WO2017077440A1 - Novel pharmaceutical compositions comprising dabigatran - Google Patents
Novel pharmaceutical compositions comprising dabigatran Download PDFInfo
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- WO2017077440A1 WO2017077440A1 PCT/IB2016/056522 IB2016056522W WO2017077440A1 WO 2017077440 A1 WO2017077440 A1 WO 2017077440A1 IB 2016056522 W IB2016056522 W IB 2016056522W WO 2017077440 A1 WO2017077440 A1 WO 2017077440A1
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- WIPO (PCT)
- Prior art keywords
- acid
- dabigatran etexilate
- composition according
- amidosulfonic
- dabigatran
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
Definitions
- Subject-matter of the present invention are novel pharmaceutical compositions comprising dabigatran, in particular in combination with amidosulfonic acid and the use thereof in therapy.
- Dabigatran etexilate is the International Nonproprietary Name (INN) of the ethyl ester of 3-(((2-(((4-(N'-(hexyloxycarbonyl-carbamimidoyl)-phenyl)amino)methyl]-l - methyl- lH-benzimidazol-5-yl)carbonyl)-pyridin-2-yl-amino)-propionic acid of formula (I)
- Dabigatran etexilate is a new generation anticoagulant acting by directly inhibiting in a reversible way the thrombin both free and linked to fibrin.
- thrombin allows the conversion of fibrinogen into fibrin and its inhibition avoids the formation of thrombi.
- Dabigatran etexilate presents poor solubility and is currently on the market as mesylate salt under the trade name Pradaxa ® in the form of hard capsules.
- Pradaxa ® obtained a specific Certificate of Complementary Protection in Italy on the basis of Patent EP1485094B1.
- Said Patent claims an oral pharmaceutical composition comprising dabigatran etexilate, in particular dabigatran etexilate mesylate, such composition comprising a spherical core containing an organic acid, in particular tartaric acid, and an external layer separated from the central core and containing the active ingredient and a binder.
- This pharmaceutical composition added with an organic acid, leads to improved solubility and bioavailability of the active ingredient.
- WO201 1/107427 describes a composition comprising dabigatran etexilate or a salt thereof, together with an inorganic acid, preferably hydrochloric acid, phosphoric acid or sulfuric acid. Even though the claims relates, in a generic way, to compositions wherein the active ingredient seems to be simply mixed with said organic acid, the patent reports that preferably the acid is microencapsulated or absorbed onto a binder.
- dabigatran etexilate is not stable and tends to lose the ester moiety, as also reported in WO2015/044375 with reference to the compositions described in WO2005/018615, wherein dabigatran etexilate is directly mixed with organic acids in conventional tablets.
- composition described in WO201 1/107427 must be necessarily pre-formulated in relation to some of its components, specifically the employed inorganic acid, which acid must be microencapsulated in order to avoid its contact with the active ingredient.
- It is an object of the invention to provide a novel pharmaceutical composition comprising dabigatran etexilate, or salts thereof, which is stable and does not require laborious industrial manipulations.
- It is another object of the invention to provide a novel pharmaceutical composition comprising dabigatran etexilate, or salts thereof, which provides good solubility and bioavailability of the active ingredient.
- Figure 1 shows the dissolution profile of two Pradaxa ® tablets.
- Figure 2 shows the dissolution profile of a composition of dabigatran etexilate mesylate alone and of compositions added with amidosulfonic, gallic and orotic acid.
- Figure 3 shows the dissolution profile of a composition of dabigatran etexilate gallate alone and of compositions added with amidosulfonic, gallic and orotic acid.
- the present Applicant has now unexpectedly and surprisingly found that a particular acid, the amidosulfonic acid, can be directly mixed with dabigatran etexilate, or with pharmaceutically acceptable salts thereof, together with conventional carriers and/or excipients, to provide a stable, soluble and bioavailable oral pharmaceutical composition.
- subject-matter of the invention is an oral pharmaceutical composition
- an oral pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salts thereof, and amidosulfonic acid.
