CA2452357A1

CA2452357A1 - Pharmaceutical formulation containing an ltb4 antagonist

Info

Publication number: CA2452357A1
Application number: CA002452357A
Authority: CA
Inventors: Thomas Bock; Robert Becker; Achim Sauer; Rene Roscher; Ulrich Roth; Siglinde Moll; Karl Weber; Anja Kohlrausch
Original assignee: Individual
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2001-07-14
Filing date: 2002-07-09
Publication date: 2003-01-30
Also published as: UY27376A1; EP1408943B1; MXPA04000384A; PL368613A1; HUP0401371A3; ATE298564T1; KR100912196B1; HUP0401371A2; EP1408943A2; BR0211090A; RU2004102399A; WO2003007922A2; KR20040016988A; AU2002333235B2; NZ530973A; WO2003007922A3; IL159493A0; CN1298316C; ES2244821T3; CN1527705A

Abstract

The invention relates to a novel pharmaceutical formulation containing an LT B4 antagonist of formula (I), wherein A, R1, R2, R3 and R4 have the designation cited in claim 1. The invention also relates to the use of said formulation as a pharmaceutical.

Description

Case 111228-FF BOEHRINGER INGELHEIM PHARMA KG
78502fft.206 Pharmaceutical formulation containing an LTB4 antagonist The invention relates to a new pharmaceutical formulation containing an LTB4 antagonist which contains a benzamidine group, processes for the preparation thereof as well as the use thereof as a pharmaceutical composition.
Background to the invention LTB4 antagonists which contain a benzamidine group are compounds with pharmacologically to valuable properties. LTB4 antagonists may provide great therapeutic benefit, for example, in the treatment of treat arthritis, asthma, chronic obstructive lung diseases, psoriasis, ulcerative colitis, Alzheimer's disease, shock, reperfusion damage/ischaemia, cystic fibrosis, atherosclerosis and multiple sclerosis.
Such compounds 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 and PCT/EPO 1 /00262 .
These compounds have the chemical structure of formula I:
R2 \ A \ NRr R3 ./ ~ .~ ( I ) R NHZ

wherein A denotes a group of formula -O-CmH~m-O-(PHE)n- ( II
wherein m is an integer from 2 to 6, preferably 2 to 5, nis0orl, PHE denotes a 1,4-phenylene group optionally substituted by one or two C1-C6 alkyl groups, preferably a 1,4-phenylene group substituted by a CZ-C4 alkyl group in the ortho position linked to the oxygen;
or A denotes a group of formula O-CHZ ( III ) preferably of formula ( IIIA ) to Rl denotes H, OH, CN, CORIO, or CHO, preferably H or COORio;
RZ denotes H, Br, Cl, F, CF3, CHFz, OH, HS03-O, C1-C6-alkyl, C1-C6-alkoxy, CS-C7-cycloalkyl, CONRgR9, aryl, O-aryl, CH2-aryl, CRSI26-aryl, or C(CH3)2-R7, preferably OH, HS03-O, CONRsR9 or CRSRb-aryl, R3 denotes H, C1-C6 -alkyl, Ci -C6-alkoxy, OH, Cl or F, preferably H or C1-C3-alkoxy, R4 denotes H or CI-C6-alkyl, preferably H;

RS denotes Ci-C4-alkyl, CF3, CHZOH, COOH or COO(C1-C4-alkyl), preferably C1-C4-alkyl, particularly methyl;

R6 denotes H, C1-C4-alkyl or CF3, preferably C1-C4-alkyl, particularly methyl;

2o R~ denotes CH20H, COOH, COO(C1-Ca-alkyl), CONR8R9 or CH2NR8R9;

