EP1682086A2

EP1682086A2 - Pharmaceutical formulation containing an ltb4 antagonist, method for the production thereof, and use thereof

Info

Publication number: EP1682086A2
Application number: EP04790806A
Authority: EP
Inventors: Thomas Bock; Siglinde Moll; Karl Weber; Ulrich Brauns
Original assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2003-10-29
Filing date: 2004-10-23
Publication date: 2006-07-26
Also published as: ZA200601360B; WO2005041855A2; JP2007513068A; WO2005041855A3; DE10350528A1; IL175293A0; AU2004285271A1; CA2544049A1; KR20060108696A; MXPA06004435A; BRPI0416121A; RU2006118273A; US20050129768A1; CN101123950A

Abstract

The invention relates to a novel pharmaceutical formulation containing an LTB4 antagonist of formula (I), wherein A, R1, R2, R3, and R4 have the meaning indicated in claim 1, the pharmacologically acceptable acid addition salt thereof, glycoside, O-sulfate, or glucuronide as an active substance, and at least one optional pharmacologically acceptable auxiliary agent and/or carrier, the active substance being provided as a solid solution or solid dispersion in a polymer matrix. The invention also relates to the production thereof, the use thereof as a medicament, and said solid solutions and dispersions.

Description

Drug formulation. containing an LTB ₄ antagonist. and processes for their manufacture and their use

The invention relates to a new pharmaceutical formulation containing an LTB ₄ antagonist which has a benzamidine group, a process for its preparation and its use as a pharmaceutical.

Background of the Invention

LTB ₄ antagonists that have a benzamidine group are compounds with pharmacologically valuable properties. LTB ₄ antagonists can be of great therapeutic benefit, for example, in the treatment of arthritis, asthma, chronic obstructive pulmonary diseases, psoriasis, ulcerative colitis, Alzheimer's disease, shock, reperfusion damage / ischemia, cystic fibrosis, arteriosclerosis and multiple sclerosis.

Such connections are known e.g. from international patent applications WO 93/16036, WO 94/11341, WO 96/02497, WO 97/21670, WO 98/11062, WO 98/11119, WO 01/25186, PCT / EP01 / 00262 and WO 03/07922.

These compounds have the chemical structure of Formula I:

where A is a group of the formula -OC _m H _2m -O- (PHE) _n - (II), where m is an integer from 2 to 6, preferably 2 to 5, n is 0 or 1, PHE for an optionally 1,4-phenylene group substituted by one or two Ci-C ₆ alkyl groups, preferably one by ortho Position to the oxygen-linked C ₂ -C alkyl substituted 1,4-phenylene group; or A is a group of the formula

preferably of the formula

where R _{x is} H, OH, CN, CORio, COOR ₁₀ , or CHO, preferably H or COOR ₁₀ ; R ₂ H, Br, Cl, F, CF ₃ , CHF ₂ , OH, HSO ₃ -O-, -C-C ₆ alkyl, QC _ö alkoxy, C ₅ -C ₇ cycloalkyl, CONR ₈ R ₉ , aryl , O-aryl, CH ₂ -aryl, CR ₅ R ₆ -aryl, or C (CH ₃ ) ₂ -R ₇ , preferably OH, HSO ₃ -O-, CONR ₈ R ₉ or CRsRe-aryl, R _{3 is} H , D-Cβ-alkyl, CrC _ö -alkoxy, OH, Cl or F, preferably H or -C ₃ - alkoxy, R _{4 is} H or -Cö-alkyl, preferably H;

R _{5 is} CC ₄ alkyl, CF ₃ , CH ₂ OH, COOH or COO (C ₁ -C alkyl), preferably d-C ₄ alkyl, in particular methyl; R _{6 is} H, Ci-Gi-alkyl or CF ₃ , preferably -CC ₄ alkyl, in particular methyl; R _{7 is} CH ₂ OH, COOH, COO (C ₁ -C ₄ alkyl), CONR ₈ R ₉ or CH ₂ NR ₈ R9;

R _{8 is} H, d-Ce-alkyl, phenyl, phenyl- (C ₁ -C ₆ -alkyl), COR ₁₀ , COOR ₁₀ , CHO, CONH ₂ , CONHRio, SO ₂ - (C ₁ -C ₆ -alkyl), SO ₂ -phenyl, wherein the phenyl group mono- or disubstituted by Cl, F, CF _3, Ci-C alkyl, OH and / or C ₁ -C - may be substituted alkoxy, preferably C ₁ -C ₄ alkyl , especially isopropyl; R _{9 is} H or C ₁ -C ₆ -alkyl, preferably H or C 1 -C 4 -alkyl, in particular isopropyl; or R ₈ and R _{9 taken} together represent a C -C ₆ alkylene group; R ₁₀ denotes Ci-Cö-alkyl, C ₅ -C ₇ cycloallcyl, aryl, heteroaryl, aralkyl or heteroaryl- (-Cι-C _ö alkyl), preferably -Q-alkyl, the radicals in the radicals R ₂ and R ₁₀ aryl groups listed are phenyl or naphthyl, the heteroaryl groups are pyrrole, pyrazole, imidazole, furanyl, thienyl, pyridine or pyrimidine and each one or more times by Cl, F, CF ₃ , C ₁ -C ₄ alkyl, OH , HSO ₃ -O- or -CC ₄ alkoxy, preferably OH or HSO ₃ -O- may be substituted.