- Hydrates and/or solvates of dabigatran etexilate salts are comprised as well in the compositions of the present invention.
- Amidosulfonic acid also known as sulfamic acid, has the following structural formula:
- dabigatran etexilate is in the form of one of its pharmaceutically acceptable salts, advantageously in the form of its mesylate salt or its gallate salt or its hydrates, e.g. dabigatran etexilate gallate monohydrate.
- dabigatran etexilate is in the form of a salt formed with an acid selected from orotic acid, p-coumaric acid, hippuric acid, ferulic acid, vanillic acid, aconitic acid, adipic acid, D-gluconic acid, a-ketoglutaric acid, itaconic acid, pyruvic acid, amidosulfonic acid, D-quinic acid, sebacic acid and glutaric acid.
- an acid selected from orotic acid, p-coumaric acid, hippuric acid, ferulic acid, vanillic acid, aconitic acid, adipic acid, D-gluconic acid, a-ketoglutaric acid, itaconic acid, pyruvic acid, amidosulfonic acid, D-quinic acid, sebacic acid and glutaric acid.
- gallate monohydrate salt examples include mesylate salt and gallate salt, preferably the gallate monohydrate salt, other preferred salts are the following: - dabigatran etexilate orotate anhydrous;
- vanillate hydrate - dabigatran etexilate vanillate hydrate.
- amidosulfonic acid is present in amount of 5- 40 wt% relative to the weight of the active ingredient, advantageously of 10-35 wt%, e.g. about 25-35 wt%, where herein the weight of the active ingredient is always relative to the unsalified dabigatran etexilate.
- composition of the invention is an oral composition, preferably solid, and comprises as well conventional excipients and/or carriers.
- the composition can be in the form of tables, capsules, granules or powders and can be prepared in a conventional way by adding carriers which are usually employed in the field of pharmaceutical art, such as an excipient, a binder, a disintegrant, a lubricant, a taste modifier, a solubilization additive, a suspension agent, a coating agent and/or the like.
- carriers which are usually employed in the field of pharmaceutical art, such as an excipient, a binder, a disintegrant, a lubricant, a taste modifier, a solubilization additive, a suspension agent, a coating agent and/or the like.
- excipients can be used such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and polyvinyl pyrrolidone; disintegrants such as anhydrous starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan ester of fatty acids, sodium lauryl sulfate, stearic monoglycerides, crospovidone, starch and lactose; absorption adjuvants such as quaternary ammonium salts and sodium lauryl sulfate; humectants such as glycerine and starch; absorbents such as starch, lactose, kaolin, bentonite and colloidal silica; glidants such as silica; and
- excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oils, kaolin and talc, gum arabic powder, tragacanth powder, gelatin, acacia, hypromellose, dimethicone, cellulose and cellulose derivatives can be used.
- a dye, a preservative, a flavor and/or a sweetener can also be incorporated.
- compositions of the invention are in the form of capsules, preferably hard capsules, and comprise dabigatran etexilate mesylate and amidosulfonic acid.
- Preferred compositions in the form of capsules comprise 50-150 mg, e.g. 75, 1 10 or 150 mg of dabigatran etexilate, in the form of mesylate and 15-30 mg of amidosulfonic acid.
- compositions are in the form of tablets and comprise 50-150 mg, e.g. 75, 1 10 or 150 mg of dabigatran etexilate, in the form of mesylate, and 15-30 mg of amidosulfonic acid.
- compositions of the invention are in the form of capsules, preferably hard capsules, and comprise dabigatran etexilate gallate, e.g. dabigatran etexilate gallate monohydrate and amidosulfonic acid.
- compositions in the form of capsules e.g. hard capsules, comprise
- compositions are in the form of tablets and comprise 50-150 mg, e.g. 75, 1 10 or 150 mg of dabigatran etexilate in the form of gallate, e.g. dabigatran etexilate gallate monohydrate, and 15-30 mg of amidosulfonic acid.
- the doses of the active ingredient are intended to be expressed for the unsalified dabigatran etexilate, and are therefore independent of the salt used.
- compositions of the invention showed to be stable over time, soluble and bioavailable.