Rg denotes H, C1-C6-alkyl, phenyl, phenyl-(C1-C6-alkyl), CORIO, COORIO, CHO, CONH2, CONHRIO, SOZ-(Cl-C6-alkyl), SOZ-phenyl, while the phenyl group may be mono- or disubstituted by Cl, F, CF3, Cl-Ca-alkyl, OH and/or Cl-C4-alkoxy, and preferably denotes C1-C4-alkyl, particularly isopropyl;

R9 denotes H or C1-C6-alkyl, preferably H or C1-C4-alkyl, particularly isopropyl;

or Rg and R9 taken together represent a C4-C6-alkylene group;
Rlo denotes C1-C6-alkyl, CS-C7-cycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl-(C1-C6-alkyl), preferably Ci-Ca-alkyl, while the aryl groups mentioned in groups RZ and Rlo denote phenyl or naphthyl, the heteroaryl groups denote pyrrole, pyrazole, imidazole, furanyl, thienyl, pyridine or pyrimidine and may each be mono- or polysubstituted by Cl, F, CF3, C1-C4-alkyl, OH, HS03-O or Ci-C4-alkoxy, preferably by OH or HS03-O-.
The aim of the present invention is to provide an orally administered pharmaceutical formulation which releases an active substance of formula I relatively fast and completely and thus leads to greater bioavailability of this active substance. A further object of the present invention is to prepare a formulation which is characterised by ease of handling during the to preparation process and thus can be produced industrially in a reproducible manner while maintaining a constant high quality.
Detailed description of the invention The objective stated above are solved by the formulation described in detail hereinafter.
The present invention relates to a tablet containing a compound of formula I
which contains a compound of formula I, the pharmacologically acceptable acid addition salts thereof and 2o glucuronides, and at least one pharmacologically acceptable excipient, the tablet containing at least one wetting agent.
A further aim is the use of a tablet according to one of claims 1 to 14 for preparing a pharmaceutical composition with increased bioavailability for the treatment or prevention of diseases in which LTB4 antagonists can be used therapeutically or preventively.
The active substance of formula I may be present in the formulation according to the invention in the form of a physiologically acceptable acid addition salt. By physiologically acceptable acid addition salts are meant, according to the invention, pharmaceutically 3o acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and malefic acid. Mixtures of the above acids may also be used to prepare the salts. According to the invention, the preferred salts of formula I

are selected from among the hydrochloride, hydrobromide, sulphate, phosphate, fumarate and methanesulphonate. The salts selected from among the hydrochloride, hydrobromide and fumarate are particularly preferred. The active substance may optionally be in the form of a hydrate. Preferably, according to the invention, the compound of formula I is added to the tablet in the form of the free base and in the anhydrous form.
Particularly preferred compounds of formula I are the compounds of formulae IA, IB and IC, particularly IA:
HsC CHs \ ~ \
HO / / O ~ / 0 \
NHz N\ /OCZHS
~,,(O
(IA) OH
/
~z NH
) O
i-C3H~~ \ O O \
N
i_C3H~ ~ / O ~ / NHz I I

(IC) The compounds of formula I wherein R1 is different from hydrogen are generally prodrugs which are converted in vivo into the corresponding compounds of formula I
wherein R1 is hydrogen.
For example, from the compound IA is formed in vivo the compound of formula IA1:

\ ~ \
X / / O ( / O \

NH
(IA1) wherein X denotes OH, HS03-O or a carbohydrate group of formula C6HuOs-O-.
to Preferably, the active substance is used in crystalline, unground form or in ground form, particularly in jet-ground form, wherein the particle size distribution is within the following limits: Dlo <_ 3 Vim, DSO 3 to 8 Vim, D9o 5 8 to 30 Vim. The abovementioned numerical data for Dio, DSQ and D9o in ~m (microns) are the particle size ranges within which a throughput total of 10 vol.%, 50 vol.% or 90 vol.% of the particles measured (cumulative volume distribution) ~s is achieved. These values were determined by the laser diffractometry method, specifically, in the present instance, using a so-called dry dispersion under a dispersion pressure of 2 bar and with a focal length f = 500 mm, e.g. using a Sympatec/RODOS apparatus. This methodology is known in the prior art.
2o Where reference is made to salts of the compounds of formula I within the scope of the present invention, this is indicated by the symbol I~. Explicit references to the free base of formula I, on the other hand, are indicated by the use of the symbol I.
In relation to the total mass of the tablets according to the invention the compound of formula 25 I, particularly IA is present in an amount of up to 0.2 to 80 wt.%, preferably 0.7 to 40 wt.%, more preferably about 5 to 38 wt.%. Particularly preferably, the content of the free base of I is between 6 and 36 wt.% based on the total mass of the tablet.

