EP1663209A1 - Novel orally administered dosage form for 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-ethyl proprionate and salts thereof - Google Patents

Abstract

The invention relates to a novel orally administered dosage form for the active substance 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-ethyl proprionate and pharmacologically compatible salts thereof.

Description

New oral dosage form for 3 - [(2 - {[4- (hexyloxycarbonyi-amino-imino-methyl) -phenylamino] -methyl} -1-methyl-1H-benzimidazol-5-carbonyl) -pyridin-2-yl -amino] -prop (onsäurΘ-ethyl ester and its salts

The invention relates to an oral administration form for the active ingredient 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl} -1-methyl-1 H -benzimidazole-5-carbonyl) -pyridine -2-yl-amino] -propionic acid ethyl ester and its pharmacologically acceptable salts. This active ingredient with the chemical formula

is already from WO 98/37075, in which compounds with a thrornbin-inhibiting and thrombin-prolonging effect are disclosed, under the name 1-methyl-2- [Λ / - [4- (Λ / -n-hexyloxycarbonylamidino ) phenyl] -amino-methyl] -benz-imidazol-5-yl-carboxylic acid / V- (2-pyridyl) -Λ / - (2-ethoxycarbonylethyl) amide. The compound of formula I is a double prodrug of the compound

ie the compound of formula I is only converted into the actually active compound, namely the compound of formula II, in the body. Main indication of the connection of chemical forms! I is the postoperative prophylaxis of deep vein thrombosis. The object of the invention is to provide an improved formulation for oral use for the compound of the formula I and its pharmacologically tolerable salts (hereinafter also referred to as “active ingredient”).

Surprisingly, it has now been found that an anhydrous formulation which contains the active ingredient 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl} - 1 -methyl- I fy-benzimidazole-δ-carbony - pyridine ^ -yl-aminol-propionic acid ethyl ester or one of its pharmaceutically acceptable salts in dispersed form in a lipophilic, pharmaceutically acceptable carrier system, leads to oral dosage forms which have significantly better properties. The carrier system can be either solid, semi-solid or liquid his.

The dosage form according to the invention comprises 5 to 40% by weight of the active ingredient, 55 to 95% by weight of a pharmaceutically acceptable, lipophilic carrier system and optionally 0 to 5% by weight of one or more stabilizers, the total amount of the ingredients being 100 Add% by weight.

A dosage form with stabilizer is preferred.

A preferred dosage form according to the invention comprises 8 to 40% by weight of the active ingredient, 60 to 92% by weight of a pharmaceutically acceptable, lipophilic carrier system and optionally 1 to 4% by weight of one or more stabilizers, the amounts of the ingredients increasing add a total of 100% by weight.

A particularly preferred dosage form according to the invention comprises 16 to 36% by weight of the active ingredient, 61 to 81% by weight of a pharmaceutically acceptable, lipophilic carrier system and, if appropriate, 2 to 3% by weight of one or more stabilizers, the amounts of the ingredients totaling Add 100% by weight. The finished formulation can be filled into hard or soft capsules, for example made of gelatin, hydroxypropylmethyl cellulose (HPMC), polulan, starch, modified starch, algae or other material that can be degraded in the gastrointestinal tract.

The active ingredient is 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] - methyl} -1-methyl-1 H -benzimidazole-5-carbonyl) -pyridin-2-yl-amino] - to understand ethyl propionate or one of its pharmaceutically acceptable salts; pharmaceutically acceptable salts of 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl} -1-methyl-1 rτ ^' -benzimidazole-5-carbonyl) -pyridine-2 are preferred -yl-amino] -propionic acid ethyl ester used. Particularly preferred is 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl} -1 - methyl-1 H-benzimidazole-5-carbonyl) -pyridin-2-yl- amino] propionic acid ethyl ester - methanesulfonate. The active ingredient can be ground before use. 3 - [(2 - {[4- (Hexyloxycarbonylamino-imino-methyl) -phenyl- ¹ amino] -methyi} -1-methyl-1 H -benzimidazol-5-carbonyl) -pyridin-2-yl is very particularly preferred -amino] -propionic acid ethyl ester - methanesulfonate in mined form.

