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    • 专利摘要:
    oral pharmaceutical compositions of dabigatran etexylate compositions comprising a mixture of at least two types of particles, in which a) the first type of particles comprises dabigatran etexilate in the form of free base or in the form of salts, polymorphs, solvates or hydrates pharmaceutically acceptable products; and b) the second type of particles comprises at least one pharmaceutically acceptable organic acid; use of compositions in reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation and / or in preventing venous thromboembolic events in adult patients who have undergone total elective hip arthroplasty or total knee replacement surgery and procedures for the preparation of the compositions.
    公开号:BR112014020474A2
    申请号:R112014020474-8
    申请日:2013-02-21
    公开日:2020-02-11
    发明作者:S. Pilgaonkar Pratibha；T. Rustomjee Maharukh；S. Gandhi Anilkumar
    申请人:Laboratorios Del Dr. Esteve, S.A.；
    IPC主号:
    专利说明:

    COMFOSXÇÕES EASmCEbTXCAS 0BAIS 0S ETOXIATO DE 0 »I0AW»
    SasBs ^ as ^ axes [GOOlj A. The present invention is kingfast with oral pharmaceutical compositions complying with csbigatraua etaxylate or a further pharmaceutically acceptable s®sw.
    Background of. invention ^ vwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww ^ wv ^ wwwwwUwwvwmw [8002] Atrial fibrillation is the most common cardiac arrhythmia that is characterized by abnormal cardiac rhythm, It is considered ama causa cornu®. irregular heartbeat e. can cause stroke e. other systemic embolic events, finally, mind-taking. It has been seen that the incidence of atrial fibrillation increases with age and about 1 in individuals over 6'5 'years are affected, while the prevalence is around -8 in individuals over B0 years of age. The lack of cardiac contractions organized in atrial fibrillation generally results in little stagnant blood in the left atrium: or left atrial appendage. This lack of blood circulation leads to the formation of thrombus or blood clots. Patients with atrial fibrillation o * '· ® <<>, *, de,, r' c ,, u < s e '' n,., <', Eu í v', <v '<> 8nV o mt '<' Ό., '' Η systemic, since the consequence of stroke or systemic embolism is devastating. a main objective of the treatment of atrial fibrillation is to reduce the risk of the formation of thrombosis artoria .. if i.rumboembe i 1 a. ãut4 coagulastes, such as vaxfarin, are used pninclpalmentfô in case of atrial fibrillation, together with other medications, such as beta blockers and calcium channel blockers or some non-invasive rhythm control methods, although warfarin antigen treatment has shown Significantly reduce stroke inoidea or systemic embolism, its use is complicated by various diets and drug interactions, a hemorrhage, which are difficult to obtain, a requirement for frequent laboratory testing, etc. The use of a new safe and effective anti-Muslim is therefore necessary »[0003] Direct inhibitors of the thrombus, not another class of anti-caking agents that act by inhibiting the enzyme thrombin. and are expected to replace heparin and derivatives) and warfarin in various clinical settings. Thrombin, a serine protease protein formed by proteolytic cleavage. from pnotrcmbína, it converts innocuous ç fi.br into insoluble fibrin chains and also catalyzes many other reactions related to coaqulaçao. Direct inhibitors of. thrombi inhibit thrombin, including fibrin-bound thrombin, thus limiting thrombus growth, forcing predictable anti-coagulant responses park: they are not bound to plasma proteins and have no drug interactionsDepending on their interaction with the trembmbi.na stoma, axis ter br types will, as well, be univalent of direct thrombin inhibitors, some of which are in olinium use, while others are in the development phase if nice. ♦ [0004] babigatran and a direct thrombin inhibitor .: powerful, reversible and univalent. tie redus the risk of stroke and systemic embolism in patients with non-valve atrial fibrillation. It is also useful in the primary prevention of venous thromboembolic events in adult patients who have undergone elective snbst.tv total hip replacement surgery or total knee replacement surgery, babiqatran inhibits free thrombin, bound thrombin, to fibrin. and the aggregation of plaguetas induced by trernMna, Dahigatraua was revealed for the first time in the worm W 9837075, which claimed compounds with an inhibiting effect of thrombin and the effect of prolonging the time of trcwbina, under the name b- (i-pirièir} “B (3-stPxicarbonilet, iX} amides of the asado 1 ~ methyl ~ -2- [d- [4-- (Nn-hexi.loxyearbóti lamidino)) phyl | amino mt '1 -a''o-u>.<·'A' m «'' [00051 Dabígatrana is currently available with dabi gatrnna etexilate mesylate (MED) under the Pradaxa * range of Boehringer Ipgelàeim as oral chaoselas of immediate release of 75 mg and 110 mg (in Burega) e .. 75 mg and 150 mg stronger (in the United States) to be administered during MED is in a form, d® pro-pharmaceutical salt dabigatrapa etexilate gw, after oral administration, is absorbed and converted to dabigatran by hydrolysis esterified in the liver, MED is a light yellow powder to yellow, nonpígroscópleo, that exists in two pídlimorficas áaídras, Form I and II, that are described in MC) 2Op503S45Bú A. ^ olub : I aqueous ID of the MED is strongly dependent on the pH and with a high ρούοα soXubllity: in : medium acid, and very weak solubilized in neutral and basic medium, while the water solubility of 1.5 mq / hand * The absolute bioavailability of the debigatran after oral administration of dabigatran ciexylate is approximately 3 to 7 % and the elimination half-life is 1.2 to .17 hours®, MED and BCS Class IX drug, indicating weak aqueous scXubility, but good membrane permeability. MED stable in the solid state and sensitive bread light irradiation, but predominastèmentè sefrè hydrolytic degradation pathways f in the presence of moisture, also and He; acid sensitive.
    [0506] Due to these physiogamic and biof anxpoetic properties of MED, some attempts have been made to provide the compositions: of MBS that are stable / provide desirable f in vitro release and biofissibility <
    [0.007} P Pedrdo de Patente VS 200.6018.3779 Al describes .compounds pharmaceutical ions of MED for oral administration in the form of tablets that comprise (a) sub-core material 1-ment® is formed by n »or more attachés pharmaceutically acceptable organic compounds, with a water solubility of> 1 q / 250 ml at 2.0 * β, such. as o: tartaric acid; is (b) a layer of active substance containing nm or more agglutinates and., optionally, a separating agent, which includes the non-toxic material. The layer, separating agent or isolating layer separates the acid core from the layer containing the active substance. The active substance layer can, in turn, be surrounded by a layer that increases the abrasion resistance and shelf life of the pellets »These layered palates are then placed in hard capsules, however, the PA'CC ' Uio kJ · p.'t: unu K> úu puloio ', cr u.credos <- tncu.ho' ^, time-consuming and uneconomical.
    [0.0-Q.ej 0 Patent Application dS 7000 (5038077 discloses a tablet which comprises dahígatran etexilate or an acceptable pharmaceutically acceptable salt thereof; one or more acceptable pharmaceutitem.eute organic acids with a water solitude of> 1 g / 250 ml at 20 S C, at nm emeipient or pharmaceutically acceptable filler material, however, due to the presence of an organic acid in close contact with the active substance, -m nr „. any special steps: taken to separate each other, can: make the active substance highly susceptible to hydrblise in the presence of moisture.
