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WO2019221488A1 - Pharmaceutical formulation comprising apixaban and method for preparing the same - Google Patents

Pharmaceutical formulation comprising apixaban and method for preparing the same Download PDF

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Publication number
WO2019221488A1
WO2019221488A1 PCT/KR2019/005795 KR2019005795W WO2019221488A1 WO 2019221488 A1 WO2019221488 A1 WO 2019221488A1 KR 2019005795 W KR2019005795 W KR 2019005795W WO 2019221488 A1 WO2019221488 A1 WO 2019221488A1
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Prior art keywords
apixaban
weight
pharmaceutical formulation
lag time
release
Prior art date
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PCT/KR2019/005795
Other languages
French (fr)
Inventor
Seokyoung KWON
Yunsang Park
Daehwan KOO
Youngbin Lee
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Sinil Pharmaceutical Co., Ltd.
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Publication date
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Publication of WO2019221488A1 publication Critical patent/WO2019221488A1/en

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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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a pharmaceutical formulation comprising an apixaban and a method for preparing the same.
  • Apixaban is a known compound represented by the following chemical formula 1:
  • apixaban is 4,5,6,7-tetrahydro-l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidinyl)phenyl]-lH-pyrazolo[3,4-c]pyridine-3-carboxamide (CAS name) or l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide.
  • Apixaban is a factor Xa inhibitor disclosed in U.S. Patent No. 6,967,208, which discloses that it may be administrated in the form of a pharmaceutical formulation containing at least one pharmaceutically acceptable diluent or carrier.
  • Apixaban is a substance that has high water solubility in the drug itself, but is difficult to obtain a constant bioavailability according to the dosage form and is hydrolyzed when exposed to moisture (Sci Pharm. 2014(82)777-785).
  • the apixaban itself is a non-hygroscopic substance, but when it is stored under high temperature and high humidity conditions due to the additives contained for formulation into oral dosage form, the moisture of the tablet is increased and the apixaban is hydrolyzed accordingly.
  • a decrease in content of apixaban by moisture, a decrease in therapeutic effect due to degraded apixaban, and an increase in side effects may occur.
  • Korean Patent Application Laid-Open No. 10-2012-0029428 discloses a bilayer osmotic controlled release dosage form of apixaban. Said application discloses that the dosage form can minimize the number of drug doses and can provide a controlled release dosage form regardless of a meal.
  • Korean Patent Laid-Open No. 10-2014-0046395 discloses a pharmaceutical composition for oral administration, comprising a factor Xa inhibitor and heavy chain fatty acid or an enhancer having a carbon chain length of from 4 to 20 carbon atoms. Said application discloses that a water-in-oil microemulsion composition provides a reproducible and predictable bioavailability.
  • Korean Patent Laid-Open No. 10-2016-0098508 discloses a formulation wherein a factor Xa inhibitor including an apixaban is micronized and a solubilizer is adsorbed on the surface.
  • Korean Patent Laying-Open No. 10-2009-0052346 discloses that a pharmaceutical composition comprising a plurality of small tablets containing an Xa inhibitor including apixaban as a pharmaceutical composition capable of having modified release.
  • Korean Patent No. 10-1796300 also discloses a pharmaceutical formulation comprising a crystalline apixaban particle having a limited maximum size.
  • Said application discloses how to use apixaban particles having a particle size of a certain value or less to provide a pharmaceutical composition that does not impose limitations on solubility and bioavailability.
  • the present invention has been devised to solve the above problems of the prior arts, and
  • an object of the present invention to provide an apixaban pharmaceutical formulation, which is capable of stably dissolving apixaban and providing its excellent bioavailability by its immediate-release property after the initial delayed release, even when short-term fluctuation of pH occurs in the stomach upon oral administration of the drug.
