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
  • A61K9/2009—Inorganic compounds
• • 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
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/695—Silicon compounds

Definitions

• the present invention relates to a pharmaceutical formulation comprising dabigatran etexilate free base, mesoporous silica and at least one pharmaceutical excipient.
• Dabigatran etexilate (Formula 1 ), which is already known from WO 98/37075, is a direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valcular atrial fibrilation.
• Thrombin is a multifunctional enzyme which converts fibrinogen to fibrin, cross-linking fibrin monomers via activation of factor XIII and augmenting further thrombin production via the activation of factors V and VIII. It also activates platelets, generates anticoagulant activity via activation of protein C and initiates numerous cellular processes.
• the methane sulphonic acid addition salt of dabigatran etexilate which is commercially available under the trade name PRADAXA® (in the strength of 75, 1 10, 150mg), 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.
• WO2012/077136 is directed to the oxalate salt of dabigatran etexilate and besides, its hydrochloride salt is identified in EP1877395.
• dabigatran etexilate salts disclosed in prior art were compared to their physicochemical properties like water solubility and stability which are important for the development of pharmaceutical formulations.
• dabigatran etexilate is a weakly basic compound and therefore it has high solubility in acidic media.
• Dabigatran is weakly basic, should be dissolved in basic environments and the dissolution of dabigatran should be pH independent. With this aim, dabigatran was disclosed in EP 2722033 A1 as a free base that has pH-independent release and its oral pharmaceutical formulation disclosed in EP 2722034 A1.
• the aim is to produce a stable pharmaceutical formulation comprising dabigatran etexilate free base, with a desired dissolution profile and an easy process.
• the main embodiment of the present invention is a pharmaceutical formulation comprising dabigatran etexilate free base, mesoporous silica and at least one pharmaceutical excipient.
• dabigatran etexilate free base refers to dabigatran etexilate which is free from other forms of the active moiety, especially acid addition salts.
• Dabigatran etexilate free base Due to sensitivity of dabigatran etexilate free base to humudity, impurities which cause undesired dissloution profile may be occured. Dabigatran etexilate free base is also open to reactions with any excipients in a formulation. Therefore, it is essential to choose suitable excipient to achieve an improved stability against humudity and chemical reactions. In this present invention, it has been surprisingly found that above problems are overcome by using mesoporous silica.
• mesoporous silica has not been used before. In this present invention, to achieve more stable pharmaceutical formulation by an easier process as compared to prior art, mesoporous silica is used.
• desired dissolution of dabigatran etexilate free base is also achieved by using mesoporous silica.
• Mesoporous silica is a mesoporous form of silica.
• the mesoporous silica has pores on its surface and the large surface area of the pores allows the particles to be filled with an active agent in a pharmaceutical formulation.
• mesoporous silica due to its large surface area and pores on it, while mesoporous silica presents improved stability, it also provides high loading capacity for dabigatran per dosage form. Small dosage forms are always desirable for patients due to easy of oral application. Even with high amount of active agent, dosage forms should be in a specific size and weight range. Therefore, in this invention, to provide high dabigatran loading capacity, mesoporous silica is used. Thus, desired weight of dosage forms with high amount of dabigatran etexilate free base is achieved.
• dabigatran etexilate free base is present in an amount of between 1.0 to 95.0 %, preferably between 5.0 to 85.0 % and more preferably it is 5.0 to 60.0 % by weight of total formulation. According to this embodiment, dabigatran etexilate free base is present in an amount of between 30 to 350 mg, preferably 50 to 300 mg and more preferably it is 50 to 250 mg.
• mesoporous silica provides desired dissolution profile as well as improved stabilty.
• Altough mesoporous silica is expected to cause as very slow dissolution rate due to its porous structure, it is surprisingly found that desired dissolution profile could be achieved by using mesoporous silica.
• spesific amount of mesoporous silica both desired dissolution profile and stability is provided for dabigatran etaxilate free base.
• mesoporous silica is used in an amount of between 1 .0 to 90.0%, preferably 5.0 to 70.0% and more preferably 5 to 50%.
• the ratio of dabigatran etexilate free base to mesoporous silica is also important to achieve above properties for the formulation.
• the ratio of dabigatran etexilate free base to mesoporous silica is between 0.05 - 17.00 (w/w), preferably 0.50 - 15.00(w/w), more preferably 0.50 to 10.00 (w/w).
• At least one pharmaceutically acceptable excipient is selected from the group comprising lubricants, stabilizers, buffering agent, disintegrants, diluents, dispersing agents, binders, glidants, plasticizers, preservatives, sweeteners, flavorings and coloring agents.
• lubricant is selected from the group comprising sodium stearyl fumarate, magnesium stearate, 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, glyseryl palmito sulphate, sodium lauryl sulphate and mixtures thereof.
• particle size of mesoporous silica also affects the flowability of total formulation.
• Particle size of mesoporous silica with finer particle size is the bulk density of total powder. When bulk density is decreased, flowability increases and capsules are filled easily.
• particle size of mesoporous silica has been measured by Malvern Mastersizer 2000 laser diffraction particle size analyzer by dry dispersion method and d 90 value of these excipients have been identified.
• d 90 or "d(0.9)” is defined as the size value corresponding to volume of the particles at 90%, which represents the size of particles below which 90% of the substance lies.
