US20030181488A1 - Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof - Google Patents

Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof Download PDF

Info

Publication number
US20030181488A1
US20030181488A1 US10383198 US38319803A US2003181488A1 US 20030181488 A1 US20030181488 A1 US 20030181488A1 US 10383198 US10383198 US 10383198 US 38319803 A US38319803 A US 38319803A US 2003181488 A1 US2003181488 A1 US 2003181488A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
methyl
acid
pharmaceutical composition
composition according
active substance
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10383198
Inventor
Ulrich Brauns
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to a new administration form for the oral application of the active substance ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate and the pharmacologically acceptable salts thereof.

Description

  • The invention relates to an administration form for the oral application of the active substance ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate and the pharmacologically acceptable salts thereof. This active substance having the chemical formula [0001]
    Figure US20030181488A1-20030925-C00001
  • is already known from WO 98/37075, which discloses compounds with a thrombin-inhibiting effect and the effect of prolonging the thrombin time, under the name 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazole-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amides. The compound of formula I is a double prodrug of the compound [0002]
    Figure US20030181488A1-20030925-C00002
  • i.e. the compound of formula I is only converted into the active compound, namely the compound of formula II, after entering the body. The main indication for the compound of chemical formula I is the post-operative prevention of deep-vein thrombosis. [0003]
  • The aim of the invention is to provide an improved formulation for oral use of the compound of formula I (which is also referred to hereinafter as the “active substance”). [0004]
  • Surprisingly it has now been found that the use of pharmaceutically acceptable organic acids with a water solubility of >1 g/250 ml at 20° C., preferably >1 g/160 ml at 25° C., in solid oral preparations leads to a significantly improved formulation of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate as well as the pharmaceutically acceptable salts thereof. [0005]
  • Pharmaceutically suitable acids for the purposes of this invention are for example tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid including the hydrates and acid salts thereof. Particularly suitable for the purposes of this invention are tartaric acid, fumaric acid, succinic acid and citric acid. [0006]
  • A preferred embodiment of the invention is a multiparticulate preparation in which the individual particles are constructed as in FIG. 1. [0007]
  • FIG. 1 shows the diagrammatic structure of the pharmaceutical composition by means of a section through a pellet suitable for the preparation of the pharmaceutical composition according to the invention. The roughly bead-shaped/spherical core region of this pellet contains/consists of the pharmaceutically acceptable organic acid. Then follows a layer, the so-called insulating layer, which separates the acid core from the layer containing the active substance. The insulating layer is in turn surrounded by the equally spherically shaped layer of active substance which may in turn be enclosed in a coating which increases the abrasion resistance and shelf life of the pellets. [0008]
  • One advantage of the formulation thus constructed is the spatial separation of the organic acid and active substance by the insulating layer. A further advantage of the construction of the pellets as described above is the fact that the organic acid does not go into solution until after the preparation has been taken and then produces an acid microclimate in which the active substance can dissolve. [0009]
  • The core material used is a pharmaceutically acceptable organic acid with a water solubility of >1 g/250 ml at 20° C., such as e.g. tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid including the hydrates and acid salts thereof, to which a small amount of 1 to 10% by weight, preferably 3 to 6% by weight of a suitable binder is optionally added. The use of a binder may be necessary, for example, if the starting acids are produced by a pan build-up process. If the method used is extrusion or spheronisation, other technological adjuvants such as microcrystalline cellulose will be needed instead of binders. It is also possible to use pure (100%) acid as the starting material if it can be obtained in a sufficiently narrow range of particle sizes. The pharmaceutically acceptable organic acids used are preferably tartaric acid, fumaric acid, succinic acid or citric acid; tartaric acid is particularly preferred. As binder, it is possible to use gum arabic or a partially or totally synthetic polymer selected from among the hydroxypropyl-celluloses, hydroxypropylmethylcelluloses, methylcelluloses, hydroxyethylcelluloses, carboxymethylcelluloses, polyvinylpyrrolidone, the copolymers of N-vinylpyrrolidone and vinyl acetate, or combinations of these polymers; gum arabic is preferred. The spherical core material preferably has an average diameter of 0.4 -1.5 mm. The content of the pharmaceutically acceptable organic acid is usually between 30 and 100% in the core material, corresponding to an amount of between 20 and 90%, preferably between 20 and 80% in the finished pellet (i.e. in the pharmaceutical composition). [0010]
  • To increase the durability of the finished product it is advantageous to coat the core material before the application of the active substance with an insulating layer based on a water-soluble, pharmaceutically acceptable polymer. Examples of such water-soluble polymers include for example gum arabic or a partially or totally synthetic polymer selected from among the hydroxypropyl-celluloses, hydroxypropylmethylcelluloses, methylcelluloses, hydroxyethylcelluloses, carboxymethylcelluloses, polyvinylpyrrolidone, the copolymers of N-vinylpyrrolidone and vinyl acetate, or combinations of these polymers. Gum arabic or a hydroxypropylmethylcellulose is preferably used. If desired, the coating with the water-soluble, pharmaceutically acceptable polymer may be carried out with the addition of suitable plasticisers, separating agents and pigments, such as for example triethylcitrate, tributylcitrate, triacetin, polyethyleneglycols (plasticisers), talc, silicic acid (separating agents), titanium dioxide or iron oxide pigments (pigments). [0011]
  • The active substance layer contains the active substance ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate (BIBR 1048) or one of the pharmaceutically acceptable salts thereof as well as binders and optionally separating agents. A preferred salt of the active substance is the mesylate of the compound of formula I Suitable binders include for example hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl acetate or combinations of these polymers. Preferably, hydroxypropylcellulose or copolymers of N-vinylpyrrolidone and vinyl acetate are used. The addition of separating agents such as e.g. talc or silicic acid serves to prevent the particles from aggregating during the process. The active substance content is 5 to 60%, preferably 10 to 50% of the pharmaceutical composition. [0012]
  • The optional outermost layer, which serves to reduce any increased abrasion during packing into capsules and/or to increase the shelf life, consists of pharmaceutically conventional film-forming agents, plasticisers and optionally pigments. Suitable film-forming agents include for example hydroxypropyl-cellulose, hydroxypropylmethylcellulose, methylcellulose, polymers and copolymers of acrylic and methacrylic acid and the esters thereof, or combinations of these polymers. Suitable plasticisers include inter alia triethylcitrate, tributylcitrate, triacetin or polyethyleneglycols. The pigments used may be e.g. titanium dioxide or iron oxide pigments. Preferably, the outer coating consists of hydroxypropylmethylcellulose and/or methylcellulose, optionally with the addition of polyethyleneglycols as plasticisers. [0013]
  • The pellets may be prepared by the method described hereinafter: [0014]
  • The acid-containing core material consists either of crystals of the particular organic acid used or, more advantageously, of roughly spherical particles of the desired size containing a large amount of organic acid, which can be produced by methods known and established in pharmaceutical technology. The core material may be produced, in particular, by pan methods, on pelleting plates or by extrusion/spheronisation. Then the core material thus obtained may be divided into fractions of the desired diameter by screening. Suitable core material has an average diameter of 0.4 to 1.5 mm, preferably 0.6 to 0.8 mm. [0015]
  • First, the insulating layer is applied to this acid-containing core material. This can be done by conventional methods, e.g. by applying an aqueous dispersion of the water-soluble, pharmaceutically acceptable polymer, optionally with the addition of plasticisers, separating agents and/or pigments, in a fluidised bed, in coating pans or in conventional film coating apparatus. If necessary the product can then be screened again. [0016]
  • Then the active substance is applied from a dispersion containing binder and optionally separating agent. The volatile dispersant is removed during or after the process by drying. Suitable binders in the dispersion may be for example hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, copoly-mers of N-vinylpyrrolidone and vinyl acetate or combinations of these polymers. Preferably, hydroxypropylcellulose or copolymers of N-vinylpyrrolidone and vinyl acetate are used. Suitable separating agents include e.g. talc or silicic acid; preferably, talc is used. The dispersants may be for example ethanol, 2-propanol, acetone or mixtures of these solvents with one another or with water, preferably 2-propanol. The application of active substance to the core material may be carried out by established methods known in pharmaceutical technology, e.g. in coating pans, conventional film coating apparatus or by the fluidised bed method. Then a further screening process may be carried out. [0017]