The compounds corresponding to formula I have an extremely low solubility in water and solubility in the physiological pH range (approx. <0.5 μg / rni) combined with poor wettability. Because of the importance of the above-mentioned LTB ₄ antagonists, there is therefore a constant need to find ways to improve the bioavailability and thus effectiveness of these compounds. For example, WO 03/007922 describes that the bioavailability of the active ingredient can be increased if the active ingredient is formulated together with a wetting agent.

It is therefore the object of the present invention to provide a dosage form with improved bioavailability for LTB ₄ antagonists, ie to develop a dosage form which releases an active ingredient of the formula I relatively quickly and completely and thus to an increased bioavailability of this active ingredient leads. Furthermore, an orally administrable pharmaceutical formulation should be able to be provided. Another object of the present invention is to provide a formulation which is easy to handle during the manufacturing process and thereby allows the technical manufacture in a reproducible manner with a consistently high quality.

Detailed description of the invention

The above object is achieved by the features of claim 1. This is followed by a pharmaceutical formulation containing an LTB antagonist of the formula I, its pharmacologically acceptable acid addition salt, Glykosϊd, O-sulfate or glucuronide as active ingredient and optionally at least one pharmacologically acceptable auxiliary and / or carrier, provided, the active ingredient being present as a solid solution or solid dispersion in a polymer matrix.

The active ingredient of the formula I can be present in the pharmaceutical formulation according to the invention, for example in the form of a physiologically tolerated acid addition salt. According to the invention, physiologically acceptable acid addition salts are understood to be pharmacologically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid. If appropriate, mixtures of the abovementioned acids can also be used to prepare the salts. According to the invention, the salts of the formula I are preferably selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate and methanesulfonate. The salts are particularly preferably selected from hydrochloride, hydrobromide and fumarate. The active ingredient may optionally be in the form of a hydrate. According to the invention, however, the compound of the formula I is preferably in the form of the free base.

A particularly preferred compound of formula I is the compound amelubant, i.e. [4- ((3 - ((4- (1- (4-Hydroxyphenyl) -l-methylethyl) phenoxy) methyl) benzyl) oxy) benzenecarboximide-amide-N-ethylcarboxylate], shown below in Formula IA:

The compounds of the formula I in which R \ is different from hydrogen are generally prodrugs which are converted in vivo to the corresponding compounds of the formula I in which Ri is hydrogen. For example, the compound of the formula IA1 is formed from the compound IA in vivo: (Formula IA1) wherein X is OH, HSO ₃ -O-, a carbohydrate radical of the formula C ₆ Hπ0 ₅ -O- or a glycosyl radical and represent Metabo lite of the above compound.

The pharmaceutical formulation according to the invention is a solid solution or dispersion of the active ingredient in the form of an LTB ₄ antagonist of the formula I, in particular the formula IA, in a matrix composed of one or more polymers. Polymers or polymer mixtures which are particularly suitable in the context of the invention are hydrophilic or water-soluble Polymers that help the active ingredient to be formulated as a solid solution / dispersion. In this context, “water-soluble” should not only be understood to mean real solutions, but also colloidal solutions of the polymer or polymers in water.

Polyethylene glycols, polypropylene glycols, cellulose ethers, polyvinylpyrrolidones, polyvinyl acetates, copolymers and mixtures thereof can be used as polymers, for example. Particularly preferred polymers are poloxamers, ie known copolymers of polyethylene glycols and polypropylene glycols, methyl cellulose, ethyl cellulose, propyl cellulose, carboxymethyl cellulose, ethylhydroxyethyl cellulose, hydroxypropyl cellulose, Kollidone ^®, mixed polymers of polyvinylpyrrolidone and polyvinyl acetate or polyethylene glycols with various chain lengths. Poloxamers, such as poloxamer 188, are very particularly preferred.

In addition to the active substance (s) and the polymer matrix, the pharmaceutical formulation according to the invention optionally contains one or more auxiliaries and / or carriers, such as fillers, binders, disintegrants, disintegrants, flow or flow regulators, lubricants, mold release agents, pH corrections, in particular buffer substances, antioxidants and dyes. Carbohydrates such as lactose or mannose, in particular finely divided lactose, or sugar alcohols such as mannitol, sorbitol or xylitol, in particular mannitol, have proven to be particularly advantageous as fillers which can be used in the context of the present invention.

Binders preferred according to the invention are selected from the group consisting of: powder cellulose, microcrystalline cellulose, sorbitol, starch, polyvinylpyrrolidone (povidone), copolymers of vinylpyrrolidone with other vinyl derivatives (copovidones), cellulose derivatives, in particular methylhydroxypropyl cellulose, e.g. Methocel A 15 LV, and mixtures of these compounds. Powder cellulose, in particular microcrystalline cellulose and / or copovidones, are preferably contained as binders.

In addition to the above-mentioned components, the pharmaceutical formulation according to the invention can also contain disintegrants, which are sometimes also referred to as disintegrants. According to the invention, these are preferably selected from the group consisting of sodium starch glycolate, cross-linked polyvinylpyrrolidones (crospovidone), croscarmellose sodium salt (cellulose-carboxymethyl ether sodium salt, cross-linked), sodium carboxymethyl cellulose, dried corn starch and mixtures thereof. In the context of the present invention, sodium starch glycolate, crospovidone and, preferably crospovidone or croscarmellose sodium salt are particularly preferably used.