    [0007 ί The above attempts have only provided compositions of © MED, which are tedious or technologically demanding to prepare or are not likely to remain stable throughout the product's useful life, hence the need for. prepare alternative compositions of datipatran etexylate that are stable, easy or inefficient to prepare, providing the desired 1 iteration is unique and bioavailability, [0010] The present inventors, after rigorous experimentation, propose oral compositions of © toll lato de dabígatrana that understand one. mixing at least two types of particles and, optionally, at least one pharmaceutically acceptable exoipient, in which a) the first type: d © particles and comprises the active agent; bj o segando r. The type of feet comprises at least a pharmaceutically acceptable organic acid; and c) additionally, less one particular type is coated with a protective coating layer, such compositions are chemically and polymorphically stable, providing desired in vitro and in vivo performance and can be prepared by a simple, non-tedious process. ethical in terms of castes, in particular, the compositions of the present invention offer rapid dissolution, particularly in early mementos, in. © Comparison with the formulation having a type of particulates / granules. Such rapid disassembly in the early moments can guarantee the availability of more quantity of the active agent, especially when (a) the absorption of the active ingredient is rapid with : Take faster (· 48. minutes to 1 hour), (b) a Significant activity is involved, and (a) insignificant and variable absorption at a higher pS.
    Detailed Description of the Invention VWfWfWfWfWAWWWVMWVmmmww <W <W <W <W <W <W <W «« WWW * WIW <WfWMWM> MVW> MMMWAWiMMM> Mi '[0011] The ptes-ehte invention provides, in one of its aspects, compositions pharmaceuticals, preferably for oral administration, comprising a mixture of at least two types, of particles and, optionally, pole minus a pharmaeeutically accelerated exeipient, in which a) the first type of particles. and comprises dybigãtrátexilatation in the form of free base o-u in the form of commonly acceptable salts, polymorphs, solvates or hydrates; and b) punching to the put: r 'comprises at least one pharmaceutically acceptable organic acid.
    [0012] In 'particular age .usa modal, the present invention provides "pharmaceutical field Lions' of the preferênçi for administration aralkyl, ds comprnendendç one arenas by mixing the two types of particles, opõíonalmeute at least one. pharmaceutically acceptable excipient, wherein a) the first type of particles comprises dabigatran etexilate in the form of free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof; b) the second type of particles comprises at least nm. fermaesutically acceptable organic nut; and o} optionally, at least one type of [«· '; ♦ .c and as is coated with a pre · eto coating layer [0013] The compositions of the present invention are stable, simple to prepare and provide the desired release la vitro gives active substance, [0014] The first type of ucrtioulas present for ' t vS <d', eSsU. <;-'ην'ρ'<ο»ό«' daMgatrana etevi.lato, Etexiláte cie dabigatrana could be used in the compositions of the present invention as the free base of ethyl acid ester (3 - [(2 {4Chexyloxycarbonyluminimino ~ me t 1 1) phenylámino jmetil ll-methyl-ld-bensimidaral-Sanrbonil) -. Píridiu-l-il-amino-propoxÔnico} or in fom; of salts, polymorphs, solvates, hydrated pharmaceutically acceptable For an issue. concisely, © term © dablgatrana etexilate is used in this specification to designate any of the aforementioned forms, except when: α term is more qualified (or quit, etexilate mesylate. dablgatrana) «Whenever it is necessary to designate the Here base of dabiqatran etexllate, the term ·> η dabigatran late (base 1x vre) ”is used. · (0015} The term pharmaceutically acceptable salt , f refers to those salts that are, according to medical judgment, suitable for use in contact with the tissues of human beings and other mammals, without undue toxicity, irritation, allergic response and the like »Any pharmaceutically acceptable salts are well known in the art .:
    [0016] In one mode, the amount: of. dahigatran etexllate (expressed as dabig atraua stexylate mesylate) in the composition can vary from about 0.011 by weight to about 90% by weight, based on the total weight of the composition »In another embodiment, the amount of etexylate of dabigatran in the field can vary from about 0.02% in. weigh about B5% by weight, based on the fatal weight of the composition »In yet another embodiment, the quantity: of etexl. can of dlabigatran: in the composition it can vary from about Q, 05% by weight: about 80% by weight, based on the total weight of the composition.
    (0Q17] In one embodiment, the cooàs of the present invention may be in the form of unit dosage forms comprising from 50 mg to 200 mg of dapigatran eteXylate mesylate, preferably from 7.5 mg to 150 mg, most preferably. in addition 75 mg, 11.0 mg: cm 150 mg.
    [OGls] In each embodiment of the present invention, dabigatran ethenylation is used in the mesylate salt forum, ie, dabigatran ethesylate * [00.19] 'In a particular modality of the present invention, dabigatran etsxylate is used in the form polymorphic shape. X of dabigatran etexylate mesylate (as described in W 2005028468).
    [0020] 'In another particular embodiment of the present invention, dabigatran etexllatb is used; at. polymorphic form II of etexyate mesylate of bi g a t r a n a (as described in W 2 0 0 5 S 2 8 46 8 j.
    [0021j The oral pharmaceutical oampesição one understand the present invention D® mixing at least two types of partfoulas and: optionally at least one farmaeeuticamente acceptable excipient with a first type of particles comprising dabigatran etexilate and a second type of particles comprises at least one acceptable pharmaceutically acceptable organic acid.
    [062: 21 In. a preferred mode of the present invention, the first: type of particles comprising ethylene of: dabigatrasa is free of organic acids and inargiums :, [0-023] Km a preferred mode of the present invention, the first type: of Particles comprising dabigatran etexilate in the form of a free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof also comprise at least one pharmaceutically effective plant.
    [δθ'24 '1 In a more preferred embodiment of the present invention, the first type of particles comprising dubigatran etexylate mesylate in the form of free base or in the forges of salts, polymorphs, solvates or h 1 dr a tos ac i ti c ame nt to the items of $ ésap ·, t <also comprises one or more containers selected from the group consisting of li # expenditures and / or lubricants ♦ (0025] In an urn. party lar modality, the first type of partfoujas comprises at least one ligand, preferably microoristatic cellulose »f0026] In another particular embodiment, the first type of particles comprises at least one disintegrating agent, preferably selected from oroscarmellose sodium. or urospovfdone '(0027] In another particular embodiment, the first type of particles comprises at least one diluent, preferably saieeiauate from marital or lactose.
    [0028] In another particular embodiment, the first type of particles comprises at least one. binder, preferably microcrystalline cellulose, a disintegrating agent, preferably # selected from audio croscarmellose cu orospovidone and a diluent # preferably, selected from marital or lactose, (0029] In : another pedality of the present invention, the second type of particles comprising at least one pharmaceutically uranium organic nut is free of etherate from the bicarbonate.
    [0030] In a more preferred embodiment of the present invention # the first type of particles which comprises dabigatran etylate and acid-free and the second type of particles which comprises at least one pharmaceutically acidic organic acid is free of etsxylate. dabigatran.
    [00311] Another preferred standard of the present invention, and according to the type of patric-ul-as, contains tartaric acid, preferably in the particle size of granulps. between 1G0 and 9 GO microns, more preferably between 400 and 700 micron® ·.
    [0032] Op acid and a substance that releases hydrogen ions and decreases the pH of an aqueous solution a. «[0033] Chronic oxides that can be used in. the present composition include:, but are not limited to, tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid and the like, or combinations thereof, including hydrates and salts of the mean-ç acids .