  • To reduce any increased abrasion during transfer into capsules or to increase the shelf life the system may finally be coated with a coating of a pharmaceutically conventional film forming agent, plasticiser and optionally pigment. This may be done by conventional methods as mentioned earlier in the description of the application of the insulating layer. [0018]
  • When core material with an average diameter of 0.4-1.5 mm is used, the process described above produces pellets containing active substance, which can then be packed into hard capsules, for example. To do this, a number of these units corresponding to the required dosage are packed into hard capsules in a standard capsule filling machine. Suitable hard capsules include, for example, hard gelatine capsules or hard capsules of hydroxypropylmethylcellulose (HPMC). The active substance content of the pharmaceutical composition is 5 to 60%, preferably 10 to 50%; the content of the pharmaceutically acceptable organic acid is usually between 20 and 90%, preferably between 20 and 80%. [0019]
  • Unless otherwise stated, percentages specified are always percent by weight. All the data on the active substance content relate to the active substance base of formula I (not to a specific salt) unless otherwise stated. [0020]
  • Clinical Trials [0021]
  • In preliminary tests on test subjects with conventional tablets containing the compound of formula I it had been established that highly variable plasma levels occurred, with individual cases of malabsorption. The variability of the plasma level patterns is significantly lower after the administration of the compound of formula I as an orally administered solution; there were no cases of malabsorption under these circumstances. [0022]
  • Tests have shown that the compound of formula I dissolves relatively well in water at low pH levels, whereas at pH levels above 5 in accordance with the definition of the European Pharmacopoeia it is virtually insoluble. Therefore the volunteers in one branch of the clinical trials were given pantoprazole, which serves to produce an elevated gastric pH. [0023]
  • For example, the pharmaceutical compositions according to Examples 1 and 2 were tested for their bioavailability by comparison with a conventional tablet. [0024]
  • To do this, the formulation prepared according to Example 1 containing 50 mg of active substance base per capsule was clinically tested for its bioavailability on a total of 15 volunteers. In one branch of the treatment, the volunteers were given the composition by mouth (=orally) on an empty stomach without any pre-treatment. In another branch of the treatment the same volunteers were pre-treated, prior to the oral administration of the composition, with 40 mg of pantoprazole b.i.d. (=twice a day) for three days by mouth to increase the gastric pH; the treatment with pantoprazole was continued during the administration of the formulation according to the invention. [0025]
  • The degree of absorption was determined by measuring the quantity of active metabolite of formula II excreted in the urine. [0026]
  • The relative bioavailability after pre-treatment with pantoprazole was 94% on average compared with administration without any pre-treatment. [0027]
  • Under comparable conditions of administration, the relative bioavailability (based on the area under the plasma concentration/time curve) of a tablet containing 50 mg of active substance, developed and produced according to the prior art and containing no water-soluble organic acid, after corresponding pre-treatment with pantoprazole, is 18%. The following list shows the precise composition of the tablet used: [0028]
    Ingredient mg/tablet
    Core mesylate of the compound of form. I 57.7
    lactose monohydrate 58.0
    microcrystalline cellulose 48.3
    crospovidone 3.4
    magnesium stearate 2.6
    Film polyethyleneglycol 6000 0.56
    coating titanium dioxide 0.80
    talc 0.64
    hydroxypropylmethylcellulose 1.92
    iron oxide yellow 0.08
    Total 174.0
  • The relative bioavailability was thus improved by about a factor of 5 by using the formulation according to the invention. [0029]
  • The formulation prepared according to Example 2 containing 50 mg of active substance base per capsule was also clinically tested for its bioavailability on a total of 15 volunteers. In one branch of the treatment, the volunteers were given the composition by mouth on an empty stomach without any pre-treatment. In another branch of the treatment the same volunteers were pre-treated, prior to the oral administration of the composition, with 40 mg of pantoprazole b.i.d. for three days by mouth to increase the gastric pH; the treatment with pantoprazole was continued during the administration of the formulation according to the invention. [0030]
  • The degree of absorption was determined by measuring the quantity of the active metabolite of formula II excreted in the urine. [0031]
  • The relative bioavailability after pre-treatment with pantoprazole was 76% on average compared with administration without any pre-treatment. [0032]
  • Under comparable conditions of administration, the relative bioavailability (based on the area under the plasma concentration/time curve) of a tablet containing 50 mg of active substance, developed and produced according to the prior art and containing no water-soluble organic acid, after corresponding pre-treatment with pantoprazole, is 18%. The following list shows the precise composition of the tablet used: [0033]
    Ingredient mg/tablet
    Core mesylate of the compound of form. I 57.7
    lactose monohydrate 58.0
    microcrystalline cellulose 48.3
    crospovidone 3.4
    magnesium stearate 2.6
    Film polyethyleneglycol 6000 0.56
    coating titanium dioxide 0.80
    talc 0.64
    hydroxypropylmethylcellulose 1.92
    iron oxide yellow 0.08
    Total 174.0
  • The relative bioavailability of the active substance compared with conventional formulations was thus improved by about a factor of 4 by using the formulation according to the invention. The bioavailability of the two formulations according to the invention compared with the tablet described above with and without the simultaneous administration of pantoprazole is graphically illustrated in FIG. 2. [0034]
  • The clinical trials show another advantage of the preparation according to the invention containing the compound of formula I, which is that it ensures adequate bioavailability of the active substance, better than that of a conventional pharmaceutical preparation and largely independent of the gastric pH, it reduces fluctuations in the bioavailability of the active substance and it prevents malabsorption. Another advantageous property of the pharmaceutical composition according to the invention is the fact that it is suitable for all patients, i.e. including those in whom the gastric pH is increased by normal physiological variability, by disease or by co-medication with drugs which raise the gastric pH. [0035]
  • The dosage for oral use is expediently 25 to 300 mg of the active substance base (per capsule), preferably 50 to 200 mg, most preferably 75 to 150 mg of the active substance base, in each case once or twice a day. [0036]
  • The preferred ratio of acid to active substance is about 0.9:1 to about 4:1, most preferably between about 1:1 and 3:1. Preferably, at least one equivalent of acid is used per mol of the compound of formula I. The upper limit of about 4:1 (acid to active substance) is generally determined by the maximum acceptable size of the preparation in the desired dosages (number of pellets per capsule). [0037]
  • The Examples that follow are intended to illustrate the invention: [0038]
  • EXAMPLE 1
  • [0039]
    percentage composition
    active per per
    core insulat- substance capsule capsule
    material ing layer layer total [mg] [mg]
    tartaric acid 61.3 61.3 176.7 353.4
    gum arabic 3.1 2.8 5.9 17.0 34.0
    talc 5.6 3.2 8.8 25.4 50.7
    hydroxypropylcellulose 4.0 4.0 11.5 23.1
    active substance 20.0 20.0 57.7* 115.3**
    (mesylate of the
    compound of formula I)
    total 100.0 288.3 576.5
  • a) Production of Core Material Containing Tartaric Acid [0040]
    Composition:
    gum arabic  1 part by weight
    tartaric acid 20 parts by weight
  • 1 part by weight of gum arabic is dissolved In 4 parts by weight of purified water at 50° C. with stirring. Then 5 parts by weight of tartaric acid are dissolved in this solution with stirring. [0041]
  • 8.3 parts by weight of tartaric acid crystals with an average particle size of 0.4 to 0.6 mm are placed in a suitable coating apparatus fitted with an air inlet and exhaust, and the pan is set in rotation. At an air inlet temperature of 60°-80° C. the tartaric acid crystals are sprayed at intervals with the solution of tartaric acid and gum arabic and sprinkled with a total of 6.7 parts by weight of powdered tartaric acid, so that roughly spherical particles are formed. [0042]
  • The spherical tartaric acid core material is then dried in the rotating pan at an air inlet temperature of 60°-80° C. [0043]
  • The core material is fractionated using a tumbler screening machine with perforated plates with a nominal mesh size of 0.6 and 0.8 mm. The product fraction between 0.6 and 0.8 mm is used in the rest of the process. [0044]
  • b) Insulation of the core material containing tartaric acid [0045]
    Composition:
    core material containing tartaric acid 23 parts by weight
    gum arabic  1 part by weight
    talc  2 parts by weight
  • 1 part by weight of gum arabic is dissolved in a mixture of 6.7 parts by weight of 96% ethanol and 13.5 parts by weight of purified water with stirring. Then 2 parts by weight of talc are dispersed in the solution with stirring. [0046]
  • In a fluidised bed processing apparatus, 23 parts by weight of core material containing tartaric acid are sprayed at an air inlet temperature of 35°-40° C. with the dispersion of gum arabic and talc by the under-bed spraying process. [0047]
