WO2016122421A1 - Compositions pharmaceutiques stables contenant une base de prasugrel - Google Patents

Compositions pharmaceutiques stables contenant une base de prasugrel Download PDF

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Publication number
WO2016122421A1
WO2016122421A1 PCT/TR2015/000033 TR2015000033W WO2016122421A1 WO 2016122421 A1 WO2016122421 A1 WO 2016122421A1 TR 2015000033 W TR2015000033 W TR 2015000033W WO 2016122421 A1 WO2016122421 A1 WO 2016122421A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
surfactant
prasugrel
tablet
Prior art date
Application number
PCT/TR2015/000033
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English (en)
Inventor
Ersin Yildirim
Tolga Ramazan KARASU
Koray YILMAZ
Başak Acar KARAKÖY
Nesrin DENIZ
Hakan Gürpinar
Pradeep Kumar VISHWAKARMA
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Pharmactive Ilaç Sanayi Ve Ticaret A.Ş.
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Application filed by Pharmactive Ilaç Sanayi Ve Ticaret A.Ş. filed Critical Pharmactive Ilaç Sanayi Ve Ticaret A.Ş.
Priority to PCT/TR2015/000033 priority Critical patent/WO2016122421A1/fr
Publication of WO2016122421A1 publication Critical patent/WO2016122421A1/fr

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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • 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

Definitions

  • the present invention relates to the preperation of stable pharmaceutical compositions containing the active ingredient; prasugrel base and relevant excipients.
  • Prasugrel chemical name is 5-[2-Cyclopropyl-1-(2-f!uorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl acetate, is a platelet inhibitor having a molecular weight of 373,441. It is currently marketed in the world in cooperation with Eli Lilly and Company for acute coronary syndromes planned for percutaneous coronary intervention (PCI).
  • PCI percutaneous coronary intervention
  • the compound having the figure 1 is known as prasugrel.
  • Prasugrel and pharmacologically acceptable salts thereof are known to have a platelet aggregation-inhibiting action (particularly, an antithrombotic or anti-embolic agent).
  • Prasugrel hydrochloride is a white solid, that is well soluble at pH 2, weakly soluble at pH3 to 4, and is substantially insoluble at pH 6 to 7.5.
  • Prasugrel and its salts have stability problems about hydrolysis or oxidation during manufacturing and storage of the formulated drugs, because prasugrel's structure (EP 1896019).
  • Prasugrel is particularly unstable in the form of aqueous solutions, pH is critical for its stability.
  • Optimum range for aqueous solutions of prasugrel is in the range of pH 4-6 at 25 • C.
  • Prasugrel can be affected from air and humidity in easily. When prasugrel is exposed to air and humidity, it degrades structurally and develops behavioral changes. Two main problems occur because of these changes. First one is stability of prasugrel products, including desired level and shelf life. Second one is prasugrel reacts the excipients in formulation. It results impurities in formulation and undesired components in formulation.
  • Prasugrel base very poorly soluble in water; maximum solubility in plain water is estimated to be about 20-50 ⁇ ; buffers, serum, or other additives may increase or decrease the aqueous solubility.
  • Many patent publications are relevant to the preparation of prasugrel salts because the solubility of the base is very low on the other hand the salts are more stable.
  • WO2011/092720 relates to pharmaceutical composition of prasugrel/its salts useful as tablet, comprises prasugrel hydrochloride, water insoluble dry binder, at least one diluent, at least one disintegrant, at least one lubricant, and composition is optionally coated with a film.
  • WO2013/150322 relates to a quickly released stable oral pharmaceutical composition, comprises micronized prasugrel base, and starch or a starch derivative.
  • EP2409701 relates to a pharmaceutical formulation which comprises granules of prasugrel hydrochloride, said granules comprising at least one coating layer containing pullulan,
  • EP2409685 relates to an orally-disintegrating pharmaceutical formulation, comprising prasugrel or its derivative and one or more pharmaceutically acceptable excipient(s).
  • WO2014/060560 describes to a solid oral composition comprises prasugrel free base and one or more pharmaceutically acceptable excipients.
  • US2009/0281136 relates to pharmaceutical formulations comprising prasugrel, including its salts, hydrates, solvates, polymorphs, and mixtures thereof and stabilizing agent e.g. sodium bisulfate.
  • Prasugrel is used in combination pharmaceutical formulation.