    (0034] In one embodiment, the organic acid is present : in the composition of the present invention in an amount of about 21% by weight to about 95% by weight of the composition In another embodiment, the organic acid is present in the composition of the present invention · in an amount of about 51 by weight to about 003 by weight of the composition ♦ In another embodiment, the organic acid is present in the composition of the present invention in an amount of germs of 104 in weight: about 851 by weight of the composition.
    [0035] In an embodiment, at least 003 by weight, preferably: at least 9h by weight, more preferably at least 903 by weight, and even more preferably 1003 am by weight of the organic acid present in the composition is contained in the second type of particles comprising at least one: pharmaceutically acceptable organic acid, the remainder (if any) of organic acid ©: being added as part of the encipisufces.
    [0036] h: furthermore, the oral pharmaceutical compositions of the present invention comprise an i> 3 mixture of less than two, types: particles, and # opcíónalmonte, by s®K ».s rm oxcipleute tarmaueuticamante aueitãyel, only when optionally my particles are coated with samads. protective coating, in one embodiment, the first particle tips are coated with a coating. Protective coating layer »In another embodiment, the second type of coating is coated with a protective coating layer. In yet another embodiment, the first and second types of particles are coated with one. protective coating layer, [0037] The term “protective coating layer, as used herein, is intended to mean a layer of a polymer mj. of a poly wedge material disposed on the surface of a particle of nusleu to avoid direct contact of the particle's nuole with and its environment, [0038] In one embodiment, the protective coating layer is formed by a polymeric or non-polymeric agent f any combination thereof, [0039] Polymeric agents are acceptable for use in ur.ilxr.adGS for the .v-csu v. : 'n <. .uí '·, ur f * ac''c.>>>'cellulose derivatives, vinyl derivatives, acrylic polymers and copolymers, gums or polymer. » of metacrilloo acid, copolymers of esters, or their derivatives, and the like or combinations thereof. Derivatives of ee.Uuloso that can be used include, but are not limited to, methylcellulose, hyeruxipropiimatilçeluluse, hydroxypropícellulose, hiclroxiet ileelalose, hldroximet i Icelulcse, ethylcellulose, hidrexxuvopiletilcelulo »©, carboxy-cellulose, carboxy-cellulose, carboxy-cellulose, carboxy-cellulose. '' d oxyethyl cellulose, hydroxyethylcarboxymethyl cellulose, hydroxyethyl methalt 1 celt lose, ç a. x boxfoe: ti 1 © e 1 u 1 as e, tx 1 hx dr ex 1 at x 1 cellulose .., msti.lhidxaxipropilcelulQse, aarboxymethyl sulfoethyl cellulose, healthy caxboxfoethyl cellulose, are similar, without combinations, lx .x ux · de vxnila, polymers and capexxmerte des s®ws that could have sex include, but are not xfoxtado, copelimeros de vlnil pixxolidona, uopalxmeros de : alcaol pallvlniliaa (Kcllieoat. The gomes qua pedfo box used lualuem, but are limited to, gum arabic, alginates, game guar, alfarreda seed gum, carrageaxna, pectin, xautana yolk, gelana yolk, maltodextrlua, galsutomanana, karaga, and the like, or. combinations. Folfo.acrylic or methacrylic abide beads, copoxymers, are textiles and their derivatives, which may be used include, but are limited to, a) copolymer formed from. Monomers selected from methacrylic acid, metheric acid beings 11iee. of acrylic acid and acrylic acid esters, a) limer layer formed from butomeric methomers from butyl metauxxlate, (2-dimethylam.ne.neetxl) and: '' ua <>'' cou '. 'was a, <-><<.'/eu' ae <'a pafo.lr from .nuxfome.ros selected from ethyl acrylate, methacrylate methacrylate and tymmethyl methaltate alotate latmnioethyl or d) lime cups from aux i lata and metaax'i.latas aem ./without a quaternary ammonia group, a combination with uarbaxymethylcellulose, for example, those available from Rafo GmbH under the Eadragití trademark as Eudragit 11FÓ (capo.límexa of mutacrilata · dis t: lamíaoetxla; ), Eudrugit RI> RS ícopOiiMix »oe mfo · ncril ato de trimethylamoaioethila), Eudragit NB30D and Eudxagit neOD (aapollmero metxfo.etacrilato etxláxo de acme; combinations of them.
    [0040; The pharmaceutically acceptable nanopolymer agents used for the protective coating loved include, but are not limited to, fatty acids; CS-Cll, CS-C22 fatty acid, in. in particular, mona, glycerol di-triester and fatty acids C8-C22. oeras, and similar oysters., or combinations thereof. Fatty acids that can be used include, but are not limited to, deoenoic acid, dooosanoic acid, cystic acid, palmitic acid, lauric acid, myrrhic acid, palm seed oil, hydrogenated, hydrogenated peanut oil, hydrogenated palm oil , hydrogenated animal seed elec, rice pheasea oil, himragenated soybean oil, hydrogenated sunflower oil, hydrogenated ricin oil, cottonseed oil, and the like, and mixtures thereof. Long chain monolithols that can be used include, but are not limited to, cetyl alcohol, stearyl alcohol and mixtures thereof. Waxes that can be used include, but are not limited to, © et® sperm wax, carnauba wax, Japan wax, laurel wax, linen wax, beeswax, Chinese wax, shellac wax , I aol car Uh. have cherries from <u; ue-m, ce from canosl '. a, water wax, microcrystalline wax, petrolatum wax, carbo ™ wax, moostostate; glycerol, glyceryl methylstearate, glyceryl tristearate, glyceryl dipalmitatu, glyceryl tripalmitate: Imitate de glioerlla manopa, glyceryl dilate, glyceryl trilaurate, glyceryl mcnolfiurate, trimir is tato; glyceryl, glyceryl monodecenoate, glyceryl dececenoabo, glyceryl tridecendate, glyceryl beate and the like, or mixtures thereof.
    [0041] In another modality, in addition to ages te pa '· * or farfeadéutíca polymicritic phytosterly acceptable or : any combination of the same, a. backing layer calls, opcienulmente comprise water or postponed onalmente bag excipients armament.icameu you acceptable such as, but not limited to such, · piastifíeantes, antíadarênula agents, pigments and the like, or combinations' thereof ^ <M plasticizer can be used .iodai, · but not limited to citrate. triethyl, aoetil triatila, propylene glycol, palietilenoglical, acetyl tributyl, moaoglice.rld.eos aeetiidos, glycerin esters, triacetin., phthalate (for example, diethyl phthalate, dibutyl oil phthalate) castor, sorbitol and dry dibyl or a combination thereof »An anti-stick agent that can be used includes, but is not limited to, talc or glyceryl monostearate, Um P 'u'-r-'; q -a, .ό'λ, m.í. , u.-vt © d < ! : <r; o, iron oxide, or a mixture thereof, can be used *
    10042) The protective coating layer, optionally, can be applied on at least one type of particles of the present invention. For example, a. protective coating layer is applied over the first type of particles comprising dabigatran etexylate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates of the masmoa [.0043-] In a preferred embodiment of the present invention the cove of roves 11 men to oter.or ΰ coated on the second type of particles which comprises at least one ergau.icu pharmaceutically available, in a particular embodiment, the coating layer comprises hydroxide and propylene. lose and talc.
    15/33 {0044] And S another modality, both particles are coated: with the protective layer of raves ,.