  • The insulated core material containing tartaric acid is then dried in the circulating air drier at 40° C. for 8 hours. [0048]
  • To remove any lumps the dried insulated core material containing tartaric acid is screened through a screen with a nominal mesh size of 1.0 mm. The fraction of material with a particle size of <1 mm is further processed. [0049]
  • c) Production of The Active Substance Layer [0050]
    Composition:
    insulated core material containing tartaric acid 91 parts by weight
    hydroxypropylcellulose  5 parts by weight
    talc  4 parts by weight
    active substance (mesylate of BIBR 1048) 25 parts by weight
  • Hydroxypropylcellulose is dissolved in 168 parts by weight of 2-propanol with stirring and then the active substance and talc are dispersed in this solution with stirring. [0051]
  • In a fluidised bed processing apparatus, 91 parts by weight of insulated core material containing tartaric acid are sprayed at an air inlet temperature of 20°-30° C. with the dispersion containing the active substance by the under-bed spraying process. [0052]
  • The pellets containing the active substance are then dried in the circulating air drier at 35° C. for 8 hours. [0053]
  • To remove any lumps the pellets containing the active substance are screened through a screen with a nominal mesh size of 1.25 mm. The fraction of material with a particle size of <1.25 mm is further processed. [0054]
  • d) Packing into Capsules [0055]
  • A quantity of active substance pellets containing in each case 50 or 100 mg of active substance base is packed into size 1 or size 0 elongated hard gelatine capsules by means of a capsule filling machine. [0056]
  • EXAMPLE 2
  • [0057]
    percentage composition
    active per per
    core insulating substance capsule capsule
    material layer layer total [mg] [mg]
    tartaric acid 38.5 38.5 55.5 166.5
    gum arabic 1.9 1.7 3.6 5.2 15.6
    talc 3.5 6.4 9.9 14.3 42.8
    hydroxypropylcellulose 8.0 8.0 11.5 34.6
    active substance 40.0 40.0 57.7* 173.0
    (mesylate of the
    compound of formula I)
    total 100.0 144.2 432.5
  • a) Production of Core Material Containing Tartaric Acid [0058]
    Composition:
    gum arabic  1 part by weight
    tartaric acid 20 parts by weight
  • 1 part by weight of gum arabic is dissolved in 4 parts by weight of purified water at 50° C. with stirring. Then 5 parts by weight of tartaric acid are dissolved in this solution with stirring. [0059]
  • 8.3 parts by weight of tartaric acid crystals with an average particle size of 0.4 to 0.6 mm are placed in a suitable coating apparatus fitted with an air inlet and exhaust, and the pan is set in rotation. At an air inlet temperature of 60°-80° C. the tartaric acid crystals are sprayed at intervals with the solution of tartaric acid and gum arabic and sprinkled with a total of 6.7 parts by weight of powdered tartaric acid, so that roughly spherical particles are formed. [0060]
  • The spherical tartaric acid core material is then dried in the rotating pan at an air inlet temperature of 60°-80° C. [0061]
  • The core material is fractionated using a tumbler screening machine with perforated plates with a nominal mesh size of 0.6 and 0.8 mm. The product fraction between 0.6 and 0.8 mm is used in the rest of the process. [0062]
  • b) Insulation of The Core Material Containing Tartaric Acid [0063]
    Composition:
    core material containing tartaric acid 23 parts by weight
    gum arabic  1 part by weight
    talc  2 parts by weight
  • 1 part by weight of gum arabic is dissolved in a mixture of 6.7 parts by weight of 96% ethanol and 13.5 parts by weight of purified water with stirring. Then 2 parts by weight of talc are dispersed in the solution with stirring. [0064]
  • In a fluidised bed processing apparatus, 23 parts by weight of core material containing tartaric acid are sprayed at an air inlet temperature of 35°-40° C. with the dispersion of gum arabic and talc by the under-bed spraying process. [0065]
  • The insulated core material containing tartaric acid is then dried in the circulating air drier at 40° C. for 8 hours. [0066]
  • To remove any lumps the dried insulated core material containing tartaric acid is screened through a screen with a nominal mesh size of 1.0 mm. The fraction of material with a particle size of <1 mm is further processed. [0067]
  • c) Production of The Active Substance Layer [0068]
    Composition:
    insulated core material containing tartaric acid 57 parts by weight
    hydroxypropylcellulose 10 parts by weight
    talc  8 parts by weight
    active substance (mesylate of BIBR 1048) 50 parts by weight
  • Hydroxypropylcellulose is dissolved in 335 parts by weight of 2-propanol with stirring and then the active substance and talc are dispersed in this solution with stirring. [0069]
  • In a fluidised bed processing apparatus, 91 parts by weight of insulated core material containing tartaric acid are sprayed at an air inlet temperature of 20°-30° C. with the dispersion containing the active substance by the under-bed spraying process. [0070]
  • The pellets containing the active substance are then dried in the circulating air drier at 35° C. for 8 hours. [0071]
  • To remove any lumps the pellets containing the active substance are screened through a screen with a nominal mesh size of 1.25 mm. The fraction of material with a particle size of <1.25 mm is further processed. [0072]
  • d) Packing Into Capsules [0073]
  • A quantity of active substance pellets containing in each case 50 or 150 mg of active substance base is packed into size 2 or size 0 hard gelatine capsules by means of a capsule filling machine. [0074]
  • The invention thus comprises the following inventive objects: [0075]
  • Pharmaceutical composition for oral administration comprising at least a) ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate or one of the pharmaceutically acceptable salts thereof and b) one or more pharmaceutically acceptable organic acids with a water solubility of >1 g/250 ml at 20° C. [0076]
  • Pharmaceutical composition as defined above, wherein the pharmaceutically acceptable organic acid is tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid or one of the hydrates or acid salts thereof. [0077]
  • Pharmaceutical composition according to the above definition, characterised in that the pharmaceutically acceptable organic acid is tartaric acid, fumaric acid, citric acid or succinic acid. [0078]
  • Pharmaceutical composition according to the above definition, characterised in that the pharmaceutically acceptable organic acid is tartaric acid. [0079]
  • Pharmaceutical composition according to one of the above definitions, wherein the content of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate or the salts thereof in the pharmaceutical composition is 5 to 60%. [0080]
  • Pharmaceutical composition according to one of the above definitions, wherein the content of pharmaceutically acceptable organic acid is 20 to 90%. [0081]
  • Pharmaceutical composition according to one of the above definitions comprising a substantially spherical core material which consists of or contains the pharmaceutically acceptable organic acid, and an active substance layer containing binder and optionally separating agent, which encloses the core material. [0082]
  • Pharmaceutical composition according to the above definition, wherein the binder consist of the group of hydroxypropylcelluloses, hydroxypropylmethylcelluloses, methylcelluloses, hydroxyethylcelluloses, carboxymethylcelluloses, the polyvinylpyrrolidones, the copolymers of N-vinylpyrrolidone and vinyl acetate or of combinations of these polymers. [0083]
  • Pharmaceutical composition according to the above definition, wherein the core material has an average particle size of 0.4 to 1.5 mm. [0084]
  • Pharmaceutical composition according to the above definition, wherein the core material and the active substance layer are separated from one another by an insulating layer consisting of a water-soluble polymer, optionally with the addition of suitable plasticisers, separating agents and pigments. [0085]
  • Pharmaceutical composition according to the above definition, wherein the water-soluble polymer consists of gum arabic or a partially or totally synthetic polymer selected from the group of hydroxypropylcelluloses, hydroxypropylm ethylcelluloses, methylcelluloses, hydroxyethylcelluloses, carboxymethylcelluloses, the polyvinylpyrrolidones, the copolymers of N-vinylpyrrolidone and vinyl acetate or of combinations of these polymers. [0086]
  • Pharmaceutical composition according to one of the above definitions, wherein the product containing the active substance is packed into hard capsules. [0087]
  • Pharmaceutical composition according to one of the above definitions, wherein ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate mesylate is used as the active substance. [0088]
  • Process for preparing a pharmaceutical composition for oral administration containing ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate or one of the physiologically acceptable salts thereof, comprising the steps of: [0089]
  • a) forming the core material from one or more pharmaceutically acceptable organic acid(s) with a water solubility of >1 g/250 ml at 20° C., optionally with the addition of binders or other technological adjuvants, by pan methods, on pelleting plates or by extrusion/ spheronisation, [0090]
  • b) applying to the core material an insulating layer consisting of one or more water-soluble, pharmaceutically acceptable polymers optionally with the addition of plasticisers, separating agents and/or pigments, [0091]
  • c) applying the active substance from a dispersion which contains a binder and optionally separating agents and simultaneously and/or subsequently drying to eliminate the dispersant, [0092]
  • d) optionally applying a coating of film-forming agents, plasticisers and optionally pigments and [0093]
  • e) packing the active substance-containing pellets thus obtained into hard capsules. [0094]

