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EP3731823A1 - A pharmaceutical formulation for oral administration comprising dabigatran etexilate - Google Patents

A pharmaceutical formulation for oral administration comprising dabigatran etexilate

Info

Publication number
EP3731823A1
EP3731823A1 EP18877294.1A EP18877294A EP3731823A1 EP 3731823 A1 EP3731823 A1 EP 3731823A1 EP 18877294 A EP18877294 A EP 18877294A EP 3731823 A1 EP3731823 A1 EP 3731823A1
Authority
EP
European Patent Office
Prior art keywords
acid
oral administration
pharmaceutical formulation
administration according
weight
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.)
Withdrawn
Application number
EP18877294.1A
Other languages
German (de)
French (fr)
Inventor
Ali TÜRKYILMAZ
Arzu Palantöken
Yildiz GÜLKOK
Gökce SÖZER BÜRKÜT
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.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret AS
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
Application filed by Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of EP3731823A1 publication Critical patent/EP3731823A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • 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

Definitions

  • the present invention relates to a pharmaceutical formulation for oral administration comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate, wherein the formulation comprising at least two types of particles.
  • Dabigatran etexilate a novel direct thrombin inhibitor
  • dabigatran etexilate 3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino- methyl)-pheny-lamino]-methyl ⁇ -1 -methyl-1 H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino] propionic acid ethyl ester, having a formula of C 3 4H 41 N705, a molecular weight of 627.74 and a chemical structural formula shown below (I):
  • Formula 1 Dabigatran etexilate Dabigatran etexilate was first approved in Germany and England in April 2008. It was approved by the U.S. Food and Drug Administration (FDA) in October 2010 for reducing the risks of stroke or systemic embolism in patients with non-valvular atrial fibrillation.
  • FDA U.S. Food and Drug Administration
  • the approved dosage form is capsules with strengths of 75 mg, 1 10mg and 150 mg, and the product name is Pradaxa. It is disclosed in EP1870100, wherein also disclosed, pellet formulation of dabigatran etexilate methanesulphonate.
  • This composition is formulated with a core material consisting of organic acid and an active layer which encloses the core.
  • Each PRADAXA® capsule contains the following inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropylcellulose, tartaric acid, carrageenan, potassium chloride, talc, titanium dioxide, and gelatin.
  • the solubility of dabigatran etexilate in water is low.
  • the active ingredient has a strong pH-dependent solubility that is greatly increased in the acidic environment. This leads to the problem that conventional oral pharmaceutical compositions have large variations in the bioavailability since the solubility of the active ingredient depends on the pH value in the patient's stomach. This is particularly problematic with patients in whom the stomach pH value is changed by physiological variability, illness, or pre-medications (for example, PP inhibitors). There is therefore a need for oral pharmaceutical compositions of the active ingredient dabigatran etexilate.
  • the organic acid is used to provide a release that is independent of the pH value of the stomach and thus, a solubility of the active ingredient and bioavailability.
  • Dabigatran etexilate has incompatibility and stability problems when it is combined with acid.
  • These various dabigatran etexilate salts disclosed in the prior art were compared for their physicochemical properties like water solubility, stability, and shelf-life which are important for the development of pharmaceutical formulations.
  • Disintegrant is important to solve the solubility problem of tablet.
  • the choice of a suitable disintegrant and using certain levels are important to ensure good solubility without the addition of significant side effect.
  • the main object of the present invention is to avoid incompatibility problems and stability between active agent and acid.
  • Another object of the present invention is to provide high solubility, high bioavailability, high stability and a long shelf life by the selection of excipients in a certain ratio.
  • Another object of the present invention is to provide an easy and cost-effective process for the preparation of the said pharmaceutical composition.
  • An object of the present invention is to obtain adequate content uniformity.
  • particles as used herein is intended to mean any solid or semi-solid portion of a substance or a composition having defined physical boundaries.
