WO2016144071A2 - Formulations pharmaceutiques comprenant du rivaroxaban - Google Patents

Formulations pharmaceutiques comprenant du rivaroxaban Download PDF

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Publication number
WO2016144071A2
WO2016144071A2 PCT/KR2016/002254 KR2016002254W WO2016144071A2 WO 2016144071 A2 WO2016144071 A2 WO 2016144071A2 KR 2016002254 W KR2016002254 W KR 2016002254W WO 2016144071 A2 WO2016144071 A2 WO 2016144071A2
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WO
WIPO (PCT)
Prior art keywords
rivaroxaban
granules
release pharmaceutical
melting
coating
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English (en)
Korean (ko)
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WO2016144071A3 (fr
Inventor
신동철
신호철
장우제
김관영
유종수
유헌승
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SK Chemicals Co Ltd
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SK Chemicals Co Ltd
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Publication of WO2016144071A2 publication Critical patent/WO2016144071A2/fr
Publication of WO2016144071A3 publication Critical patent/WO2016144071A3/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • the present invention relates to a fast-release pharmaceutical formulation capable of rapid release of ribaroxaban, an active ingredient, and a method for preparing the same.
  • Rivaroxaban is a low molecular weight inhibitor of coagulation factor Xa that can be used for various thromboembolic diseases and their secondary treatment and / or prevention depending on the dose (see WO 2001/147919, the disclosure of which is incorporated herein by reference).
  • rivaroxaban is party relto ® (there are on the market under the name Xarelto ®), it is commercially available as a crystalline form I (polymorph form I) of the three crystalline forms (polymorph form), known until now.
  • Rivaroxaban requires the physical, chemical and biological properties of Rivaroxaban.
  • formulations should be developed in consideration of the low water solubility (about 7 mg / L: 25 ° C.) and relatively high melting point (230 ° C.) of Rivaroxaban, which causes low bioavailability in oral formulations. Because it becomes.
  • WO 2005/060940 discloses a method for preparing a pharmaceutical composition in hydrophilic form by wet granulation by mixing a hydrophilic binder with Rivaroxaban. Tablets containing a pharmaceutical composition in hydrophilic form are described to have increased bioavailability than those that do not.
  • the wet granules employed in the patent require a special device, and more energy use is required for the removal of the solvent to prepare the granules.
  • WO 2007/039122 discloses pharmaceutical compositions comprising ribaroxaban, which is an amorphous or thermodynamic metastable crystalline form. Such pharmaceutical compositions have increased dissolution and solubility. However, in order to obtain an amorphous or thermodynamic metastable crystalline ribaroxaban, it is necessary to dissolve or dissolve the ribaroxaban, which causes problems. For example, a large amount of purified water or a pharmaceutically acceptable organic solvent should be used to dissolve the ribaroxaban, a poorly soluble drug. In addition, in order to melt the Riva Loxban, it is necessary to raise it to a temperature above the high melting point of Riva Loxban, so that the Riva Loxban is decomposed.
  • WO 2011/042156 discloses a method for producing molten granules. However, it must be manufactured at a high temperature of 80-190 ° C. and requires a special device to cause decomposition of Rivaroxaban due to the high temperature.
  • WO 2010/146179 discloses melt granulation. Formulations containing molten granules are in the form of uncoated tablets, and uncoated tablets are more susceptible to destructive exposure due to air or moisture, and inadvertent contact with drugs. However, the composition disclosed in the patent provides only the uncoated form of the composition and does not consider the coating composition and the preparation method thereof at all.
  • Coated tablets can block moisture, air and light, making them more stable physically and chemically.
  • the coating can be easily distinguished between products to prevent misuse.
  • There are four doses of Rivaroxaban and there are differences in indications to make it easier to distinguish products of different doses. Therefore, in consideration of advantages such as improved stability, ease of taking, improved packaging cost, and improved functionality, it is necessary to provide a pharmaceutical formulation containing ribaroxane.