The term "wetting agent" as used hereinbefore and hereinafter denotes an excipient which lowers the surface tension of water or other liquids so that they can penetrate into the surfaces of the tablets according to the invention and soak through them, displacing the air, thereby wetting them. The substances used as wetting agents are usually interface-active surfactants.
These surfactants are amphiphilic (bifunctional) compounds with at least one hydrophobic and one hydrophilic part of the molecule. The hydrophobic group is usually a hydrocarbon chain, if possible a straight chain, with eight to 22 carbon atoms. Particular surfactants may also have (dimethyl)-siloxane chains or perfluorinated hydrocarbon chains as the hydrophobic 1o part of the molecule. The hydrophilic group is either a negatively or positively charged (hydratable) or a neutral polar head group. Of the surfactants, anionic surfactants, particularly the long-chain alkylsulphates, especially sodium laurylsulphate and alkylbenzenesulphonates are preferred.
According to the invention, the weight ratio between the components, namely wetting agent and active substance I , contained in the tablet is in a range from about 1:200 to about 1:5, preferably between about 1:150 and about 1:10.
The phamaceutical formulation according to the invention contains in addition to the active 2o substance at least one excipient as a filler/dry binder.
Within the scope of the present invention carbohydrates such as lactose or mannose, particularly finely divided lactose or sugar alcohols such as mannitol, sorbitol or xylitol, particularly mannitol, are of particular importance as excipients. These excipients have proved particularly advantageous in the formulation according to the invention. In a preferred aspect, therefore, the present invention relates to a tablet containing at least one compound of formula I, which contains, in addition to the active substance and the wetting agent, lactose, particularly finely divided lactose; more preferably lactose monohydrate or mannitol as excipient.
According to the invention the weight ratio between the components lactose or mannitol to active substance I contained in the tablet is in a range from about 20:1 to about 1:4.
Preferably, the ratio of lactose to I is in a range from about 1.8: I to about 1:1.2, more preferably in a range from about 1.4:1 to I .6:1. Preferably, the proportion by weight of lactose based on the total mass of the tablet according to the invention is in a range of about I - 70 wt.%, preferably about 2 - 60 wt.%.
Preferably, the ratio of mannitol to I is in a range of about 20:1 to about 1:2, more preferably in a range of about 15:1 to 3:1. Preferably the proportion by weight of mannitol based on the total mass of the tablet according to the invention is in a range of about 20 -90 wt.%, preferably between about 40 - 75 wt.%.
1o The tablet according to the invention may also contain, in addition to lactose, wetting agent and active substance, further excipients or fillers. According to the invention, it is preferable to use compounds capable of acting as binders.
The term "binder" used hereinbefore and hereinafter denotes excipients which are suitable for binding other components to one another. Preferred binders according to the invention are selected from among:
powdered cellulose, microcrystalline cellulose, sorbitol, starch, polyvinylpyrrolidone (povidone), copolymers of vinylpyrrolidone with other vinyl derivatives (copovidone), cellulose derivatives, particularly methylhydroxypropylcellulose, e.g.
Methocel A IS LV, and 2o mixtures of these compounds. The preferred binders are powdered cellulose, particularly microcrystalline cellulose and/or copovidone. Most preferred is a mixture of microcrystalline cellulose and a copolymer of vinylpyrrolidone and vinyl acetate, namely copovidone VA 64, the ratio of vinylpyrrolidone and vinyl acetate being about 3:2 (m/m). As a rule the tablet according to the invention has a weight ratio of microcrystalline cellulose to copovidone VA
64 of 20:1 to 1: I, preferably 15:1 to 2:1, particularly about 10:1 to 3:1.
Thanks to this particularly preferred binder combination of microcrystalline cellulose and copovidone, tablets are obtained having a high bioavailability of the compounds of formula I.
If one of the abovementioned binders is added to the formulation according to the invention, 3o the weight ratio of lactose to binder is preferably about 10:1 to about 1:2, preferably about 5:1 to about 1:1, more preferably about 4.5:1 to 3.5:2.