  • particles include, but are not limited to, powder, granules, pellets, beads, mini-tablets or the like.
  • the granules may be prepared by methods such as, but not limited to, wet granulation, melt granulation, dry granulation or roll compaction or the like.
  • mini-tablet refers to small tablets with a diameter equal to or less than 4 mm that are typically filled into a capsule or further compressed into larger tablets. Thickness of this mini-tablets equal to or less than 3 mm.
  • the mini-tablets have round shape and smooth surface to ease coating process.
  • the present invention relates to a pharmaceutical formulation for oral administration comprising at least two types of particles wherein; a) the first type of particles comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and
  • the second type of particles comprising at least one pharmaceutically acceptable organic acid wherein said organic acid is coated with an isolation solution.
  • the particles are in the form of powder, granules, pellets, beads, mini tablets or mixtures thereof.
  • the first type of particles is in the form of powder or granule.
  • the second type of particles is in the form of a pellet.
  • the reproducibility of the pellet formulations is also much better than the reproducibility of the single-unit dosage forms. They are suitable systems for film coating with respect to the low surface area-volume ratios. Also, one of the advantageous properties of the pellet formulations is their good resistance to external factors such as moisture, air and light.
  • At least one type of particles is coated with an isolation solution.
  • the isolation solution is formed by a polymeric or a non-polymeric pharmaceutically acceptable excipient or any combination thereof.
  • the organic acid pellet is coated with an isolation solution.
  • Suitable organic acid comprises at least one carboxylic group. It is selected from the group comprising citric acid, tartaric acid, gallic acid, orotic acid, p-coumaric acid, hippuric acid, ferulic acid, vanillic acid, fumaric acid, maleic acid, succinic acid, malic acid, glutamic acid, aspartic acid, oxalic acid, lactic acid, formic acid, acetic acid, propionic acid, caproic acid, benzoic acid, carbonic acid or mixtures thereof.
  • the organic acid is citric acid or tartaric acid or mixtures thereof.
  • selected organic acid keeps the pH of the micro-environment low, for a long time whilst remain undissolved in tablets or capsules and increases the solubility of the active agent.
  • the total amount of dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is 20.0% to 70.0% by weight and the total amount of the isolated organic acid is 10.0% to 70.0% by weight.
  • the total amount of dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is 30.0% to 50.0% by weight and the total amount of the isolated organic acid is 30.0% to 50.0% by weight.
  • the weight ratio of isolated organic acid to dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is between 0.1 and 10.0, preferably the ratio is between 0.2 and 5.0, more preferably between 0.2 and 2.0.
  • excipients provided in a formulation may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. the solubility, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while a formulation is developed.
  • the formulations should have no physicochemical incompatibility between the active ingredient and the excipients.
  • At least one pharmaceutically acceptable excipient is selected from disintegrants, lubricants, glidants, binders, fillers or mixtures thereof.
  • the selection of excipients has more importance to obtain the ideal disintegrating time during the shelf life.
  • the choice of the disintegrant has a major role in the manufacture of the tablet or mini-tablet. Therefore, the choice of a suitable disintegrant and an optimal use level is critical to ensure a high disintegration rate.
  • Disintegrant is important to solve the problem solubility of tablet.
  • the choice of a suitable disintegrant and use certain level are important to ensure good solubility without the addition of significant side effect.
  • Suitable disintegrants are selected from a group comprising croscarmellose sodium, microcrystalline cellulose, starch, sodium starch glycolate, crospovidone (cross-linked polyvinylpyrrolidone), poloxamer, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
  • the disintegrant is croscarmellose sodium.
  • the total amount of croscarmellose sodium is between 1.0% to 15.0% by weight.
  • the pharmaceutical formulation for oral administration of dabigatran comprises croscarmellose sodium as disintegrant.
  • croscarmellose sodium is used as disintegrant, stability problems are solved and better stability is gained.