The pharmaceutical formulation according to the invention can contain flow or flow regulating agents and lubricants as further constituents. In the context of the present invention, silicon dioxide, talc, stearic acid, sodium stearyl fumarate, magnesium stearate and glycerol tribehenate are suitable for this purpose. Magnesium stearate is preferably used according to the invention.

Furthermore, the pharmaceutical formulation according to the invention can contain one or more synthetic or natural, pharmaceutically acceptable dyes, preferably indigo carmine.

Of course, further auxiliaries and carriers known to the person skilled in the art can be contained in the pharmaceutical formulation of the invention. The proportion of auxiliaries and / or Carriers, based on the total mass of the formulation, are preferably in a range from about 50 to about 99.5% by weight, in particular about 90 to about 99% by weight.

Based on the total mass of the pharmaceutical formulation according to the invention, the compound of the formula I, for example of the formula IA, according to the invention is preferably about 0.5 to about 50% by weight, particularly preferably about 0.5 to about 25% by weight, in particular about 1 to about 10% by weight. % contain. The proportion of the free base, based on the total mass of the formulation, is preferably between about 0.5 and about 25% by weight, particularly preferably between about 1 and about 10% by weight.

The respective active ingredient is preferably used in crystalline, unmilled form or ground form, in particular in jet-ground form.

Without being bound by any particular theory, it is assumed that the pharmaceutical formulation according to the invention can act as follows:

In the novel galenical dosage form in the form of solid solutions / dispersions provided according to the invention, when using water-soluble polymers, in the sense of the above definition for "water-soluble", the polymer matrix first dissolves after administration. This takes place in an aqueous environment, ie in the gastrointestinal tract Tract, and there remains the active ingredient dissolved or finely distributed in the polymer matrix. This partially goes parallel to the dissolution of the polymer matrix, and sometimes subsequently in solution, resulting in a supersaturated solution. Here, the present, dissolved concentration of the active ingredient is higher, as theoretically achievable and even available in thermodynamically stable form. Nevertheless, according to the invention, it is surprisingly possible to generate supersaturation. This can be supported by appropriate selection of suitable auxiliaries and the polymers used Solutions / dispersions stabilized to the desired extent for different times. The high, dissolved active substance concentration thus leads to increased absorption of the active substance in vivo, ie the active substance is available to a greater extent to an organism and can therefore have a significantly greater effect. This supersaturation of the active ingredient concentration achieved according to the invention on the basis of the specially developed pharmaceutical dosage form could be demonstrated on the basis of in vitro release studies and also in vivo bioavailability studies, which is shown in detail in the examples.

The invention also relates to a method for producing the pharmaceutical formulation described above, comprising the steps:

(1) melting a polymer or mixture of polymers;

(2) dissolving or dispersing an active ingredient, selected from the LTB ₄ antagonists of the formula I defined above, in the melt;

(3a) pouring the melt into suitable molds and allowing the melt to cool while cooling; or (3b) allowing the solid solution or solid dispersion obtained to solidify with cooling and then comminuting the solid solution or solid dispersion obtained into suitable molds.

First, in step (1) according to the invention, a melt of one or more polymers is produced. These are the polymers already described in detail. This is followed in step (2) by dissolving or dispersing the LTB ₄ antagonist active ingredient of the formula I defined above, for example the formula IA, in the melt of the polymer or polymers. It is particularly preferred to use the active ingredient in step (2) in crystalline, unmilled form or in milled form, in particular in jet milled form. In addition, it was found to be particularly useful to sieve the active ingredient after grinding. The active ingredient used then preferably has an average particle size (D 50) of approximately 1 μm to approximately 7 μm, in particular approximately 1.5 μm to approximately 3 μm. This was determined with the method of laser diffractometry (eg Sympatec device with HELOS software, dry disperser RODOS).

As soon as the active ingredient (s) are dissolved or dispersed in the melt, two alternatives can be used. Either the melt is poured into suitable molds and allowed to solidify while cooling (step 3a), or the solid solution or solid dispersion obtained is allowed to cool and then comminuted into the appropriate mold (Step 3b). The crushing is preferably achieved by grinding, but can be carried out using any known technique. An additional sieving can then be carried out.

After cooling, so-called solid solutions are formed, in which the active ingredient is present in a molecularly dispersed form in the solidified polymer matrix. If the active ingredient recrystallizes during cooling or does not completely dissolve in the melt, so-called solid dispersions are formed. The products obtained in step (3a) or (3b) can expediently be processed further into tablets, film-coated tablets, dragées, powders or powder sachets, or, for example, filled directly into capsules, such as hard gelatin capsules.

The invention also relates to a solid solution or solid dispersion containing an LTB ₄ antagonist of the formula I, as previously defined, in a polymer matrix.

The invention also relates to a solid solution or solid dispersion containing an LTB antagonist of the formula IA, as previously defined, in a polymer matrix.

A further embodiment of the present invention, to represent the pharmaceutical formulation or the solid solutions or dispersions, is the production by means of a melt extrusion process, which is also known per se to the person skilled in the art and does not require any detailed explanation.

Another object of the invention is the use of the pharmaceutical formulation according to the invention for the manufacture of a pharmaceutical with increased bioavailability for the treatment or prevention of diseases in which LTB ₄ antagonists can be used therapeutically or preventively.