    [0045] The protective coating layer, optionally, can be applied over at least one type of particles of the present invention in any adapted equipment, where the coating can be achieved, such as, but not limited to, coating pan, appliance of conventional film coating or fluidized bed apparatus, or the like »In addition, in a measure, the protective xcveatíítoto layer can be applied from one. aqueous or organic solution or dispersion. In another embodiment, the particles to be cured, coated with. the protective coating layer can be coated, with a crown weight gain of 3% to about 50% in. Weight.
    [0046] In one embodiment, it will reduce damage to the protective coating layer during transfer in capsules, particles coated with protective coating layer can still be coated with a conventional sealing film. pharmaceutics is acceptable. forming agents that can be combined optional. ask with p last! Suitable yarns or pigments The suitable film-forming agents include, but are not limited to, 1. they do not contain, or they do not contain. p r o p i 1 m t i 1 cellulose, polymers, <e.- »> n> '<t'. '. of acrylic acid »and motacn flieo, and others added .bar. tea or combinations of metaphors. Plasticizers and pigments, as discussed above, have the option of being used with film forming agents.
    [0047] The compositions of the present invention comprise a mixture of at least two types of particles and, optionally, at least less than an acceptable amount of eukaryotic material. It was another modality »the ρχίοοίνο type of paztfculaa gun compréende etnxilatu de dabigatrana. it can optionally also comprise at least one acceptable excipient U.rweutfewnte acceptable, In another embodiment, the second type of particular gun comprises at least one organic acid, it can, optionally f understand alludes to at least one pharmaceutically acceptable exoipinnte., In yet another modality , at least two types of particular that are present in. The pharmaceutical composition further comprises, optionally, skin less a pharmaceutically acceptable carrier.
    (0048] The excipients fiirmauuutically acceptable lenses that can be incorporated into the composition of the present invention Include, but are not limited to, grease, disintegrating agents, thinners, agents: non-chemicals, glidants, lubricants f and the like or combinations of themselves.
    [0049] The term "disintegrating agent", as used herein, means a compound used in solid dosage formulations to promote the breakdown of the solid mass into smaller particles that are more easily dispersed or dissolved. Exemplary degrant agents include, by way of example and without limitation, natural, modified or pregelatinised starch, modified starches (eg sodium glyclic starch) and parellially pre-gelatinized starches (eg Starch Χ5δ0)> polrvini Ιρίϊ lol.idona, exospovidone, croscarmelos-e sodium, calcium silicate clays, such as: bentonite, mierdexistaline cellulose, gems:, such as agar, guar, ai f. arrob, Xaraya, pectin, tragacanth, alginates, phenolic exchange resins (for example, potassium polacrylin, bolacrílex), Neusilins, little substituted hydroxylpropylcululose and the like: combinations of the same and other materials known to those skilled in the art.
    [G05Q J S term binders ”, such as used agpi, u <'t <, âO' ca <í1 u sua-d ..uc. v.-> t ''. ... ceu) e .. cause the powder particles to stick to the granulations. Examples of suitable binders include, but are not limited to, cellulose, such as microcrystalline cellulose, modified aelsloses (such as poorly substituted hydroxypropylcelslose, hydroxyprapylcellulose (or BFü), hydroxypropyl.methylcellulose, or hydroxyl, hydroxyl, hydroxyl, hydroxyl, hydroxyl, hydroxyl, hydroxy, hydroxy, hydroxy cellulose acetate, cellulose gum, xanthan gamma, sugars (such as sucrose, glucose, amylose, maltodextrin, dextrose, and the like), starches, such as corn or potato starch, pre-gelatinized amide (such as Starch 1503), polyvinyl acetate (Eolliccat SR), polyvinyl-polyethylene glycol alcohol graft copolymer (Eõliicoat IR), cupovidone, polyvinylpyrrolidine retioulada, polymer of 111 co. (Carbopol), poloxamer, poloxamer, poloxamer. polyethylene oxide, polyethylene glycol, and the like, combinations thereof and other known known to those skilled in the art.
    (0SS1J The term "diluent" or filler material, as used herein, is intended to mean inert substances used as fillers to create the desired volume, flume properties and compression characteristics in the preparation of solid dosage formulations. include, but are not limited to, microcrystalline cellulose, pre-processed niiorocrystalline cellulose (such as Avloe.l CI-E11, avieei RC-581, Avicel RC59.1, Avicel CE, Avicel CG, Arlee] EFB), lactose, sucrase, xylitol, mannital, maltose., polyols, fructose, guar gum, sorbitol, magnesium hydroxide, dibasic calcium phosphate, kaolin, calcium sulfate, carrageenan, guitosan, pectinic acid, sodium alginate, silicate of hallucinic magnesium, calcium carbonate and the like, combinations of the same and other materials known to those skilled in the art * [0052] The term '' lubricant · ', as used herein, means substance used in dosage formulations. solids to reduce friction during solid dosage compression. Such compounds include, but are not limited to, magnesium stearate, calcium stearate, ninc stearate, stearic whey, talc, oil: mineral and sodium fumarate stearate, combinations thereof and other materials known to ib '·' Ui V. '!' '< a.
    [D053] The tablet compositions of the invention may also include one. shutdown agent. The term '' slippery agent ', as used herein, is intended to mean agents used in solid dosage formulations to improve the fluid properties of the compressed product and to produce an anti-agglomeration effect. Such compounds: ® include, but are not limited to, colloidal silica, silica gel, precipitated silica, calcium silicate, magnesium silicate, corn starch, talc, combinations thereof in other known materials: technical.
    [06-54.] The term thy sentiment ! I , as used here, means substances used to reduce the saperfieial tension of the acute solutions that contain them :. Examples of surfactants include, but are not limited to, sodium decusate, glyceryl mono-oleate, polyethylene alkyl ether, about polluxietllene serbitan fatty acids, healthy lauryl sulfate, sodium bicarbonate, fatty acid sorbitan ester, mixtures thereof and other materials known to you in the art.
    [0055] The compositions of the present invention comprise a mixture of ice minus two types of particles and, at least, at least one pharmaceutically acceptable excipients, with the first type of particles comprising dabigatran etexilate and second type of. particles comprising at least one organic acid.
    [0058] The term particle 1 *, as I use it here, is intended to mean any solid or semi-solid portion of a substance or composition that has defined physical limits :. Examples of particles include, but are not limited to, powders, granules, lozenges, pellets, mini-tablets or the like. The granules can be prepared by methods such as, but not limited to, granulation (bonded, granulation melting, air canceling or roll compacting or the like. In one embodiment of the present invention, pellets can be prepared by spherical beads In another embodiment of the present invention, dabigatran sturylate presets in the first set of particles, or at least one organic acid present in the second set of particles can be loaded into an inert vehicle. The inert vehicle® can be selected from, but not limited to, spheres, pellets, granules or similar particles that do not contain an active ingredient. Non-limiting examples of an inert carrier include microcrystalline cellulose, sugar or silicic acid. the present invention, in powder form, can be incorporated into the compositions of the present invention.
    [GG-57] In. a embodiment of the present invention, the first type of particles has a particle size between 50 and 100.0 microns and the second type of particles has a particle size between 100 and 1000 microns »[0058] The compositions of the present invention they comprise from 51 to about 1001 beeswax by the mixture of at least two types of particles. The ratio of the first and second types of particles is from about 1:99 to about 99: 1.
    [0059] The term "composition" or termv mmo * has been used interchangeably for the purpose of the present invention.