_$_ If one of the abovementioned binders is added to the formulation according to the invention, the weight ratio of mannitol to binder is preferably about 10:1 to about 1:2, preferably about 5:1 to about 1:1, more preferably about 3.5:1 to 3.0:1.
s The tablet according to the invention may also contain disintegrants in addition to the abovementioned ingredients. Within the scope of the present invention these disintegrants may optionally also be known as breakdown agents. These are preferably selected, according to the invention, from among sodium starch glycolate, crosslinked polyvinylpyrrolidone (crospovidone), croscarmellose sodium salt (sodium salt of cellulose carboxymethyl ether, to crosslinked), sodium-carboxymethylcellulose (?), dried maize starch and mixtures thereof.
Within the scope of the present invention it is particularly preferred to use sodium starch glycolate, crospovidone and, preferably, the sodium salt of crospovidone or croscarmellose.
If the abovementioned disintegrants are used, the amount by weight, based on the total mass of the tablet according to the invention, is preferably in a range of about 0.5 - 10 wt. %, more 15 preferably about 1.5 -7.5 wt.%.
The tablet according to the invention may also contain flow agents or flow regulators and also lubricants, as additional ingredients. These include, within the scope of the present invention, for example, silicon dioxide, talc, stearic acid, sodium stearylfumarate, magnesium stearate 2o and glycerol tribehenate. According to the invention magnesium stearate is preferably used. If the abovementioned flow agents or flow regulators or lubricants are used, the amount by weight thereof, based on the total mass of the tablet according to the invention, is preferably in a range of about 0.1 - 10 wt.%, preferably about 0.5 - 5 wt.%, more preferably between 0.6 and 1.5 wt.%.
In addition, the tablet according to the invention may contain one or more synthetic or natural, pharmaceutically acceptable dyes or colourings, preferably indigo carmine. If the abovementioned colourings are used the amount by weight thereof based on the total mass of the tablet according to the invention is 0.01 to 0.5 wt.%.
Particularly preferred is a tablet consisting essentially of the following ingredients:
~ a compound of formula I, preferably 5 wt.% to 50 wt.%, particularly 6 wt.%
to 45 wt.% of a compound of formula IA;