In particular, the invention also relates to the use of the pharmaceutical formulation according to the invention for the manufacture of a pharmaceutical for the treatment or prevention of arthritis, asthma, chronic obstructive pulmonary diseases, psoriasis, ulcerative colitis, Alzheimer's disease, shock, reperfusion damage / ischemia, cystic fibrosis, arteriosclerosis and multiple sclerosis , The advantages associated with the present invention are multifaceted: According to the invention, a new pharmaceutical dosage form is made available which represents a solid solution or solid dispersion of an LTB ₄ antagonist as an active ingredient in a polymer matrix. This achieves an extraordinary improvement in the dissolution behavior and thus the bioavailability of the active ingredient, which provides an inherently thermodynamically unstable and therefore supersaturated active ingredient concentration. Nevertheless, the teaching according to the invention allows a physically and chemically stable formulation to be provided. Surprisingly, therefore, it is possible to stabilize supersaturated solutions / dispersions with a high concentration of active substance, which means that if the active substance is released, it is available to an organism to a greater extent and can have a significantly greater effect.

This is proven not only by in vitro release tests; this could also be found in in-vivo investigations, as shown, for example, by the bioavailability study and the release studies on mini-pigs in the examples. _;

The extremely favorable stability of the pharmaceutical preparation according to the invention and the excellent bioavailability in humans and animals were not to be expected and were also not predictable.

The following examples serve to illustrate formulations according to the invention. They are only to be understood as possible exemplary procedures, without restricting the invention to its content.

Examples

In the examples below, the pharmaceutical formulation according to the invention is simply referred to as “melt embedding” or “polymer melt embedding” and abbreviated as “JPSE”.

Example 1:

Production of a melt embedding according to the invention with 1% active ingredient loading Active ingredient: BILL 284 BS (LTB ₄ antagonist of formula IA in the form of the base), amount: 75 mg polymer matrix amount: 7.5 g (1% melt embedding)

I. COMPOSITION. ingredients

(01) BIIL 284 BS spray-blasted 75 mg *)

(02) Poloxamer 188 Pharm 7 425 mg

TOTAL 7 500 mg *) Before weighing, the content of the active ingredient must be determined

π. PRODUCT DESCRIPTION

Granules / powder

Appearance: fine-grained, white, wax-like powder Grain size: <500 μm Color: white Filling volume 7.5 g

m. Methods of Preparation

1 batch = 606 g

1.Melt Poloxamer 188 Pharm

650,000 g of Poloxamer 188 Pharrn (02) are melted in a vacuum drying cabinet at an absolute pressure of 100 to 200 mbar over a period of 4 hours in a crystallizing dish with 0 190 mm. 2. Active ingredient seven

6.0606 g of BILL 284 BS (01) are jet-ground and sieved in an analytical sieve with a mesh size of 800 μm.

3. Make melt embedding

The laboratory reactor is preheated for approx. 30 minutes at a water bath temperature of 90 ° C. The laboratory reactor is filled with 600.0000 g of Poloxamer 188 Pharm (02) (liquid). The anchor stirrer is set to 20 rpm, the direction of rotation to the right and an absolute pressure of 100 to 200 mbar is applied. After 5 minutes the reactor is opened and the entire BILL 284 BS (01) in jet-milled form is placed in the laboratory reactor (6.0606 g) in one go and sealed. The anchor stirrer is left at 20 rpm and the direction of rotation remains on the right. 3 minutes after the addition of the active ingredient, the absolute pressure is set to 100 to 200 mbar. 5 minutes after the addition of active ingredient, the starter stirrer speed is increased to 100 rpm. 10 minutes after the active ingredient has been added, the direction of rotation of the anchor stirrer is set to the left. The laboratory reactor is opened from the 15th to the 20th minute and any active ingredient residues on the anchor stirrer, temperature sensor and the glass wall are stripped off and returned to the melt. The laboratory reactor is closed again, an absolute pressure of 100 to 200 mbar is applied, the speed is left at 100 rpm and the anchor stirrer is set to the right-hand direction of rotation. 20 minutes after the active ingredient has been added, the water bath temperature setting is reset to 86 ° C. 25 minutes after adding the active ingredient, the direction of rotation of the anchor stirrer is set to the left. 35 minutes after adding the active ingredient, the direction of rotation of the anchor stirrer is then set to the right again. 40 minutes after the addition of the active ingredient, the anchor stirrer speed is set to 20 rpm. The laboratory reactor is opened 60 minutes after the active ingredient has been added and the melt bed is poured out thinly on a glass plate or a stainless steel sheet.

Process / device data:

Laboratory reactor: IKA laboratory reactor system LR-A 1000

Agitator: IKA agitator - drive: RE 162 A - control unit: RE 162 P analog circulation thermostat: mgw Lauda C3 type: T l 4. Freeze

The melt embedding is poured out thinly on a glass plate or a stainless steel sheet (layer thickness approx. 1.5 to 2.5 mm) and allowed to solidify. The solidification time is approx. 2 to 3 hours. The solidified melt embedding is scraped off the glass pane or the stainless steel sheet with a dough scraper and stored temporarily in a brown wide-necked glass.

5. Grind and sieve

The individual flakes are ground with a water-cooled IKA universal mill and the regrind is sieved with a 500 μm Kressner sieve. The grinding and sieving process is repeated until the entire melt embedding <500 μm has been ground

Process / device data Mill: IKA cross-stroke / universal mill Type: M 20 Grinding time: 3 x approx. 5 sec / filling

6. Bottling

Under GMP (Good Manufacturing Practice) conditions, the granulate is filled into the low-germ glass bottles and the pilfer proof closure is sealed with a PfP flaring machine. Filling quantity: 7.500 g tolerance when filling 7.470 g to 7.530 g

rv. process controls

1.Melt embedding liquid Approx. 30 to 35 min after the addition of the active ingredient, it is advantageous if the active ingredient is dissolved. From this point on, the melt embedding becomes clear. Shortly before the laboratory reactor is emptied, no undissolved BIIL flakes should be visible in the melt embedding. 2. Melt embedding firmly

As the melt embedding solidifies, its appearance changes from liquid clear to waxy white.

