention for active ingredient A was a solid oral dosage form available deliver a good release and resolution of the Active ingredient ensures and thereby improved Bioavailability of the drug results. The solid Dosage form should not contain any toxicologically harmful excipients contained, simple and manufacturable.

Surprisingly could provide a preparation that meets these requirements if they contain one or more sugar alcohols in addition to the active substance and / or one or more sugars as filler (s). The subject of the present invention is therefore 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-oxo-morpholin-4-yl) -phenyl] -amide} -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid can be used in the pharmaceutical preparation as a free base or in Form of one of its acid addition salts such. B. as hydrobromide, Hydrochloride, dihydrochloride, acetate, aspartate, benzoate, citrate, Fumarate, glutamate, malest, methanesulfonate or tartrate be. 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 as the hydrochloride salt. Especially preferred is the free base.

When Sugar can be used monosaccharides such. Hexoses or pentoses and disaccharides, which are two simple by a glycolisidic one linked monosaccharides exist. Preferably contains the preparation according to the invention as monosaccharides Glucose, fructose or mannose and as disaccharides lactose, sucrose or maltose. Particularly preferred is lactose.

Under Sugar alcohols are understood to be monosaccharides whose reactive Carbonyl group is reduced to the alcohol group, such as. Eg hexites or Pentite. Preferably, the inventive solid preparation as sugar alcohol / e Hexite such. Eg mannitol, Lactitol, maltitol, xylitol or sorbitol. Particularly preferred Mannitol and / or maltitol, very particularly preferred is mannitol contain.

The solid pharmaceutical preparation can be used as powder, granules, pellets, Capsule or tablet are present. While capsules and tablets the amount of active ingredient intended for use as clearly defined Can provide single dose, by means of powders, Pellets and granules each required amount of active ingredient be easily adapted.

granules are free-flowing granular aggregates of powders which can be produced by granulation. pellets are solid small spherical drug forms such. B. Granules or microtablets, preferably a have narrow grain size range. Granules and Pellets are an independent form of medication but also as an intermediate for the production of tablets serve. Are predetermined amounts of active ingredient by means of powders, granules or pellets can be administered to ensure this a sufficient dosing accuracy as a separate powder / granules or bottled in capsules. Prefers is the pharmaceutical preparation of the invention as a granule, capsule or tablet, more preferably as a capsule or tablet, most preferably as a tablet.

ever After dosage form, the inventive solid Preparation of different adjuvants such. B. binder, 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 responsible inter alia for the cohesion of the powder particles in the granule. 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 preparation according to the invention preferably contains 1 to 5% by weight, especially preferably 1.5 to 3 wt .-% binder.

explosives can be included to the disintegration time of tablets to shorten, so that the active ingredient from the tablets quickly is released. Examples of usable according to the invention Disintegrators are microcrystalline cellulose cross-linked polyvinylpyrrolidone such as As cross-povidone or crosslinked carboxymethylcellulose. Particularly preferably, the inventive solid preparation carboxymethylcellulose, very particularly preferred cross-linked carboxymethylcellulose, as disintegrant. Depending on Type of disintegrant can this in the inventive solid preparation in a proportion by weight of 0.01 to 20 wt .-% be included. Preferably, the inventive solid preparation 0.1 to 10 wt .-%, particularly preferably 0.5 to 5% by weight of disintegrant.

Flow regulators can be and will be contained in powders or granules added to this to increase their flowability. Similarly, flow control agents in tablets be included, as far as these by compression of powders or Granules are produced. Also in this case they will be the Powders / granules added to their flowability to increase, especially to a uniform Fill the matrices before compression to the tablet and thus ensuring a high dosage accuracy. As flow regulator can be used, for example, fumed silica (Aerosil) or dried starch. Preferably, the inventive solid preparation fumed silica as flow regulator. Flow regulators are in the inventive solid preparation preferably in a proportion of 0.1 to 5 wt .-% contain, preferably 0.2 to 3 wt .-%, more preferably are 0.3 to 2 wt .-%.

