Patent Application
20100087488
The invention relates to new salt forms of the active substance ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]propionate, the polymorphs, the enantiomers, the mixtures and the hydrates thereof. This active substance with the chemical formula
is already known from WO 98/37075, wherein compounds with a thrombin-inhibiting and thrombin time-prolonging activity are disclosed, under the name 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide. The compound of formula (I) is also known as BIBR 1048. The compound of formula I is a double prodrug of the compound
i.e. the compound of formula I is first converted into the actual effective compound, namely the compound of formula II, in the body. The main type of indication for the compound of chemical formula I is the post-operative prophylaxis of deep vein thrombosis and the prevention of strokes.
The aim of the invention is to prepare new salts of the compound of formula I with advantageous properties for pharmaceutical use.
In addition to being effective for the desired indication, an active substance must also conform to additional requirements in order to be allowed to be used as a pharmaceutical composition. These parameters are to a large extent connected with the physicochemical nature of the active substance.
Without being restrictive, examples of these parameters are the stability of effect of the starting material under various environmental conditions, stability during production of the pharmaceutical formulation and stability in the final medicament compositions. The pharmaceutically active substance used for preparing the pharmaceutical compositions should therefore have a high stability which must be guaranteed even under various environmental conditions. This is absolutely essential to prevent the use of pharmaceutical compositions which contain, in addition to the actual active substance, breakdown products thereof, for example. In such cases the content of active substance in pharmaceutical formulations might be less than that specified.
The absorption of moisture reduces the content of pharmaceutically active substance on account of the weight gain caused by the uptake of water. Pharmaceutical compositions with a tendency to absorb moisture have to be protected from damp during storage, e.g. by the addition of suitable drying agents or by storing the medicament in a damp-proof environment. In addition, the uptake of moisture can reduce the content of pharmaceutically active substance during manufacture if the medicament is exposed to the environment without being protected from damp in any way. Preferably a pharmaceutically active substance should therefore have only limited hygroscopicity.
As the crystal modification of an active substance is important to the reproducible active substance content of a preparation, there is a need to clarify as far as possible any existing polymorphism of an active substance present in crystalline form. If there are different polymorphic modifications of an active substance care must be taken to ensure that the crystalline modification of the substance does not change in the pharmaceutical preparation later produced from it. Otherwise, this could have a harmful effect on the reproducible potency of the drug. Against this background, active substances characterised by only slight polymorphism are preferred.
Another criterion which may be of exceptional importance under certain circumstances depending on the choice of formulation or the choice of manufacturing process is the solubility of the active substance. If for example pharmaceutical solutions are prepared (e.g. for infusions) it is essential that the active substance should be sufficiently soluble in physiologically acceptable solvents. It is also very important for drugs which are to be taken orally that the active substance should be sufficiently soluble.
The problem of the present invention is to provide a pharmaceutically active substance which not only is characterised by high pharmacological potency but also satisfies the above-mentioned physicochemical requirements as far as possible.
Surprisingly it has now been found that the salt forms of the compound of formula I (dabigatran etexilate) according to the invention, the polymorphs, the enantiomers, mixtures and hydrates thereof, meet these requirements and have thus advantageous properties.
The invention therefore relates to the salts of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate with the inorganic and organinc acids listed in table I as “used acid”, as well as the polymorphs, the enantiomers, mixtures, solvates and hydrates thereof. The invention further relates to pharmaceutical compositions containing at least of one of the above-mentioned salts, their polymorphs, hydrates, solvates or co-crystals, and methods of preparing these pharmaceutical compositions which are suitable for the prevention of venous thromboses and stroke.
The salts according to the invention and also ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate in the form of the free base and as a salt with methanesulphonic acid are also suitable for the treatment and prevention of deep vein thromboses in patients with heparin-induced thrombocytopenia and for the prevention of thrombosis in patients with intraarterial or intravenous lines or catheters as well as AV shunts.
The starting compound ethyl 3-[(2-{[4-(amino-hexyloxycarbonylimino-methyl)-phenyl-amino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate (BIBR 1048) may for example be prepared as described in International Application WO 98/37075, Example 113.