  • an object of the present invention to provide an apixaban pharmaceutical formulation, which is capable of being formulated into a form which is hardly affected by the digestion process of food by its immediate-release property after the initial delayed release even when it is taken with meals or after meals to be very convenient to take and have more excellent therapeutic effect; and which is capable of being formulated into a form which is hardly affected by other drugs even when taken along with other drugs to be very convenient to take and have more excellent therapeutic effect.
  • the present invention provides
  • a pharmaceutical formulation for delayed release of drug comprising: a core comprising at least one selected from the group consisting of an apixaban and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and a coated layer for the core,
  • a lag time is from 5 to 360 minutes and 60% or more by weight of the apixaban dissolve within 60 minutes after the lag time, wherein the lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 10% by weight, as measured in 900 mL of dissolution medium at 37°C using a USP Apparatus 2 at a rotation speed of 75 rpm.
  • the present invention provides a method for preparing a pharmaceutical formulation of the present invention, comprising the steps of:
  • step (b) compressing the mixture from step (a) by a direct compression method to produce a core tablet, or dry-granulating and compressing the mixture from step (a) to produce a core tablet;
  • An apixaban pharmaceutical formulation provides the effect of stably dissolving apixaban and providing its excellent bioavailability by having its immediate-release function after the initial delayed release by a coated layer, even when short-term fluctuation of pH occurs in the stomach upon administration of the drug.
  • the pharmaceutical formulation of the present invention can be formulated into a form which is hardly affected by the digestion process of food even when it is taken with meals or after meals to provide excellent convenience of taking as well as provide more excellent therapeutic effect; and can be formulated into a form which hardly affected by other drugs even when taken along with other drugs to provide excellent convenience of taking as well as provide more excellent therapeutic effect.
  • the apixaban pharmaceutical formulation of the present invention prevents moisture from penetrating into the formulation by a coated layer to prevent the hydrolysis of apixaban and the production of impurities, thereby providing the excellent storage stability.
  • the method for preparing a pharmaceutical formulation of the present invention provides a method for efficiently preparing an apixaban pharmaceutical formulation having the above effects.
  • Fig. 1 is a graph showing apixaban dissolution profiles of apixaban pharmaceutical formulations of example 2 and comparative example 1.
  • Fig. 2 is a graph showing apixaban dissolution profiles of apixaban pharmaceutical formulations of examples 1 to 5.
  • Fig. 3 is a graph showing the blood apixaban concentration profile in a beagle dog of a commercially available Eliquis Tab. 5 mg and a pharmaceutical preparation of example 2.
  • Fig. 4 is a graph showing a relationship between a lag time of apixaban drug and 60% by weight of a release time after initial delayed release according to the content of Eudragit E as a coating material.
  • Fig. 5 is a graph showing a relationship between a lag time of apixaban drug and 60% by weight of a release time after initial delayed release according to the content of EC;PVA as a coating material.
  • Fig. 6 is a graph showing a relationship between a lag time of apixaban drug and 60% by weight of a release time after initial delayed release according to the content of EC;HPMC as a coating material.
  • the present invention relates to an apixaban pharmaceutical formulation for delayed release of drug, comprising: a core comprising at least one selected from the group consisting of an apixaban and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and a coated layer for the core, characterized in that
  • a release lag time is from 5 to 360 minutes and 60% or more by weight of the apixaban dissolve within 60 minutes after the release lag time, wherein the release lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 10% by weight, as measured in 900 mL of dissolution medium at 37°C using a USP Apparatus 2 at a rotation speed of 75 rpm.
  • an apixaban pharmaceutical formulation is designed to release the drug from the start after the administration of the formulation without the delayed release of a certain period of time as in the prior arts, a change in the drug release pattern due to short-term fluctuation in gastric pH by food and co-administered drug may occur, and furthermore apixaban may be degraded by food and co-administered drug and decreased absorption due to competitive absorption and increased absorption by lipid materials may occur.
  • the gastric pH is between 1 and 2 on fasting but increases to 3.5 to 5.0 on meals, and this short-term rise in pH has a large effect on the absorption of the drug according to the pH-partition theory (Kor. J. Clin. Pharm 16(2) 2006 147-154).