  • US8569325 relates to composition for treating and preventing in which diseases of thrombus or embolus comprises prasugrel, aspirin and one or more pharmaceutically acceptable excipients.
  • the present invention is directed to the pharmaceutical composition
  • the pharmaceutical composition comprising prasugrel base and pharmaceutically acceptable excipients, characterized in that at least one of the excipients is a surfactant.
  • Surfactant are used as wettability agent and solubilizing agents in poorly soluble drug products. They enhance the bioavailability of pharmaceutical compounds within the body by promoting more effective drug release.
  • surfactants suitable for use in accordance with the present invention are included polyoxyethylene hardened castor oil, ethoxylated hydrogenated castor oil, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polyoxyethylene polyoxypropylene block copolymers, polysorbate 80, sodium laurylsulfate, rrracrogols, sucrose esters of fatty acids and mixtures thereof.
  • the surfactant is ethoxylated hydrogenated castor oil, polysorbate 80 and sodium laurylsulfate and mixtures thereof. Most preferably the surfactant is polysorbate 80 or mixture with sodium laurylsulfate or ethoxylated hydrogenated castor oil or mixture with sodium laurylsulfate.
  • the amount of surfactant is in the range of about 0.1 -5% by weight core tablet.
  • Ethoxylated hydrogenated castor oil Polyoxyl 40 hydrogenated castor oil
  • polysorbate 80 is known SEPITRAP as commercial name.
  • SEPITRAP 80 Two solubilizers specially selected for their solubilization efficacy: SEPITRAP 80, SEPITRAP 4000.
  • SEPITRAP 80 includes solubiiizer (polysorbate 80) and specific carrier in particular weight.
  • SEPITRAP 4000 includes solubiiizer (Polyoxyl 40 hydrogenated castor oil) and specific carrier in particular weight.
  • SEPITRAP is a solubiiizer based on microencapsulate in powder form directly compressible.
  • SEPITRAP for use in solid oral dosage forms such as tablets and capsules, is a functional excipient designed especially to simplify the manufacture of dry forms.
  • SEPITRAP improves the bioavailability of APIs with low solubility.
  • SEPITRAP can be used in direct compression processes, without an intermediary wet granulation.
  • SEPITRAP has some advantages: improving bioavailability, increasing drug solubiiisation and/or permeation; using less active pharmaceutical ingredient (API) for same efficiency. It has some properties about good ability to settle, particle size ⁇ 200pm, free flowing powder, solubilizing properties on poorly soluble API, effect of pH.
  • the present invention is directed to the pharmaceutical composition
  • the pharmaceutical composition comprising prasugrel base and pharmaceutically acceptable excipients, characterized in that at least one of the excipients is a surfactant and additionally the composition comprises a cyc!odextrine derivative.
  • the pharmaceutical composition may comprise prasugrel base and cyclodextrine in the separate layers.
  • a preferred embodiment of the present invention is characterized in that prasugrel base granules comprise at least one coating containing cyclodextrine derivatives.
  • Cyclodextrins are wellknown compounds to improve the dissolution rate of drugs, in general.
  • prasugrel base granules comprise at least one coating containing cyclodextrine with external phase of Sepitrap 80 or
  • the amount of cyclodextrine derivatives in said coating layer with respect to the total granule amount interval can be changed.
  • Cyclodextrins are cyclic oligosaccharides, which are composed of cyclic ct-(1- ⁇ 4) linked D- gfucopyranose units. Cyclic oligosaccharides of cyclodextrins with six to eight units have been named ⁇ -, ⁇ - and ⁇ -cyclodextrin, respectively. The number of units determines the size of the cavity which characterizes cyclodextrins and into which drugs may be included to form stable complexes. Cyclodextrine compounds are thus known complexing agents and have been previously used in the pharmaceutical field to form inclusion complexes with water-insoluble drugs and to thus solubilize them in aqueous media.
  • the complexes formed are, however, also stable in aqueous solution, so that the improvement in dissolution is accompanied by an increase in the saturation solubility of the drug.
  • the pharmaceutical composition comprises a film coating.
  • the film coating may comprise specific moisture barrier compound.
  • Film coating with specific moisture barrier system can be used in many manufacturing method.
  • This barrier may consisting of Sepifilm LP and Opadry A B.