  • Suitable lubricants are selected from a group comprising magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyceryl palmitostearate sulphate, sodium lauryl sulphate or mixtures thereof, preferably the lubricant is magnesium stearate.
  • the amount of the lubricant is between 0.1% to 5.0% by weight.
  • Suitable glidants are selected from a group comprising colloidal silicon dioxide, talc, aluminium silicate or mixtures thereof, preferably the glidant is colloidal silicon dioxide.
  • the amount of colloidal silicon dioxide is between 0.5% to 3.0% by weight.
  • Suitable binders are selected from the group comprising hydroxypropyl methyl cellulose, pregelatinized starch, povidone, copovidone, copolyvidone, carnauba wax, pullulan, polymethacrylate, glyceryl behenate, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, ethyl cellulose, microcrystalline cellulose, polymethacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophil, polyvinyl acetate and its copolymers, gelatin, starch, xanthan gum, guar gum, alginate, carrageen, collagen, agar, pectin, hyaluronic acid, carbomer, cellulose acetate phthalate, hydroxypropyl starch, hydroxyethyl methyl cellulose, poloxamer, polyethylene glycol, sugars, glucose syrups, natural gum
  • the amount of the binder is between 10.0% to 30.0% by weight.
  • the weight ratio of croscarmellose sodium to the binder is between 0.2 and 40.0, preferably the ratio is between 0.5 and 30.0, more preferably between 1.0 and 25.0.
  • Suitable fillers are selected from a group comprising microcrystalline cellulose, lactose, mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate, polyols, dextrose, maltitol or mixtures thereof, preferably the filler is microcrystalline cellulose.
  • the amount of the filler is between 10.0% to 50.0% by weight.
  • the formulation is in the form of tablets or mini-tablets.
  • the formulation is in the form of mini-tablets.
  • the mini-tablets are filled into capsule.
  • the tablet or mini-tablet may be prepared by a granulation process.
  • a characteristic of the methods is given below based on wet granulation and used for the production of the formulations of the invention.
  • Suitable granulation solutions are selected from a group comprising pure water, ethyl alcohol, glycerin, sorbitol, polyethylene glycol, propylene glycol, isopropyl alcohol, or mixtures thereof, preferably the granulation solution is pure water.
  • Direct compression method is the most commonly used method in producing tablet or mini-tablet because it is the easiest method in tablet manufacturing, can use conventional manufacturing instrument, short procedure, relatively cheap, can be loaded with thermolabile and moisture sensitive drugs and can be made into high dose.
  • the pharmaceutical formulations of dabigatran etexilate that are stable, cost-effective, easy to prepare, provide the desired in vitro release, improved dissolution profile and bioavailability.
  • the pharmaceutical formulation for oral administration comprises;
  • microcrystalline cellulose • 10.0-50.0% by weight of microcrystalline cellulose
  • magnesium stearate • 0.1 -5.0% by weight of magnesium stearate
  • HPMC and sucrose are added to purified water and mixed.
  • Talc is added to the obtained mixture and mixed.
  • HPMC and triethyl citrate are added to purified water and mixed.
  • Talc is added to the obtained mixture and mixed.
  • Organic acid pellets are coated with isolation solution which is selected from formula 1 , formula 2.
  • isolation solution which is selected from formula 1 , formula 2.
  • the process for preparation of the pharmaceutical formulation for oral administration comprises the following steps:
  • the tablet or mini-tablet can be coated with a film coating.
  • the process for preparation of the pharmaceutical formulation for oral administration comprises the following steps:
  • the tablet can be coated with a film coating.
  • the process for preparation of the pharmaceutical formulation for oral administration comprises the following steps:
  • mini-tablet can be coated with a film coating.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The present invention relates to a pharmatical formulation for oral administration comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate, wherein the formulation comprising at least two types of particles.

Description

A PHARMACEUTICAL FORMULATION FOR ORAL ADMINISTRATION
COMPRISING DABIGATRAN ETEXILATE
Field of Invention
The present invention relates to a pharmaceutical formulation for oral administration comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate, wherein the formulation comprising at least two types of particles.