Claims (16)

    We claim:
  1. 1. Pharmaceutical composition for oral administration comprising:
    a) ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate or one of the pharmaceutically acceptable salts thereof and
    b) one or more pharmaceutically acceptable organic acids with a water solubility of >1 g/250 ml at 20° C.
  2. 2. Pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable organic acid is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid or aspartic acid and one of the hydrates or acid salts thereof.
  3. 3. Pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable organic acid is selected from the group consisting of tartaric acid, fumaric acid, citric acid and succinic acid.
  4. 4. Pharmaceutical composition according to claim 3, wherein the pharmaceutically acceptable organic acid is tartaric acid.
  5. 5. Pharmaceutical composition according to claim 1, wherein the content of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate or the salts thereof in the pharmaceutical composition is 5 to 60%.
  6. 6. Pharmaceutical-composition according to claim 1, wherein the content of pharmaceutically acceptable organic acid is 20 to 90%.
  7. 7. Pharmaceutical composition according to claim 1 comprising a substantially spherical core material further comprised of a pharmaceutically acceptable organic acid, and active substance layer comprised of a binder and optionally a separating agent, which encloses said core material.
  8. 8. Pharmaceutical composition according to claim 7, wherein said binder is selected from the group consisting of hydroxypropylcelluloses, hydroxypropyl-methylcelluloses, methylcelluloses, hydroxyethylcelluloses, carboxymethyl-celluloses, the polyvinylpyrrolidones, the copolymers of N-vinylpyrrolidone and vinyl acetate or combinations thereof.
  9. 9. Pharmaceutical composition according to claim 7, wherein said core material has an average particle size of 0.4 to 1.5 mm.
  10. 10. Pharmaceutical composition according to claim 7, wherein said core material and the active substance layer are separated from one another by an insulating layer comprised of a water-soluble polymer, optionally with the addition of suitable plasticisers, separating agents and pigments.
  11. 11. Pharmaceutical composition according to claim 10, wherein said water-soluble polymer is comprised of gum arabic.
  12. 12. Pharmaceutical composition according to claim 10, wherein said water-soluble polymer is comprised of a partially or totally synthetic polymer selected from the group consisting of hydroxypropylcelluloses, hydroxypropylmethyl-celluloses, methylcelluloses, hydroxyethylcelluloses, carboxymethylcelluloses, the polyvinylpyrrolidones, the copolymers of N-vinylpyrrolidone and vinyl acetate, or a combination thereof.
  13. 13. Pharmaceutical composition according to claim 7, wherein the composition containing the active substance is packed into hard capsules.
  14. 14. Pharmaceutical composition according to claim 1, wherein ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate mesylate is used as the active substance.
  15. 15. Process for preparing a pharmaceutical composition for oral administration containing ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate or one of the physiologically acceptable salts thereof, comprising the steps of:
    a) forming the core material from one or more pharmaceutically acceptable organic acid(s) with a water solubility of >1 g/250 ml at 20° C., optionally with the addition of binders or other technological adjuvants, by pan methods, on pelleting plates or by extrusion/spheronisation,
    b) applying to the core material an insulating layer comprised of one or more water-soluble, pharmaceutically acceptable polymers optionally with the addition of plasticisers, separating agents and/or pigments,
    c) applying the active substance from a dispersion which contains a binder and optionally separating agents and simultaneously and/or subsequently drying to eliminate the dispersant,
    d) optionally applying a coating of film-forming agents, plasticisers and optionally pigments and
    e) packing the active substance-containing pellets thus obtained into capsules.
  16. 16. A composition comprised of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate methanesulphonate.
US10383198 2002-03-07 2003-03-06 Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof Abandoned US20030181488A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
DE2002109985 DE10209985A1 (en) 2002-03-07 2002-03-07 Oral pharmaceutical composition comprises the thrombin inhibitor ethyl 3-(2-(4-(hexyloxycarbonylamidino)phenylaminomethyl)-1-methyl-1H-benzimidazole-5-carbonyl)-2-pyridylamino)propionate and an organic acid
DE10209985 2002-03-07
US40976202 true 2002-09-11 2002-09-11
DE2002145624 DE10245624A1 (en) 2002-09-30 2002-09-30 Oral pharmaceutical composition comprises the thrombin inhibitor ethyl 3-(2-(4-(hexyloxycarbonylamidino)phenylaminomethyl)-1-methyl-1H-benzimidazole-5-carbonyl)-2-pyridylamino)propionate and an organic acid
DE10245624 2002-09-30
US42189602 true 2002-10-29 2002-10-29
US10383198 US20030181488A1 (en) 2002-03-07 2003-03-06 Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US10383198 US20030181488A1 (en) 2002-03-07 2003-03-06 Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
US11381890 US9925174B2 (en) 2002-03-07 2006-05-05 Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof
US14489892 US20150005350A1 (en) 2002-03-07 2014-09-18 Administration of ethyl 3-[(2--1-methyl-1h-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionate
US15946096 US20180221359A1 (en) 2002-03-07 2018-04-05 Administration of ethyl 3-[(2-{[4-(hexyloxycarbonyl-aminoiminomethyl)phenyl-amino]methyl}-1-methyl-1h-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionate

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US11381890 Continuation US9925174B2 (en) 2002-03-07 2006-05-05 Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof
US14489892 Continuation US20150005350A1 (en) 2002-03-07 2014-09-18 Administration of ethyl 3-[(2--1-methyl-1h-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionate

Publications (1)

Publication Number Publication Date
US20030181488A1 true true US20030181488A1 (en) 2003-09-25

Family

ID=28046818

Family Applications (4)

Application Number Title Priority Date Filing Date
US10383198 Abandoned US20030181488A1 (en) 2002-03-07 2003-03-06 Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
US11381890 Active 2023-06-14 US9925174B2 (en) 2002-03-07 2006-05-05 Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof
US14489892 Abandoned US20150005350A1 (en) 2002-03-07 2014-09-18 Administration of ethyl 3-[(2--1-methyl-1h-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionate
US15946096 Pending US20180221359A1 (en) 2002-03-07 2018-04-05 Administration of ethyl 3-[(2-{[4-(hexyloxycarbonyl-aminoiminomethyl)phenyl-amino]methyl}-1-methyl-1h-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionate

Family Applications After (3)

Application Number Title Priority Date Filing Date
US11381890 Active 2023-06-14 US9925174B2 (en) 2002-03-07 2006-05-05 Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof
US14489892 Abandoned US20150005350A1 (en) 2002-03-07 2014-09-18 Administration of ethyl 3-[(2--1-methyl-1h-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionate
US15946096 Pending US20180221359A1 (en) 2002-03-07 2018-04-05 Administration of ethyl 3-[(2-{[4-(hexyloxycarbonyl-aminoiminomethyl)phenyl-amino]methyl}-1-methyl-1h-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionate

Country Status (1)

Country Link
US (4) US20030181488A1 (en)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050038077A1 (en) * 2003-08-16 2005-02-17 Boehringer Ingelheim International Gmbh Tablet containing 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H- benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethylester or the salts thereof
US20050234104A1 (en) * 2003-08-29 2005-10-20 Boehringer Ingelheim International Gmbh 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as medicament
US20060131204A1 (en) * 2004-12-21 2006-06-22 Boehringer Ingelheim International Gmbh Film container
US20060183779A1 (en) * 2002-03-07 2006-08-17 Boehringer Ingelheim Pharma Gmbh & Co., Kg Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
US20060247278A1 (en) * 2005-04-27 2006-11-02 Boehringer Ingelheim International Gmbh Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester
US20070298095A1 (en) * 2004-05-24 2007-12-27 Shionogi Qualicaps Co., Ltd. Surface-Modified and Solubility-Improved Hard Capsule
US20080200514A1 (en) * 2006-07-17 2008-08-21 Boehringer Ingelheim International Gmbh Indications for Direct Thrombin Inhibitors
US20110123635A1 (en) * 2008-07-14 2011-05-26 Boehringer Ingelheim International Gmbh Method for manufacturing medicinal compounds containing dabigatran
US20110129538A1 (en) * 2008-03-28 2011-06-02 Boehringer Ingelheim International Gmbh Process for preparing orally administered dabigatran formulations
US20110190352A1 (en) * 2008-08-19 2011-08-04 Boehringer Ingelheim International Gmbh Use of dabigatranetexilate for treating patients with pulmonary hypertension
US20120301541A1 (en) * 2011-05-24 2012-11-29 Haronsky Elina Compressed core for pharmaceutical composition
US20130052262A1 (en) * 2010-03-01 2013-02-28 Sandra Brueck Dabigatran etexilate-containing oral pharmaceutical composition
WO2013110567A1 (en) * 2012-01-24 2013-08-01 Boehringer Ingelheim International Gmbh Novel orally administered dabigatran formulation
EP2740471A1 (en) * 2012-12-07 2014-06-11 Hexal AG Oral pharmaceutical composition comprising dabigatran etexilate
US8962574B2 (en) 2008-11-11 2015-02-24 Boehringer Ingelheim International Gmbh Method for treating or preventing thrombosis using dabigatran etexilate or a salt thereof with improved safety profile over conventional warfarin therapy
WO2016009405A1 (en) 2014-07-18 2016-01-21 Sifavitor S.R.L. Crystalline compounds of dabigatran etexilate
US20170035745A1 (en) * 2014-04-11 2017-02-09 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Pharmaceutical combinations of dabigatran and proton pump inhibitors
EP2588090B1 (en) 2010-07-01 2017-04-19 KRKA, tovarna zdravil, d.d., Novo mesto Pharmaceutical oral dosage forms comprising dabigatran etexilate and its pharmaceutically acceptable salts

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7803817B2 (en) 2005-05-11 2010-09-28 Vecta, Ltd. Composition and methods for inhibiting gastric acid secretion
US7981908B2 (en) 2005-05-11 2011-07-19 Vecta, Ltd. Compositions and methods for inhibiting gastric acid secretion
US9233092B2 (en) * 2006-07-25 2016-01-12 Vecta, Ltd. Compositions and methods for inhibiting gastric acid secretion using derivatives of small dicarboxylic acids in combination with PPI
CA2864423A1 (en) 2012-02-21 2013-08-29 Pratibha S. Pilgaonkar Oral pharmaceutical compositions of dabigatran etexilate
WO2014001220A1 (en) 2012-06-25 2014-01-03 Boehringer Ingelheim International Gmbh Method for prevention of stroke
WO2014020546A3 (en) 2012-07-31 2014-03-27 Ranbaxy Laboratories Limited Crystalline forms of dabigatran etexilate and process for their preparation
WO2014178017A1 (en) 2013-04-30 2014-11-06 Ranbaxy Laboratories Limited Dabigatran etexilate impurity, process of its preparation, and its use as a reference standard

Citations (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3887705A (en) * 1972-05-17 1975-06-03 Fabre Sa Pierre Medicaments intended for the prevention and treatment of capillary-venous deficiencies
US3968111A (en) * 1974-12-06 1976-07-06 Eli Lilly And Company 8,8-Disubstituted-6-methylergolines and related compounds
US4367217A (en) * 1980-01-12 1983-01-04 Boehringer Ingelheim Gmbh Dipyricamole sustained release forms comprising lacquer-coated particles and the preparation thereof
US4427648A (en) * 1981-06-19 1984-01-24 Dr. Karl Thomae Gmbh Dipyridamole-containing pharmaceutical form
US4427468A (en) * 1976-01-16 1984-01-24 Her Majesty The Queen In Right Of Canada Curable propellant binding systems with bonding agent combination
US4438091A (en) * 1981-07-07 1984-03-20 Dr. Karl Thomae Gmbh Bromhexine delayed-release pharmaceutical form
US4572833A (en) * 1982-08-13 1986-02-25 A/S Alfred Benzon Method for preparing a pharmaceutical controlled release composition
US4675405A (en) * 1984-09-21 1987-06-23 American Home Products Corporation Quinoline compounds as antiallergic and antithrombotic agents
US4728660A (en) * 1984-06-11 1988-03-01 University Of Miami Method of treating diseases arising from platelet hyperactivation
US5051262A (en) * 1979-12-07 1991-09-24 Elan Corp., P.L.C. Processes for the preparation of delayed action and programmed release pharmaceutical forms and medicaments obtained thereby
US5286736A (en) * 1990-11-22 1994-02-15 Dr. Karl Thomae Gmbh Pyridyl compounds and pharmaceutical compositions containing these compounds
US5387593A (en) * 1991-12-13 1995-02-07 Briston-Myers Squibb Piperazinyl-and piperidinyl-cyclohexanols
US5416099A (en) * 1991-10-29 1995-05-16 Merck & Co., Inc. Fibrinogen receptor antagonists
US5434150A (en) * 1991-09-06 1995-07-18 Dr. Karl Thomae Gmbh Condensed 5-membered heterocyclic compounds, processes for preparing them and pharmaceutical preparations containing these compounds
US5482948A (en) * 1991-12-14 1996-01-09 Dr. Karl Thomae Gmbh Pyridyl derivatives and pharmaceutical compositions comprising these compounds
US5637320A (en) * 1990-01-15 1997-06-10 Elan Corporation, Plc Controlled absorption naproxen formulation for once-daily administration
US5800836A (en) * 1992-08-05 1998-09-01 F. H. Faulding & Co. Limited Pelletized pharmaceutical composition
US5912014A (en) * 1996-03-15 1999-06-15 Unigene Laboratories, Inc. Oral salmon calcitonin pharmaceutical products
US6015577A (en) * 1986-08-13 2000-01-18 Dr. Karl Thomae GmbH Pharmaceutical compositions containing dipyridamole or mopidamol and acetylsalicylic acid or the physiologically acceptable salts thereof, processes for preparing them and their use in treating clot formation
US6039975A (en) * 1995-10-17 2000-03-21 Hoffman-La Roche Inc. Colon targeted delivery system
US6087380A (en) * 1949-11-24 2000-07-11 Boehringer Ingelheim Pharma Kg Disubstituted bicyclic heterocycles, the preparations and the use thereof as pharmaceutical compositions
US6120802A (en) * 1995-10-23 2000-09-19 Basf Aktiengesellschaft Method of producing multi-layer medicaments in solid form for oral or rectal administration
US6248770B1 (en) * 1998-07-09 2001-06-19 Boehringer Ingelheim Pharma Kg Benzimidazoles having antithrombotic activity
US20010010825A1 (en) * 1998-07-28 2001-08-02 Toshihiro Shimizu Rapidly disintegrable solid preparation
US6309666B1 (en) * 1995-07-20 2001-10-30 Tanabe Seiyaku Co., Ltd. Pharmaceutical preparation in form of coated capsule releasable at lower part of digestive tract
US6387917B1 (en) * 1999-10-20 2002-05-14 West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited Salts of opioid analgesics, particularly morphine, and methods of using same
US6414008B1 (en) * 1997-04-29 2002-07-02 Boehringer Ingelheim Pharma Kg Disubstituted bicyclic heterocycles, the preparation thereof, and their use as pharmaceutical compositions
US20030017203A1 (en) * 2001-03-08 2003-01-23 Unigene Laboratories, Inc. Oral peptide pharmaceutical dosage form and method of production
US20040258749A1 (en) * 2001-10-09 2004-12-23 Peter Guldner Oral dosage form for propiverine or its pharmaceutically acceptable salts with an extended release of the active ingredient
US6900229B2 (en) * 2002-08-02 2005-05-31 Boehringer Ingelheim Pharma Gmbh & Co. Kg Prodrugs of 1-methyl-2-(4-amidinophenylaminomethyl)-benzimidazol-5-yl-carboxylic acid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide
US20050234104A1 (en) * 2003-08-29 2005-10-20 Boehringer Ingelheim International Gmbh 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as medicament
US7148067B2 (en) * 2004-08-31 2006-12-12 The Board Of Trustees Of The University Of Illinois Thromboplastin reagents
US7202368B2 (en) * 2004-06-25 2007-04-10 Boehringer Ingelheim International Gmbh Process for the preparation of 4-(benzimidazolymethylamino) benzamidines