    [0860] The dosage thermoform, as used here, is intended to mean a pharmaceutical field that is suitable for administration to a patient. In one embodiment, the compositions: of the present '<' · *> m <· 'in the form of capsules, tablets, mini-tablets f formulation stick, dispersíveia tablets, dry suspension for reconstitution, powder or granules for solution or suspension, granules # and the like, or whichever cms of the same.
    'vo'<»<. u ''<<·<·'the' present invention may comprise suitable pharmaceutically acceptable eveipientes such eat those mentioned above and t s' additional, and t, r and limauados to, sweeteners, aromauisantos, colorants and the like or combinations thereof furthermore, it is within the scope of the invention that the dosage form can be encapsulated or coated. "In one embodiment, the composition of the present invention is in the form of a capsule, the instant capsules, for example, hard capsules of gelatin or hydramípropylmethylcellulose and the like. In another embodiment, the compositions of the present invention can be manufactured using conventional oche-metal techniques at the moment.
    [OOS1] The term unit dosage form refers to a unit: physically discrete suitable as a dosage, unitary for a human patient, such as a capsule, a pill in a bottle.
    [0062] Another aspect, the present one: prooercione invention. a single dosage form prepared in conjunction with the aforementioned composites comprises two types of particles :.
    [003] The compositions of the present invention provide the floafbility of mixing at least two types of particles to obtain different release patterns. In one embodiment, the compositions of the present invention prepare adapted Ir vitro profiles and corresponding vivo profiles. In another embodiment, the compositions of the present invention can provide adapted profiles, in which the dissolution of <· © νροη'ç <. The present invention can be faster in inxial moments when compared with formulations with only one type of particles which comprises either cabigarrano stexilaro or pharmaceutically acceptable salts of the same and organic acid. Without being connected to. any theory, it is believed that a quick dissolution in the initial moments can guarantee the availability of more active agent, especially when (a) the absorption of the active ingredient is fast with faster Tman (-45 minutes at 1 hour), (b) significant bioactivation is caused by the action of dabigatran and (c) insignificant and variable absorption is observed in mayx * pH.
    [0064] In another aspect, the presence invention provides a process for the preparation of a composition '<' c r <'> s c u <u - ·, .... u. d. i, comprising the step of mixing the first type of particles and the second type of particles with. at least one pharmaceutically acceptable excipient- In a particular embodiment of the present invention, the first type of particles is prepared by granting »[006.5] In one embodiment, the process of preparing the compositions of the present invention comprises the steps of:
    (i) mixing dablgatran etexilate and skin with a pharmaceutically acceptable excipients, such as diluent;
    (li) granular a. mixing step (1) with a binder solution to form granules of the active agent;
    (ill) mix at least nm. organic acid and at least an acceptable pharmaceutical excipient, such as a diluent
    (iv) granulating the mixture from step (iii) with a binder solution to form granules of organic acids;
    (I saw coating the granules of <. * <. organic with a protective coating layer;
    (vi) mixing the granules of. step (11) with the coated granules of step (v) to form a mixture of at least two types of grantIas;
    (vii) Optionally, combining the mixture of at least two types of granules from step (vi) with at least one pharmaceutically acceptable carrier;
    (viii) lubricate the mixture from step (vii);
    (ix) fill the lubricated mixture of the step (vil.i.) in. suitable capsules «[0066] In another embodiment, the process of preparing the compositions of the present invention comprises the steps of;
    (1) mixing dabigatran etexilate and: at least a pharmaceutically excipient. acceptable, such as thinner;
    (ü) granulate a: mixture from step (1) cob an agglutinating solution to form granules of: active agent;
    (fix) mísfceia. ·: at least one organic and at least one. excipient, pharmaceutically / eutically acceptable f such as diluent;
    (iv) granulating the mixture from step (xxx) with a binder solution to form granules of organic aches;
    (V) coat the active agent granules with a protective coating layer:
    (vi) mixing the granules from step (iv) with the coated granules from step (v) to form a mixture of at least two types of granules;
    (vií) optionally combine to. mixing at least two types of granules from step (vi) with at least one faxmaceutically acceptable excipient;
    (feasible) lubricate the mixture from step (vii);
    (in) fill the lubricated mixture of the step (viiij in appropriate capsules.
    [0067] In yet another age fashion, the prep.c · ί η process! of compositions d: the present invention comprises the names: de;
    (i) mixing dabigatm ana stexylate and at least one pharmaceutically acceptable excipieute, such as diluent;
    (li) granulating the CM step mixture with an -o, „i. t art fx »» '' - ' t cx. »G't <>, '> * (iii) mixing at least one organic acid and at least one pharmaceutically acceptable ingredient, such as diluent or binding agent;
    (iv) extrude and spheronize the mixture from step (11.1) to form pellets of organiamj acids (v) by coating the granules of o: minic acid from step (iv) with a protective coating layer;
    (vi) mixing the granules from step (1.1) oom. the coated granules from step (v) to form a mixture of at least two types of particles;
    (vile) optionally, combining the mixture of at least two types of granules from step (vi) with at least one pharmaceutically acceptable excipient;
    (viii) lubricate until the mixture of step (vii);
    (ix) fill the lubricated mixture from step (viii) in appropriate capsules, t OOes | In another : In this regard, the present invention prepares the use of the pharmaceutical composition. of eta>; 1 1 n of dabigatran. of the present invention for the manufacture of a medicament to reduce the risk of stroke and systemic embolism in. patients with non-valvular atrial fibrillation and / or preventing venous trumboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery, (00691 In yet another aspect, the present invention provides a method for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation and / or preventing venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or knee replacement surgery, campuses: come to administration to a rm'v.am mo υ '<ηη »ide c <' ^ oom ijcmt ms of dacation ecexilacraua of the present ií) v-cao.
    [0070] In another embodiment of the present invention, dabigatran ethexylate can be combined with other pharmaceutically acceptable active agents including, but not limited to, atorvastatin, dipyridamoX, mepídámoX are similar, or their combinations »[0071] invention is further illustrated by:
    following examples, which : are for illustrative purposes and should not be interpreted as limiting: the scope of the invention in any way.
    1: formulation in oral capsule of etexylate mesylate <áa dábigatrana
    h) Preparation of coated pellets: ® of: tartâriçó acid (a) Preparation of tartaric acid pellets Table X: Composition of tartaric acid pellets
    Ingredients mg / ufslda.àe
    Ac gone tadar
    CM * B · »η ιΧ · ι · vt í'U, Ί; na g, s
    Total
    120 * not present in the final product [0072] Procedure: tartaric acid and macrocrisical celluloseXin were mixed and to this mixture was added a solution of hydroxypropyl cellulose in alcohol i sopr opí. X i co, to obtain a moist mass, · This moist mass has been extruded, spheronized, soaked and sieved to produce these skin. . were then coated with ccrn. a protective coating layer, as described below : to produce pallets coated with tartaric acid.
    26/33 (b) Fret ^ race of tartarΙαα acid coated pellets
    Tahela : 2. Composition of tartarloo acid pellets
    X ng r edi «s n tes ®g / unit® Tartaric acid pellets 120 Hydroxypropyl çelulpse IS Baby powder and Ãlacal isuprapílice * * X & Total
    * not present in the final product [0013) F r on and d i m e n: Tele t..e e do ac id ©:
    tartaric prepared in such a way were coated with dispersion of hydrepipropyl celluloid and talc in isopropyl alcohol. The pellets: coated: they were then dried to produce pellets coated with tartaric acid.