So far the solid preparation according to the invention is a tablet This may also contain lubricant to during of the tableting process, the sliding friction of the Tablettierguts and the To lower the press die in the die and to stick it to the die Avoid stamping. Suitable lubricants are alkaline earth metal salts of fatty acids such as magnesium stearate, higher Fatty alcohols or talc. Preferably, the inventive solid preparation Magnesium stearate as lubricant. lubricant are in the solid preparation according to the invention preferably in a proportion of 0.1 to 10 wt .-%, preferably are 0.5 to 5 wt .-%, particularly preferably 1 to 4 wt .-%.

is the solid preparation according to the invention a tablet, this can be provided with a coating. As a coating are film-forming polymers such. B. from the group of cellulose derivatives, dextrins, starches, natural Gums, such as Gum arabic, xanthans, alginates, polyvinyl alcohol, Polymethacrylates and its derivatives such. B. Eudragite, by means of the various standard pharmaceutical methods, such as As film coating, as solutions or suspensions can be applied to the tablet. Usually In this case solutions / suspensions are used, in addition to the film-forming polymer, other auxiliaries such as hydrophilizers, Plasticizers, surfactants, dyes and white pigments, such as z. B. titanium dioxide.

The Preparation of the solid preparation according to the invention can according to the methods known in the art respectively.

The Production of powders can be carried out, for example, by adding the active ingredient with the sugar alcohol and optionally with other auxiliaries as flow control agents added and then is mixed.

The Production of the granules is carried out by granulation, the principle can be done on a wet or dry way. For wet granulation For example, a powder mixture containing the active ingredient together with the sugar alcohol and optionally further suitable Excipients, with a granulating liquid, preferably contains a binder, in the aggregates suitable Size (granules) transferred and then dried. The active ingredient can also be through Suspension in the granulation in the granules be introduced. The transfer of the powder mixture in aggregates of suitable size z. B. by the so-called build-up granulation, for example in the coating kettle, by plate granulation or fluidized bed process, for. B. after the smooth or Wurster process, or by the so-called Decay granulation take place in the powder mixture first moistened and processed to a plastically deformable mass and subsequently, for example by extrusion through a sieve with mesh of suitable size, in the Aggregates of the desired size transferred becomes. In dry granulation, the powder mixture becomes, for example by means of compacting between two counter-rotating Compacting rollers pressed into scabs, which then be crushed into granules.

pellets can by granulation and subsequent rounding (Spheronizing), for example by means of plate granulation, or by compressing powders or granules into microtablets getting produced.

The Preparation of the preparation according to the invention in the form of tablets can be made by compressing powder mixtures (Direct tableting) or by pressing granules done. In the simplest case of direct tableting is first the active ingredient with the sugar and / or sugar alcohol (in a direct tablet Quality) and optionally other excipients and the resulting powder mixture directly to the inventive compressed solid preparation.

Becomes the preparation according to the invention in the form of a Tablet made by pressing granules can For this granules are used by wet or dry granulation were manufactured. The granules are advantageous before their compression still containing a so-called outer phase an adjuvant or a mixture of several excipients, in particular Lubricants, flow regulators and / or disintegrants, mixed.

To a preferred embodiment of the invention is the solid preparation of a tablet and 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, From 30 to 99.8% by weight of lactose and / or mannitol and from 0.1 to 10% by weight cross-linked carboxymethylcellulose.

To a particularly advantageous embodiment is the fixed Preparation of one 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 wt .-% mannitol and 2 to 7 wt .-% cross-linked carboxymethylcellulose.

object the present patent application is still a method for Preparation of a solid pharmaceutical preparation in the form of a Tablet characterized in that by direct tableting or by pressing by means of wet or dry granulation produced granules and then optionally is provided with a coating.

To a preferred embodiment of the invention is that Process for the preparation of the tablet, characterized in that the active ingredient with lactose monohydrate and fumed silica, croscarmellose Na and magnesium stearate is mixed and that this mixture into tablets is pressed.