• Mesoporous silica has a particle size diameter range with a d 90 value between 0.1 to 3000 nm and preferably 1 to 100 nm and more preferably 2 to 10 nm.
• said pharmaceutical formulation is administering orally.
• the pharmaceutical form of said formulation is in the form of solid dosage form.
• the solid dosage form is selected from the group comprising tablets, bilayer tablets, multilayer tablets, buccal tablets, sublingual tablets, tablet in tablets and in-lay tablets.
• Suitable stabilizers may include but not limited to citric acid, fumaric acid, tartaric acid, sodium citrate, sodium benzoate, sodium dihydrogen phosphate, calcium carbonate, magnesium carbonate, arginine, lysine, meglamine, tocopherol, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), ascorbic acid, gallic acid esters and the mixtures thereof, and preferably, citric acid, fumaric acid, arginine or mixtures thereof.
• Suitable buffering agent may include but not limited to alkali metal citrate, citric acid/sodium citrate, tartaric acid, fumaric acid, sorbic acid, citric acid, succinic acid, adipic acid, ascorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid/sodium hydroxide and mixtures thereof, and preferably citric acid, fumaric acid, ascorbic acid, sodium dihydrogen phosphate or mixtures thereof.
• Suitable disintegrants may include but not limited to crospovidone (cross-linked polyvinil pyrrolidone), povidone, croscarmellose sodium (cross-linked carboxymethyl cellulose), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
• crospovidone cross-linked polyvinil pyrrolidone
• povidone povidone
• croscarmellose sodium cross-linked carboxymethyl cellulose
• Suitable diluents may include but not limited to microcrystalline cellulose, mannitol, dibasic calcium phosphate, spray-dried mannitol, lactose, 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 or mixtures thereof.
• Suitable dispersing agents may include but not limited to calcium silicate, magnesium aluminum silicate or mixtures thereof.
• Suitable binders may include but not limited to polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, collagens, proteins like gelatin, agar, alginate, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminium hydroxide, laponit, bentonit, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
• Suitable glidants may include but not limited to silicon dioxide, colloidal silicon dioxide, talc, aluminium silicate, silica or mixtures thereof.
• Suitable plasticizers may include but not limited to polyethylene glycols of different molecular weights, propylene glycol or mixture thereof.
• Suitable preservatives may comprise but not limited to methyl paraben and propyl paraben and their salts (such as sodium, potassium), sodium benzoate, citric acid, benzoic acid, butylated hydroxytoluene and butylated hydroxyanisole or mixtures thereof.
• Suitable sweeteners may include but not limited to aspartame, potassium acesulfame, sodium saccharinate, neohesperidine dihydrochalcone, sucralose, saccharin, sugars such as sucrose, glucose, lactose, fructose and sugar alcohols such as mannitol, sorbitol, xylitol, erythritol or mixtures thereof.
• Suitable flavorings may include but not limited to menthol, peppermint, cinnamon, chocolate, vanillin and fruit essences such as cherry, orange, strawberry, grape, black currant, raspberry, banana, red fruits, wild berries or mixtures thereof.
• Suitable coloring agents may include but not limited to ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.
• FD&C Food, Drug & Cosmetic
• Suitable solvents may include but not limited to water, acetic acid, Heptane, Acetone, Isobutyl acetate, Anisole, Isopropyl acetate, 1 -Butanol Methyl acetate, 2-Butanol 3- Methyl-1-butanol, Butyl acetate, Methylethylketone, tert-Butylmethyl ether, Methylisobutylketone, propanol, Dimethyl sulfoxide, Pentane, Ethanol, 1 -Pentanol, Ethyl acetate, 1 -Propanol, Ethyl ether, 2-Propano,l Ethyl formate, Propyl acetate, Formic acid or mixtures thereof
• using mesoporous silica simplified the process of the formulation. This process reduce the time and cost of the pharmaceutical formulation comprising dabigatran etexilate free base.
• the process for preparing the pharmaceutical formulation comprises the steps of;
• Sodium stearyl fumarate 0.25 - 2.0 The process of the formulation is carried out as follows: Dabigatran etexilate free base diluted in solvent and added to granulater containing mesoporous silica powder dropwise. Solvent is evaporated by heating or mixing. Mannitol, crospovidon, silicon dioxide, sodium stearyl fumarate are added to this mixture and mixed. Mixture is pressed into tablets. Optionally coating is performed with Opadry AMB/ Kollicoat IR.
• the process of the formulation is carried out as follows: Dabigatran etexilate free base diluted in solvent and added to granulater containing mesoporous silica powder dropwise. Solvent is evaporated by heating or mixing. Microcrystalline cellulose, sodium starch glycolate, silicon dioxide, sodium stearyl fumarate are added to this mixture and mixed. Mixture is pressed into tablets. Optionally coating is performed with Opadry AMB/ Kollicoat IR.
• Sodium stearyl fumarate 0.25 - 2.0 The process of the formulation is carried out as follows: Dabigatran etexilate free base diluted in solvent and added to granulater containing mesoporous silica powder dropwise. Solvent is evaporated by heating or mixing. Dibasic calcium phosphate, sodium starch glycolate, silicon dioxide, sodium stearyl fumarate are added to this mixture and mixed. Mixture is pressed into tablets. Optionally coating is performed with Opadry AMB/ Kollicoat IR.
• the process of the formulation is carried out as follows: Dabigatran etexilate free base diluted in solvent and added to granulater containing mesoporous silica powder dropwise. Solvent is evaporated by heating or mixing. Dibasic calsium phosphate, croscarmellose sodium, silicon dioxide, sodium stearyl fumarate are added to this mixture and mixed. Mixture is pressed into tablets. Optionally coating is performed with Opadry AMB/ Kollicoat IR.

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• 2016
  • 2016-07-19 WO PCT/EP2016/067154 patent/WO2017013106A1/en unknown
  • 2016-07-19 MA MA042480A patent/MA42480A/fr unknown
  • 2016-07-19 EP EP16745648.2A patent/EP3324946A1/de not_active Withdrawn

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