The pharmaceutically acceptable lipophilic carrier systems for the purposes of this invention include a) microemulsion concentrates such as, for example, macrogol glycerol laurates according to Ph. Eur. NT 2001 and b) low-melting lipophilic systems comprising: i) 20 to 90% by weight (based on the finished formulation) lipophilic component and ii) 0 to 90% by weight (based on the finished formulation) of a surface-active compound.

Microemulsion concentrates are preferably used.

A preferred carrier system according to b) comprises i) 40 to 70% by weight (based on the finished formulation) of a lipophilic component and ii) 5 to 30% by weight (based on the finished formulation) of a surface-active compound.

A preferred embodiment of the low-melting lipophilic systems according to b) relates to those systems which have been homogenized under high pressure.

One advantage of the dosage form according to the invention is that the active substance is stabilized chemically and physically by it. In addition, the dosage form is characterized by good bioavailability of the active ingredient.

A preferred micro-emulsion concentrate is Gelucire ^®, Gelucire 44/14 ^® is particularly preferred, that is Gelucire ^® having a melting point of 44 ° C and an HLB value (hydrophilic / lipophilic balance value) 14 days.

Gelucire ^® is understood to mean polyglycolized glycerides which are produced by alcoholysis of natural oils with polyoxyethylene glycols. These are mixtures of monoesters, diesters and / or diesters of glycerides of long-chain fatty acids with 8 to 18 carbon atoms and polyethylene glycol mono- and / or diesters of long-chain fatty acids. These preparations have a wide range of melting points between about 33 ° C and 64 ° C and a wide range of HLB values between about 1 and 14. For the present invention are of particular ^Gelucires-® having an HLB value 10-14 of interest.

A low-melting system is a system with a melting point below 50 ° C.

Suitable lipophilic components (i) are fats and oils such as hard fat (e.g. Witepsol W 45), neutral oil, olive oil, corn oil, peanut oil, wheat germ oil, castor oil. Neutral oil is preferred.

As surface-active compound (ii) may, for example lipophilic or hydrophilic emulsifiers such as mono- and di-glycerides of fatty acids having 8 to 18 carbon atoms, and polysorbates (eg polysorbate 80 = polyoxyethylene (20) ~ sorbitan monooleate), Cremophore ^® (ethoxylates of fatty alcohols or hydrogenated Castor oil, for example RH 40 (= macrogol glycerol hydroxystearate)) or Tagate (polyoxyethylene glycerol mono fatty acid ester, for example Tagat S2 = polyoxyethylene (20) glycerol stearate) can be used.

Antioxidative auxiliaries such as e.g. Tocopherols, butyihydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic or gallic acid esters, nordihydroguajaretic acid (NDGA) or other compounds such as e.g. Flavonoids are used. Tocopherols, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) are preferred according to the invention. The use of stabilizers serves to increase the storage stability of the finished product. Tocopherol is usually used in a weight ratio of 1: 412 (tocopherol: active ingredient), BHT in a weight ratio of 1: 2306 (BHT: active ingredient).

In addition, the use of pH stabilizers such as weak organic or inorganic bases (e.g. sodium bicarbonate) as well as water-binding additives, which also act as stabilizers (e.g. dried ß-cyclodextrin; ß-cyclodextrin with a water content of 4% is preferred) is advantageous.

By suitably choosing the composition, in particular by choosing the surface-active compound and by varying the particle size of the active ingredient, it is readily possible for the person skilled in the art to control the release profile of the dosage form according to the invention over a broad spectrum. Depending on the desired product properties, both instant-release formulations ("instant release") and pharmaceutical compositions with "modified release" properties can be produced.