  • Sepifilm LP is in granule form. It has advantages in a formulation process, for example, improving the stability of moisture-sensitive active ingredients, improving the stability of hygroscopic formulations and preventing degradation of tablets caused by ambient humidity. Its property is quick and easy dispersion in a composition.
  • Opadry AMB is a pigmented or white film coating system for the coating of oral solid-dosage forms that need to be protected from environmental moisture. This system provides fast hydration, excellent logo definition, smooth tablet finish, rapid equipment clean down with water.
  • the manufacturing process of core tablet is direct compression or wet granulation process.
  • Direct compression is by far the simplest means of production of a pharmaceutical tablet.
  • the term "direct compression” is defined as the process by which tablets are compressed directly from powder mixture of API and suitable excipients. No pretreatment of the powder blend by wet or dry granulation procedure is required.Three key factors for successful tableting are flow and compactability of the compression mix, and drug content uniformity in the mix and the final tablets.
  • Direct compression involves comparatively few steps: i)Milling of drug and excipients, ii)Mixing of drug and excipients, iii)Tablet compression.
  • Direct compression excipients mainly include diluents, binders and disintegrants.
  • Fluid bed granulation method has advantages in manufacturing pharmaceutical products. Fluid bed granules are homogeneous. All particles in the powder mix are sprayed evenly with liquid starting materials. The type of granulate (size, density, porosity) can be influenced over a wide range by the adjustment of various parameters.
  • One embodiment of the present invention is characterized in that prasugrel base granules with external phase of surfactant such as Sepitrap 80 or Sepitrap 4000 using direct compression method.
  • Method's steps are: i) blending drug and excipients. ii) mixing of drug with Sepitrap 80 or Sepitrap 4000 and excipients. iii) tablet compression stage.
  • film coating with specific moisture barrier is performed in the last stage of process.
  • These coatings are a film-coating system to protect against moisture (Sepifilm LP and Opadry AMB as commercial name).
  • a further preferred embodiment according to the second present invention provides a method for preparing pharmaceutical granules in wet granulation, comprising the steps of
  • SEPITRAP 80 or SEPITRAP 4000 is used as a solubilizer in external phase
  • film coating with specific moisture barrier compound is performed in the last stage of process.
  • Potential materials for increasing solubility like HPC, PEG, beta-cyclodextrine, Sodium Laurylsulfate etc. can be used in wet granulation method.
  • the pharmaceutical composition is tablet or capsule for oral administration. It may be in the form of immediate release or in the form of prolonged release.
  • Present invention provides a pharmaceutical composition, which comprises of;
  • composition which comprises of;
  • a further preferred embodiment according to the second present invention provides a method for preparing pharmaceutical granules in wet granulation, comprising the steps of
  • surfactant such as Sepitrap 80 or Sepitrap 4000 is used as a solubi!izer in external phase
  • prasugre! granules and the other excipients can be used in the content of medicaments which are efficient in preventing or treating thrombosis and cardiovascuiar diseases.
  • One object of the present invention is to obtain a stable and coated granule with antithrombotic activity.
  • cyclodextrin means a compound including, but not limited to: ⁇ - cyclodextrin, hydroxypropylp-cyclodextrin, sulfobutylether -cyclodextrin, random meth lated ⁇ - cyclodextrin, dimethyi -cyclodextrin, trimethyl ⁇ -cyclodextrin, hydroxypropyl ⁇ -cyclodextrin, hydroxybutyi ⁇ -cyclodextrin, glucosy ⁇ -cyclodextrin, maltosy ⁇ -cyclodextrin, 2- ⁇ ⁇ - ⁇ cyclodextrin or a combination thereof and their pharmaceutically acceptable salts.
  • cyclodextrin compound one means cyclodextrin as well as their pharmaceutically acceptables salts, enantiomeric forms, diastereoisomers and racemates.
  • Prasugrel means a compound including, but not limited to, the drug compound prasugrel, its pharmaceutical acceptable salts and their polymorphs and hydrates thereof.
  • granule means a powder, particle, or pellet form of prasugrel or a pharmaceuticallyacceptable salt of prasugrel.
  • salts refers to salts including but not limited to, hydrohalides like hydrochloride; lower-alkyl sulfonic acid salts such as methanesulfonate, or ethanesulfonate; arylsulfonic acid salts such as benzene sulfonate or p-toluenesu!fonate; inorganic acids such as nitrate, perchloric acid salt; organic acid salts such as acetate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate or maleate; or an amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt or aspartic acid salt, preferably hydrohalides or organic acid salts, more preferably hydrochloride or maleate and most preferably hydrochloride.