- solubility proved to be significantly higher than the compositions containing salified dabigatran etexilate alone and also than compositions containing salified dabigatran etexilate and organic acid.
- Subject-matter of the invention is the use of the composition of the invention in therapy, in particular of a composition comprising dabigatran etexilate mesylate and amidosulfonic acid or dabigatran etexilate gallate and amidosulfonic acid, advantageously in the anticoagulation therapy and for the prevention of venous thromboembolic events and for the prevention of stroke and systemic embolism in adult patients with atrial fibrillation.
- the compositions of the invention will be advantageously administered orally 1 to 3 times daily, according to need and the condition of the subject. Health professionals can determine the effective dose for any kind of therapy.
- Subject-matter of the invention is a method for the treatment of coagulation disorders and the prevention of venous thromboembolic events which comprises administering a composition according to the invention to a subject in need thereof.
- composition in the form of tablets Composition in the form of tablets
- Tablets are prepared, containing 75 g of dabigatran etexilate mesylate; 15 mg of amidosulfonic acid; excipients: mannitol, crospovidone, esters of sucrose fatty acids, magnesium stearate.
- composition in the form of tablets Tablets are prepared, containing 50 g of dabigatran etexilate mesylate; 10 mg of amidosulfonic acid; excipients: mannitol, crospovidone, esters of sucrose fatty acids, sodium stearyl fumarate.
- composition in the form of tablets Composition in the form of tablets
- Tablets are prepared, containing 150 g of dabigatran etexilate mesylate; 30 mg of amidosulfonic acid; excipients: mannitol, crospovidone, esters of sucrose fatty acids, sodium stearyl fumarate.
- composition in the form of capsules are provided.
- Capsules are prepared, containing 1 10 g of dabigatran etexilate mesylate; 20 mg of amidosulfonic acid; excipients: mannitol, crospovidone, esters of sucrose fatty acids, magnesium stearate.
- Dissolution medium Phosphate buffer pH 6.8
- Peak width > 0.0031 min (0.63 s resp. Time) (80 Hz)
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Abstract
Object of the invention are novel pharmaceutical compositions comprising dabigatran, in particular in combination with amidosulfonic acid and the use thereof in therapy.
Description
"Novel pharmaceutical compositions comprising dabigatran" Abstract of the Invention
Subject-matter of the present invention are novel pharmaceutical compositions comprising dabigatran, in particular in combination with amidosulfonic acid and the use thereof in therapy.
Technical Field
Dabigatran etexilate is the International Nonproprietary Name (INN) of the ethyl ester of 3-(((2-(((4-(N'-(hexyloxycarbonyl-carbamimidoyl)-phenyl)amino)methyl]-l - methyl- lH-benzimidazol-5-yl)carbonyl)-pyridin-2-yl-amino)-propionic acid of formula (I)
Dabigatran etexilate is a new generation anticoagulant acting by directly inhibiting in a reversible way the thrombin both free and linked to fibrin. As it is known, in the coagulation cascade thrombin allows the conversion of fibrinogen into fibrin and its inhibition avoids the formation of thrombi.
Dabigatran etexilate presents poor solubility and is currently on the market as mesylate salt under the trade name Pradaxa® in the form of hard capsules. Pradaxa® obtained a specific Certificate of Complementary Protection in Italy on the basis of Patent EP1485094B1. Said Patent claims an oral pharmaceutical composition comprising dabigatran etexilate, in particular dabigatran etexilate mesylate, such composition comprising a spherical core containing an organic acid, in particular tartaric acid, and an external layer separated from the central core and containing the active ingredient and a binder. This pharmaceutical composition, added with an organic acid, leads to improved solubility and bioavailability of the active ingredient. The industrial process for the preparation of such compositions is complex and expensive.