  • the low bioavailability of Rivaroxaban is further reduced by the coating, thereby rapidly controlling the initial release of the drug, and that there is a possibility that the components may be modified during the coating process (e.g., crystalline deformation, etc.). It is difficult to develop fast-release pharmaceutical preparations.
  • an object of the present invention is to provide a pharmaceutical composition and a method for preparing the Rivaroxaban, which can avoid the disadvantages of the above-described techniques and ensure optimal stability and bioavailability.
  • the present invention is to provide a fast-release pharmaceutical formulation and a method for preparing the same as well as ensuring a high bioavailability of Rivaroxaban, while retaining its superiority as a coated pharmaceutical formulation.
  • the present invention comprises a ribaroxaban-containing non-aqueous hydrophilic combined granules, the granules are coated, provides a fast-release pharmaceutical formulation and a method for producing the same.
  • the inventors of the present invention have studied to develop a rivaroxaban-containing pharmaceutical formulation capable of ensuring optimal stability and bioavailability, and prepared a rivaroxaban-containing non-aqueous hydrophilic binding granule, and developed a formulation coated therewith.
  • Rivaroxaban is rapidly released early to ensure excellent bioavailability and at the same time show usefulness as a coated pharmaceutical preparation, and in particular, it is confirmed that the above-mentioned effects can be maximized by controlling the coating temperature. Completed.
  • ribaroxaban includes a free base or a pharmaceutically acceptable salt.
  • the active ingredient may include a ribaroxaban derivative in addition to or in combination with ribaroxaban. Therefore, the pharmaceutical preparation according to the present invention may include a derivative having a pharmaceutical activity equivalent to that of Rivaroxaban.
  • a "pharmaceutically acceptable salt” is a concentration that has a relatively nontoxic and harmless effective action in a patient, and any organic or inorganic side effects caused by this salt do not degrade the beneficial efficacy of Rivaroxaban.
  • suitable acid addition salts are hydrochloride, bromate, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isnicotinate, acetate, lactate, salicylate, citrate, tartarate, pentothenate, Bisulphate, Ascorbate, Succinic Acid, Maleate, Gentisate, Fumarate, Gluconate, Glucaronate, Gluconate, Formate, Benzoate, Glutamate, Methanesulfonate, Ethanesulfonate, Benzenesulfonate , p-toluenesulfonate and pamonate salts, including but not limited to.
  • Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.
  • ribaroxaban may be used in crystalline form, and more preferably ribaroxaban of Form I form may be used.
  • Rivaroxaban of Form I Form can be used in finely divided form.
  • the Rivaroxaban of the crystalline Form I has an average particle size D50 of less than 50 ⁇ m, particularly 1 ⁇ m to 10 ⁇ m, and a D90 (90% ratio) of less than 100 ⁇ m, particularly 20 ⁇ m.
  • Rivaroxaban is isolated from a natural source, obtained from a natural source, prepared by chemical modification, or can be prepared by a person skilled in the art by chemical synthesis by a known synthesis method, or commercially available. It is also possible to purchase and use a product manufactured and distributed in the market.
  • ribaroxaban may comprise 0.5 to 80% by weight, more preferably 2 to 50% by weight, and most preferably 2 to 25% by weight relative to the total weight of the pharmaceutical formulation. This is not restrictive. (However, up to 20 mg of Rivaroxaban)
  • non-aqueous hydrophilic binder granules is a form containing a low-melting hydrophilic binder, means that the low-melting hydrophilic binder is physically bound to the drug by a method such as coating, coating or contacting.
  • non-aqueous hydrophilic combined granules pellets, powders and the like may be included instead of granules, and are not limited to granules.
  • non-aqueous hydrophilic binder granules a variety of methods known in the art may be used to physically bind the ribaroxaban and the low melting hydrophilic binder.
  • the ribaroxaban is mixed with the low melting hydrophilic binder, granulated, Methods such as pelletization can be used, but are not limited thereto.