  • pharmaceutical composition may be formulated, for example, in the form of pharmaceutical compositions for oral administration such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, sofutions and the like, or in the form for sublingual a buccal administration, or in the form of pharmaceutical compositions for parenteral administrations such as injections for intravenous, intramuscular, or subcutaneous administration, drip infusions, transdermal preparations, transmucosal preparations, nasal drops, inhalants, suppositories and the like.
  • parenteral administrations such as injections for intravenous, intramuscular, or subcutaneous administration, drip infusions, transdermal preparations, transmucosal preparations, nasal drops, inhalants, suppositories and the like.
  • Injections or drip infusions may be prepared as powdery preparations such as in the form of lyophilized preparations, and may be used by dissolving just before use in an appropriate aqueous medium such as physiological saline.
  • the formulation according to the present inventions may be in the form of a tablet, dragee, capsule, caplet, orally-disintegrating tablet, film-coated tablet, enteric tablet, buccal tablet, sublingual tablet, chewable tablet, effervescent tablet, slow-release tablet, rapid-release tablet, modified-release tablet, delayed-release tablet, prolonged- release tablet, controlled-release tablet, sachet, granule, pilule, powder, pellet, suppository, pastille and similar solid oral dosage forms, or syrup, elixir, solution, suspension, drop (concentrated solution), potion, emulsion, ampoule, or similar liquid oral dosage forms.
  • the preferred dosage form according to the present invention is the solid dosage form, preferably a tablet form.
  • pharmaceutical composition may developed in the form of a unit dosage form, such as tablet, minitablet, bilayer tablet, caplet, granules/pellets, and in the form of capsule or sachet filled with tablets, minitablets, granules/pellets.
  • a unit dosage form such as tablet, minitablet, bilayer tablet, caplet, granules/pellets, and in the form of capsule or sachet filled with tablets, minitablets, granules/pellets.
  • composition of the present inventions may comprise one or more pharmaceutically acceptable excipient(s).
  • Pharmaceutically acceptable excipients comprise, but are not limited to fillers, disintegrants, binders, lubricants, glidants, sweeteners, aromatic agents, preservatives, coloring agents, and the mixtures thereof, to facilitate the physical formulation of various dosage forms like orally disintegrating tablets, chewable tablets and suspensions (including dry powders or granules for suspension).
  • pharmaceutical composition can be prepared by various formulation techniques known to the person skilled in the art, such as, but not limited to direct compression, wet or dry granulation, slugging, hot melt granulation, extrusion-spheronization, hot melt extrusion, fluidized bed granulation, extrusion, spray drying, spray coating, and solvent evaporation and the like.
  • pharmaceutical composition may comprise single or plurality of multiple- compression tablets which are formed by two or more compression cycles. This results in a multiple-compression tablet which has at least two discrete layers defined by the presence of the said parts in the layer.
  • a multiple-compression tablet can exist as, for example, a layered tablet, as a compression-coated tablet, or as an inlay tablet.
  • a layered tablet is a tablet which is made up of two or more distinct cores of granulation compressed together with the individual layers lying one on top of another.
  • layered tablets are generally prepared by compressing a granulation onto a previously compressed granulation. The operation may be repeated to produce multilayered tablets of more than two layers.
  • a compression-coated tablet is a tablet which is made up of an inner core and one or more outer core or coats wherein the inner core is completely surrounded by the outer coat or coats. These tablets have at least three discrete zones of components compressed together, i.e., an inner core, middle core, and an outermost coat. Such tablets also referred to as press-coat or dry-coated tablets are prepared by feeding a previously compressed inner core into a special tableting machine and compressing one or more other granulation coats around the preformed inner core.
  • inlay tablets instead of an inner core being completely surrounded by an outer coat, one surface of the inner core is exposed.
  • These tablets have at least two cores of components compressed together, i.e., an inlay core and a base core.
  • the preparation of inlay tablets is similar to the preparation of compression-coated tablets except that a surface of coating is eliminated. It will be within the pursuit of the skilled artisan to select any component or mixture thereof for preparing inlay core and base core.
  • the barrier layer may be formed by any method, including compression, molding, dipping, or spray coating.