Approx. 750 mg of the free base of BIBR 1048 are dissolved in 10 ml of a mixture of acetone/tetrahydrofuran=80:20. 96 well plates were charged by dosing first this concentrated solution of the free base of BIBR 1048 in acetone/tetrahydrofuran=80:20 and than the respective acids dissolved in water or acetone/tetrahydrofuran=80:20 (for saccharin and salicylic acid). The ratio of BIBR 1048 BS to the respective acid was kept 1:1 for all used acids (see Table I). The plates containing the stock solution were placed in a vacuum chamber (1 kPa) at room temperature for 24 h in order to remove the stock solvent. Afterwards different solvents were added according to table I and the whole 96 well plate is sealed afterwards and heated up with a heating rate of approx. 5° C./min to 50° C. at which the plate stays for an additional 30 minutes. Afterwards the plate is cooled with a cooling rate of 1° C./h, 2° C./h, 3° C./h or 30° C./h to a final temperature of 3, 5, 20 or 25° C. At this temperature the plate remained for a holding time of 1 h, 24 h or 72 h. The plates are opened afterwards and the solids were obtained by filtration.
Analytics:
The harvested crystals were analysed by X-ray powder diffraction and thermal analysis (DSC and in some cases also TGA). The following equipment was used:
X-Ray Powder Diffraction (=XRPD):
XRPD patterns were obtained using a high throughput XRPD set-up. The plates were mounted on a Bruker GADDS diffractometer equipped with a Hi-Star area detector. The diffractometer was calibrated using Silver Behenate for the long d-spacings and corundum for the short d-spacings.
The data collection was carried out at room temperature using monochromatic CuKα radiation in the region of 20 between 1.5 and 41.5°. The diffraction pattern of each well was collected with an exposure time of 3-4 minutes.
Thermal Analysis (DSC and TGA):
Melting properties were obtained from differential scanning calorimetry (=DSC) thermograms recorded on a DSC822e (Mettler-Toledo GmbH, Switzerland). The DSC822e was calibrated for temperature and enthalpy with a small piece of indium (Tfus=156.6° C., ΔHfus=28.45 J/g). Samples were sealed in standard 40 μl aluminium pans and heated in the DSC from 25 to 300° C. with a heating rate of 20° C./min. Dry nitrogene gas was used to purge the DSC equipment during measurements at a flow rate of 50 ml/min.
The melting temperature used was the onset temperature of the corresponding melting peak in the DSC diagram. The accuracy of the melting points given is about ±3° C.
The mass loss due to solvent or water loss from the crystals was determined by thermo garvimetric analysis (=TGA). During heating of a sample in a TGA/SDTA851e (Mettler-Toledo GmbH, Switzerland) the weight of the sample was monitored resulting in a weight vs. temperature curve. The TGA/SDTA851e was calibrated for temperature with indium and aluminium. Samples were weighed in 100 μl corundum crucibles and heated in the TGA from 25 to 300° C. with a heating rate of 20° C./min. Dry nitrogene gas was used for purging.
Dry Ampoule Containing 75 mg Active Substance Per 10 ml
Composition:
Preparation:
Active substance and mannitol are dissolved in water. After packaging the solution is freeze-dried. To produce the solution ready for use for injections, the product is dissolved in water.
Dry ampoule containing 35 mg of active substance per 2 ml
Composition:
Preparation:
Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried.
To produce the solution ready for use for injections, the product is dissolved in water.
Tablet containing 50 mg of active substance
Composition:
Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 9 mm.
Tablet containing 350 mg of active substance
Composition:
Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 12 mm.
Capsules containing 50 mg of active substance
Composition:
Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.
Capsules containing 350 mg of active substance
Composition:
Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 0 hard gelatine capsules in a capsule filling machine.
Suppositories containing 100 mg of active substance
1 suppository contains:
The preparation and the structure of the pellets according to Examples H and I is described in detail in WO 03/074056.
| Number | Date | Country | Kind |
|---|---|---|---|
| 06122047.1 | Oct 2006 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2007/060711 | 10/9/2007 | WO | 00 | 12/15/2009 |