The Embodiments, without being limited thereto to be explain the invention.

example 1

• Tab. 1: Wirkstofffreisetzung von mikronisiertem (mic) und nicht-micronisiertem (n-mic) Wirkstoff A im Blattrührer-Modell (Mittelwerte, n = 3, rel. Standardabweichung
• (RSD)): 100 mg Wirkstoff A freigesetzt in 1000 ml 0,1 N HCl + 0,5% Natriumlaurylsulfat bei 50 Umdrehungen pro Minute

Influence of Particle Size of Drug A on its Release Behavior Drug A is micronized with an air jet mill and tested for release behavior in vitro compared to non-micronised drug. The release results are summarized in Table 1. Time [min] mic [%] RSD [%] n-mic [%] RSD [%] 0 0 0 0 0 5 66.3 0.5 86.9 1.8 10 79.7 0.4 90.0 1.1 15 86.7 0.3 93.3 3.3 20 92.3 3.8 92.5 0.8 30 92.6 3.1 92.7 0.9

• Tab. 1: Drug release of micronized (mic) and non-micronized (n-mic) drug A in a paddle stirrer model (mean, n = 3, rel. Standard deviation
• (RSD)): 100 mg of drug A released in 1000 ml of 0.1 N HCl + 0.5% sodium lauryl sulfate at 50 revolutions per minute

It that results in the reduction of the drug particle size to no increase in the dissolution rate leads.

Example 2

• Tab. 2: Wirkstofffreisetzung aus Mischungen von 100 mg Wirkstoff mit unterschiedlichen LMG-Anteilen (Blattrührermodell, Mittelwerte, n = 3) in 1000 ml 0,1 N HCl bei 50 Umdrehungen pro Minute

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. LMG [mg] 0 min 5 min 15 minutes 30 min 45 min 60 min 90 min 120 min 180 min 0 0 - - 44.08 - 54.01 60.31 65.27 - 50 0 7.77 21.97 38,99 53.49 61.57 73.32 79.17 84.57 100 0 13.81 33.25 55.33 64.28 71.97 79.59 83.15 85.98 200. 0 15.61 42,63 70.52 81.89 86.51 90.51 94.21 92.70 400 0 25.74 61.68 81.06 89.41 92.44 95.05 95,80 94.32 800 0 60,00 82.19 89,75 93.55 93.25 94.23 94.08 93.67

• 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 0.1 N HCl at 50 revolutions per minute

It it follows that the dissolution rate of 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 disperse silica 2 mg magnesium stearate 6 mg

The Ingredients are mixed together in hard gelatin capsules Size 0 bottled and in terms of their In vitro release tested. The results are in table 3 compiled.

• Tab. 3: Wirkstofffreisetzung aus Hartgelatinekapseln (Blattrührermodell, Mittelwerte, n = 6) in 1000 ml 0,1 N HCl bei 75 Umdrehungen pro Minute

Beispiel 4 Granulat enthaltend Wirkstoff A 100 mg Lactose 100 mg Maisstärke 10 mg mikrokristalline Cellulose 36 mg Croscarmellose-Na 6 mg Hochdisperses Siliciumdioxid 1 mg Magnesiumstearat 2 mg Time [min] 0 5 10 20 30 40 50 60 Drug release [%] 0.00 21.88 46.35 76.33 89.58 94.12 97.19 98.29

• 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 disperse silica 1 mg magnesium stearate 2 mg

Of the Active substance is mixed together with the lactose and with a corn starch paste Classically granulated. The granules can be directly to the patient be administered 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 5 Containing granules Active ingredient A 100 mg mannitol 116 mg Hydroxypropylmethlycellulose 5 mg Croscarmellose Na 2.3 mg Highly disperse silica 1.2 mg magnesium stearate 5.8 mg

Of 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 to a tablet be further processed.

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 disperse 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.