  • the pharmaceutical formulation of the present invention has an important technical feature that a release lag time is from 5 to 360 minutes and 60% or more by weight of the apixaban is controlled to dissolve within 60 minutes after the release lag time. That is, the pharmaceutical formulation of the present invention has immediate-release property after the initial delayed release.
  • the release lag time is defined as a time at which the dissolution rate of apixaban is detected to be less than 10% by weight or it may be defined as a time from zero to the last time point in minute at which the dissolution rate of apixaban is detected to be less than 10% by weight.
  • the apixaban passes through the stomach and small intestine to be released in the large intestine where the water is relatively small, and thus the drug may not be sufficiently dissolved due to a small amount of water and absorption may not be smooth.
  • the drug release lag time is appropriately from 5 to 360 minutes.
  • the enteric coated layer is collapsed due to short-term fluctuation of gastric pH to be able to result in unwanted drug release, and there is a possibility that the dissolution of the drug is changed due to the pH change to be able to change the drug release rate of the sustained release formulations, and thus the effect of the present invention is not obtained.
  • the drug release lag time is from 5 to 360 minutes and the apixaban may dissolve by 70 % or more within 60 minutes after the release lag time.
  • the drug release lag time is from 10 to 150 minutes and the apixaban may dissolve 77 % or more by weight within 60 minutes after the release lag time.
  • the pharmaceutical formulation of the present invention is characterized in that the release lag time is from 5 to 360 minutes and 60 % or more by weight of the apixaban dissolve within 60 minutes after the release lag time, wherein the release lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 1 % by weight, as measured in 900 mL of dissolution medium at 37°C using a USP Apparatus 2 at a rotation speed of 75 rpm.
  • the pharmaceutical formulation of the present invention is characterized in that the release lag time is from 30 to 150 minutes and 70 % or more by weight of the apixaban dissolve within 60 minutes after the release lag time, wherein the release lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 3 % by weight, as measured in 900 mL of dissolution medium at 37°C using a USP Apparatus 2 at a rotation speed of 75 rpm.
  • the apixaban dissolves 70 % or more by weight within 30 minutes after the release lag time.
  • the pharmaceutical formulation of the present invention is characterized in that the lag time is from 30 to 150 minutes and 70 % or more by weight of the apixaban dissolve within 60 minutes after the release lag time, wherein the release lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 1 % by weight, as measured in 900 mL of dissolution medium at 37°C using a USP Apparatus 2 at a rotation speed of 75 rpm.
  • the apixaban dissolves 70 % or more by weight within 30 minutes after the release lag time.
  • the pharmaceutical formulation having the above-described release lag time of 30 to 150 minutes may be taken in the form which is hardly affected by the digestion process of food even when it is taken with meals or after meals to be very convenient to take and have more improved therapeutic effect accordingly, and thus it may be a very desirable form.
  • the pharmaceutical formulation may be taken a form which is hardly affected by other drugs even when co-administered with other drugs to be very convenient to take and have more improved therapeutic effect accordingly, and thus it may be a very desirable form.
  • an apixaban pharmaceutical formulation is designed to release the drug from the beginning after the administration of the formulation without the delayed release of a certain period of time as in the prior arts, a change in the drug release pattern due to short-term fluctuation in gastric pH by food and co-administered drug may occur, and furthermore apixaban may be degraded by food and co-administered drug and decreased absorption due to competitive absorption and increased absorption by lipid materials may occur.
  • the present invention may be said to overcome the limitations of the prior arts as described above.
  • the 60 % by weight release time after a drug release lag time of apixaban is within 35 minutes after the release lag time;
  • the 60 % by weight release time after a drug release lag time of apixaban is within 40 minutes after the release lag time;
  • the 60 % by weight release time after a drug release lag time of apixaban is within 60 minutes after the release lag time.
