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WO2016017993A1 - Formulation pharmaceutique comprenant du rivaroxaban thermodynamiquement métastable ou amorphe - Google Patents

Formulation pharmaceutique comprenant du rivaroxaban thermodynamiquement métastable ou amorphe Download PDF

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Publication number
WO2016017993A1
WO2016017993A1 PCT/KR2015/007667 KR2015007667W WO2016017993A1 WO 2016017993 A1 WO2016017993 A1 WO 2016017993A1 KR 2015007667 W KR2015007667 W KR 2015007667W WO 2016017993 A1 WO2016017993 A1 WO 2016017993A1
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WO
WIPO (PCT)
Prior art keywords
formulation
pharmaceutical formulation
specific gravity
rivaroxaban
amorphous
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2015/007667
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English (en)
Korean (ko)
Inventor
박준성
신동철
류근호
신호철
황상욱
김관영
김훈택
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SK Chemicals Co Ltd
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SK Chemicals Co Ltd
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Filing date
Publication date
Application filed by SK Chemicals Co Ltd filed Critical SK Chemicals Co Ltd
Publication of WO2016017993A1 publication Critical patent/WO2016017993A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to an active ingredient in a high dose (e.g. 15 or 20 mg) formulation with an effect on diet, comprising an amorphous and / or thermodynamically metastable crystal of Rivaroxaban solid dispersion.
  • the present invention relates to a pharmaceutical preparation that can release phosphorus ribaroxane rapidly but improve the dietary effect and thus have the same effect regardless of the meal.
  • rivaroxaban the active component (I)
  • rivaroxaban is a drug which is administered orally rivaroxaban is on the market under the name of party relto TM (TM Xarelto And three commercially available polymorph forms, polymorph form I.
  • Rivaroxaban is used for various thromboembolic diseases and their secondary treatment and / or prophylaxis depending on the dose.
  • Low molecular weight inhibitor of coagulation factor Xa (WO2001 / 147919).
  • Rivaroxaban is designed in a dosage form that can reach 100% bioavailability with or without meals for a 10 mg dose. However, 15 mg and 20 mg must be taken mid-meal to achieve the desired effect (high doses (15 mg and 20 mg) of Rivaroxaban for health care professionals at the US FDA with dinner. Taking warnings to prevent potential decreased efficacy). Such high doses of ribaroxaban formulations present a hassle in taking the desired effect. In particular, food intake is indicated as a general cause of drugs in which blood concentrations differ depending on whether food is taken (Xia et al., British Journal of Clinical Pharmacology, 2009, 68: 1, p77-88).
  • Rivaroxaban which has a solubility in water (37 ° C) of 9 ⁇ g / ml, dissolves 90% or more in the general eluate volume (900 ml) for 10 mg. can see.
  • the bioavailability of about 66% is shown in pre-meal administration.
  • the remaining insoluble drugs are absorbed by surfactants such as bile acids secreted in the body and the oil component present in the food when taken with the food to reach the bioavailability of 100% (Samama et al. Thrombosis Journal 2013, 11:11, p 1-7).
  • solubilization of ribaroxaban is made to have high bioavailability even when taken regardless of meal, so that the patient can have the same effect no matter how and when it is taken, and provide the patient with higher convenience of taking the drug. And, as a result, it is essential to develop a formulation that will have higher medication compliance.
  • thermodynamically stable crystalline form a thermodynamically unstable form
  • thermodynamic metastable state that is an amorphous or incomplete crystalline state between an amorphous and a crystalline state, that is, a non-crystal state. It can be prepared as.
  • a ribaxaban solid dispersion with improved solubility it is possible to prepare a ribaxaban solid dispersion with improved solubility, and to produce such amorphous or thermodynamic metastable ribaroxaban solid dispersion.
  • a method for example, a method (manufactured by using a high temperature melting method or a melt extrusion method with various polymers) and a method for preparing by dissolving in a suitable solvent and various polymers (prepared by coprecipitation) International Patent Publication WO2014 / 016842) and the like can be used.
  • the problem to be solved by the present invention is a pharmaceutical formulation containing a high dose (so greater than 10 mg 20 mg or less, preferably 15 or 20 mg) of solubilized ribaroxaban, regardless of whether a high-fat diet, fasting and eating It is to provide a pharmaceutical formulation that can exhibit the same or similar bioavailability.
  • the present invention comprises more than 10 mg of ribaroxaban, which is an amorphous or thermodynamic metastable crystalline form (preferably 15 or 20 mg, more preferably 20 mg), pharmaceutically acceptable
  • ribaroxaban which is an amorphous or thermodynamic metastable crystalline form (preferably 15 or 20 mg, more preferably 20 mg)
  • pharmaceutical formulation is characterized in that the value of the specific gravity of the formulation is one or more.
  • specific gravity is used as follows. Specific gravity is the ratio of the mass of a substance to the mass of a standard substance with the same volume. Specific gravity, unlike density, has no units. As a standard for comparison with unknown samples, water at 4 ° C (density 0.999973 g / cm 3 ) for liquids and air at 0 ° C and 1 atm is generally used. Specific gravity depends on temperature and pressure (in the case of gases). In general, specific gravity corresponds to density for solids and liquids up to five decimal places, so specific gravity and density may be considered equal. To determine the specific gravity of a formulation, it is calculated by weight and volume in the finished form as it is prepared without breaking the formulation.