3. Granules / powder fine dust, white, grain size <500 μm.

The grain size is reached when everything has passed through the 500 μm sieve.

4. Filling quantity

The filled masses contain between 7.470 g and 7.530 g.

Example 2:

The melt embedding produced in Example 1 with 1% active ingredient loading (75 mg BIIL 284 BS) was tested on humans. A tablet which also contained 75 mg BUL 284 BS served as a comparison. The plasma concentration of BIIL 315 ZW was determined. BIIL 315 ZW is the compound BIIL 284 BS, the structure of which was explained in Example 1, but the ethyl carboxyl group is split off (= N-CO ₂ C ₂ Hs -> = NH) and at the same time the hydroxyl group on the "left" Phenyl ring has been glycosylated (LTB ₄ antagonist with the formula IA1). BILL 315 ZW is present as a zwitterion. The compound BIIL 284 BS is converted in the human body in the manner described into BUL 315 ZW and represents its active metabolite.

The results are shown in FIGS. 1 to 4. Figures 1 to 4 show the mean plasma concentration of BIIL 315 ZW, plotted against the time after a single dose of 75 mg BILL 284 BS, either as a melt embedding according to the invention (PSE) or in the form of a WIF tablet (wettability improved formulation, a formulation accordingly the prior art according to WO 03/007922, containing a wetting agent) - under fasting conditions (parallel groups), in each case at different times.

It is very clear from the studies on humans that the plasma concentration of the dosage form according to the invention exceeds that of a conventional tablet with the same active ingredient and the same dosage amount, ie the available one The amount of active substance in the dosage form according to the invention is many times higher than in a conventional tablet.

Example 3:

Release results of melt embedding with different drug loading

The following examples 3a) and 3b) relate to a suspension of the PSE powder in water. Release studies were then carried out with this suspension. The results are shown in FIGS. 5 and 6. On the one hand, the total amount of BUL 284 BS released (“unfiltered”) and on the other hand the colloidally dissolved fraction with particle sizes <220 nm, which are designated as “filtered” in FIGS. 5 and 6, were evaluated.

On the one hand, therefore, the total amount of active ingredient released from the pharmaceutical form was shown. The release curves commonly used for the characterization of solid oralia were used.

On the other hand, the proportions of drug that cannot be filtered with a 0.22 μm filter are also shown. Their particle size is therefore below 220 nm. The active substance is thus dissolved or at least colloidally dissolved, that is to say finely distributed, even if these concentrations are far above the saturation concentrations of the active substance. This supersaturation is maintained for a certain time before the active ingredient crystallizes and can therefore be removed by filtration, i.e. has a particle size> 220 nm.

The other examples 3c) and 3d) below relate to release studies of PSE powder that was filled into hard gelatin capsules. Again, both were released. The total amount of BIIL 284 BS and the colloidally dissolved portion were examined.

3a) PSE ground - 10% active ingredient loading (suspended) Composition PSE 10%: 67.41 g BILL 284 BS (LTB ₄ antagonist of the formula IA in the form of the base) 600 g Poloxamer 188 Pharm (polymer matrix)

Production: In a beaker

Release of 499.8 mg PSE, grain size <0.5 mm, suspended in 5 ml deionized water, added to the release medium after 5 minutes

Release medium: 500 mL 0.1N HCl with 50 mg Methocel A 15 LV

The results are shown in FIG. 5.

3b) PSE ground - 5% active ingredient loading (suspended) Composition PSE 5%: 31.9369 g BIIL 284 BS 600.09 g Poloxamer 188 Pharm Production: In the laboratory reactor

Release of 1000.2 mg PSE, particle size <0.5 mm, suspended in 5 ml deionized water, added to the release medium after 5 minutes Release medium: 500 ml 0.1N HCl with 50 mg Methocel A 15 LV

The results are shown in Figure 6.

3c) capsule with PSE granules - 10% active ingredient loading

Composition of PSE 10%:

1002.4 mg BILL 284 BS

9021.8 mg poloxamer 188 Pharm

Capsule filled with 300 mg PSE, grain size 0.5-0.8 mm

Release medium: 400 mL 0.1N HCl with 20mg Methocel A 15 LV

The results are shown in Figure 7.

3d) capsule with PSE granules - 15% active ingredient loading

Composition PSE 15%: 4.5037 g BILL 284 BS

25.5067 g poloxamer 188 Pharm

Capsule filled with 332.7 mg PSE, grain size <0.5 mm

Release medium: 500 mL 0.1N HCl with 50mg Methocel A 15 LV

The results are shown in Figure 8.