Family Cites Families (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4003909A (en) 1974-07-22 1977-01-18 E. R. Squibb & Sons, Inc. [(1,2,4-Oxadiazol-3-yl)phenyl]carbamic or thiocarbamic acid esters
LU81503A1 (en) 1978-07-15 1980-08-08 Boehringer Sohn Ingelheim Drug release form diffusioshuellen with insoluble porous
JPS58134033A (en) 1982-02-02 1983-08-10 Fujisawa Pharmaceut Co Ltd Drug composition
EP0088191A3 (en) 1982-03-08 1986-02-19 Imperial Chemical Industries Plc Polyester fibrefill blend
DE3237575A1 (en) 1982-10-09 1984-04-12 Thomae Gmbh Dr K New Oral mopidamolformen
GB8610572D0 (en) 1986-04-30 1986-06-04 Haessle Ab Pharmaceutical preparation
US4999226A (en) 1988-06-01 1991-03-12 Merrell Dow Pharmaceuticals Inc. Pharmaceutical compositions for piperidinoalkanol-ibuprofen combination
JPH03112928U (en) 1990-03-05 1991-11-19
ES2073301T3 (en) * 1991-05-20 1995-08-01 Marion Laboratories Inc Composition multi-layer controlled release.
KR100221695B1 (en) * 1991-08-12 1999-09-15 그린 마틴, 브라이언 쥐 테슬리 Pharmaceutical spheroid formulation
EP0540051B1 (en) 1991-10-31 1996-04-03 Daiichi Pharmaceutical Co., Ltd. Aromatic amidine derivatives and salts thereof
US5914132A (en) * 1993-02-26 1999-06-22 The Procter & Gamble Company Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery
JPH06340619A (en) 1993-05-03 1994-12-13 Bristol Myers Squibb Co Guanidinyl-or amidinyl-substituted methylaminoheterocycle as thrombin inhibitor
CA2134192A1 (en) 1993-11-12 1995-05-13 Michael L. Denney 5, 6-bicyclic glycoprotein iib/iiia antagonists
US5395626A (en) 1994-03-23 1995-03-07 Ortho Pharmaceutical Corporation Multilayered controlled release pharmaceutical dosage form
WO1996001621A1 (en) 1994-07-08 1996-01-25 Astra Aktiebolag New beads for controlled release and a pharmaceutical preparation containing the same
US5705190A (en) 1995-12-19 1998-01-06 Abbott Laboratories Controlled release formulation for poorly soluble basic drugs
FR2745500B1 (en) 1996-03-04 1998-04-03 Synthelabo Pharmaceutical formulations containing a sustained release of mizolastine
FR2752162B1 (en) 1996-08-07 1998-11-06 Jouveinal Lab Compresses trimebutine maleate film
WO1998025601A1 (en) 1996-12-13 1998-06-18 Merck & Co., Inc. Fibrinogen receptor antagonists
CA2277949C (en) 1997-02-18 2006-10-03 Boehringer Ingelheim Pharma Kg Disubstituted bicyclic heterocycles, the preparation and the use thereof as pharmaceutical compositions
EP1078925A1 (en) 1997-06-10 2001-02-28 Synthon B.V. 4-Phenylpiperidine compounds
DE19752843C2 (en) 1997-11-28 2003-01-09 Byk Gulden Lomberg Chem Fab Pharmaceutical preparation in tablet or pellet form for pantoprazole and omeprazole
CN1951371A (en) 1998-09-03 2007-04-25 阿斯特拉曾尼卡有限公司 Immediate release tablet
FR2793791B1 (en) 1999-05-19 2002-01-25 Univ Paris 7 Denis Diderot Novel compounds specific inhibitors of phospholipases A2
US6620439B1 (en) * 2000-10-03 2003-09-16 Atul M. Mehta Chrono delivery formulations and method of use thereof
DK1383731T3 (en) 2000-10-20 2009-12-07 Biocryst Pharm Inc Biaryl compounds as serine protease inhibitors
JP2004522759A (en) 2001-02-02 2004-07-29 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト Antithrombotic compound, use as their preparation and pharmaceutical compositions
DE10133786A1 (en) 2001-07-16 2003-02-06 Boehringer Ingelheim Pharma Use of thrombin inhibitors for the treatment of arthritis
DE10209982A1 (en) 2002-03-07 2003-09-25 Boehringer Ingelheim Pharma Oral dosage form to be administered for poorly soluble basic drugs
US20030181488A1 (en) 2002-03-07 2003-09-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
DK1870100T3 (en) 2002-03-07 2012-05-14 Boehringer Ingelheim Int 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) phenylamino] methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] -propionic acid ethyl ester methanesulfonate
DE10245624A1 (en) 2002-09-30 2004-04-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg Oral pharmaceutical composition comprises the thrombin inhibitor ethyl 3-(2-(4-(hexyloxycarbonylamidino)phenylaminomethyl)-1-methyl-1H-benzimidazole-5-carbonyl)-2-pyridylamino)propionate and an organic acid
KR100653334B1 (en) 2003-03-07 2006-12-04 주식회사 엘지생명과학 New process for preparing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulphonate
CN1812792A (en) 2003-04-24 2006-08-02 贝林格尔.英格海姆国际有限公司 Use of dipyridamole or mopidamole for treatment and prevention of thromboembolic diseases and disorders caused by excessive formation of thrombin and/or by elevated expression of thrombin receptors
DE10337697A1 (en) 2003-08-16 2005-03-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tablet containing 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] - propionate or its salts
US20050107438A1 (en) 2003-09-03 2005-05-19 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising 3-[(2-{[4-(Hexyloxycarbonylaminoiminomethyl) phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester or a salt therefore
CA2543650C (en) 2003-12-25 2010-10-26 Eisai Co., Ltd. A crystalline form of the salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide or the solvate of the salt and a process for preparing thesame
EP1574516A1 (en) 2004-03-05 2005-09-14 Sanofi-Aventis Antithrombotic compound
WO2006070878A1 (en) 2004-12-28 2006-07-06 Astellas Pharma Inc. Carboxylic acid derivative or salt thereof
US20060222640A1 (en) 2005-03-29 2006-10-05 Boehringer Ingelheim International Gmbh New pharmaceutical compositions for treatment of thrombosis
DE102005020002A1 (en) 2005-04-27 2006-11-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg New hexyloxycarbonylamino-imino-methyl-phenylamino-methyl-benzimidazole-pyridine-propionic acid-ethyl ester salts such as hydrochloride useful for the prophylaxis of vein thrombosis and stroke
DE102005025728A1 (en) 2005-06-04 2006-12-07 Boehringer Ingelheim Pharma Gmbh & Co. Kg Polymorphs of 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] -propionic acid ethyl ester
DE102005061623A1 (en) 2005-12-21 2007-06-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg An improved process for preparing 4- (Benzimidazolylmethylamino) -Benzamidinen and salts thereof
DE102005061624A1 (en) 2005-12-21 2007-06-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg An improved process for the preparation of salts of 4- (Benzimidazolylmethylamino) -Benzamidinen
US8399678B2 (en) * 2009-11-18 2013-03-19 Boehringer Ingelheim International Gmbh Process for the manufacture of dabigatran etexilate
CN102858762A (en) 2010-02-02 2013-01-02 埃吉斯药物股份公开有限公司 Novel salts for the manufacture of pharmaceutical compositions
WO2011107427A1 (en) * 2010-03-01 2011-09-09 Ratiopharm Gmbh Dabigatran etexilate-containing oral pharmaceutical composition
EP2806858A1 (en) 2012-01-24 2014-12-03 Boehringer Ingelheim International Gmbh Novel orally administered dabigatran formulation
CN103304539A (en) 2012-03-07 2013-09-18 天津药物研究院 Dabigatran etexilate malate, and preparation method and application thereof