  • nonaqueous hydrophilic combined granules in the nonaqueous hydrophilic combined granules, the term "nonaqueous" means that the nonaqueous hydrophilic combined granules are substantially free of water (preferably, a solvent including water), and more preferably the nonaqueous hydrophilic combined granules. It means that substantially no water is used during the preparation of, and even more preferably means that substantially no water-containing solvent is used.
  • substantially free means that the water (preferably water-containing solvent) relative to the total weight of the granules in the non-aqueous hydrophilic combined granules is 1 wt% or less, 0.5 wt% or less, 0.3 It means to include less than 0.1% by weight, less than 0.1% by weight, less than 0.01% by weight, less than 0.001% by weight, most preferably 0% by weight.
  • substantially free refers to up to 5% by weight, up to 4% by weight, 3% by weight of water (preferably, a solvent comprising water) relative to the total weight of the composition for preparing the non-aqueous hydrophilic bonded granules. Or less, 2 wt% or less, 1 wt% or less, 0.1 wt% or less, 0.01 wt% or less, and most preferably 0 wt%.
  • the non-aqueous hydrophilic binding granules may be employed in various forms known in the art such that the non-aqueous hydrophilic binding granules are substantially free of water (preferably, water-containing solvent).
  • water preferably, water-containing solvent
  • Various known methods can be used.
  • a variety of methods known in the art can be used to substantially eliminate the use of water water (preferably water-containing solvents) during the preparation of the non-aqueous hydrophilic binding granules.
  • the non-aqueous hydrophilic combined granules may be melt granules.
  • the "melt granules" means that the melt of the low-melting hydrophilic binder and the drug mixture is formed while cooling without water (preferably water-containing solvent).
  • the melt of the low-melting hydrophilic binder may be formed by melting the low-melting hydrophilic binder after mixing of the drug and the low-melting hydrophilic binder, and may be formed by melting the low-melting hydrophilic binder before mixing with the drug.
  • the prognosis of the water formation and the timing of the mixing process with the drug is not a problem.
  • it can be heated above the melting temperature of the low melting hydrophilic binder, but only below the melting temperature of the drug. If heated above the melting temperature of the drug, deformation of the drug may be a problem.
  • the "low melting point” refers to the melting temperature is lower than this, based on the boiling point of water 100 °C, melting temperature is 100 °C or less, 90 °C or less, 80 °C or less, 80 °C or less, 70 °C Hereinafter, it may be 60 ° C. or less, but is not limited thereto, and may be 40 ° C. or more.
  • the melting temperature exceeds 100 ° C., the break point of water, the hydrate of water or other additives contained in the granules (eg, lactose hydrates commonly used as excipients) in the low-melting hydrophilic binder, This causes unexpected changes in physical properties and requires additional attention or safety management of the hydrated steam, which requires additional effort on the facility or manufacturing facility.
  • the granules eg, lactose hydrates commonly used as excipients
  • Low-melting hydrophilic binders include, for example, polyethylene glycol (average molecular weight 15,000 or less, more preferably average molecular weight 1,500 to 10,000), poloxamers, macrocol glycerides (e.g., gelsier®), fatty acid glycols ( Examples include, but are not limited to, glycerol behenate, glycerol monostearate), and mixtures thereof.
  • the low melting hydrophilic binder may include, but is not limited to, 0.5-80% by weight, more preferably 2-50% by weight relative to the total weight of the pharmaceutical formulation. (However, up to 20 mg of Rivaroxaban)
  • the fast-release pharmaceutical preparation according to the present invention includes a non-aqueous hydrophilic binding granules and a coating agent for coating the non-aqueous hydrophilic binding granules.
  • the coating may have advantages such as ease of taking, improvement in stability, reduction in packaging cost, and improvement in functionality, but have the disadvantage of inadvertently undergoing chemical and physical changes in preparation before coating due to the nature of the coating process. Due to the problem of the coating process, even in the case of the present invention, problems such as the change in the dispersibility of the low-melting hydrophilic binder and the modification of the low-melting hydrophilic binder when coating the non-aqueous hydrophilic binding granules were expected. There was concern that improvement in utilization would not be possible.