Example 4:

Production of a melt embedding according to the invention with 10% active ingredient loading:

Active ingredient: BILL 284 BS, amount: 75 mg polymer matrix amount: 0.750 g (10% melt embedding)

I. COMPOSITION

ingredients

(01) BILL 284 BS spray-blasted 98.9% 75 mg *)

(02) Poloxamer 188 Pharm 675 mg

TOTAL 750 mg *) Before weighing, the content of the active ingredient must be determined

II. PRODUCT DESCRIPTION Granules / powder

Appearance: fine-grained, white, slightly waxy powder grain size: <500 μm color: white filling volume 750 mg

III. Methods of Preparation

1 batch = 667 g = 89 bottles

1.Melt Poloxamer 188 Pharm

Since the melting poloxamer in the laboratory reactor would overload the anchor stirrer, the poloxamer is melted separately. 650,000 g of Poloxamer 188 Pharm (02) are melted in a vacuum drying cabinet at an absolute pressure of 100 to 200 mbar over a period of 4 hours in a crystallizing dish with 0 190 mm. ,

2. Active ingredient seven

66.6667 g BUL 284 BS (01) are jet-ground and sieved in an analytical sieve with a mesh size of 800 μm.

3. Make melt embedding

The laboratory reactor is preheated for about 30 minutes at a water bath temperature of 90 ° C. The laboratory reactor is filled with 600.0000 g of Poloxamer 188 Pharm (02) (liquid). The anchor stirrer is set to 20 rpm, the direction of rotation to the right and an absolute pressure of 100 to 200 mbar is applied. After 5 min the reactor is opened and the entire BIIL 284 BS (01) in jet-milled form is placed in the laboratory reactor (66.6667 g) and closed within 5 min. The anchor stirrer is left at 20 rpm and the direction of rotation remains on the right. 3 minutes after the addition of the active ingredient, the absolute pressure is set to 100 to 200 mbar. 5 minutes after the addition of the active ingredient, the anchor stirrer speed is increased to 100 rpm. 10 minutes after the active ingredient has been added, the direction of rotation of the anchor stirrer is set to the left. From the 15th to the 20th min the laboratory reactor is opened and any Material residues on the anchor stirrer, temperature sensor and the glass wall are stripped off and returned to the melt. The laboratory reactor is closed, an absolute pressure of 100 to 200 mbar is applied, the speed is left at 100 rpm, and the anchor stirrer is turned to the right. 25 minutes after adding the active ingredient, the direction of rotation is set to the left by the anchor stirrer. 35 minutes after adding the active ingredient, the water bath temperature setting is reset to 86 ° C and the direction of rotation of the anchor stirrer is then set to the right again. 40 minutes after the addition of the active ingredient, the anchor stirrer speed is set to 20 rpm. The laboratory reactor is opened 60 minutes after the active ingredient has been added and the melt bed is poured out thinly on a glass plate or a stainless steel sheet.

Process / device data (as in example 1)

4. Freeze

5. Grind and sieve

The individual flakes are ground with a water-cooled IKA universal mill and the regrind is sieved with a 500 μm Kressner sieve. The grinding and sieving process is repeated until the entire melt embedding <500 μm has been ground.

Process / device data (as in example 1)

5. Bottling

Under GMP conditions, the granulate is filled into the low-germ glass bottles and the pilfer proof closure is closed with a PfP flaring machine. Filling quantity: 750 mg tolerance when filling 745 mg to 755 mg IV. INPROCESS CONTROLS (see example 1)

Example 5:

The melt embeddings according to the invention with 5 and 10% active ingredient loading, produced in Example 4, were tested on mini-pigs. A bioavailability study was carried out, the results of which are shown in FIGS. 9 and 10.

a) Summary

A relative bioavailability study with various BUL 284 BS formulations (5% PSE, 10% PSE and tablet) was carried out after oral administration to mini-pigs. Two PSE formulations, one with 5% drug loading and one with 10% drug loading on BIIL 284 BS were examined.

b) goal

The absorption of various pharmaceutical formulations of BILL 284 BS in mini-pigs should be investigated.

c) Procedure cl) Animal testing

Two PSE formulations were used, one containing 5% BILL 284 BS and one containing 10% BIIL 284 BS. The PSE were stored in glass containers and suspended in 50 ml of tap water immediately before use. After administration of the dose, the bottles were washed once with a further 50 ml of tap water, which was also administered to the animals.

6 tablets containing 75 mg BIIL 284 BS were each placed in a capsule (size 000). After the capsules had been administered, they were rinsed with 50 ml of tap water. Food was provided 3 to 4 hours after ingestion, except for group 2, where the food was given 15 minutes after ingestion. Table 1

M male W female c2) Bioanalytical parameters The BIIL 315 ZW plasma concentrations were quantified by HPLC-MS / MS. d) Results The dose-normalized concentrations of BILL 315 ZW, the individual and average dose-normalized AUCO- _24h and C _max values and the t _max values are shown in section f). In addition, the pharmacokinetic parameters are summarized in Table 2.

The results are also shown in FIGS. 9 and 10. FIG. 9 shows the plasma concentrations of BIIL 315 ZW, normalized to a dose of 1 mg / kg oral administration of various BILL 284 BS ^' formulations to mini-pigs. FIG. 10 shows the dose-normalized C _m aχ and AUC _0-2 h values of BILL 315 ZW after oral administration of various pharmaceutical formulations of BILL 284 BS to mini-pigs.