  • the characteristics of the present invention as described above indicate the features of the present invention as immediate-release after initial delayed release and that it is possible to provide a formulation capable of having faster immediate-release when the release lag time is short.
  • the core may comprise at least one selected from the group consisting of 1 to 10 % by weight of an apixaban and a pharmaceutically acceptable salt thereof, with 90 to 99 % by weight of a pharmaceutically acceptable carrier, based on the total weight of the core.
  • the pharmaceutically acceptable carrier may include fillers, binders, disintegrators, surfactants, lubricants, and the like.
  • the filler includes starch, lactose, anhydrous lactose, microcrystalline cellulose, silicified microcrystalline cellulose, silicic anhydride, calcium phosphate, calcium phosphate anhydrous, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium silicate, dextrin, dextrose, dextrates, mannitol, maltose, sorbitol, sucrose, and the like, and these may be used alone or in combination of two or more.
  • the binding agent includes povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, xanthan gum, and the like, and these may be used alone or in combination of two or more.
  • the disintegrator includes crospovidone, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, low-substituted hydroxypropyl cellulose, grain starch, and the like, and these may be used alone or in combination of two or more.
  • the surfactant is generally used to help wet the hydrophobic drug and include, for example, sodium lauryl sulfate, sodium stearate, polysorbate 80, poloxamer, and the like, and these may be used alone or in combination of two or more.
  • the lubricant includes magnesium stearate, stearic acid, talc, silicon dioxide, sodium stearyl fumarate, sodium lauryl sulfate, poloxamer, and the like, and these may be used alone or in combination of two or more.
  • the pharmaceutical formulation of the present invention may comprise a disintegrator, as the pharmaceutically acceptable carrier, from 1 to 40 % by weight, preferably from 2 to 20 % by weight, more preferably from 5 to 10 % by weight, based on the total weight of the core.
  • a disintegrator as the pharmaceutically acceptable carrier, from 1 to 40 % by weight, preferably from 2 to 20 % by weight, more preferably from 5 to 10 % by weight, based on the total weight of the core.
  • the disintegrator is included in the above-mentioned range, it is preferable since immediate-release of apixaban can be effectively performed at the time of immediate-release after initial delayed release.
  • the pharmaceutical formulation of the present invention may comprise one or more filler selected from the group consisting of microcrystalline cellulose, anhydrous lactose, and silicified microcrystalline cellulose, as the pharmaceutically acceptable carrier, from 10 to 80 % by weight, preferably from 30 to 60 % by weight, more preferably from 40 to 50 % by weight, based on the total weight of the core.
  • the filler is included in the above-mentioned range, it is preferable since immediate-release of apixaban can be effectively performed after initial delayed release.
  • the pharmaceutical formulation of the present invention relates to a pharmaceutical formulation for delayed release of drug, comprising: a core comprising at least one selected from the group consisting of an apixaban and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and a coated layer for the core; and also provides an in vitro drug release rate capable of securing pharmacokinetic parameters similar to those of a commercially available formulation (Eliquis Tab.®), while effectively inhibiting the increase in moisture in the core by the coated layer.
  • a pharmaceutical formulation for delayed release of drug comprising: a core comprising at least one selected from the group consisting of an apixaban and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and a coated layer for the core; and also provides an in vitro drug release rate capable of securing pharmacokinetic parameters similar to those of a commercially available formulation (Eliquis Tab.®), while effectively inhibiting the increase in moisture in the core by the coated layer.
  • the coating material for forming the coated layer at least one selected from the group consisting of hypromellose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, polyvinyl alcohol, povidone, ethylcellulose, methylcellulose, methyl methacrylate-ethyl acrylate copolymer, ethyl methacrylate-chlorotrimethyl ammonium ethyl methacrylate copolymer, and the like may be used.
  • the coated layer may comprise the coating material in an amount of 1 to 30 parts by weight, preferably 2 to 15 parts by weight, more preferably 2 to 10 parts by weight, based on 100 parts by weight of the core.