  • the rapid-release pharmaceutical preparation according to the present invention has an excellent effect of substantially no difference in dissolution rate of the pharmaceutical preparation under the same conditions before and after coating.
  • substantially no difference in the dissolution rate of the pharmaceutical preparations under the same conditions before and after coating means that the USP 2 method (paddle, 900ml, 37 °C, 50rpm, acetate buffer solution) is the same in all aspects, except the coating pH dissolution test according to (4.0) means that the elution rate measured at the same time has little difference before and after coating.
  • substantially free of difference means a value of ⁇ 15% or less, preferably ⁇ 10% or less, more preferably ⁇ 8% or less, when the dissolution rate before and after coating is calculated according to the following formula under the same conditions. It may mean to indicate.
  • '-' value means that the dissolution rate after coating is reduced
  • '+' value means that the dissolution rate after coating is increased
  • the coating is carried out at or below the melting temperature of the low melting hydrophilic binder.
  • low melting temperature means a temperature which is equal to or lower than the melting temperature, preferably at least 3 ° C, 5 ° C, 6 ° C, 7 ° C, or 8 ° C based on the melting temperature. It is possible to coat at a low temperature of at least 9 ° C, at least 10 ° C, at least 11 ° C, at least 12 ° C, at least 13 ° C, at least 14 ° C, at least 15 ° C, and at least 16 ° C.
  • the coating may be performed at a temperature lower than or equal to the melting temperature of the poloxamer based on about 52 to 57 ° C., preferably the melting temperature. It can be coated at a low temperature of at least 3 °C or more, that is, 49 ⁇ 57 °C based on.
  • an example of using poloxamer as a low melting hydrophilic binder and coating at or below the melting temperature of poloxamer of about 52 to 57 ° C. shows an initial rapid dissolution rate and a difference in dissolution rate compared to before coating. None could be confirmed.
  • the coating agent should be a material suitable for coating at or below the melting temperature of the low-melting hydrophilic binder, more specifically, 100 °C or less, 90 °C or less, 80 °C or less, 80 °C or less, 70 °C or less, 60 It should be a coating agent suitable for coating at temperatures below 20 ° C. and above 20 ° C.
  • hydroxypropylmethylcellulose polyvinylalcohol, shellac, propylene glycol, polyethylene glycol, glycerol triacetate, triethyl citrate or colorant / dye (e.g. titanium dioxide, iron oxide, indigotin or suitable colored lakes) color lake)
  • colorant / dye e.g. titanium dioxide, iron oxide, indigotin or suitable colored lakes) color lake
  • the coating agent may preferably include 1 to 10% by weight, more preferably 3 to 8% by weight relative to the total weight of the pharmaceutical formulation, but is not limited thereto. (However, up to 20 mg of Rivaroxaban)
  • a device such as a fan coater or a fluidized bed granulator may be used, and preferably a fan coater may be used.
  • the pharmaceutical preparation according to the present invention may further include pharmaceutically acceptable additives such as surfactants, diluents, disintegrants, adsorbents, lubricants, and the like.
  • Surfactants usable in the present invention include sodium salts of fatty alcohol sulfates, such as sodium lauryl sulfate, sulfosuccinates such as sodium dioctyl sulfosuccinate, partially fatty acid esters of polyhydric alcohols, for example Glycerol monostearate, partial fatty acid esters of sorbitan, for example sorbitan monolaurate, partial fatty acid esters of polyhydroxyethylene sorbitan, for example polyethylene glycol sorbitan monolaurate, monostearate or monoole Components selected from the group consisting of ates, polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acid esters, ethylene oxide-propylene oxide block copolymers (Pluronic®) or ethoxylated triglycerides and mixtures thereof Can be used, but is not limited to The.
  • fatty alcohol sulfates such as sodium lauryl sulfate, sulfo
  • the surfactant may preferably comprise from 0.05 to 50% by weight, more preferably from 0.1 to 20% by weight, most preferably from 0.1 to 0.5% by weight relative to the total weight of the pharmaceutical preparation, This is not restrictive. (However, the range including up to 20 mg of Rivaroxaban.)