  • excipients that can increase such pharmaceutically acceptable specific gravity are described in the article Pharmaceutical Technology, Vol. Excipients having one or more specific gravity may be added to the formulations of the present invention as described in 27 (4), p64-80 (2003). Specifically, excipients having a specific gravity such as magnesium oxide of 3.5 or more may be used.
  • the process can be changed in another way to increase specific gravity.
  • densification such as granulation, roller compaction and coating of metal oxides (iron oxide, titanium dioxide, etc.) having a specific gravity higher than 4 may be applied.
  • the specific gravity of the pharmaceutical formulation is 1 to 3.6, more preferably 1 to 2.
  • the inventors have prepared a solid or thermodynamically metastable crystal of Rivaroxaban solid dispersion that solubilizes poorly soluble Rivaroxaban in various forms of formulation, for example, capsules, tablets, etc.
  • a pharmacokinetic study was conducted. Unexpectedly, Jarelto TM, taken with a high-fat diet when taking solubilized Rivaroxaban before meals, unexpectedly Despite boyeoteum equal pharmacokinetic results and 20 mg, and if hayeoteul taken with high fat diet pharmacokinetic parameter of the solubilized rivaroxaban were rather chair relto TM A decrease of 20 mg of C max and AUC was observed.
  • Rivaroxaban is one of several important factors that has a specific gravity higher than the specific gravity value of the oil that can form a layer inside the stomach (e.g., the typical specific gravity is 0.8). Will be important for high doses of Rivaroxaban formulation with high fat diets.
  • the effect of the formulation of the present invention is not limited to this theoretical conjecture.
  • the preparation reaches the absorption site without the disintegration or dissolution of the amorphous or thermodynamic metastable Rivaroxaban preparation after the water has passed through the small intestine or is absorbed by the gastric emptying time. It is believed that the absorption of the drug does not occur, but the present invention is not limited to this theoretical mechanism.
  • the pharmaceutical formulation is a tablet or capsule formulation, more preferably a tablet formulation.
  • the pharmaceutical formulation of the present invention contains solubilized ribaroxaban, and more preferably comprises ribaroxaban, prepared as a solid dispersion and maintained in the form of an amorphous or thermodynamic metastable form.
  • the present invention provides a pharmaceutical formulation, wherein the pharmaceutical formulation comprises a solid dispersion of a hydrophilic excipient and ribaroxaban, wherein the formulation is prepared using a hydrophilic excipient.
  • the solid dispersion may be prepared through a conventional melt extrusion method or a co-precipitation method, preferably through a melt extrusion method.
  • Rivaroxaban solid dispersion is dissolved in a variety of excipients and methods using high temperature melting or melt extrusion methods (International Patent Publication WO2007 / 039122) and various excipients and suitable solvents. After the method is prepared by coprecipitation (International Patent Publication WO2014 / 016842) and the like can be used, but the present invention is not limited to such a manufacturing method.
  • International Patent Publication WO2014 / 016842 International Patent Publication WO2014 / 016842
  • the international patent publications WO2007 / 039122 and WO2014 / 016842 are incorporated herein in their entirety.
  • hydrophilic excipients used in the preparation of the solid dispersion according to the present invention include urea, citric acid, benzoic acid, maleic acid, fumaric acid, sugars, sugar alcohols, polyethylene glycol (PEG), polyethylene oxide, polyoxyethylene-polyoxy Propylene block copolymers, vinylpyrrolidone-vinylacetate copolymers, polyethylene glycol-polyvinyl caprolactam-polyvinyl acetate copolymers, polyvinylpyrrolidone, hydroxypropylcellulose (HPC), saturated polyglycolated glycerides (e.g.
  • Gelucire TM may be used, in particular for the purposes of the present invention vinylpyrrolidone-vinyl acetate copolymers, polyethylene glycol-polyvinyl caprolactam-polyvinyl acetate aerials Preference is given to coalescing or mixtures thereof.
  • the solid dispersions of the present invention may comprise (S1) (a) ribaroxaban and (b) vinylpyrrolidone-vinyl acetate copolymers, polyethylene glycol-polyvinyl caprolactam-polyvinyl acetate copolymers, or these Mixing a polymer selected from the mixture of (preferably vinylpyrrolidone-vinyl acetate copolymer) in a ratio of 1: 0.5 to 1: 9, preferably in a ratio of 1: 3 to 1: 5 Step, and (S2) melt extrusion of the mixture at 100 to 230 ° C, preferably melt extrusion at 130 to 180 ° C, the water solubility is more than 18 ug / ml It can be prepared by a process for the preparation of the composition comprising the loxaban in the form of amorphous and / or thermodynamic metastable crystalline forms.
  • the content (weight) ratio of Rivaroxaban and the polymer is 1: 0.5 to 1: 9 (Rivaroxaban: total polymer content).
  • the pharmaceutical formulation of the present invention may further include pharmaceutically acceptable additives for preparing the pharmaceutical formulation in addition to the solid dispersion comprising the active ingredient ribaroxaban.
  • Such additives may include pharmaceutically acceptable diluents, binders, disintegrants, carriers, solubilizers, crystallization retardants, glidants, or mixtures thereof, but the invention is not limited to these additional additives.