    B) Preparation : of etexilate mesylate pellets: debigetran
    Table 3: Fields of the etexilate: dabigatrain mesylate pelates
    Ingredients ] sig / unB Êtexílatu de-dábigátrana mssilata |equivalent to 110 mg: of ethexylate |dabigatran | 126.0 Jnicrocxistalàna cellulose | 40.1
    Anhydrous lactose] 30
    H id i'ox i prop! 1 cs 1 u 1 use à 1 c oo 1 í s o p rep í. 11 with *
    Crespovidone | 4
    I q »® ΐΰΐ ................................
    ........................... j * is not present in the final product [0074] Fraedimentation: Cabigatran etexylate mes1late, myorerosaline cellulose, anhydrous lactose and crospavidoaa were mixed. The mixture was granulated using a solution: from nidrexipropyl cellulose to isopropyl alcohol. The pellets were sized and filtered to form pellets of dabigatxan etexylate mesylate.
    C) Preparation of the form; action on. oral capsule of dabigatran mesylate ^ -ethexylate
    Table 4: Composition of the formulation of daòigatran etexilate mossilate capsule
    Ingredients ssar / un age Dabigátrane etexylate mesylate pelletspgã '· ’’ #idos 3r> aeíCo stát iocEstear11 sodium fumarate 364: Total 345
    [0'073] Procedure I Dabigatran etexylate mesylate pellets prepared according to the composition of Table 3 above .50200 taxr coated pellets prepared according to Table 2 above were mixed. The mixture was lubricated with stearing, 1 audio fumarate and placed inside capsules by means of a capsule filling machine.
    Example 2: fors & ulation in an oral dabigatrwa etexylate mesylate cup
    A) Price comparison of t: rtr 'acid caps Table. 5: Composition of tartaric acid pellets
    ingrodientos mg / unit tartaric acid 60 C and Iulose mis recreated! 18 Hydrox1propi1 cellulose 4 À1cooI 1sopropi1ico * q.s To such 82
    «Not present in the final product [0S7.6J Procedure: tart âri.eó acid and mictonristaline cellulose were mixed and to this mixture was added a solution of hydroxoxyprapyl. Cellulose in alcohol λ ', ο. · To isopropyl, to obtain this mass timid. This wet mass was extracted, dried, dried, and sieved for. produce pellets. These pellets were coated with one. protective coating layer, as described below to produce crazy coated pellets
    t n .t n r: co. B ) Breparation of coated pellets in <mesilate atex11ate moth dabi ça.( The ) Breparation ds mesylate pellets of etherylate dab iça t rana.
    Table Composition of dabigatran etexilate mesylate pellets
    Xngredientss ®g / uriirfade Dabiqatran etexylate masliaio equivalent to 110 ms of dabiqatran etexilafcô 16.4 8 Microcrystalline cellulose 3 2.52 anhydrous laetosis 25 Crospovidone 3 Uidraxipropyl cellulose 3 Isopropyl Alcohol*Total its
    * not present in the final product [0 0 7 7] B rooed ime: from s .11 to dabigatran ctexylate, microcrystalline cellulose, anhydrous lactose or croapovidone were mixed, the mixture was granulated u tills without a solution: de hydroxypropyl 1 cellulose in. isopropyl alcohol ieo .. The palettes were sized and filtered to form dabigutran ethesylate mesylate pellets.
    29/33 (b) Preparation of pellets. rovestides of dabigatran etexylate mesylate.a
    Table 7i Composition of pellets coated with '> dablgatran etepylate
    Ingredients ®g / unit «te Mesylate pelet.es from etexylate 1 É Λ dabigatraáaP c li v i nil p ir roll idon a: 2 2 Baby powder .................................................. .......................3 Isopropyl Alcohol*· g, s Total 17S.
    aha sst: 3rd present in the final predate, [G07B] Procedure: Dabigatran etexylate mesylate pellets. prepared according to the aforementioned process were coated with a polyvinylpyrrolidone and talc coating dispersion in isopropyl to form coated pellets of dabigatran etexylate masslate.
    C) Preparation of the oral capsule formulation of dabigatran etexylate myylate
    Table .: E: Composition of the up to z Mesylate capsule formulation. à αto do dnb> gaf '' ana :
    j Ingredient®] mgZunit | Covered palates of etexylate mesylate | | from dabigat.rana j 17 S | Palettes from aside tartar S3 | Sodium esteariJ fnearate 3 i Total [ 2®
    [0079] Procedure: Deletes of dahigatran etexilate meeylate prepared according to Table 7 above and pellets of tartaric acid prepared according to Table 5 above were mixed. The mixture was lubricated with sodium stearyl fumarate and placed inside capsules by means of a capsule filling machine.
    Example 3; Two different approaches to formulating WsXXate dahigatrána etexilate [00S.0] Formulations of two approaches to dabigatran etexilate mssilate, as shown below, were evaluatedí : (.í) the first approach is that (.í) the first approach is that the present invention has two types of particles / pellets (one of dabigatran etaxylate mesylate and the other of organic acid) s (ii) the second approach is that it has one. type of partiesIgs / psletex having both dabigatran etexylate meaylate and organic acid, Bata formulation was prepared according to the teachings of the patent PS 2.006 / 074.05.6 and, in particular, of Example 1 »formulation (d) (A) ' Preparation of Formulation A with two types of partioelas / pellets (ie, mesylate dices etc, dabigatran action or sealed coated pellets of tartaric acid)
    Table 17: Cemposlection of stexi.l. t : dabigatran .it.o
    Ingredients mg / capsule Intr «granular Debiqatran etexylate mesylate equivalent to 150 mg dgbigatran etexilate 172.95 XPA q. s Extragxanular Pulp n.Lcroct: istmi ina 6 7.0 5 Odesic Croseariasis 50 In spite of the total number of fishes of eteaciXatc is dabigatran 2SG
    Table 18 Composition of pellets · coated with tartanic acid soles ©
    XngxcdientusTaxtamic Acids (TAF * δδΟ) 196.34 acid sealed jewelstartarHidr ox iprop1loo t i1 eelula s e S, S3 tactose .5 f .ãl Baby powderÁ.l with iscpropyl 1 ico-water c <s Total sealed coated film thickness Z: G
    (0 0 81 | pre oced1mooto:
    (1) Preparation of the portion of pellets of etexilate dabigatrate [0082] with the amount of mesylate of etexilate: dabigatran. heavy and loaded to granulator © granulated using iseprooyl alcohol. The grains were then dried in a fluid bed dryer. The granules were soguida, sized, sieved and mixed with michlorouristaline delulose, croscarmellose sodium in a suitable mixer to produce a portion of dablgatran etexylate mosylate pellets.
    fii) Preparation of sealed pellets of tartaric acid (0033) Sidroxiptopil. cellulose was added to an appropriate amount of the isopropyl alcohol water mixture with stirring to obtain a solution * Lactose was added to this mixed solution, followed by the addition of the tale and stirring. , to the suspension thus formed was filtered through an appropriate sieve and sprayed under continuous agitation on pellets of tartaric acid using a bed: fluidized coating with a Wurster column to achieve the desired weight gain. The tartaxic acid coated pallets were then dried.
    [GÕSA] Pellets coated, sealed, lubricated with tartaric acid and pellets of dabigatran mesylate etcxylate were filled & capsules using the machine, automatic filling of capsules in HRMC capsules of size 0.