  • the non-aqueous hydrophilic binding granules according to the present invention may include the above-mentioned surfactant in addition to Rivaroxaban, a low melting hydrophilic binder, and more preferably the three components. It may be made of.
  • a component selected from the group consisting of lactose (hydrates as well as anhydrides), microcrystalline cellulose (eg, Avicel®), mannitol, sorbitol, phosphate, and mixtures thereof may be used. It is not limited.
  • the diluent may preferably include 5 to 90% by weight, more preferably 20 to 70% by weight relative to the total weight of the pharmaceutical formulation, but is not limited thereto. (However, up to 20 mg of Rivaroxaban)
  • Disintegrants usable in the present invention include croscarmellose sodium, carboxymethyl cellulose calcium (CMC-Ca, Carboxymethylcellulose Sodium (CMC-Na), starch glyconate, corn starch, wheat starch And it may be used a component selected from the group consisting of, but is not limited thereto.
  • Adsorbents usable in the present invention include silica, colloidal silica (eg, hard silicic anhydride (Aerosil 200)), colloidal silicon dioxide, magnesium aluminum silicate, magnesium trisilicate, calcium silicate, talc and its A component selected from the group consisting of mixtures may be used, but is not limited thereto.
  • colloidal silica anhydride hard silicic anhydride
  • colloidal silicon dioxide and mixtures thereof may be used.
  • it may include 0.5 to 12% by weight, more preferably 0.5 to 6% by weight relative to the total weight of the pharmaceutical formulation, but is not limited thereto (but it includes a range of up to 20mg of Rivaroxaban).
  • Lubricants usable in the present invention include components selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate (SSF), polyethylene glycol (PEG) 4000-8000, talc and mixtures thereof May be used, but is not limited thereto.
  • SSF sodium stearyl fumarate
  • PEG polyethylene glycol
  • talc polyethylene glycol
  • the lubricant may preferably include 0.5 to 3% by weight, more preferably 0.5 to 2% by weight relative to the total weight of the pharmaceutical formulation, but is not limited thereto. (However, up to 20 mg of Rivaroxaban)
  • the pharmaceutical preparation according to the present invention may be formulated in an oral dosage form, and may be, for example, tablets, hard capsules, granules, pellets, powders, and the like, and preferably tablets and hard capsules. Most preferably, it may be a coated tablet for oral administration.
  • conventional mixing methods such as granulation, mixing, filling and compression can be used to formulate into tablets, for example granulation processes and / or direct tableting processes.
  • When formulated as a tablet it may be formed into a structure of a shell including a core and a coating including ribovaxan-containing low melting hydrophilic granules, but is not limited thereto.
  • the pharmaceutical preparation according to the present invention may be prepared by the following method, but is not limited thereto.
  • Rivaroxaban with a low melting hydrophilic binder and granulating to prepare Rivaroxaban containing non-aqueous hydrophilic binding granules
  • the present invention provides a Rivaroxaban-containing non-aqueous hydrophilic combined granules, wherein the granules are coated, and provide a fast-release pharmaceutical preparation and a method for preparing the same. According to the present invention, it is possible to provide a fast-release pharmaceutical formulation and a method for preparing the pharmaceutical formulation having a high bioavailability of Rivaroxaban while retaining its superiority as a coated pharmaceutical formulation.
  • Figure 1 is an elution in pH 4.0 acetate buffer (37 °C, 900 ml, evaluated using Comparative Example 1 (jarelto 2.5mg tablet), Comparative Example 2, Example 1 and Example 2 according to the present invention) 50 rpm) comparative evaluation result.
  • Figure 2 is a comparative evaluation results of the dissolution (37 °C, 900 ml, 50 rpm) in pH 4.0 acetate buffer solution, evaluated using Comparative Example 3, Example 3 and Example 4 according to the present invention.