  • Binders can be selected from the group, but are not limited to methylcellulose, sodium carboxymethycellulose, calcium carboxymethycellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, silicified microcrystalline cel!ulose(SMCC), polyvinyl pyrrolidone, gelatine, polyvinyl alcohol, acacia, tragacanth, guar, pectin, starch paste, pre ⁇ gelatinized starch, alginic acid, compressible sugar, liquid glucose, dextrates, dextrin, dextrose, maltodextrin, guar gum, magnesium aluminium silicate, polymethacrylates, sorbitol and other materials known to one of ordinary skill in the art.
  • a preferred binder is hydroxypropyl methylcellulose.
  • a mixture of binders may also be used.
  • the binder is preferably used in an amount of from about 2 to about 15% by
  • Diluents may be water-soluble or water insoluble. Diluents can be selected from the group, but are not limited to spray-dried or anhydrous lactose, sucrose, dextrose, starch, pre-gelatinized starch, mannitol, maltitol, sorbitol, xylitol, dextrin, cellulose derivatives including powdered cellulose, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate and calcium sulfate, kaolin, precipitated calcium carbonate, maltodextrin and other materials known to oneof ordinary skill in the art. A preferred diluent is mannitol. A mixture of diluents may also be used.
  • Mannitol is commercially available from under the brand name Pearlitol®.
  • the diluent is preferably used in an amount of from about 10% to about 70% by weight.
  • Disintegrants can be selected from the group, but are not limited to a!ginic acid, carboxymethylcellulose calcium, carboxymethyl cellulose, carboxymethylcellulose sodium, cross-linked sodium carboxymethylcellulose, low substituted hydroxypropyf cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidones, polacrifin potassium, starch, pregelatinised starch, sodium alginate, sodium lauryl su!phate,sodium starch glycoliate, crystalline cellulose, hydroxypropyl starch and other materia!sknown to one of ordinary skill in the art. The combination of above-mentioned disintegrants
  • Lubricants can be selected from the group, but are not limited to vegetable oils, such as hydrogenated vegetable oil or hydrogenated castor oil; polyethylene glycols, such as polyethylene glycol (PEG)-4000 and PEG-6000; stearic acid; derivatives of stearic acid, such as magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate and sodium stearyi fumarate; mineral salts, such as talc; inorganic salts; organic salts, such as sodium benzoate, sodium acetate, sodium chloride and sodium oleate; and polyvinyl alcohols, microcrystalline cellulose, sodium lauryl sulphate, silica, colloidal silica, cornstarch, calcium silicate, magnesium silicate, silicon hydrogel and other materials known to one of ordinary skill in the art.
  • the preferred lubricant is magnesium stearate.
  • lubricant is used in an amount
  • Glidants can be selected from the group, but are not limited to colloidal silicon dioxide, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, magnesium trisilicate, amorphous silica, colloidal silicon, silicon hydrogel, powdered cellulose, silicon dioxide, talc, tribasic calcium phosphate and other materials known to one of ordinary skill in the art. Glidants are used in an amount from about 1 to about 30 percent by weight. Preferably, from about 5 to about 15 percent by weight.
  • Fillers can be selected from the group, but are not limited to calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1 , kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, ma!todextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, and xylitol and other materials known to one of ordinary skill in theart.
  • Polymers can be selected from the group, but are not limited to hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate; methacrylic polymers, aminoalkyl methacrylate copolymer, methacrylic acid copolymer (e.g. Eudragit®), polyvinyl acetate phthalate and polyvinyl alcohol (PVA).
  • Plasticizer can be selected from the group, but are not limited to Acetylated monoglycerides, Triethyl citrate, Acetyl triethyl citrate, Tributyl citrate, Acetyl tributyl citrate, Trioctyl citrate, Acetyl trioctyl citrate, Trihexyl citrate, Acetyl trihexyl citrate, Butyryl trihexyl citrate, Trimethyl citrate, PEG, Epoxidized vegetable oils, Bis(2-ethylhexyl)adipate, Dimethyl adipate, Monomethyl adipate, Dioctyl adipate, Dibutyl sebacate, Tributyl sebacate, Dibutyl maleate, Diisobutyl maleate.
  • Surfactants can be selected from the group, but are not limited to, also polyoxyethylene hardened castor oil, Ethoxyiated hydrogenated castor oil (Sepitrap 4000), glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polyoxyethylene polyoxypropylene block copolymers, polysorbate 80 (Sepitrap 80), sodium laurylsulfate, macrogols, sucrose esters of fatty acids and other materials known to one of ordinary skill in theart.