• Tab. 4: Wirkstofffreisetzung der Tabletten (Blattrührermodell, Mittelwerte, n = 6) in 1000 ml 0,1 N HCl bei 50 Umdrehungen pro Minute

The tablets are tested for their in vitro release. The results are summarized in Table 4. Time [min] 0 5 10 ` 20 30 45 60 75 Drug release [ % ] 0.00 38.39 59.62 81,00 90.53 97.24 100.08 102.12

• 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 stability the preparations

The Stability of the preparations according to the invention is checked in shelf life studies. For this The solid preparations at 25 ° C with a relative Humidity (RH) of 60% in HDPE (= High Density Polyethylene) bottles stored, outsourced at certain times and with appropriate investigated analytical methods.

• Tab. 5: Daten zur Stabilität von Zubereitungen gemäß Beispiel 6 in Abhängigkeit von der Zeitdauer der Lagerung (25°C, 60% r. F.)

Beispiel 7 Tablette enthaltend Wirkstoff A 100 mg Mannit 270 mg Croscarmellose-Na 12 mg Hochdisperses Siliciumdioxid 6 mg Magnesiumstearat 12 mg The stability data of a preparation according to the invention according to Example 6 are summarized in Table 5. investigations Storage period 0 month 1 month 2 months 3 months 6 months 9 months 12 months Appearance white - almost white n / A white - almost white white - almost white white - almost white white - almost white white - almost white hardness 74 n / A 67 63 65 66 63 Water content [%] 3.3 n / A 3.3 3.3 3.3 3.5 3.4 Decay [min] <15 mm n / A <15 mm <15 mm <15 mm <15 mm <15 mm Dissolution [% after 45 min] 99 n / A 94 96 91 94 97 Salary (% LC) 98 n / A 100 102 99 98 99 Total decomposition products [%] 0.2 n / A 0.2 0.2 0.2 0.2 0.2

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

Example 7 Containing tablet Active ingredient A 100 mg mannitol 270 mg Croscarmellose Na 12 mg Highly disperse silica 6 mg magnesium stearate 12 mg

The Tablets are made by mixing the active ingredient with mannitol, Croscarmellose Na, fumed silica and magnesium stearate and subsequent compression of this mixture.

Analytical test methods:

Identity, content, purity

to quantitative determination of the active substance content of the impurities in tablets, a chromatographic separation process with UV Detection according to Ph Eur 2.2.29 uses: Reversed Phase HPLC with a LiChroCHART 250-4 LiChrospher 60 RP-select B (5 μm) Pillar. To calculate the content and the purity is used an external standard.

In vitro drug release

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

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited non-patent literature

• - Guideline for Industry "Waiver of in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage forms based on biopharmaceutics classification system (August 2000) [0004]

Claims (10)

Containing solid pharmaceutical preparation 1 - [(4-chloro-phenyl) -amide] 2 - {[4- (3-oxo-morpholin-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. 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. Solid pharmaceutical preparation according to claim 1 and / or 2, characterized in that glucose, fructose, Mannose, lactose, sucrose and / or maltose and / or as sugar alcohol Sorbitol, mannitol and / or maltitol is included. Solid pharmaceutical preparation according to claim 3, characterized in that they contain lactose and / or mannitol is. Solid pharmaceutical preparation according to one or several of claims 1 to 4, characterized that this is present as granules, capsule or tablet. Solid pharmaceutical preparation according to claim 5, characterized in that it is a tablet. Solid pharmaceutical preparation according to one or several of claims 1 to 6, characterized that this contains a disintegrant. Solid pharmaceutical preparation according to one or several of claims 1 to 10, characterized from 0.1 to 50% by weight of 1 - [(4-chloro-phenyl) -amide] -2 - {[4- (3-oxomorpholin-4-yl) -phenyl] -amide} -4 -hydroxy-pyrrolidine-1,2-dicarboxylic acid, From 30 to 99.8% by weight of lactose and / or mannitol and from 0.1 to 10% by weight cross-linked carboxymethylcellulose. Process for the preparation of a solid pharmaceutical Preparation according to one or more of the claims 1 to 8, characterized in that this by direct tableting or by pressing by means of wet or dry granulation produced granules and then optionally is provided with a coating. Method according to claim 9, characterized that this procedure is a direct tabletting