~ microcrystalline cellulose, preferably 0., wt.% to 25 wt.%, particularly 5 wt.% to 20 wt.% microcrystalline cellulose;
~ lactose, preferably 15 wt.% to 80 wt.%, particularly 20 wt.% to 75 wt.%
lactose; or mannitol, preferably 20 wt.% to 90 wt.%, particularly 40 wt.% to 75 wt.%
mannitol;
~ optionally a copolymer of vinylpyrrolidone and vinyl acetate, preferably 0.2 wt.%
to 5 wt.%, particularly 0.5 wt.% to 2.5 wt.% of copovidone V64, ~ sodium lauryl sulphate, preferably 0.01 wt.% to 10 wt.%, particularly 0.06 wt.%
to 7 wt. % of sodium lauryl sulphate;
to ~ crosslinked polyvinylpyrrolidone, preferably 0.4 wt.% to 8 wt.%, particularly 0.8 wt.% to 6 wt.%; or crosslinked cellulose carboxymethylether sodium salt, particularly croscarmellose sodium salt;
~ magnesium stearate, preferably 0.1 wt.% to 5 wt.%, particularly 0.5 wt.% to 1.5 wt. % of magnesium stearate; and ~ optionally a colouring.
The tablet according to the invention may be prepared by directly mixing and compressing the ingredients or by granulation and compression. To prepare the tablet according to the invention the following procedure may be used, for example.
The active substance of formula I, the wetting agent and optionally a copolymer of vinylpyrrolidone and vinyl acetate as binder are dissolved or suspended in water, granulated with the excipients, particularly lactose monohydrate and optionally microcrystalline cellulose as an additional binder, screened and then dried. The product obtained is optionally mixed with the flow agent, particularly magnesium stearate and screened. Then a disintegrant, particularly crospovidone, is optionally added. The mixture of active substance and excipient thus obtained is then compressed in a suitable tablet press to form the tablets according to the invention.
3o The compression forces which are needed to produce tablets of suitable breaking resistance and hence with the required breakdown times are dependent on the shapes and sizes of the punching tools used. Compression forces in the range from 2 - 20 kN are preferred. Higher compression forces may lead to tablets with a delayed released of active substance. Lower compression forces rnay produce mechanically unstable tablets. The tablet cores may have different shapes; the preferred shapes are round biplanar or biconvex and oval or oblong forms.
The Examples that follow serve to illustrate some formulations according to the invention.
They are intended solely as possible procedures described by way of example, without restricting the invention to their content.

Example 1:
r Ingredients mg/tablet volatile part (O1) compound IA, jet-ground 75,000 (02) microcrystalline cellulose 22,500 (03) lactose 114,560 (04) copovidone VA 64 3,750 (05) sodium laurylsulphate 0,750 (06) water 39,000 (07) crospovidone 6,750 (08) magnesium stearate 1,690 225,000 39,000 Preparation (variant 1) 1 batch = 2992.5 g = 13,300 tablets 1. Premix In a suitable intensive mixer, e. g. Diosna P 10, 997.500 g of j et-ground compound of formula IA, 299.250 g of rnicrocrystalline cellulose and 1523.648 g of lactose monohydrate are mixed for 3 minutes.
2. Granulating liquid 518,700 g of water are placed in a suitable container. 49,875 g of copovidone VA 64 are slowly stirred in using a suitable stirrer. After the povidone VA 64 has dissolved, 9.975 g of sodium laurylsulphate are stirred in.
3. Granules After the addition of the granulating liquid 2. using a liquid funnel the premix 1. is mixed wet and granulated in an intensive mixer.
Moist screening 2o The moist granules thus produced are moist screened with a suitable screening machine, e.g.
Erweka AR401, with a mesh size of 1.6 mm .

in In a suitable drying cupboard, e.g. a WTB Binder, the granules are dried for 10 hours in a layer thickness of about 1 cm at a temperature of 50°C.
Dry screening Using a suitable screening machine, e.g. Erweka AR401, the dried granules are dry-screened with a mesh size of 0.8 mm.
4. Final mixture to In a suitable container with a suitable mixer, e.g. an Rm 100 gyrowheel mixer, 2880.248 g of the screened granules 3. are added to 89.775 g of crospovidone at 30 rpm and the components are homogeneously mixed for 10 minutes. Then 22.477 g of magnesium stearate are added to the mixture and it is homogeneously mixed for 5 minutes.
5. Tablet making In a suitable tablet press, e.g. EK 0 (pressing tool: 9 mm with radius of convexity of 13.5 mm and faceted), 2992.500 g of the final mixture 4. are compressed at a compression speed of 25 tablets./min. to produce tablets weighing 225 mg each.
2o The tablets thus obtained have the following properties:
weight 225 mg diameter 9 mm height about 3.6 mm breaking strength 100 N