  • the preferred surfactant is sodium laurylsulfate.
  • surfactant is used in an amount of from about 0.1% to about 5% weight. A mixture of surfactants may also be used.
  • Dispersing agents or dispersants can be selected from the group, but are not limited to colloidal silicon dioxide, talc, magnesium stearate and titanium dioxide and other materials known to one of ordinary skill in the art.
  • the preferred dispersing agent is colloidal silicon dioxide.
  • Preferably dispersing agent is used in an amount of from about 1 to about 5 percent by weight.
  • coating agents can be selected from the group, but are not limited to hydroxypropyl cellulose, hydroxymethyl cellulose, ethyl cellulose, talc, polyethylene glycol, titanium dioxide and color.
  • Sweeteners can be selected from the group, but are not limited to aspartame, sucralose, saccharine; glucose, lactose, fructose and other sugars, and mannitol, sorbitol, xylitol, erythritol and other sugar alcohols, and the mixtures thereof.
  • Aromatic agents can be selected from the group, but are not limited to menthol, mint, cinnamon, chocolate, vanillin, and fruit extracts such as of cherry, orange, strawberry, grape, and the mixtures thereof.
  • Colorants including, but not limited to Food, Drug, and Cosmetic (FD&C) dyes (e.g. FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lake), ponceau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (e.g. iron oxide red, yellow, black), quinoline yellow, flame red, brilliant red (carmine), carmoisine, sunset yellow, and the mixtures thereof.
  • Preservatives including, but not limited to methylparaben and propylparaben and the salts thereof (e.g. sodium or potassium salts), sodium benzoate, citric acid, benzoic acid, butylated hydroxyioluene and butylated hydroxyanisoie, and the mixtures thereof.
  • flavoring agents for the composition of the present invention are black currant, sodium chloride, strawberry flavor, and peppermint flavor.
  • sweetners for the composition of the present invention include sucralose, acesulfame potassium and aspartame.
  • a combination of sweeteners and flavoring agents can also be used.
  • flavoring agents are used in an amount of from about 0.5 to about 5 percent by weight.
  • sweeteners are used in an amount of from about 1 to about 5 percent by weight.
  • This invention can include production method which is for increasing solubility. These methods can be spraying granulation from above and solid dispersion techniques.
  • the present inventions provide pharmaceutical formulations comprising prasugrel base characterized by 1 ) good stability, 2) to control / program the release of the active ingredient according to desired therapeutical needs, and 3) a simple and competitive manufacturing process.
  • the major subject of the present inventions are to provide a prasugrel formulation which has resistant against physical and enviromental conditions and also have a high bioavailability.
  • Prasugrel base and salts are sensitive to moisture and oxygen content of the air.
  • the prasugrel formulations can be designed and processed in order to obtain pH-independent, fast or slow release drugs.
  • the coated granules surprisingly give results which are good dissolution rates and stability. Coating with cyclodextrine of prasugrel granules and using Sepitrap 80 or Sepitrap 4000 can increase dissolution rates. Also it protects stability rates in composition. This step also avoids the aggregation of granules and any reduction in their flowabiiity. The flowabiiity of the granules obtained is high, and their humidity-permeability is low.
  • Mannitol, Sodium lauryl sulphate, Crosspovidon XL-10, Sepitrap 80 and PVPK30 are passed through 600 ⁇ screen and dry mix in High shear mixer. The mixture is granulated by Prasugrei base solution in acetone. Dry and sieve. Sieved Crospovidone XL-10 and Avicel PH 112 are added to dried granule and mixed. Sieved Magnesium Stearate is added, mixed, compressed and coated.

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Abstract

La présente invention concerne la préparation de compositions pharmaceutiques stables contenant une base de prasugrel et des excipients appropriés. Ladite composition comprend au moins un tensioactif et éventuellement un composé cyclodextrine.