Background of the Invention
Dabigatran etexilate, a novel direct thrombin inhibitor, is a prodrug of dabigatran and is a non-peptide thrombin inhibitor. It was developed by Boehringer Ingelheim Pharmaceuticals, Inc. The oral drug is absorbed by the gastrointestinal tract and converts to dabigatran which has the direct anticoagulant activity. Dabigatran binds to the specific fibrin-binding sites of thrombin, preventing cleavage of fibrinogen to fibrin and blocking the final steps in the coagulation cascade network and thrombosis. Dabigatran can be dissociated from a fibrin-thrombin complex and play reversible anticoagulant effect.
The chemical name of dabigatran etexilate is 3-[(2-{[4-(hexyloxycarbonylamino-imino- methyl)-pheny-lamino]-methyl}-1 -methyl-1 H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino] propionic acid ethyl ester, having a formula of C34H41N705, a molecular weight of 627.74 and a chemical structural formula shown below (I):
Formula 1 : Dabigatran etexilate Dabigatran etexilate was first approved in Germany and England in April 2008. It was approved by the U.S. Food and Drug Administration (FDA) in October 2010 for reducing the risks of stroke or systemic embolism in patients with non-valvular atrial fibrillation. Currently, the approved dosage form is capsules with strengths of 75 mg, 1 10mg and 150 mg, and the product name is Pradaxa. It is disclosed in EP1870100, wherein also disclosed, pellet formulation of dabigatran etexilate methanesulphonate. This composition is formulated with a core material consisting of organic acid and an active layer which encloses the core. Each PRADAXA® capsule contains the following inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropylcellulose, tartaric acid, carrageenan, potassium chloride, talc, titanium dioxide, and gelatin.
In the prior art, the most of formulations are in the form of capsules and tablet. However, many of the formulations in the art rely on complex formulation which can add to the cost of the manufacture of the drug and/or can be subject to malfunction leading to incorrect/inappropriate administration of the drug.
The solubility of dabigatran etexilate in water is low. Moreover, the active ingredient has a strong pH-dependent solubility that is greatly increased in the acidic environment. This leads to the problem that conventional oral pharmaceutical compositions have large variations in the bioavailability since the solubility of the active ingredient depends on the pH value in the patient's stomach. This is particularly problematic with patients in whom the stomach pH value is changed by physiological variability, illness, or pre-medications (for example, PP inhibitors). There is therefore a need for oral pharmaceutical compositions of the active ingredient dabigatran etexilate.
In this present invention, the organic acid is used to provide a release that is independent of the pH value of the stomach and thus, a solubility of the active ingredient and bioavailability.
Dabigatran etexilate has incompatibility and stability problems when it is combined with acid. We have found an easy way to separate the organic acid from the dabigatran etexilate formulation. Isolated organic acid pellet and dabigatran etexilate is pressed in tablet or mini-tablet so they did not interact with each other, so this overcomes the problems. Also, this provides easy and cost-effective process, it also provides improvement in dissolution profile. These various dabigatran etexilate salts disclosed in the prior art, were compared for their physicochemical properties like water solubility, stability, and shelf-life which are important for the development of pharmaceutical formulations.
Disintegrant is important to solve the solubility problem of tablet. The choice of a suitable disintegrant and using certain levels are important to ensure good solubility without the addition of significant side effect.
Detailed Description of the Invention
The main object of the present invention is to avoid incompatibility problems and stability between active agent and acid.
Another object of the present invention is to provide high solubility, high bioavailability, high stability and a long shelf life by the selection of excipients in a certain ratio.
Another object of the present invention is to provide an easy and cost-effective process for the preparation of the said pharmaceutical composition.
An object of the present invention is to obtain adequate content uniformity.