Table 2 Summary of pharmacokinetic parameters

Group formulation AUCo-Mh c ^, -τnax 4nax N g medium gCV N g medium gCV medium range [ng-h / ml] [%] [ng / ml] [%] MM / dose / dose

1 PSE (10%) 4 320 78 4 31 98 1.5 1-2

3 PSE (5%) 4 630 57 4 56 84 3 1-4

2 tablets + 2 390 57 4 16 190 14 2-24 food

4 tablets 4 807 63 4 66 75 8 4-8

N. Number of experimental animals

AUC ₀ . ₂ h .. ..Area under the curve from 0 to 24 hours ..maximum plasma concentration tma. Time to reach the maximum plasma level g average., Geometric mean value g CV .. geometric standard deviation

Average .... average

Variability: The interindividual variability of the plasma concentrations was high. Differences in release in female and male mini-pigs were observed. However, the differences between the molding groups were not uniform.

PSE: The dose-normalized AUC _0-24 h and Cmax values of the PSE formulations containing 5% BILL 284 BS were about twice higher than the corresponding values of the PSE formulations containing 10% BILL 284 BS.

Tablet: Oral administration of the tablets also resulted in substantial release in the animals. It should be noted that this formulation has been tested on animals other than the PSE. The direct comparison of the values could be misleading due to the high inter-individual variability. However, the AUCo _-2 h and Cma values were comparable to the 5% PSE values. Tm x was significantly delayed compared to the PSE formulations.

e) Conclusions The differences in release in male and female mini-pigs were not uniform between the different formulation groups and are therefore attributed to inter-individual variability rather than to actual gender differences.

It could be shown that the ratio of BIIL 284 BS to Pluronics (= poloxamer, polymer matrix) influences the release of BILL 315 ZW in the animals. A lower loading of the PSE with the active ingredient BIIL 284 BS, i.e. a higher amount of Pluronics (polymer matrix) resulted in higher BILL 315 ZW plasma concentrations.

With a more classic formulation, a BUL 284 BS tablet, a systemic release was also achieved in the animals, which was comparable to the release in the PSE with a 5% active ingredient load. f) Compilation of the measured values Table 3: Dose-normalized plasma concentration of BIIL 315 ZW, after oral administration of 10 mg / kg or 1350 mg (tablet) / mini pig, BUL 284 BS

Group 2, dose normalized time 51853 51726 51828 51830 N mean CV (%) g-mean gCV (%) [] MMWW [ng mL] [ng / mL] 1 6,822 13.45 2,500 2,500 4 6,318 81.9 4,894 98.5 2 23.96 65.46 0.4588 2,779 4 23.16 130.0 6.687 1170.6 4 20.530 74.07 2.324 5.155 4 25.52 130.6 11.62 305.5 8 7.945 21.17 4.317 3.456 4 9.222 88.9 7.078 96.4 24 11.150 7.599 5.049 6.822 4 7.655 33.5 7.350 33.6

CV standard deviation (coefficient of variation) gC V geometric standard deviation g average geometric mean average mean

Table 4: Individual and average dose normalized AUC _{0-2 h} of BLTL 315 ZW, after oral administration of various BIIL 284 BS formulations to mini-pigs.

Table 5: Individual and average dose-normalized C _max of BIIL 315 ZW, after oral administration of various formulations of BUL 284 BS to mini-pigs

Table 6: Individual and average dosisnormalisierte t χ _ma of BITL 315 ZW, after oral administration of formulations of verscMedenen BUL 284 BS to mini-pigs

M male W female

Claims

claims

Drug formulation containing an LTB ₄ antagonist of the formula I,

in which

A is a group of the formula -OC _m H _2m -O- (PHE) _n - (II), in which m is an integer from 2 to 6, n is 0 or 1, PHE for one optionally by one or two -Cö -Alkyl groups substituted 1,4-phenylene group; or

A is a group of the formula

means what

Ri represents H, OH, CN, COR ₁₀ , COORio or CHO; R ₂ H, Br, Cl, F, CF ₃ , CHF ₂ , OH, HSO ₃ -O-, - -alkyl, - -alkoxy, C ₅ -C ₇ - cycloalkyl, CONR ₈ R ₉ , aryl, O-aryl , CH ₂ aryl, CR ₅ R ₆ aryl, or C (CH ₃ ) ₂ -R ₇ ,

R _{3 is} H, d-Ce alkyl, C ₁ -C ₆ alkoxy, OH, Cl or F,

R4 represents H or -C _Ö alkyl;

Rs - represents alkyl, CF ₃ , CH ₂ OH, COOH or COO (Ci-C-alkyl); Re is H, -C ₄ - alkyl or CF ₃ ;

R _{7 represents} CH ₂ OH, COOH, COO (Ci-C ₄ alkyl), CONR ₈ R ₉ or CH ₂ NR ₈ R ₉ ; R ₈ H, d-Ce-alkyl, phenyl, phenyl- (-CC ₆ alkyl), COR ₁₀ , COOR ₁₀ , CHO, CONH ₂ , CONHR ₁₀ , SO ₂ - (C ₁ -C ₆ alkyl), SO ₂ -phenyl, the phenyl group being mono- or disubstituted by Cl, F, CF ₃ , C ₁ -C 4 AUζyl, OH and / or C ₁ -C -. Alkoxy may be substituted; Is RH or Ci-Ce-alkyl; or R ₈ and R _{9 taken} together represent a C -C ₆ alkylene group; R ₁₀ Ci-Cö-alkyl, C ₅ -C ₇ cycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl- (C ₁ - C ₆ alkyl) means wherein the aryl groups listed in the radicals R ₂ and R ₁₀ are phenyl or naphthyl are, the heteroaryl groups are pyrrole, pyrazole, imidazole, furanyl, thienyl, pyridine or pyrimidine and. each can be substituted one or more times by Cl, F, CF ₃ , C ₁ -C ₄ alkyl, OH, HSO ₃ -O- or CrGα.- alkoxy, its pharmacologically acceptable acid addition salt, glycoside, O-sulfate or glucuronide as Active ingredient and optionally at least one pharmacologically acceptable auxiliary and / or carrier, characterized in that the active ingredient is present as a solid solution or solid dispersion in a polymer matrix.