PCT/TR2015/000033 2015-01-29 2015-01-29 Compositions pharmaceutiques stables contenant une base de prasugrel WO2016122421A1 (fr)

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GR1009230B (el) * 2016-10-12 2018-02-22 Φαρματεν Αβεε Φαρμακευτικο σκευασμα που περιλαμβανει βεσυλικη πρασουγρελη

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US6693115B2 (en) 2000-07-06 2004-02-17 Sankyo Company, Limited Acid addition salts of hydropyridine derivatives
EP1896019A2 (fr) 2005-06-10 2008-03-12 Eli Lilly And Company Formulation d'une thienopyridine, comme inhibiteur de l'agregation plaquettaire
EP2100610A1 (fr) * 2006-12-07 2009-09-16 Daiichi Sankyo Company, Limited Composition pharmaceutique contenant de l'hydroxypropylcellulose faiblement substituée
US20090281136A1 (en) 2008-05-08 2009-11-12 Sandeep Mhetre Prasugrel pharmaceutical formulations
WO2010094471A1 (fr) * 2009-02-17 2010-08-26 Krka, D. D., Novo Mesto Compositions pharmaceutiques comprenant du prasugrel ou ses sels d'addition d'acide pharmaceutiquement acceptables, et leurs procédés de préparation
WO2011036533A1 (fr) * 2009-09-23 2011-03-31 Glenmark Pharmaceuticals Limited Composition pharmaceutique contenant du prasugrel et du triflusal
WO2011092720A2 (fr) 2010-02-01 2011-08-04 Msn Laboratories Limited Composition pharmaceutique de prasugrel et ses sels pharmaceutiquement acceptables
EP2409701A1 (fr) 2010-07-19 2012-01-25 Sanovel Ilac Sanayi ve Ticaret A.S. Granules de prasugrel dotés d'une meilleure stabilité
EP2409685A2 (fr) 2010-07-19 2012-01-25 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations de prasugrel à désintégration orale
WO2013150322A1 (fr) 2012-04-02 2013-10-10 Egis Pharmaceuticals Public Limited Company Compositions pharmaceutiques orales stables à libération immédiate et contenant du prasugrel
US8569325B2 (en) 2000-12-25 2013-10-29 Daiichi Sankyo Company, Limited Method of treatment with coadministration of aspirin and prasugrel
WO2014060560A1 (fr) 2012-10-19 2014-04-24 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulations orales solides de prasugrel

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6693115B2 (en) 2000-07-06 2004-02-17 Sankyo Company, Limited Acid addition salts of hydropyridine derivatives
US8569325B2 (en) 2000-12-25 2013-10-29 Daiichi Sankyo Company, Limited Method of treatment with coadministration of aspirin and prasugrel
EP1896019A2 (fr) 2005-06-10 2008-03-12 Eli Lilly And Company Formulation d'une thienopyridine, comme inhibiteur de l'agregation plaquettaire
EP2100610A1 (fr) * 2006-12-07 2009-09-16 Daiichi Sankyo Company, Limited Composition pharmaceutique contenant de l'hydroxypropylcellulose faiblement substituée
US20090281136A1 (en) 2008-05-08 2009-11-12 Sandeep Mhetre Prasugrel pharmaceutical formulations
WO2010094471A1 (fr) * 2009-02-17 2010-08-26 Krka, D. D., Novo Mesto Compositions pharmaceutiques comprenant du prasugrel ou ses sels d'addition d'acide pharmaceutiquement acceptables, et leurs procédés de préparation
WO2011036533A1 (fr) * 2009-09-23 2011-03-31 Glenmark Pharmaceuticals Limited Composition pharmaceutique contenant du prasugrel et du triflusal
WO2011092720A2 (fr) 2010-02-01 2011-08-04 Msn Laboratories Limited Composition pharmaceutique de prasugrel et ses sels pharmaceutiquement acceptables
EP2409701A1 (fr) 2010-07-19 2012-01-25 Sanovel Ilac Sanayi ve Ticaret A.S. Granules de prasugrel dotés d'une meilleure stabilité
EP2409685A2 (fr) 2010-07-19 2012-01-25 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations de prasugrel à désintégration orale
WO2013150322A1 (fr) 2012-04-02 2013-10-10 Egis Pharmaceuticals Public Limited Company Compositions pharmaceutiques orales stables à libération immédiate et contenant du prasugrel
WO2014060560A1 (fr) 2012-10-19 2014-04-24 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulations orales solides de prasugrel

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR1009230B (el) * 2016-10-12 2018-02-22 Φαρματεν Αβεε Φαρμακευτικο σκευασμα που περιλαμβανει βεσυλικη πρασουγρελη

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