  • ingredient Composition amount per unit dose (mg) F1 F2 F3 Riva Roxanne 2.5 2.5 2.5 Poloxamer 6.3 2 2 Sodium lauryl sulfate 0.2 0.1 0.1 Microcrystalline cellulose 68 65.5 65.5 Crospovidone 7 5 5 Light anhydrous silicic acid One 5 5 Magnesium stearate One One One Opadry 3.6 Opadry II 3.6 3.6 Total 89.6 84.7 84.7
  • micronized ribaroxaban, poloxamer, sodium lauryl sulfate After mixing the microcrystalline cellulose (10mg) to prepare a granule for 10-30 minutes in a high speed mixer of 60 ⁇ 80 °C. After cooling to room temperature, the mixture was mixed with the remaining excipients (except Opadry or Opadry II), and then compressed into tablets.
  • Example 1 Coated tablet coated with Comparative Example 2 at 40 ⁇ 45 °C
  • Opadry II (Calcon) was prepared by dissolving / dispersing in purified water for 2 hours to prepare a tablet by coating the uncoated tablet according to Comparative Example 2 under the conditions of the purification temperature of 40 ⁇ 45 °C.
  • Example 2 coated tablet coated with Comparative Example 2 at 60 ⁇ 65 °C
  • Opadry II (Calcon) was prepared by dissolving / dispersing in purified water for 2 hours to prepare a tablet by coating the uncoated tablet according to Comparative Example 2 under the conditions of the tablet temperature 60 ⁇ 65 °C.
  • Example 3 Coated tablet coated with Comparative Example 3 at 30 ⁇ 35 °C
  • Opadry color cone was prepared by dissolving / dispersing in a dispersion (component: 80% ethanol) for 2 hours to prepare a tablet by coating the uncoated tablet of Comparative Example 3 under the condition that the tablet temperature is 30 ⁇ 35 °C.
  • Example 4 Coated tablet coated with Comparative Example 3 at 60 ⁇ 65 °C
  • Opadry II color cone
  • Opadry II color cone
  • the dissolution test was carried out according to the USP method 2 (paddle, 900ml, 37 °C, 50rpm, acetate buffer pH4.0), and summarized in Table 3 by comparing the respective dissolution profiles, the overall dissolution profile in Figure 2 Indicated

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Abstract

La présente invention concerne une formulation pharmaceutique à libération rapide comprenant des granulés liés hydrophiles non-aqueux contenant du rivaroxaban, les granulés étant enrobés, et son procédé de préparation. La présente invention est capable de fournir une formulation pharmaceutique à libération rapide, qui garantit une biodisponibilité élevée de rivaroxaban et est excellente comme formulation pharmaceutique revêtue, et son procédé de préparation.
PCT/KR2016/002254 2015-03-06 2016-03-07 Formulations pharmaceutiques comprenant du rivaroxaban Ceased WO2016144071A2 (fr)

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WO2020060336A1 (fr) * 2018-09-21 2020-03-26 동아에스티 주식회사 Composition de solubilisation comprenant du rivaroxaban

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DE102004062475A1 (de) * 2004-12-24 2006-07-06 Bayer Healthcare Ag Feste, oral applizierbare pharmazeutische Darreichungsformen mit modifizierter Freisetzung
WO2010017948A2 (fr) * 2008-08-11 2010-02-18 Ratiopharm Gmbh Compositions pharmaceutiques à propriétés de libération modifiées comprenant du 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phényl]-1,3-oxazolidin-5-yl)-méthyl)-2-thiophène carboxamide
HRP20161617T4 (hr) * 2009-06-18 2019-06-28 Krka, Tovarna Zdravil, D.D., Novo Mesto Čvrsti farmaceutski sastav koji sadrži rivaroksaban
WO2011042156A1 (fr) * 2009-10-06 2011-04-14 Ratiopharm Gmbh Compositions pharmaceutiques contenant du rivaroxaban
EP2808011A1 (fr) * 2013-05-29 2014-12-03 Sandoz Ag Procédé de préparation d'une composition pharmeceutique de Rivaroxaban

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KR101818761B1 (ko) 2018-01-15
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