The term "particle" as used herein is intended to mean any solid or semi-solid portion of a substance or a composition having defined physical boundaries. Examples of particles include, but are not limited to, powder, granules, pellets, beads, mini-tablets or the like. The granules may be prepared by methods such as, but not limited to, wet granulation, melt granulation, dry granulation or roll compaction or the like.
The term“mini-tablet”, as used herein, refers to small tablets with a diameter equal to or less than 4 mm that are typically filled into a capsule or further compressed into larger tablets. Thickness of this mini-tablets equal to or less than 3 mm. The mini-tablets have round shape and smooth surface to ease coating process.
The present invention relates to a pharmaceutical formulation for oral administration comprising at least two types of particles wherein; a) the first type of particles comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and
b) the second type of particles comprising at least one pharmaceutically acceptable organic acid wherein said organic acid is coated with an isolation solution.
In one embodiment, the particles are in the form of powder, granules, pellets, beads, mini tablets or mixtures thereof.
In one embodiment, the first type of particles is in the form of powder or granule.
In one embodiment, the second type of particles is in the form of a pellet.
The reproducibility of the pellet formulations is also much better than the reproducibility of the single-unit dosage forms. They are suitable systems for film coating with respect to the low surface area-volume ratios. Also, one of the advantageous properties of the pellet formulations is their good resistance to external factors such as moisture, air and light.
In one embodiment, at least one type of particles is coated with an isolation solution.
In one embodiment, the isolation solution is formed by a polymeric or a non-polymeric pharmaceutically acceptable excipient or any combination thereof.
In one embodiment, the organic acid pellet is coated with an isolation solution.
Suitable organic acid comprises at least one carboxylic group. It is selected from the group comprising citric acid, tartaric acid, gallic acid, orotic acid, p-coumaric acid, hippuric acid, ferulic acid, vanillic acid, fumaric acid, maleic acid, succinic acid, malic acid, glutamic acid, aspartic acid, oxalic acid, lactic acid, formic acid, acetic acid, propionic acid, caproic acid, benzoic acid, carbonic acid or mixtures thereof.
In one preferred embodiment, the organic acid is citric acid or tartaric acid or mixtures thereof.
Accordingly, selected organic acid keeps the pH of the micro-environment low, for a long time whilst remain undissolved in tablets or capsules and increases the solubility of the active agent. According to one embodiment of the present invention, the total amount of dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is 20.0% to 70.0% by weight and the total amount of the isolated organic acid is 10.0% to 70.0% by weight.
According to one embodiment of the present invention, the total amount of dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is 30.0% to 50.0% by weight and the total amount of the isolated organic acid is 30.0% to 50.0% by weight.
According to one embodiment of the present invention, the weight ratio of isolated organic acid to dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is between 0.1 and 10.0, preferably the ratio is between 0.2 and 5.0, more preferably between 0.2 and 2.0.
In general terms, excipients provided in a formulation may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. the solubility, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while a formulation is developed. The formulations should have no physicochemical incompatibility between the active ingredient and the excipients.
According to one embodiment of this present invention, wherein at least one pharmaceutically acceptable excipient is selected from disintegrants, lubricants, glidants, binders, fillers or mixtures thereof.
The selection of excipients has more importance to obtain the ideal disintegrating time during the shelf life. Especially, the choice of the disintegrant has a major role in the manufacture of the tablet or mini-tablet. Therefore, the choice of a suitable disintegrant and an optimal use level is critical to ensure a high disintegration rate.
Disintegrant is important to solve the problem solubility of tablet. The choice of a suitable disintegrant and use certain level are important to ensure good solubility without the addition of significant side effect. Suitable disintegrants are selected from a group comprising croscarmellose sodium, microcrystalline cellulose, starch, sodium starch glycolate, crospovidone (cross-linked polyvinylpyrrolidone), poloxamer, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
In one preferred embodiment, the disintegrant is croscarmellose sodium.
In one embodiment, the total amount of croscarmellose sodium is between 1.0% to 15.0% by weight.