    (C) Cooperative profile evaluation, of. dissolution of the formulation of. present inxe-oae that also two types of particles / pellets (Formulation Á above) and formulation having a type of particles / pellets {Formulation B above] [ÓQáS] The dissolution profiles of the formulations in HC1 0.6.1 õ, pH medium 2 to 10Q rpm 0SP Type I (basket) are co®5 described in A and B below:
    I'empo (minutes) 1 from * il eu · â - Formulation A (two types of particles / pellets) Formuiation S(xsm type of particles / pellets) 10 65.1 19.2 15 7 9.2 57 20 AG, 7 yeah, i 10 9 / 97 45 95.5 9 7.6 60 95, S 95 t 5:
    [0005] The comparative evaluation of the dissolution profiles of the formulation of the present invention which has two types of particles / pellets (Formulation A above) and formulation having a type of paxtiedas / paletas (Formulation B above) indicates that the formalizations of the present invention that it has two types of particles / pellets can provide the quickest dissolution of powder at early times, compared to the formulation having a type of particles / pellets. Fax dissolution faster; early moments a 'c'< t <<c ! and »- 1 ''<'· of the active agent, especially when (a) the absorption of the active ingredient is rapid with. Faster Tmax (Md minutes to 1 hour), (b) a significant bioutxagon is involved, and (o) an insignificant and variable absorption with a higher pH.
    权利要求:
    Claims (20)
    [1]
    1. A composition comprising a mixture of at least two types of particles, wherein a) the first type of particles comprises dabigatran ethexylate in the form of free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof; and b) the second type of particles comprises at least one pharmaceutically acceptable organic acid, and is characterized by the fact that at least one type of particles is coated with a protective coating layer.
    [2]
    A composition according to claim 1, in which at least one type of particles is. coated with a protective coating layer.
    2/5
    2. Composition according to claim 1, characterized by the fact that the first type of particles is free of acids.
    [3]
    Composition according to any one of claims 1 and 2, comprising at least a pharmaceutically acceptable excipient.
    3/5 (i) mixing dabigatran etexilate in the form of free base or in the form of pharmaceutically acetable salts, polymorphs, solvates or hydrates thereof and at least one pharmaceutically acceptable excipient;
    (ii) granulating the mixture from step (i) with a binder solution to form dabigatran etexilate granules;
    (iii) mixing at least one organic acid and at least one pharmaceutically acceptable excipient;
    (iv) granulating the mixture from step (iii) with a binder solution to form granules of organic acids;
    (v) coating the organic acid granules with a protective coating layer;
    (vi) mixing the granules from step (ii) with the coated granules from step (v) to form a mixture of at least two types of granules;
    (vii) optionally combining the mixture of at least two types of granules from step (vi) with at least one pharmaceutically acceptable excipient;
    (viii) adding a lubricant to the mixture of step (vii);
    (ix) fill the lubricated mixture from step (viii) in appropriate hard capsules.
    Composition according to either claim 1 or claim 2, characterized in that the second type of particles is free of dabigatran etexilate.
    [4]
    Composition according to any one of claims 1, 2 or 3, wherein the first type of particles is acid-free.
    4/5 (iii) mixing at least one organic acid and at least one pharmaceutically acceptable excipient;
    (iv) granulating the mixture from step (iii) with a binder solution to form granules of organic acids;
    (v) coating the dabigatran etexilate granules with a protective coating layer;
    (vi) mixing granules from step (iv) with the coated granules from step (v) to form a mixture of at least two types of granules;
    (vii) optionally combining the mixture of at least two types of granules from step (vi) with at least one pharmaceutically acceptable excipient;
    (viii) adding a lubricant to the mixture of step (vii);
    (ix) fill the lubricated mixture from step (viii) in appropriate hard capsules.
    Composition according to any one of claims 1, 2 or 3, characterized in that it comprises from 0.01% by weight to 90% by weight of dabigatran etexilate (expressed as dabigatran etexilate mesylate).
    [5]
    Composition according to any one of claims 1, 2, 3 or 4, wherein © second type of particles and free of dabigatran etexilate.
    5/5 (vii) optionally combining the mixture of at least two types of granules from step (vi) with at least one pharmaceutically acceptable excipient;
    (viii) adding a lubricant to the mixture of step (vii);
    (ix) fill the lubricated mixture from step (viii) in appropriate hard capsules.
    Mivxmxcàçms
    ί. A composition comprising a mixture of at least two types of particles, in which a) the first type of particles comprises dabigatran ethexylate in the form of free base or in the form of acceptable salts, polymorphs, salts or hydrates faxmaoeutinating thereof; and b) the sucking type of particles comprises at least pharmaceutically acceptable organic acid.
    Composition according to any one of claims 1, 2, 3 or 4, characterized by the fact that at least 90% by weight of the organic acid present in the composition is contained in the second type of particles and the remainder (if any) of organic acid forms part of the pharmaceutically acceptable excipients.
    [6]
    A composition according to any one of claims I, 2, 3, 4 or b, comprising d © 0.011 by weight at 90% by weight of dabigatran etexilate (expressed as dabíuatran etexiate aamo mesilate).
    Composition according to any one of claims 1, 2, 3, 4 or 5, characterized in that the first type of particles is coated with a protective coating layer.
    [7]
    7. Composition, according to c : any number of claims 1, 2, 3, 4, S or-6, where at least 901 by weight of present® organic acid in the composition is contained in: second type of : left and the remaining cells (if: any) of the organic acid far aceitávels pharmaceutically excipients.
    S. Composition, according to anyone. of claims 1, 2, 3, 1, 5, 6 or 7, wherein the first type of particles is coated with. a layer. protective coating.
    Composition, according to the agreement I have any: W of claims 1, 2, 3, 4-, 5, 6, 7 qq 8, M that the second type : of particles is coated with: a protective coating layer,
    Composition according to any one of claims 1, 2, 3, 4, 5 or 6, characterized in that the second type of particles is coated with a protective coating layer.
    [8]
    Composition according to any one of claims 1, 2, 3, 4, 5, 6 or 7, characterized in that it comprises from 2% by weight to 95% by weight of at least one pharmaceutically acceptable organic acid.
    [9]
    9. Unit dosage form characterized by the fact that it is prepared from a composition according to any one of claims 1 to 8, comprising from 50 mg to 200 mg of dabigatran etexilate mesylate.
    [10]
    10. Composition according to any of claims 1, 2, 3, 4, 3, S, 7, 8 or 8, with a weight of 2.% by weight at> 5% by weight at least one less organic acid. 'and <<ntr
    IX. Composition, according to. which laser one of claims 1, 2 t 3 t 4, 5, 6, 7, 8, 9, or 10, wherein at least 80% in. weight of organic acid present in. compcsioac is contained in: following: type of particles, the remainder (if any) of organic acid forming part of the excipients,
    10. Composition according to any one of claims 1 to 8, or a unit dosage according to claim 9, characterized by the fact that they are for use in reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation and / or in prevention of venous thromboembolic events in adult patients who underwent elective total hip replacement surgery or total knee replacement surgery.
    [11]
    (11) granulating the mixture from step (1) with a binder solution for former dabigatran etexilate granules;
    (iii) mixing at least one organic acid and at least one pharmaceutically acceptable excipients;
    (iv) granulating the mixture from step (iii) with a binder solution to form granules of organic nuts;
    (v) coating the granules of organic acids with a layer of protective coating;
    (vi) mixing the granules from step (ii) with the coated granules from step (v) to form a mixture of at least two types of granules;
    (vii) Optionally, · combining the mixture of at least two types of granules from step (vi) with at least one pharmaceutically acceptable compound;
    (vlli) adding a lubricant to the mixture of step (vii);
    (x) fill the luprified mixture from step (viii) in appropriate hard capsules.