Patent Citations (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6087380A (en) * 1949-11-24 2000-07-11 Boehringer Ingelheim Pharma Kg Disubstituted bicyclic heterocycles, the preparations and the use thereof as pharmaceutical compositions
US3887705A (en) * 1972-05-17 1975-06-03 Fabre Sa Pierre Medicaments intended for the prevention and treatment of capillary-venous deficiencies
US3968111A (en) * 1974-12-06 1976-07-06 Eli Lilly And Company 8,8-Disubstituted-6-methylergolines and related compounds
US4427468A (en) * 1976-01-16 1984-01-24 Her Majesty The Queen In Right Of Canada Curable propellant binding systems with bonding agent combination
US5051262A (en) * 1979-12-07 1991-09-24 Elan Corp., P.L.C. Processes for the preparation of delayed action and programmed release pharmaceutical forms and medicaments obtained thereby
US4367217A (en) * 1980-01-12 1983-01-04 Boehringer Ingelheim Gmbh Dipyricamole sustained release forms comprising lacquer-coated particles and the preparation thereof
US4427648A (en) * 1981-06-19 1984-01-24 Dr. Karl Thomae Gmbh Dipyridamole-containing pharmaceutical form
US4438091A (en) * 1981-07-07 1984-03-20 Dr. Karl Thomae Gmbh Bromhexine delayed-release pharmaceutical form
US4572833A (en) * 1982-08-13 1986-02-25 A/S Alfred Benzon Method for preparing a pharmaceutical controlled release composition
US4728660A (en) * 1984-06-11 1988-03-01 University Of Miami Method of treating diseases arising from platelet hyperactivation
US4675405A (en) * 1984-09-21 1987-06-23 American Home Products Corporation Quinoline compounds as antiallergic and antithrombotic agents
US6015577A (en) * 1986-08-13 2000-01-18 Dr. Karl Thomae GmbH Pharmaceutical compositions containing dipyridamole or mopidamol and acetylsalicylic acid or the physiologically acceptable salts thereof, processes for preparing them and their use in treating clot formation
US5637320A (en) * 1990-01-15 1997-06-10 Elan Corporation, Plc Controlled absorption naproxen formulation for once-daily administration
US5286736A (en) * 1990-11-22 1994-02-15 Dr. Karl Thomae Gmbh Pyridyl compounds and pharmaceutical compositions containing these compounds
US5434150A (en) * 1991-09-06 1995-07-18 Dr. Karl Thomae Gmbh Condensed 5-membered heterocyclic compounds, processes for preparing them and pharmaceutical preparations containing these compounds
US5416099A (en) * 1991-10-29 1995-05-16 Merck & Co., Inc. Fibrinogen receptor antagonists
US5387593A (en) * 1991-12-13 1995-02-07 Briston-Myers Squibb Piperazinyl-and piperidinyl-cyclohexanols
US5478828A (en) * 1991-12-13 1995-12-26 Bristol-Myers Squibb Company Piperazinyl-and piperidinyl-cyclohexanols
US5482948A (en) * 1991-12-14 1996-01-09 Dr. Karl Thomae Gmbh Pyridyl derivatives and pharmaceutical compositions comprising these compounds
US5800836A (en) * 1992-08-05 1998-09-01 F. H. Faulding & Co. Limited Pelletized pharmaceutical composition
US6309666B1 (en) * 1995-07-20 2001-10-30 Tanabe Seiyaku Co., Ltd. Pharmaceutical preparation in form of coated capsule releasable at lower part of digestive tract
US6039975A (en) * 1995-10-17 2000-03-21 Hoffman-La Roche Inc. Colon targeted delivery system
US6120802A (en) * 1995-10-23 2000-09-19 Basf Aktiengesellschaft Method of producing multi-layer medicaments in solid form for oral or rectal administration
US6086918A (en) * 1996-03-15 2000-07-11 Unigene Laboratories, Inc. Oral peptide pharmaceutical products
US5912014A (en) * 1996-03-15 1999-06-15 Unigene Laboratories, Inc. Oral salmon calcitonin pharmaceutical products
US6710055B2 (en) * 1997-02-18 2004-03-23 Boehringer Ingelheim Pharma Gmbh & Co., Kg Disubstituted bicyclic heterocycles, the preparation thereof, and their use as pharmaceutical compositions
US20030004181A1 (en) * 1997-02-18 2003-01-02 Boehringer Ingelheim Pharma Kg Disubstituted bicyclic heterocycles, the preparation thereof, and their use as pharmaceutical compositions
US6469039B1 (en) * 1997-02-18 2002-10-22 Boehringer Ingelheim Pharma Kg Disubstituted bicyclic heterocycles, the preparation and the use thereof as pharmaceutical compositions
US6414008B1 (en) * 1997-04-29 2002-07-02 Boehringer Ingelheim Pharma Kg Disubstituted bicyclic heterocycles, the preparation thereof, and their use as pharmaceutical compositions
US6248770B1 (en) * 1998-07-09 2001-06-19 Boehringer Ingelheim Pharma Kg Benzimidazoles having antithrombotic activity
US7070805B2 (en) * 1998-07-28 2006-07-04 Takeda Pharmaceutical Company Limited Rapidly disintegrable solid preparation
US20010010825A1 (en) * 1998-07-28 2001-08-02 Toshihiro Shimizu Rapidly disintegrable solid preparation
US6387917B1 (en) * 1999-10-20 2002-05-14 West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited Salts of opioid analgesics, particularly morphine, and methods of using same
US7316819B2 (en) * 2001-03-08 2008-01-08 Unigene Laboratories, Inc. Oral peptide pharmaceutical dosage form and method of production
US20030017203A1 (en) * 2001-03-08 2003-01-23 Unigene Laboratories, Inc. Oral peptide pharmaceutical dosage form and method of production
US20040258749A1 (en) * 2001-10-09 2004-12-23 Peter Guldner Oral dosage form for propiverine or its pharmaceutically acceptable salts with an extended release of the active ingredient
US20080317848A2 (en) * 2001-10-09 2008-12-25 Apogepha Arzneimittel Gmbh Oral Dosage Forms for Propiverine or Pharmaceutically Acceptable Salts Thereof Having Prolonged Release of the Active Agent
US7189743B2 (en) * 2002-08-02 2007-03-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Prodrugs of 1-methyl-2-(4-amidinophenylaminomethyl)-benzimidazol-5-yl-carboxylic acid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide
US6900229B2 (en) * 2002-08-02 2005-05-31 Boehringer Ingelheim Pharma Gmbh & Co. Kg Prodrugs of 1-methyl-2-(4-amidinophenylaminomethyl)-benzimidazol-5-yl-carboxylic acid-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amide
US7932273B2 (en) * 2003-08-29 2011-04-26 Boehringer Ingelheim International Gmbh 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl) phenylamino]methyl}-1-methyl-1H-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as a medicament
US20050234104A1 (en) * 2003-08-29 2005-10-20 Boehringer Ingelheim International Gmbh 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as medicament
US7202368B2 (en) * 2004-06-25 2007-04-10 Boehringer Ingelheim International Gmbh Process for the preparation of 4-(benzimidazolymethylamino) benzamidines
US7148067B2 (en) * 2004-08-31 2006-12-12 The Board Of Trustees Of The University Of Illinois Thromboplastin reagents