In one embodiment, the pharmaceutical formulation for oral administration of dabigatran comprises croscarmellose sodium as disintegrant. When croscarmellose sodium is used as disintegrant, stability problems are solved and better stability is gained.
Suitable lubricants are selected from a group comprising magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyceryl palmitostearate sulphate, sodium lauryl sulphate or mixtures thereof, preferably the lubricant is magnesium stearate.
In one embodiment, the amount of the lubricant is between 0.1% to 5.0% by weight.
Suitable glidants are selected from a group comprising colloidal silicon dioxide, talc, aluminium silicate or mixtures thereof, preferably the glidant is colloidal silicon dioxide.
In one embodiment, the amount of colloidal silicon dioxide is between 0.5% to 3.0% by weight.
Suitable binders are selected from the group comprising hydroxypropyl methyl cellulose, pregelatinized starch, povidone, copovidone, copolyvidone, carnauba wax, pullulan, polymethacrylate, glyceryl behenate, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, ethyl cellulose, microcrystalline cellulose, polymethacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophil, polyvinyl acetate and its copolymers, gelatin, starch, xanthan gum, guar gum, alginate, carrageen, collagen, agar, pectin, hyaluronic acid, carbomer, cellulose acetate phthalate, hydroxypropyl starch, hydroxyethyl methyl cellulose, poloxamer, polyethylene glycol, sugars, glucose syrups, natural gums, tragacanth gum, polyacrylamide, aluminum hydroxide, cetostearyl alcohol, polyoxyethylene-alkyl ethers, acacia mucilage, polydextrose or mixtures thereof, preferably the binder is hydroxypropyl methyl cellulose.
At the present invention, the amount of the binder is between 10.0% to 30.0% by weight.
According to one embodiment of the invention, the weight ratio of croscarmellose sodium to the binder is between 0.2 and 40.0, preferably the ratio is between 0.5 and 30.0, more preferably between 1.0 and 25.0.
Suitable fillers are selected from a group comprising microcrystalline cellulose, lactose, mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate, polyols, dextrose, maltitol or mixtures thereof, preferably the filler is microcrystalline cellulose.
At the present invention, the amount of the filler is between 10.0% to 50.0% by weight.
According to one embodiment of the present invention, the formulation is in the form of tablets or mini-tablets.
In one preferred embodiment, the formulation is in the form of mini-tablets.
According to this embodiment, the mini-tablets are filled into capsule.
The tablet or mini-tablet may be prepared by a granulation process. A characteristic of the methods is given below based on wet granulation and used for the production of the formulations of the invention. Suitable granulation solutions are selected from a group comprising pure water, ethyl alcohol, glycerin, sorbitol, polyethylene glycol, propylene glycol, isopropyl alcohol, or mixtures thereof, preferably the granulation solution is pure water.
Direct compression method is the most commonly used method in producing tablet or mini-tablet because it is the easiest method in tablet manufacturing, can use conventional manufacturing instrument, short procedure, relatively cheap, can be loaded with thermolabile and moisture sensitive drugs and can be made into high dose.
According to one embodiment of this present invention, the pharmaceutical formulations of dabigatran etexilate that are stable, cost-effective, easy to prepare, provide the desired in vitro release, improved dissolution profile and bioavailability.
The pharmaceutical formulation for oral administration comprises;
• 20.0-70.0% by weight of dabigatran etexilate free base or pharmaceutically acceptable salts thereof
• 10.0-70.0% by weight of isolated organic acid pellet
• 10.0-50.0% by weight of microcrystalline cellulose
• 10.0-30.0% by weight of hydroxypropyl methyl cellulose
• 0.5-3.0% by weight of colloidal silicon dioxide
• 1 .0-15.0% by weight of croscarmellose sodium
• 0.1 -5.0% by weight of magnesium stearate
Preparation of Isolated Organic Acid Pellets (Coated Organic Acid Pellets):
Preparation isolation solution:
Formula 1 :
HPMC and sucrose are added to purified water and mixed. Talc is added to the obtained mixture and mixed.