Pharmaceutical formulation in particular according to claim 1, characterized in that the LTB antagonist is the compound [4 - ((3 - ((4- (1- (4-hydroxyphenyl) -l-methylethyl) phenoxy) methyl) benzyl) oxy) benzenecarboximidamide -N-ethylcarboxylate] of the formula IA:

3. Pharmaceutical formulation according to one of claims 1 or 2, characterized in that the polymer matrix comprises one or more water-soluble polymers.

4. Pharmaceutical formulation according to claim 3, characterized in that the polymer or polymers are selected from the group consisting of polyethylene glycols, polypropylene glycols, cellulose ethers, polyvinylpyrrolidones, polyvinyl acetates, copolymers and mixtures thereof.

5. Pharmaceutical formulation according to claim 3 or 4, characterized in that the polymer or polymers are selected from the group consisting of copolymers of polyethylene glycols and polypropylene glycols, methyl cellulose, ethyl cellulose, propyl cellulose, carboxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, Kollidonen ^® , copolymers of PolyvinylpyrroHdon and polyvinyl acetate as well as polyethylene glycols with different chain lengths.

6. Pharmaceutical formulation according to one of claims 1 to 5, characterized in that the polymer matrix is a poloxamer.

7. Pharmaceutical formulation according to one of claims 1 to 6, characterized in that the formulation, based on the total mass, contains about 0.5 to about 50% by weight, preferably about 0.5 to about 25% by weight, of a compound of the formula I.

8. Pharmaceutical formulation according to one of claims 1 to 7, characterized in that contain at least one auxiliary and / or carrier selected from fillers, binders, disintegrants, disintegrants, flow or flow regulating agents, lubricants, release agents, pH correctants, antioxidants and dyes is.

9. Pharmaceutical formulation according to one of claims 1 to 8, characterized in that the proportion of auxiliaries and / or carriers, based on the total mass of the formulation, in a range from about 50 to about 99.5% by weight, in particular about 90 to about , 99% by weight.

10. Solid solution or solid dispersion containing an LTB antagonist of the formula I according to claim 1 in a polymer matrix.

11. Solid solution or solid dispersion containing an LTB ₄ antagonist of the formula IA according to claim 2 in a polymer matrix.

12. Solid solution or solid dispersion according to claim 10 or 11, characterized in that the polymer matrix comprises one or more water-soluble polymers.

13. Solid solution or solid dispersion according to claim 12, characterized in that the polymer or polymers are selected from the group consisting of polyethylene glycols, polypropylene glycols, cellulose ethers, polyvinylpyrrolidones, polyvinyl acetates, copolymers and mixtures thereof.

14. Solid solution or solid dispersion according to claim 12 or 13, characterized in that the polymer or polymers are selected from the group consisting of copolymers of polyethylene glycols and polypropylene glycols, methyl cellulose, ethyl cellulose, propyl cellulose, carboxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, KoHidonen ^® , Mixed polymers of polyvinylpyrrohdon and polyvinyl acetate as well as polyethylene glycols with different chain lengths.

15. Solid solution or solid dispersion according to one of claims 10 to 15, characterized in that the polymer matrix is a poloxamer.

16. A process for the preparation of the pharmaceutical formulation according to any one of claims 1 to 9 or the solid solution or solid dispersion according to any one of claims 10 to 15, comprising the steps of: (1) melting a polymer or a mixture of polymers; (2) dissolving or dispersing an active ingredient, selected from the LTB ₄ antagonists of the formula I, in the melt; (3a) pouring the melt into suitable molds and allowing the melt to cool while cooling; or (3b) allowing the solid solution or solid dispersion obtained to solidify with cooling and then comminuting the solid solution or solid dispersion obtained into suitable molds.

17. The method according to claim 16, characterized in that the active ingredient in step (2) is used in crystalline, unmilled or ground form, in particular in jet-ground form.

18. The method according to claim 16 or 17, characterized in that the active ingredient is used in step (2) sieved.

19. The method according to any one of claims 16 to 18, characterized in that the active ingredient used in step (2) has an average particle size of approximately 1 μm to approximately 7 μm, in particular approximately 1.5 μm to approximately 3 μm.

20. The method according to claim 16, characterized in that the grinding in step (3b) is carried out by grinding.

21. The method according to claim 20, characterized in that is sieved after grinding.

22. The method according to claim 16, characterized in that the products obtained after step (3a) or (3b) are filled into capsules.

23. A process for the preparation of the pharmaceutical formulation according to one of claims 1 to 9 or the solid solution or solid dispersion according to one of claims 10 to 15 with a melt extrusion process.

24. Use of a pharmaceutical formulation according to any one of claims 1 to 9 for the manufacture of a pharmaceutical for the treatment or prevention of diseases in which LTB ₄ antagonists can be used therapeutically or preventively.

25. Use of a pharmaceutical formulation according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment or prevention of arthritis, asthma, chronic obstructive pulmonary diseases, psoriasis, ulcerative colitis, Alzheimer's disease, shock, reperfusion damage / ischemia, cystic fibrosis, arteriosclerosis and Multiple sclerosis.