WO201 1/107427 describes a composition comprising dabigatran etexilate or a salt thereof, together with an inorganic acid, preferably hydrochloric acid, phosphoric acid or sulfuric acid. Even though the claims relates, in a generic way, to compositions wherein the active ingredient seems to be simply mixed with said organic acid, the patent reports that preferably the acid is microencapsulated or absorbed onto a binder. As a matter of fact it is known that, in presence of acids, dabigatran etexilate is not stable and tends to lose the ester moiety, as also reported in WO2015/044375 with reference to the compositions described in WO2005/018615, wherein dabigatran etexilate is directly mixed with organic acids in conventional tablets.
Therefore, also the composition described in WO201 1/107427 must be necessarily pre-formulated in relation to some of its components, specifically the employed inorganic acid, which acid must be microencapsulated in order to avoid its contact with the active ingredient.
There is therefore the real need to have new pharmaceutical compositions which improve stability, bioavailability and pharmacokinetics of dabigatran etexilate, while not worsening the industrial production of the composition itself with laborious and expensive steps in the preparation of the pharmaceutical form.
Objects of the Invention
It is an object of the invention to provide a novel pharmaceutical composition comprising dabigatran etexilate, or salts thereof, which is stable and does not require laborious industrial manipulations.
It is another object of the invention to provide a novel pharmaceutical composition comprising dabigatran etexilate, or salts thereof, which provides good solubility and bioavailability of the active ingredient.
Brief Description of the Drawings
Figure 1 shows the dissolution profile of two Pradaxa® tablets.
Figure 2 shows the dissolution profile of a composition of dabigatran etexilate mesylate alone and of compositions added with amidosulfonic, gallic and orotic acid. Figure 3 shows the dissolution profile of a composition of dabigatran etexilate gallate alone and of compositions added with amidosulfonic, gallic and orotic acid.
Description of the Invention
The present Applicant has now unexpectedly and surprisingly found that a particular acid, the amidosulfonic acid, can be directly mixed with dabigatran etexilate, or with pharmaceutically acceptable salts thereof, together with conventional carriers and/or excipients, to provide a stable, soluble and bioavailable oral pharmaceutical composition.
Therefore subject-matter of the invention, according to one of the aspects thereof, is an oral pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salts thereof, and amidosulfonic acid.
Hydrates and/or solvates of dabigatran etexilate salts are comprised as well in the compositions of the present invention.
Amidosulfonic acid, also known as sulfamic acid, has the following structural formula:
O
I I
0=S- NH.
I 2
OH
According to a preferred embodiment, dabigatran etexilate is in the form of one of its pharmaceutically acceptable salts, advantageously in the form of its mesylate salt or its gallate salt or its hydrates, e.g. dabigatran etexilate gallate monohydrate.
According to another preferred embodiment, dabigatran etexilate is in the form of a salt formed with an acid selected from orotic acid, p-coumaric acid, hippuric acid, ferulic acid, vanillic acid, aconitic acid, adipic acid, D-gluconic acid, a-ketoglutaric acid, itaconic acid, pyruvic acid, amidosulfonic acid, D-quinic acid, sebacic acid and glutaric acid.
These salts, as well as the salt with gallic acid, can be prepared as described in the Patent Application PCT/IB2015/055436, filed on 17 July 2015 and claiming a priority of 18 July 2014, in the name of the same Applicant, herein incorporated as reference. Such PCT Application will be available to the general public on the date of the publication of the present application.
In addition to mesylate salt and gallate salt, preferably the gallate monohydrate salt, other preferred salts are the following:
- dabigatran etexilate orotate anhydrous;
- dabigatran etexilate aconitate anhydrous;
- dabigatran etexilate adipate anhydrous;
- dabigatran etexilate p-coumarate acetone solvate;
- dabigatran etexilate ethyl D-gluconate acetone solvate;
- cc-ketoglutarate dabigatran etexilate anhydrous;
- dabigatran etexilate hippurate anhydrous;
- dabigatran etexilate itaconate hydrate;
- dabigatran etexilate pyruvate hydrate;
- dabigatran etexilate sulfamate anhydrous;
- dabigatran etexilate D-(-)-quinate anhydrous;
- dabigatran etexilate ferulate anhydrous;
- dabigatran etexilate sebacate anhydrous;
- dabigatran etexilate glutarate anhydrous; and
- dabigatran etexilate vanillate hydrate.