The active ingredient dispersion can be prepared by the process described below:

The liquid (molten) carrier system is placed in a batch vessel at 50 to 70 ° C. and, if appropriate, stabilizers such as, for example, antioxidants and / or pH stabilizers and internal desiccants are dissolved or suspended therein. The active ingredient is then incorporated with stirring and the dispersion homogenized. The dispersion is then degassed and can then be filled into hard or soft capsules, for example. For this purpose, an amount of dispersion corresponding to the dosage is filled on standard capsule filling machines, for example in hard capsules. Suitable hard capsules are, for example, hard gelatin capsules or hard capsules made of hydroxypropylmethyl cellulose (HPMC). The active substance content of the pharmaceutical composition in the solidified melt is 5 to 40% by weight, preferably 8 to 36% by weight, based on the methanesulfonate of the compound of the formula I.

Unless otherwise noted, the percentages are always percentages by weight. Unless otherwise stated, all information on the active substance content relates to the methanesulfonate of the formula 1.

The dosage in the case of oral administration is expediently 25 to 300 mg of the active substance base (per capsule), preferably 50 to 200 mg, in each case 1 to 2 times a day.

Clinical trials

In the first test with conventional tablets containing the compound of formula I, it was found that highly variable plasma levels up to occasional malabsorption occurred.

Composition of the conventional tablet:

The variability of the plasma level curves is significantly lower after application of the compound of formula I as an orally administered acidic solution; malabsorption was not observed. However, the acidic solution is unpleasant in taste and unstable, so it cannot be used for commercial purposes.

Composition of the acidic solution:.

Studies have shown that the compound of the formula I is relatively readily soluble in water at low pH values, while at pH values above 5 it is practically insoluble according to the definition of the European Pharmacopoeia. Therefore, the subjects were given pantoprazole in a treatment branch of the clinical trials, which serves to induce an increased gastric pH.

For example, the pharmaceutical composition according to Example 1 was tested for its bioavailability in comparison to the acidic solution.

For this purpose, the formulation prepared according to Example 1 with an active substance base content of 50 mg per capsule (corresponds to 57.66 mg of the mesylate of the compound of the formula I) was clinically tested on a total of 12 test persons with regard to their bioavailability. In a treatment branch, the subjects received the composition fasted orally (= oral administration) without pretreatment. In a further treatment branch, the same subjects were pretreated per ore - application of the composition to increase the gastric pH with 40 mg of pantoprazole bid (= twice a day); treatment with pantoprazole was discontinued during the Administration of the formulation according to the invention continued. The treatment lasted 3 days in each case.

The extent of absorption was determined via the quantitative determination of the urine excretion of the active metabolite of the formula II.

The relative bioavailability (based on the area under the plasma concentration-time curve) was 116% compared to the acidic solution (100% in each case) with pretreatment with pantoprazole and 131% without pretreatment with pantoprazole. This made it possible to improve the bioavailability of the formulation according to the invention compared to the acidic solution.

The clinical trial shows a further advantage of the dosage form according to the invention containing the compound of formula I, which consists in providing a sufficient pharmaceutical composition over a conventional pharmaceutical preparation. improved bioavailability of the. To ensure active ingredient, reduce fluctuations in the bioavailability of the active ingredient and prevent malabsorption. Another advantageous property of the pharmaceutical composition according to the invention is its suitability for all patients, including those in whom the gastric pH is increased by normal physiological variability, by an illness or by comedication with medicaments which increase the gastric pH is.

The following examples are intended to explain the invention in more detail:

example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

Preparation of 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] - methyl} -1-methyl-1 - / - benzimidazole-5-carbonyl) -pyridin-2-yl-amino] - ethyl propionate - methanesulfonate

To a solution of 3139 mg (5.0 mmol) of 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl} -1-methyl-1 H-benzimidazole-5-carbonyl) -pyridine- Ethyl 2-ylamino-propionate - base (as described in WO 98/37075), in 250 ml of ethyl acetate, a solution of 5.0 mmol of methanesulfonic acid in 25 ml of ethyl acetate was added dropwise with stirring at room temperature. After a few minutes the product started to crystallize Sieren. The mixture was stirred for a further hour at room temperature and another with ice-cooling, then the precipitate was filtered off with suction, washed with about 50 ml of ethyl acetate and 50 ml of diethyl ether and dried at 50 ° C. in a forced-air drying cabinet. Yield: 94% of theory Melting point: 178 - 179 ° C C34H ₄ 1N7O5 x CH4SO3 (723.86)