    Process for preparing a composition according to any one of claims 1 to 8, characterized in that it comprises the step of mixing the first type of particles and the second type of particles with at least one pharmaceutically acceptable excipient.
    [12]
    12. Dosage form, unitary prepared from a composition according to one of claims 1 to 11, comprising 50 mg a. 2 02 jng most la to dabigatran ethylene.
    12. Process according to claim 11, characterized by the fact that the first type of particles is prepared by granulation.
    [13]
    The conform® composition any of claims 1 to 11, or one. unit dosage according to claim .1.2, for the purpose of reducing the risk of stroke is systemic embolism in patients with fibrillation attwv 'à veivulax e / cu in the prevention of events txombpc -χ 1 vanos out adult patients who were T & ubw>' .ac- surgery, elective total svdastitnicao quaco or total knee replacement surgery.
    13. Process according to claim 12, characterized by the fact that it comprises the steps of:
    [14]
    14. Cso of a composition according to any nurse. of claims 1 to 11 or a dosage. 'A to cn ^ -O-nr claim 12, for the preparation of a' vmca 'otio to reduce the risk of stroke and systemic embolism in patients with. non-valve atrial fibrillation w / o prevent wnogo thromboembolic events in adult patients who have undergone elective total queer replacement surgery: 1 or total knee replacement surgery.
    14. Process, according to claim 12, characterized by the fact that it comprises the steps of:
    (i) mixing dabigatran etexilate in the form of the free base or in the form of pharmaceutically acetable salts, polymorphs, solvates or hydrates thereof and at least one pharmaceutically acceptable excipient;
    (ii) granulating the mixture from step (i) with a binder solution to form dabigatran etexilate granules;
    [15]
    15 «Process to reduce the risk of stroke and systemic embolism in patients ^ too fibrillation atria., Non-valvular and / or prevent venous thromboembolism events in adult patients who have undergone elective subsvotu.çu surgery total hip or the urge to urge. total knee replacement: comprising administering to the patient the necessities of the composition: according to any one of claims 1 to 11 or a single unit according to claim 12.
    15. Process, according to claim 12, characterized by the fact that it comprises the steps of:
    (i) mixing dabigatran etexilate in the form of free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof and at least one pharmaceutically acceptable excipient;
    (ii) granulating the mixture from step (i) with a binder solution to form dabigatran etexilate granules;
    (iii) mixing at least one organic acid and at least one pharmaceutically acceptable excipient;
    (iv) extrude and spheronize the mixture from step (iii) to form granules of organic acids;
    (v) coating the organic acid granules from step (iv) with a protective coating layer;
    (vi) mixing the granules from step (ii) with the coated granules from step (v) to form a mixture of at least two types of particles;
    [16]
    16. Process for the preparation of a composition according to any one of claims 3 to 11 comprising the step of mixing the prime ir : type of particles and the second type of particular with at least one: pharmaceutically acceptable product.
    [17]
    17. Process according to claim If, in which the first type of particles is prepared by granulation, wool.
    [18]
    Process of: according to claim 17, comprising the steps of (i) mixing dabigatran etexilate in the form of free base or in the form of salts, polymorphs, rare sols or acetate pharmaceutically acceptable in the same or at least one pharmaceutically excipient acceptable feed;
    [19]
    19. Process according to claim 17, comprising the steps of:
    (i) mixing dahigatran etexilate in the form of the free base or in the form of pharmaceutically acetatable salts, polymorphs, solvates or hydrates of the same and at least one pharmaceutically acceptable excipients;
    (ii) mixing the step (i) with an agglutinated solution to form dabigatran etexilate granules;
    (iii) mixing at least one organic amide and at least one pharmaceutically acceptable excipient;
    (iv) granulating the mixture from step (ill) -dps · an agglutinating solution to form granules of organic acids;
    (v) coating the dabigatxan etexilate granules with a protective coating layer;
    (vl) mixing granules from step, (iv) curing the coated granules from step (v) to form a hair mixture in both types of granules;
    (vii) optionally, combining the polo mixture minus two types of granules from step (vi) with at least one pharmaceutically acceptable excipient®;
    (viii) add a lubricant to the mixture. step, (vii);
    (ix) fill the Iwrified mixture from step (viü) in suitable hard liquids.
    [20]
    20 «arocesso, according to claim 17, undertaking the steps given (to mix dabigatran etexilate in the form of free base or in the boiling of the salts, pplyrphons, solvates or hydrates • arvacnuticurente accepted: only the at least one t cip tarrsaneuticamunte acceptable;
    (granulate the mixture: from step (i) with an agglutinated solution to form ntexylate granules Õ is dabigatran;
    (iii) mixing at least one organic acid and at least one fataccently acceptable excipients .;
    (iv) extruding and sphering the mixture from step (iii) to form granules of organic acids;
    (v) coating the organic acid granules from step (iv) with one. protective coating layer;
    (VI) mixing the granules of step (ii) with the coated granules of step (v) to form a mixture of at least two types of particles;
    (vii) çpuíona Imente f coMínar ndstura the at least two types of granules of step (vi) at least one hundred farmtefôuticamentu acceptable excipients;
    (viii) adding a lubricant to the mixture, from step (vii);
    (ix) fill the lubricated mixture to the stage, (vii) in appropriate hard capsules «
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    同族专利:
    公开号 | 公开日
    CA2864423C|2021-08-10|
    CA2864423A1|2013-08-29|
    IL234032A|2020-06-30|
    ES2895918T3|2022-02-23|
    EP2817000A1|2014-12-31|
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    US20210244719A1|2021-08-12|
    JP6215239B2|2017-10-18|
    US11013729B2|2021-05-25|
    NZ628301A|2015-07-31|
    LT2817000T|2021-11-10|
    WO2013124340A1|2013-08-29|
    RU2633482C2|2017-10-12|
    MX2014010040A|2014-11-10|
    RU2014138036A|2016-04-20|
    IN2014DN06734A|2015-05-22|
    HRP20211606T1|2022-01-21|
    JP2015511241A|2015-04-16|
    AU2013224146A1|2014-08-28|
    CN110123774A|2019-08-16|
    EP3858337A3|2021-09-29|
    HK1203832A1|2015-11-06|
    EP3858337A2|2021-08-04|
    PT2817000T|2021-11-02|
    ZA201405855B|2015-11-25|
    EP2817000B1|2021-08-04|
    AU2013224146B2|2017-06-08|
    IL234032D0|2014-09-30|
    KR102090242B1|2020-03-18|
    DK2817000T3|2021-10-11|
    MX368868B|2019-10-11|
    KR20140135216A|2014-11-25|
    US20150030680A1|2015-01-29|
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    法律状态:
    2020-03-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-03-24| B25D| Requested change of name of applicant approved|Owner name: ESTEVE PHARMACEUTICALS, S.A. (ES) |
    2020-04-14| B25G| Requested change of headquarter approved|Owner name: ESTEVE PHARMACEUTICALS, S.A. (ES) |
    2020-06-30| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-09-29| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-10-06| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-10-13| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    2022-02-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    IN461/MUM/2012|2012-02-21|
    IN461MU2012|2012-02-21|
    PCT/EP2013/053426|WO2013124340A1|2012-02-21|2013-02-21|Oral pharmaceutical compositions of dabigatran etexilate|
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