According to a preferred embodiment, amidosulfonic acid is present in amount of 5- 40 wt% relative to the weight of the active ingredient, advantageously of 10-35 wt%, e.g. about 25-35 wt%, where herein the weight of the active ingredient is always relative to the unsalified dabigatran etexilate.
The composition of the invention is an oral composition, preferably solid, and comprises as well conventional excipients and/or carriers.
The composition can be in the form of tables, capsules, granules or powders and can be prepared in a conventional way by adding carriers which are usually employed in the field of pharmaceutical art, such as an excipient, a binder, a disintegrant, a lubricant, a taste modifier, a solubilization additive, a suspension agent, a coating agent and/or the like.
For example for the formation of tablets, excipients can be used such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and polyvinyl pyrrolidone; disintegrants such as anhydrous starch, sodium alginate, agar powder, sodium bicarbonate, calcium
carbonate, polyoxyethylene sorbitan ester of fatty acids, sodium lauryl sulfate, stearic monoglycerides, crospovidone, starch and lactose; absorption adjuvants such as quaternary ammonium salts and sodium lauryl sulfate; humectants such as glycerine and starch; absorbents such as starch, lactose, kaolin, bentonite and colloidal silica; glidants such as silica; and lubricants such as purified talc, stearates, boric acid powder and polyethylene glycol. Tablets can be optionally coated, just with a sugar film or polymers in order to obtain particular pharmaceutical forms, e.g. gastro- resistant or sustained release, according to known techniques.
For the formation of capsules, excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oils, kaolin and talc, gum arabic powder, tragacanth powder, gelatin, acacia, hypromellose, dimethicone, cellulose and cellulose derivatives can be used.
If needed or desired, a dye, a preservative, a flavor and/or a sweetener can also be incorporated.
Preferably, the compositions of the invention are in the form of capsules, preferably hard capsules, and comprise dabigatran etexilate mesylate and amidosulfonic acid. Preferred compositions in the form of capsules comprise 50-150 mg, e.g. 75, 1 10 or 150 mg of dabigatran etexilate, in the form of mesylate and 15-30 mg of amidosulfonic acid.
Other preferred compositions are in the form of tablets and comprise 50-150 mg, e.g. 75, 1 10 or 150 mg of dabigatran etexilate, in the form of mesylate, and 15-30 mg of amidosulfonic acid.
According to another preferred embodiment, the compositions of the invention are in the form of capsules, preferably hard capsules, and comprise dabigatran etexilate gallate, e.g. dabigatran etexilate gallate monohydrate and amidosulfonic acid.
Other preferred compositions in the form of capsules, e.g. hard capsules, comprise
50-150 mg, e.g. 75, 1 10 or 150 mg of dabigatran etexilate in the form of gallate, e.g. dabigatran etexilate gallate monohydrate, and 15-30 mg of amidosulfonic acid.
Other preferred compositions are in the form of tablets and comprise 50-150 mg, e.g. 75, 1 10 or 150 mg of dabigatran etexilate in the form of gallate, e.g. dabigatran etexilate gallate monohydrate, and 15-30 mg of amidosulfonic acid.
In the present description and in the following claims, the doses of the active ingredient are intended to be expressed for the unsalified dabigatran etexilate, and are therefore independent of the salt used.
Illustrative compositions are reported in the Experimental Section of the present description purely by way of example.
The compositions of the invention showed to be stable over time, soluble and bioavailable.
In particular, the solubility proved to be significantly higher than the compositions containing salified dabigatran etexilate alone and also than compositions containing salified dabigatran etexilate and organic acid.
Subject-matter of the invention, according to another of the aspects thereof, is the use of the composition of the invention in therapy, in particular of a composition comprising dabigatran etexilate mesylate and amidosulfonic acid or dabigatran etexilate gallate and amidosulfonic acid, advantageously in the anticoagulation therapy and for the prevention of venous thromboembolic events and for the prevention of stroke and systemic embolism in adult patients with atrial fibrillation. For therapy, the compositions of the invention will be advantageously administered orally 1 to 3 times daily, according to need and the condition of the subject. Health professionals can determine the effective dose for any kind of therapy.