Elemental analysis: calc .: C 58.07% H 6.27% N 13.55% S 4.43% found :: 58.11% 6.30% 13.50% 4.48%

Claims

claims: 1. Pharmaceutical composition for oral administration comprising at least a) 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl} -1-methyl-1 H-benzimidazoil-5-carbonyl) -pyridin-2-yl-amino] -propionic acid ethyl ester or one of its pharmaceutically acceptable salts and b) a lipophilic, pharmaceutically acceptable, liquid, solid or semi-solid carrier system. 2. Pharmaceutical composition comprising 5 to 40 wt .-% 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenyl-amino] -methyl} -1-methyl-1 H -benzimidazole-5-carbonyl ) -pyridin-2-yl-amino] - ethyl propionate or one of its pharmaceutically acceptable salts, 55 to 95 wt .-% of a pharmaceutically acceptable, lipophilic carrier system and optionally 0 to 5 wt .-% of one or more stabilizers, where add up to a total of 100% by weight of the ingredients. 3. Pharmaceutical composition according to claim 1 or 2, in which the pharmaceutically suitable lipophilic carrier system is a microemulsion concentrate. 4. Pharmaceutical composition according to claim 3; characterized in that the microemulsion concentrate is a macrogol glycerol laurate according to Ph. Eur. NT 2001 is. 5. Pharmaceutical composition according to claim 1 or 2, characterized in that the lipophilic carrier system is a low-melting, lipophilic system comprising a lipophilic component, which optionally contains one or more surface-active compounds. 6. Pharmaceutical composition according to claim 4, characterized in that the macrogolglycerol laurate is Gelucire. 7. Pharmaceutical composition according to one of claims 1 to 6, wherein the content of 3 - [(2 - {[4- (Hexyloxycarbonyiamino-imino-methyi) -phenylamino] -methyl} - 1-methyl-1 H-benzimidazole- 5-carbonyl) pyridin-2-yl-amino] propionic acid ethyl ester or its salts in the pharmaceutical composition 8 to 40% 3 - [(2- {[4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl } -1-methyl-1 H -benzimidazole-5-carbonyl) -pyridin-2-yl-amino] -propionic acid ethyl ester - methanesulfonate. 8. Pharmaceutical composition according to one of claims 1 to 7, characterized in that the composition is filled into hard capsules. 9. Pharmaceutical composition according to claim 8, characterized in that the hard capsules are hard gelatin capsules or hard capsules made of hydroxypropylmethyl cellulose. 10. Pharmaceutical composition according to one of claims 1 to 9, in which 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl} - 1 -methyl- 1Λ- benzimidazole-5-carbonyl) -pyridin-2-yl-amino] -propionic acid ethyl ester mesylate is used as the active ingredient. 11. A process for producing an orally administered pharmaceutical composition comprising 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) - phenylamino] -methyl} -1-methyl-1 / Y-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] - ethyl propionate or one of its physiologically compatible salts and a pharmaceutically acceptable, liquid, solid or semi-solid lipophilic carrier system, characterized in that the active ingredient is incorporated into the liquid carrier system until a homogeneous dispersion is achieved becomes. 12. The method according to claim 11, characterized in that stabilizers are dissolved or suspended in the liquid carrier system melt before incorporation of the active ingredient. 13. The method according to claim 12, characterized in that the stabilizers are antioxidant and / or pH stabilizers. 14. The method according to any one of claims 11 to 13, characterized in that the homogeneous dispersion is degassed before filling. 15. The method according to any one of claims 11 to 14, characterized in that the homogeneous dispersion is filled into hard capsules.