(n = IO hrs) disintegration < 8 minutes friability - abrasion < 0.5 Example Z:
Ingredients mg/tablet volatile part (O1) compound IA, jet-ground 75,000 (02) microcrystalline cellulose 22,500 (03) fine lactose 114,560 (04) copovidone VA 64 3,750 (05) sodium laurylsulphate 7,500 (06) water 39,000 (07) crospovidone 6,750 (08) magnesium stearate 1,740 231,800 39,000 The tablets are prepared analogously to Example 1. The tablets obtained have comparable physical data.
Example 3:
Ingredients mg/tablet volatile part (O1)compound IA, jet-ground 75,000 (02)microcrystalline cellulose 68,250 (03)fine lactose 68,250 (04)Methocel A 15 LV 3,750 (05)sodium laurylsulphate 0,750 (06)water 39,000 (07)crospovidone 6,750 (08)magnesium stearate 2,250 225,000 39,000 The tablets are prepared analogously to Example 1. The tablets obtained have comparable physical data, but lower hardness and a slower rate of dissolution.

Example 4:
Ingredients mg/tablet volatile part (O1) compound IB, jet-ground 75,000 (02) microcrystalline cellulose 22,500 (03) fine lactose 114,560 (04) copovidone VA 64 3,750 (05) sodium laurylsulphate 0,750 (06) water 39,000 (07) crospovidone 6,750 (08) magnesium stearate 1,690 225,000 39,000 The tablets are prepared analogously to Example 1. T'he tablets obtained have comparable physical data.
Example 5:
Ingredients mg/tablet volatile part (O1)compound IC, jet-ground 75,000 (02)microcrystalline cellulose 22,500 (03)fine lactose 114,560 (04)copovidone VA 64 3,750 (05)sodium laurylsulphate 0,750 (06)water 39,000 (07)crospovidone 6,750 (08)magnesium stearate 1,690 225,000 39,000 to The tablets are prepared analogously to Example 1. The tablets obtained have comparable physical data.

Example 6 Ingredients mg/tablet volatile part (O1) compound IA, jet-ground 75,000 (02) microcrystalline cellulose 22,500 (03) lactose 114,560 (04) copovidone VA 64 3,750 (05) sodium laurylsulphate 0,750 (06) water 39,000 (07) crospovidone 6,750 (08) magnesium stearate 1,690 225,000 39,000 Preparation (variant 2) 1. Premix In a suitable one-pot granulator, e.g. Zanchetta Roto P 50, 4.6500 kg of jet-ground compound of formula IA, 1.3950 kg of microcrystalline cellulose, 7.1028 kg lactose and 0.4185 kg crospovidone are mixed for 3 minutes.
to 2. Granulating liquid 2.1762 kg of water (corresponding to 90% of the quantity in process 1) are placed in a suitable container. 0.2325 kg of copovidone VA 64 are slowly stirred in using a suitable stirrer. After the povidone VA 64 has dissolved, 0.0465 kg of sodium laurylsulphate are stirred in.
3. Granules After the addition of the granulating liquid the premix 1. is mixed wet and granulated in a one-pot granulator.
D in The granules are dried for 50 minutes in a one-pot granulator at a temperature of 49°C.