Subject-matter of the invention, according to another of the aspects thereof, is a method for the treatment of coagulation disorders and the prevention of venous thromboembolic events which comprises administering a composition according to the invention to a subject in need thereof.
Experimental Section
Example 1
Composition in the form of tablets
Tablets are prepared, containing 75 g of dabigatran etexilate mesylate; 15 mg of amidosulfonic acid; excipients: mannitol, crospovidone, esters of sucrose fatty acids, magnesium stearate.
Example 2
Composition in the form of tablets
Tablets are prepared, containing 50 g of dabigatran etexilate mesylate; 10 mg of amidosulfonic acid; excipients: mannitol, crospovidone, esters of sucrose fatty acids, sodium stearyl fumarate.
Example 3
Composition in the form of tablets
Tablets are prepared, containing 150 g of dabigatran etexilate mesylate; 30 mg of amidosulfonic acid; excipients: mannitol, crospovidone, esters of sucrose fatty acids, sodium stearyl fumarate.
Example 4
Composition in the form of capsules
Capsules are prepared, containing 1 10 g of dabigatran etexilate mesylate; 20 mg of amidosulfonic acid; excipients: mannitol, crospovidone, esters of sucrose fatty acids, magnesium stearate.
Example 5
Solubility Tests
Instruments and conditions
Instrument for dissolution: Hanson's Vision Classic 6 dissolution tester
Dissolution medium: Phosphate buffer pH 6.8
Temperature: 37±0.5°C
Volume: 80 mL
Time: 24 hours
Stirring: 100 rpm
Sampling times: 5, 15, 30, 45, 60, 120, 180, 240, 280, 1440 min
Repetitions: 2 per each sample
1 mL of the sample is collected, filtered with 0.20 μπι filter and injected into HPLC system.
HPLC
Instrument: 1200 Infinity Series AGILENT
G4220B - 1290 BinPumpVL
G4226A - 1290 Sampler
G1316A - 1260 TCC
G1314F - 1260 VWD
Column: inetex 1.7 μm C8 100A, 100 x 3 mm, Phenomenex
Temperature of the Column: 30 ± 0.3 °C
Mobile Phase: A: 0.1% Formic Acid in H20
B: ACN
Linear Gradient: t=0 A 75% - B 25%
t=4 A 25% - B 75%
t=6 A 0% - B 100%
Post run: 2 min.
Flux: 0.6 mL/min
Initial pressure: 600 bar
Detection wavelength: 220 nm
Peak width: > 0.0031 min (0.63 s resp. Time) (80 Hz)
Injection volume: 3 μΐ
Stop analysis: 7 min
Retention time: 2.62 min
Diluent: H2O+0.1% Formic
Example 5a
Solubility tests on Pradaxa®
Two capsules from the same blister underwent the kinetic dissolution test of example 3. As shown in Figure 1 , the samples showed different behavior in the first 45 minutes. The event has been probably caused by the difficult disaggregation of the capsules that, in one case, produced a gel limiting the active ingredient release.
Example 5b
Solubility comparison test
Solubility tests have been performed on tablets made of
a. 50% dabigatran etexilate mesylate and 50% microcellulose
b. 40% dabigatran etexilate mesylate, 50% microcellulose and 10% amidosulfonic acid
c. 40% dabigatran etexilate mesylate, 50% microcellulose and 10% gallic acid d. 40% dabigatran etexilate mesylate, 50% microcellulose and 10% orotic acid
e. 40% dabigatran etexilate gallate, 50% microcellulose
f. 40% dabigatran etexilate gallate, 50% microcellulose and 10% amidosulfonic acid
g- 40% dabigatran etexilate gallate, 50% microcellulose and 10% gallic acid h. 40% dabigatran etexilate mesylate, 50% microcellulose and 10% orotic acid The percentages are expressed by weight relative to the total weight of the composition.