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060183779A1 (en) * 2002-03-07 2006-08-17 Boehringer Ingelheim Pharma Gmbh & Co., Kg Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
US9925174B2 (en) 2002-03-07 2018-03-27 Boehringer Ingelheim International Gmbh Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof
US20050038077A1 (en) * 2003-08-16 2005-02-17 Boehringer Ingelheim International Gmbh Tablet containing 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H- benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethylester or the salts thereof
US7932273B2 (en) 2003-08-29 2011-04-26 Boehringer Ingelheim International Gmbh 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl) phenylamino]methyl}-1-methyl-1H-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as a medicament
US20080119523A1 (en) * 2003-08-29 2008-05-22 Boehringer Ingelheim International Gmbh 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl) phenylamino]methyl}-1-methyl-1h-benzimidazol-5- carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as a medicament
US20050234104A1 (en) * 2003-08-29 2005-10-20 Boehringer Ingelheim International Gmbh 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as medicament
US20070298095A1 (en) * 2004-05-24 2007-12-27 Shionogi Qualicaps Co., Ltd. Surface-Modified and Solubility-Improved Hard Capsule
US7866474B2 (en) 2004-12-21 2011-01-11 Boehringer Ingelheim International Gmbh Film container
US20060131204A1 (en) * 2004-12-21 2006-06-22 Boehringer Ingelheim International Gmbh Film container
US20060247278A1 (en) * 2005-04-27 2006-11-02 Boehringer Ingelheim International Gmbh Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester
US20080200514A1 (en) * 2006-07-17 2008-08-21 Boehringer Ingelheim International Gmbh Indications for Direct Thrombin Inhibitors
US20100173947A1 (en) * 2006-07-17 2010-07-08 Boehringer Ingelheim International Gmbh New Indications for Direct Thrombin Inhibitors
US20110129538A1 (en) * 2008-03-28 2011-06-02 Boehringer Ingelheim International Gmbh Process for preparing orally administered dabigatran formulations
US9089488B2 (en) 2008-07-14 2015-07-28 Boehringer Ingelheim International Gmbh Method for manufacturing medicinal compounds containing dabigatran
US20110123635A1 (en) * 2008-07-14 2011-05-26 Boehringer Ingelheim International Gmbh Method for manufacturing medicinal compounds containing dabigatran
US20110190352A1 (en) * 2008-08-19 2011-08-04 Boehringer Ingelheim International Gmbh Use of dabigatranetexilate for treating patients with pulmonary hypertension
US8962574B2 (en) 2008-11-11 2015-02-24 Boehringer Ingelheim International Gmbh Method for treating or preventing thrombosis using dabigatran etexilate or a salt thereof with improved safety profile over conventional warfarin therapy
US20130052262A1 (en) * 2010-03-01 2013-02-28 Sandra Brueck Dabigatran etexilate-containing oral pharmaceutical composition
EP2588090B1 (en) 2010-07-01 2017-04-19 KRKA, tovarna zdravil, d.d., Novo mesto Pharmaceutical oral dosage forms comprising dabigatran etexilate and its pharmaceutically acceptable salts
US20120301541A1 (en) * 2011-05-24 2012-11-29 Haronsky Elina Compressed core for pharmaceutical composition
WO2012162492A1 (en) 2011-05-24 2012-11-29 Teva Pharmaceutical Industries Ltd. Compressed core comprising organic acids for a pharmaceutical composition
WO2013110567A1 (en) * 2012-01-24 2013-08-01 Boehringer Ingelheim International Gmbh Novel orally administered dabigatran formulation
EP2740471A1 (en) * 2012-12-07 2014-06-11 Hexal AG Oral pharmaceutical composition comprising dabigatran etexilate
WO2014086857A1 (en) * 2012-12-07 2014-06-12 Hexal Ag Oral pharmaceutical composition comprising dabigatran etexilate
US20170035745A1 (en) * 2014-04-11 2017-02-09 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Pharmaceutical combinations of dabigatran and proton pump inhibitors
WO2016009405A1 (en) 2014-07-18 2016-01-21 Sifavitor S.R.L. Crystalline compounds of dabigatran etexilate

Also Published As

Publication number Publication date Type
US9925174B2 (en) 2018-03-27 grant
US20180221359A1 (en) 2018-08-09 application
US20060183779A1 (en) 2006-08-17 application
US20150005350A1 (en) 2015-01-01 application

Similar Documents

Publication Publication Date Title
US6013281A (en) Method of making a pharmaceutical dosage form comprising a proton pump inhibitor
US6048547A (en) Process for manufacturing solid compositions containing polyethylene oxide and an active ingredient
US6379705B1 (en) Stable multi-unitary pharmaceutical preparations containing substituted benzimidazoles
US6391342B1 (en) Pharmaceutical formulation comprising a 2- [(2-pyridinyl) methyl] sulfinyl benzimidazole having anti-ulcer activity and a process for the preparation of such formulation
US6328994B1 (en) Orally disintegrable tablets
US20040213847A1 (en) Delayed release pharmaceutical compositions containing proton pump inhibitors
US20080038347A1 (en) Extended release tablet formulations of flibanserin and method for manufacturing the same
US20020098242A1 (en) Oral pharmaceutical preparation comprising an antiulcer activity compound, and process for its production
US20040019096A1 (en) Novel formulations of carvedilol
US20020064555A1 (en) Proton pump inhibitor formulation
US6780436B1 (en) Solid oral pharmaceutical formulation of modified release that contains an acid labile benzimidazole compound
US6515010B1 (en) Carvedilol methanesulfonate
EP0342522A1 (en) Peroral preparation of an acid-unstable compound
WO2002065834A2 (en) Novel formulations of carvedilol
US6855336B2 (en) Omeprazole formulation
US20090263475A1 (en) Dexlansoprazole compositions
US20090098199A1 (en) Methods of treating gastrointestinal disorders independent of the intake of food
US20050095293A1 (en) Administration form for the oral application of poorly soluble drugs
WO2010140111A1 (en) Pharmaceutical compositions containing a combination of an antihistamine and a decongestant
US20040220250A1 (en) Novel oral dosage form for carvedilol
US6620432B2 (en) Phenytoin sodium pharmaceutical compositions
WO2008064202A2 (en) Modified-release formulations of calcium receptor-active compounds
US7838027B2 (en) Pantoprazole multiparticulate formulations
WO2005065660A2 (en) Ziprasidone formulations
US20060051421A1 (en) Stable pharmaceutical formulations of benzimidazole compounds

Legal Events

Date Code Title Description
AS Assignment

Owner name: BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HAUEL, NORBERT;SIEGER, PETER;REEL/FRAME:023102/0029;SIGNING DATES FROM 20090528 TO 20090717

AS Assignment

Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG;REEL/FRAME:028825/0475

Effective date: 20120806