Dry screening Using a suitable screening machine, e.g. Comil 197 S, the dried granules are dry-screened with a mesh size of RS 2007.
4. Final mixture In a suitable gravity mixer, e.g. Servolift Kubus 601, 13,8453 kg of the screened granules 3.
and 0.1047 kg magnesium stearate are homogeneously mixed at 10 rpm for 5 minutes.
5. Tablet making to In a suitable tablet press, e.g. Fette P 1200 (pressing tool: 9 mm with radius of convexity of 13.5 mm and faceted), 13.9500 kg of the final mixture 4. are compressed at a compression speed of 100,000 tablets./hr to produce tablets weighing 225 mg each.
Example 7 Ingredients mg/tablet (0l)compound IA, jet-ground 5,000 (02)microcrystalline cellulose 15,000 (03)mannitol 52,250 (04)croscarmellose sodium 1,500 (05)sodium laurylsulphate 0,050 (06)indigo carmine (11-14 %) 0,075 (07)magnesiumstearate 1,125 75,000 The direct compression comprises producing a premix of ingredients (O1), (05), (06) and some of (03) with a Diosna~ intensive mixer. The premix is screened and mixed with 2o ingredients (02), (04) and the remainder of (03) in a Turbula~ gravity mixer. After the mixture has been screened again, ingredient (07) is added. A corresponding flow diagram is shown in Figure 2.

Biconvex tablets 6 mm thick with rounded edges, containing 5 mg of the compound of formula IA with a total weight of 75 mg are compressed Example 8 The tablets of Examples 1 to 3 according to the invention are administered to healthy male subjects by oral route in a single dose. The plasma concentration of the active substance is determined from time to time. The mean data thus obtained are shown graphically in Figure 1.
1o In Fig. 1 the blood plasma concentration in ng/ml of the glycoside of the compound of fomlula IA1 produced in vivo from the compound of formula IA is plotted against the time in hours. According to this, the highest concentration of active substance in the plasma is obtained with the tablet according to Example 1.
The symbols used in Fig. 1 have the following meanings:
tablet of Example 1 D . tablet of Example 2 -O-. tablet of Example 3

Claims

1. Pharmaceutical formulation in the form of a tablet containing an LTB4 antagonist of formula I, wherein A denotes a group of formula -O-C m H2m-O-(PHE)n- (II) wherein m is an integer from 2 to 6, n is 0 or 1, PHE denotes a 1,4-phenylene group optionally substituted by one or two C1-C6 alkyl groups;
or A denotes a group of formula R1 denotes H, OH, CN, COR10, or CHO;
R2 denotes H, Br, Cl, F, CF3, CHF2, OH, HSO3-O, C1-C6-alkyl, C1-C6-alkoxy, C5-C7-cycloalkyl, CONR8R9, aryl, O-aryl, CH2-aryl, CR5R6-aryl, or C(CH3)2-R7, R3 denotes H, C1-C6 -alkyl, C1 -C6-alkoxy, OH, Cl or F, R4 denotes H or C1-C6-alkyl;
R5 denotes C1-C4-alkyl, CF3, CH2OH, COOH or COO(C1-C4-alkyl);
R6 denotes H, C1-C4-alkyl or CF3;
R7 denotes CH2OH, COOH, COO(C1-C4-alkyl), CONR8R9 or CH2NR8R9;
R8 denotes H, C1-C6-alkyl, phenyl, phenyl-(C1-C6-alkyl), COR10, COOR10, CHO, CONH2, CONHR10, SO2-(C1-C6-alkyl), SO2-phenyl, while the phenyl group may be mono- or disubstituted by Cl, F, CF3, C1-C4-alkyl, OH and/or C1-C4-alkoxy;
R9 denotes H or C1-C6-alkyl; or R8 and R9 taken together represent a C4-C6-alkylene group;
R10 denotes C1-C6-alkyl, C5-C7-cycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl-(C1-C6-alkyl), while the aryl groups mentioned in groups R2 and R10 denote phenyl or naphthyl, the heteroaryl groups denote pyrrole, pyrazole, imidazole, furanyl, thienyl, pyridine or pyrimidine and may each be mono- or polysubstituted by Cl, F, CF3, C1-C4-alkyl, OH, HSO3-O or C1-C4-alkoxy, as well as the pharmacologically acceptable acid addition salts and glycosides and 0-sulphates thereof;
and at least one pharmacologically acceptable excipient, characterised in that the tablet contains at least one wetting agent.