  • diluents that may be additionally included include pharmacological activities such as starch, sorbitol, citric acid, mannitol, sucrose, colloidal silica, spray dried lactose, anhydrous lactose, calcium dihydrogen phosphate, anhydrous dibasic calcium phosphate and microcrystalline cellulose.
  • low cost components may be used alone or in combination.
  • the present invention is not limited to the above-mentioned diluent.
  • a disintegrant which may be additionally included may include lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or a mixture of two or more thereof, but the present invention may It is not limited.
  • binders that may additionally be included include hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (sodium salt and calcium salt), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxy Polymers of propylcellulose (HPC), L-HPC (HPC of low degree of substitution), polyvinylpyrrolidone, polyvinyl alcohol, acrylic acid and salts thereof, gelatin, guar gum, partially hydrolyzed starch, alginate or xanthan Or a mixture thereof may be used, but the present invention is not limited thereto.
  • HPMC hydroxypropylmethylcellulose
  • carboxymethylcellulose sodium salt and calcium salt
  • ethylcellulose methylcellulose
  • hydroxyethylcellulose ethylhydroxyethylcellulose
  • HPC propylcellulose
  • L-HPC L-HPC of low degree of substitution
  • polyvinylpyrrolidone polyvinyl alcohol
  • the lubricant may be additionally included colloidal silica (Aerosil), talc, magnesium stearate, a mixture of two or more thereof, and the like, but the present invention is not limited thereto.
  • solubilizers that may additionally be included 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, such as Glycerol monostearate, sorbitan esters, for example polyethylene glycol sorbitan monolaurate, monostearate or monooleate, polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acid esters, ethylene oxide-propylene Oxide block copolymers (Pluronic TM ) or Gelucire or mixtures thereof may be used, but the present invention is not limited thereto.
  • fatty alcohol sulfates such as sodium lauryl sulfate
  • sulfosuccinates such as sodium dioctyl sulfosuccinate
  • partially fatty acid esters of polyhydric alcohols such as Glycerol monostea
  • the present invention contains high doses of solubilized ribaroxaban (above 10 mg up to 20 mg, preferably 15 or 20 mg), and have the same or similar bioavailability (eg, C max and AUC last ) are provided.
  • Figure 1 is a graph showing the change in blood concentration after taking Comparative Example 1 fasted (fed) or between (fed).
  • Figure 2 is a graph showing the release of the drug appearing after the test of Comparative Example 2 and Example 1 in various pH dissolution medium.
  • FIG. 3 Comparative Example 1 is taken between meals
  • Comparative Example 2 is a graph showing the change in blood concentration after taking between fasting or between meals.
  • Figure 4 is a graph showing the release of drugs appearing after the dissolution test in Comparative Examples 1 and 2 and Example 1 in a specific dissolution medium.
  • FIG. 5 is a graph showing changes in blood concentration after Comparative Example 1 is taken between meals and Example 1 is taken on an empty stomach or between meals.
  • Rivaroxaban either amorphous or thermodynamic metastable
  • Rivaroxaban and the vinylpyrrolidone-vinyl acetate copolymer were prepared by melt extrusion at a temperature ratio of 1: 3 at a temperature in the range of 130 to 220 ° C. using a solid extrusion method.
  • microcrystalline cellulose, crospovidone, Aerosil, and magnesium stearate which are commonly known excipients, were mixed with the solid dispersion and filled into capsules to prepare a formulation having a specific gravity of 0.8.
  • Rivaroxaban either amorphous or thermodynamic metastable
  • Rivaroxaban and the vinylpyrrolidone-vinyl acetate copolymer were prepared by melt extrusion at a temperature ratio of 1: 3 at a temperature in the range of 130 to 220 ° C. using a solid extrusion method. Thereafter, microcrystalline cellulose, crospovidone, Aerosil, and magnesium stearate, which are commonly known excipients, were mixed with the solid dispersion. This mixture was then compressed to prepare a tablet, which had a specific gravity of 1.24.
  • Comparative Example 1 The pharmacokinetic evaluation of the formulation was made. Three patients per group were divided into two groups, and Comparative Example 1 was dosed with fasting and between meals, and blood was collected at predetermined time intervals. Each pharmacokinetic profile was identified and the results are shown in Table 2 and FIG. 1. For reference, Comparative Example 1, which contains 20 mg of active ingredient (I), is recommended to be administered with meals because of low bioavailability when fasting administration ( The Journal of Clinical Pharmacology , 46, 549-558, 2006). ).
  • Dissolution Rate Difference (%) between Comparative Example 2 and Example 1 15 minutes 30 minutes 60 minutes pH1.2 3 2 2 pH4.0 One One 2 pH6.8 6 One 2
  • Comparative Example 2 and Example 1 can be confirmed that the dissolution rate difference between the two formulations within 15%, 15 minutes, 30 minutes, 60 minutes difference is less than 15%.
  • Comparative Example 2 of the solubilized active ingredient (I) was found to have the same level of Cmax and AUClast as Comparative Example 1, which must be administered with a meal despite being administered on an empty stomach. It became. On the other hand, when Comparative Example 2 was administered with a meal, it was confirmed that Cmax and AUClast showed about 14% lower results than Comparative Example 1 administered between meals.