In Table 1 the solubility data for the a-d samples are reported and compared (average of two tests per each sample)
Table 1
In Table 2 the solubility data for the e-h samples are reported and compared (average of two tests per each sample)
Table 2
N/D = not detectable
The dissolution profiles are shown in Figures 2 and 3. It can be confirmed that dissolution is significantly improved in the presence of amidosulfomc acid with respect to compositions containing dabigatran etexilate mesylate or gallate alone and to compositions containing the gallic acid or orotic acid organic acids.
Claims
1. An oral pharmaceutical composition comprising dabigatran etexilate, or pharmaceutically acceptable salts thereof, and amidosulfonic acid.
2. The composition according to claim 1 , characterized in that amidosulfonic acid is present in an amount of 5-40 % by weight with respect to dabigatran etexilate weight.
3. The composition according to claim 2, characterized in that amidosulfonic acid is present in an amount of 25-35% by weight with respect to dabigatran etexilate weight.
4. The composition according to any one of the preceding claims, characterized in that it is in solid form, together with conventional excipients and/or carriers.
5. The composition according to any one of the preceding claims, characterized in that it is in the form of tablets or capsules.
6. The composition according to any one of the preceding claims, characterized in that it comprises dabigatran etexilate mesylate and amidosulfonic acid.
7. The composition according to any one of the preceding claims, characterized in that it comprises dabigatran etexilate gallate, or a hydrate thereof, and amidosulfonic acid.
8. The composition according to any one of the preceding claims, characterized in that it comprises 50-100 mg of dabigatran etexilate, in the form of mesylate or gallate, and 15-30 mg of amidosulfonic acid.
9. The composition according to any one of claims 1 to 5, characterized in that dabigatran etexilate is in the form of a salt formed with an acid selected from orotic acid, p-coumaric acid, hippuric acid, ferulic acid, vanillic acid, aconitic acid, adipic acid, D-gluconic acid, a-ketoglutaric acid, itaconic acid, pyruvic acid, amidosulfonic acid, D-quinic acid, sebacic acid and glutaric acid.
10. The composition according to any one of the preceding claims for its use in therapy.
1 1. The composition according to claim 10, for its use in the anticoagulation therapy and in the prevention of venous thromboembolic events and in the
prevention of stroke and systemic embolism in adult patients suffering from atrial fibrillation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITUB2015A005035A ITUB20155035A1 (en) | 2015-11-02 | 2015-11-02 | New pharmaceutical compositions including dabigatran. |
| ITUB2015A005035 | 2015-11-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2017077440A1 true WO2017077440A1 (en) | 2017-05-11 |
Family
ID=55410023
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2016/056522 WO2017077440A1 (en) | 2015-11-02 | 2016-10-28 | Novel pharmaceutical compositions comprising dabigatran |
Country Status (2)
| Country | Link |
|---|---|
| IT (1) | ITUB20155035A1 (en) |
| WO (1) | WO2017077440A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2722033A1 (en) * | 2012-10-19 | 2014-04-23 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical Compositions of Dabigatran Free Base |
| CN104434867A (en) * | 2013-09-12 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Composition of Pradaxa and preparation method thereof |
| WO2015044375A1 (en) * | 2013-09-27 | 2015-04-02 | Ratiopharm Gmbh | Pharmaceutical preparation comprising dabigatran etexilate bismesylate |
-
2015
- 2015-11-02 IT ITUB2015A005035A patent/ITUB20155035A1/en unknown
-
2016
- 2016-10-28 WO PCT/IB2016/056522 patent/WO2017077440A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2722033A1 (en) * | 2012-10-19 | 2014-04-23 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical Compositions of Dabigatran Free Base |
| CN104434867A (en) * | 2013-09-12 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Composition of Pradaxa and preparation method thereof |
| WO2015044375A1 (en) * | 2013-09-27 | 2015-04-02 | Ratiopharm Gmbh | Pharmaceutical preparation comprising dabigatran etexilate bismesylate |
Also Published As
| Publication number | Publication date |
|---|---|
| ITUB20155035A1 (en) | 2017-05-02 |
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