2. Tablet according to claim 1, characterised in that the LTB4 antagonist is a compound selected from among formulae IA, IB and IC:

3. Tablet according to one of claims 1 or 2, characterised in that the wetting agent is an anionic surface-active substance.

4. Tablet according to one of claims 1 to 3, characterised in that the wetting agent is sodium laurylsulphate.

5. Tablet according to one of claims 1 to 4, characterised in that it contains lactose or mannitol as excipient.

6. Tablet according to one of claims 1 to 5, characterised in that it additionally contains at least one dry binder, at least one lubricant, at least one disintegrant and/or at least one separating agent and optionally a colouring.

7. Tablet according to claim 6, characterised in that the dry binder is selected from among powdered cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, copolymers of vinylpyrrolidone with other vinyl derivatives, cellulose derivatives and mixtures of these compounds.

8. Tablet according to claim 6 or 7, characterised in that the dry binder is microcrystalline cellulose or a mixture of microcrystalline cellulose and a copolymer of vinylpyrrolidone and vinyl acetate.

9. Tablet according to one of claims 1 to 8, characterised in that it contains 0.2 to 80 wt.%, preferably 0.7 to 40 wt.% of a compound of formula I.

10. Tablet according to one of claims 1 to 9, characterised in that the weight ratio between the wetting agent and the active substance of formula I is in a range of about 1 : 200 to about 1 : 5, preferably between about 1 : 150 to about 1 : 10.

11. Tablet according to one of claims 5 to 10, characterised in that the weight ratio between lactose or mannitol and the active substance of formula I is in the range from about 20 :
1 to about 1 : 4, preferably about 12 : 1 to about 1 : 1.2.

12. Tablet according to one of claims 5 to 11, characterised in that the weight ratio between lactose and the active substance of formula I is in the range from about 4 : 1 to about 1 :
4, preferably about 1.8 : 1 to about 1 : 1.2.

13. Tablet according to one of claims 5 to 11, characterised in that the weight ratio between mannitol and the active substance of formula I is in a range of about 20:1 to about 1:2, more preferably in a range of about 15:1 to 3:1.

14. Tablet according to one of claims 6 to 13, characterised in that the amount by weight of the disintegrant based on the total mass of the tablet is in a range from about 0.5 to 10 wt. %.

15. Tablet according to one of claims 5 to 14, characterised in that the amount by weight of the flow agent, lubricant and separating agent based on the total mass of the tablet is in a range from about 0.1 to 5 wt. %.

16. Tablet according to one of claims 1 to 15, characterised in that it consists essentially of the following ingredients:
.cndot. a compound of formula I;
.cndot. microcrystalline cellulose;
.cndot. lactose or mannitol;
.cndot. optionally a copolymer of vinylpyrrolidone and vinyl acetate;
.cndot. sodium laurylsulphate;

.cndot. crosslinked polyvinylpyrrolidone or a crosslinked cellulosecarboxymethylether sodium salt, particularly croscarmellose sodium salt;
.cndot. magnesium stearate; and .cndot. optionally a pharmaceutically acceptable colouring.

17. Process for preparing a tablet according to one of claims 1 to 16 [comprising]
(a) mixing a compound of formula I with a wetting agent and optionally other pharmacologically acceptable excipients, optionally in the presence of a volatile diluent;
(b) screening the mixture obtained;
(c) optionally adding a lubricant, and (d) compressing with a suitable tablet press.

18. Use of a tablet according to one of claims 1 to 16 for preparing a pharmaceutical composition for the treatment or prevention of diseases in which LTB4 antagonists can be used therapeutically or preventively.

19. Use of a tablet according to one of claims 1 to 16 for preparing a pharmaceutical composition for the treatment or prevention of arthritis, asthma, chronic obstructive pulmonary diseases, psoriasis, ulcerative colitis, Alzheimer's disease, shock, reperfusion damage/ischaemia, cystic fibrosis, atherosclerosis and multiple sclerosis.