Formula 2:
HPMC and triethyl citrate are added to purified water and mixed. Talc is added to the obtained mixture and mixed.
Organic acid pellets are coated with isolation solution which is selected from formula 1 , formula 2. The preparation process of the invention is simple and suitable for industrial production.
The process for preparation of the pharmaceutical formulation for oral administration comprises the following steps:
- weighing, sieving and mixing microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide, croscarmellose sodium and dabigatran etexilate free base or pharmaceutically acceptable salt of dabigatran etexilate
- granulating the powder mixture with water
- drying in an oven at 50-55Ό and sieving.
- adding magnesium stearate and isolated organic acid pellets to the mixture and mixing.
- Then, pressing to form tablets or mini-tablets. Furthermore, the tablet or mini-tablet can be coated with a film coating.
Example 1 : Tablet
The process for preparation of the pharmaceutical formulation for oral administration comprises the following steps:
- weighing, sieving and mixing microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide, croscarmellose sodium and dabigatran etexilate free base or pharmaceutically acceptable salt of dabigatran etexilate - granulating the powder mixture with water
- drying in an oven at 50-55Ό and sieving.
- adding magnesium stearate and isolated organic acid pellets to the mixture and mixing.
- Then, pressing to form tablets.
Furthermore, the tablet can be coated with a film coating.
Example 2: Mini-tablet in capsule
The process for preparation of the pharmaceutical formulation for oral administration comprises the following steps:
- weighing, sieving and mixing microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide, croscarmellose sodium and dabigatran etexilate free base or pharmaceutically acceptable salt of dabigatran etexilate
- granulating the powder mixture with water
- drying in an oven at 50-55Ό and sieving.
- adding magnesium stearate and isolated organic acid pellets to the mixture and mixing.
- Then, pressing to form mini-tablets,
- Filling the mini-tablets into capsules.
Furthermore, mini-tablet can be coated with a film coating.

Claims

1. A pharmaceutical formulation for oral administration comprising at least two types of particles wherein;
a) the first type of particles comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and, b) the second type of particles comprising at least one pharmaceutically acceptable organic acid, wherein said organic acid is coated with isolation solution.
2. The pharmaceutical formulation for oral administration according to claim 1 , wherein said particles are in the form of powder, granules, pellets, beads, mini tablets or mixtures thereof.
3. The pharmaceutical formulation for oral administration according to claim 2, wherein the first type of particles is in the form of powder or granule.
4. The pharmaceutical formulation for oral administration according to claim 2, wherein said second type of particles is in the form of a pellet.
5. The pharmaceutical formulation for oral administration according to claim 1 , wherein said organic acid is selected from the group comprising citric acid, tartaric acid, gallic acid, orotic acid, p-coumaric acid, hippuric acid, ferulic acid, vanillic acid, fumaric acid, maleic acid, succinic acid, malic acid, glutamic acid, aspartic acid, oxalic acid, lactic acid, formic acid, acetic acid, propionic acid, caproic acid, benzoic acid, carbonic acid or mixtures thereof.
6. The pharmaceutical formulation for oral administration according to claim 5, wherein said organic acid is citric acid or tartaric acid or mixtures thereof.
7. The pharmaceutical formulation for oral administration according to claim 1 , wherein the total amount of dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is 20.0% to 70.0% by weight and the total amount of isolated organic acid is 10.0% to 70.0% by weight.
8. The pharmaceutical formulation for oral administration according to claim 7, wherein the total amount of dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is 30.0% to 50.0% by weight and the total amount of isolated organic acid is 30.0% to 50.0% by weight.
9. The pharmaceutical formulation for oral administration according to claim 1 , wherein the weight ratio of isolated organic acid to dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is between 0.1 and 10.0, preferably between 0.2 and 5.0.