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  • Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une formulation pharmaceutique incluant, en tant que principe actif, une dose élevée (de préférence, 15 ou 20 mg) de 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phényl]-1,3-oxazolidin-5-yl}-méthyl]-2-thiophène carboxamide (rivaroxaban) possédant une solubilité accrue sous une forme cristalline thermodynamiquement métastable ou amorphe, le médicament présentant une variation d'absorption (biodisponibilité) réduite en fonction de l'apport alimentaire.
PCT/KR2015/007667 2014-08-01 2015-07-23 Formulation pharmaceutique comprenant du rivaroxaban thermodynamiquement métastable ou amorphe Ceased WO2016017993A1 (fr)

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KR10-2014-0099174 2014-08-01
KR1020140099174A KR101535586B1 (ko) 2014-08-01 2014-08-01 무정형 또는 열역학적 준 안정형 리바록사반을 포함하는 약학 제제

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108186577A (zh) * 2018-03-09 2018-06-22 武汉工程大学 一种利伐沙班固体分散体及其制备方法和制剂

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020060336A1 (fr) 2018-09-21 2020-03-26 동아에스티 주식회사 Composition de solubilisation comprenant du rivaroxaban
KR102362787B1 (ko) 2019-12-30 2022-02-15 단국대학교 천안캠퍼스 산학협력단 리바록사반 함유 고체분산체 및 이의 제조방법

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KR20070094631A (ko) * 2004-12-24 2007-09-20 바이엘 헬스케어 아게 경구적으로 투여될 수 있는 변형 방출을 갖는 리바록사반함유 고형 약제학적 투약형
WO2011102506A1 (fr) * 2010-02-22 2011-08-25 第一三共株式会社 Préparation solide à libération prolongée pour usage oral
JP2012525323A (ja) * 2009-04-30 2012-10-22 武田薬品工業株式会社 固形製剤
JP2012254993A (ja) * 2004-05-11 2012-12-27 Bayer Pharma AG バルデナフィルを含有する制御放出製剤

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JP2012254993A (ja) * 2004-05-11 2012-12-27 Bayer Pharma AG バルデナフィルを含有する制御放出製剤
KR20070094631A (ko) * 2004-12-24 2007-09-20 바이엘 헬스케어 아게 경구적으로 투여될 수 있는 변형 방출을 갖는 리바록사반함유 고형 약제학적 투약형
JP2012525323A (ja) * 2009-04-30 2012-10-22 武田薬品工業株式会社 固形製剤
WO2011102506A1 (fr) * 2010-02-22 2011-08-25 第一三共株式会社 Préparation solide à libération prolongée pour usage oral

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Title
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108186577A (zh) * 2018-03-09 2018-06-22 武汉工程大学 一种利伐沙班固体分散体及其制备方法和制剂

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