10. The pharmaceutical formulation for oral administration according to any preceding claims, further comprising at least one pharmaceutically acceptable excipient which is selected from disintegrants, lubricants, glidants, binders, fillers or mixtures thereof.
1 1. The pharmaceutical formulation for oral administration according to claim 10, wherein said disintegrants are selected from a group comprising croscarmellose sodium, microcrystalline cellulose, starch, sodium starch glycolate, cross-linked polyvinylpyrrolidone, poloxamer, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
12. The pharmaceutical formulation for oral administration according to claim 1 1 , wherein the disintegrant is croscarmellose sodium.
13. The pharmaceutical formulation for oral administration according to claim 12, wherein the total amount of croscarmellose sodium is 1 .0% to 15.0% by weight.
14. The pharmaceutical formulation for oral administration according to any preceding claims, wherein the formulation is in the form of tablets or mini-tablets.
15. The pharmaceutical formulation for oral administration according to claim 14, wherein the mini-tablets are filled into capsule.
16. The pharmaceutical formulation for oral administration according to any preceding claims, wherein the formulation comprising;
20.0-70.0% by weight of dabigatran etexilate free base or pharmaceutically acceptable salts thereof
10.0-70.0% by weight of isolated organic acid pellet
10.0-50.0% by weight of microcrystalline cellulose
10.0-30.0% by weight of hydroxypropyl methyl cellulose
0.5-3.0% by weight of colloidal silicon dioxide
1.0-15.0% by weight of croscarmellose sodium
0.1 -5.0% by weight of magnesium stearate
17. A process for preparation of the pharmaceutical formulation for oral administration according to claim 16, wherein the process comprising the following steps:
• weighing, sieving and mixing microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide, croscarmellose sodium and dabigatran etexilate free base or pharmaceutically acceptable salt of dabigatran etexilate
• granulating the powder mixture with water
• drying in an oven at 50-55Ό and sieving
• adding magnesium stearate and isolated organic acid pellets to the mixture and mixing.
• Then, pressing to form tablets or mini-tablets.
18. The pharmaceutical formulation for oral administration according to claim 16, wherein the tablet or mini-tablet is coated with film coating.
EP18877294.1A 2017-12-27 2018-12-26 A pharmaceutical formulation for oral administration comprising dabigatran etexilate Withdrawn EP3731823A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2017/22353A TR201722353A2 (en) 2017-12-27 2017-12-27 PHARMACEUTICAL FORMULATION FOR ORAL APPLICATION WITH DABIGATRAN SKIRT
PCT/TR2018/050903 WO2019132840A1 (en) 2017-12-27 2018-12-26 A pharmaceutical formulation for oral administration comprising dabigatran etexilate

Publications (1)

Publication Number Publication Date
EP3731823A1 true EP3731823A1 (en) 2020-11-04

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EP (1) EP3731823A1 (en)
TR (1) TR201722353A2 (en)
WO (1) WO2019132840A1 (en)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA009664B1 (en) 2002-03-07 2008-02-28 Бёрингер Ингельхайм Фарма Гмбх Унд Ко. Кг Form of presentation for 3-[(2-{(4-(hexylloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino] propionic acid ethyl ester and the pharmaceutically compatible salts thereof
EP3858337A3 (en) * 2012-02-21 2021-09-29 Towa Pharmaceutical Europe, S.L. Oral pharmaceutical compositions of dabigatran etexilate
CN104095830A (en) * 2014-05-22 2014-10-15 万特制药(海南)有限公司 Preparation method for mesylate dabigatran capsule
KR20170070635A (en) * 2015-12-14 2017-06-22 한미약품 주식회사 Composite capsule formulation comprising dabigatran etexilate
WO2017111637A1 (en) * 2015-12-23 2017-06-29 Zaklady Farmaceutyczne Polpharma Sa Pharmaceutical composition comprising dabigatran or a pharmaceutically acceptable salt thereof

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TR201722353A2 (en) 2019-07-22

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