  • the weight ratio of the coated layer is too small, moisture permeation becomes easy, and thus there is a problem that moisture increment becomes large. If the weight ratio of the coated layer is too large, it is effective to prevent moisture permeation, but it may slow the drug release lag time and drug release rate to adversely affect bioavailability.
  • the amount of the coating material is more than 30% by weight, the release of the drug become too delayed or the release rate of the drug become too lower, and thus the drug is released after about 6 hours, which is the transit time to the small intestine of a human, to be undesirable in terms of absorption of the drug.
  • At least one selected from the group consisting of ethyl cellulose and methyl methacrylate-ethyl acrylate copolymer is preferably used in consideration of the digestion environment of the formulation.
  • the ethyl cellulose may be used in admixture with at least one selected from hypromellose and polyvinyl alcohol in order to control the release delay performance.
  • the ethyl cellulose and at least one selected from hypromellose and polyvinyl alcohol are mixed in a weight ratio of 1.5 to 50:1 in order to easily satisfy the requirement according to the digestion environment of the formulation.
  • the coating materials make it easy to prepare the formulation such that the drug release lag time is 5 to 360 minutes and the apixaban dissolves 60 % or more by weight within 60 minutes after the lag time.
  • the coating materials may be preferably used to achieve delayed release and immediate-release after the release lag time as described above.
  • the 60 % by weight release time after a drug release lag time of apixaban is within 60 minutes after the release lag time;
  • the 60 % by weight release time after a drug release lag time of apixaban is within 60 minutes after the release lag time.
  • the pharmaceutical formulation of the present invention can appropriately control the release time of 60% by weight after the drug release lag time within 60 minutes despite the increase or decrease of the used amount of the coating material.
  • the coating composition for forming the coated layer may further comprise conventional fillers such as plasticizers (polyethylene glycol, triacetin, lactose, and the like), and pigments (titanium oxide, iron oxide, titanium, and the like) together with the coating material.
  • plasticizers polyethylene glycol, triacetin, lactose, and the like
  • pigments titanium oxide, iron oxide, titanium, and the like
  • the coating composition for forming the coated layer may comprise 40 to 100% by weight of the coating material and 0 to 60% by weight of the filler, based on the total weight of the composition. Wherein, 0 % by weight represents the case where no filler is comprised.
  • a secondary coating may be provided for aesthetic purposes or to facilitate identification of the tablet.
  • the dissolution rate of apixaban may be the result of performing the dissolution test in vitro in accordance with the following dissolution standards.
  • the dissolution test may be carried out at 900 mL of dissolution medium at 37°C using a USP Apparatus 2 (paddle) method at a rotation speed of 75 rpm. After a period of time from the start of the test, the sample is removed and analyzed for apixaban at 280 nm by HPLC. 0.05 M sodium phosphate at a pH 6.8 with 0.05% by weight SLS solution as the dissolution medium may be used.
  • the dissolution test may be carried out with reference to the method disclosed in Korean Patent No. 10-1796300.
  • the apixaban pharmaceutical formulations of the present invention may be used for the treatment or prevention of thromboembolic disorders.
  • the thrombotic disorders include deep vein thrombosis, acute coronary syndrome, apoplexy, pulmonary embolism, and the like.
  • the amount of apixaban included in the pharmaceutical formulation of the present invention may be generally from 2.5 to 5 mg, and the apixaban may be usually administered orally twice a day, but may be used for treatment in amounts outside of the range and other administration frequency depending on the condition of the patient and the like.
  • the present invention relates to
  • step (b) compressing the mixture from step (a) by a direct compression method to produce a core tablet, or dry-granulating and compressing the mixture from step (a) to produce a core tablet;
  • the pharmaceutical formulation of the present invention is characterized in that it is prepared without using moisture except for the film coating process in order to suppress the hydrolysis of apixaban by moisture exposure during the manufacturing process.
  • a wet granulation method is a manufacturing method in which granulation is carried out after combining raw materials using a solvent and drying them at a high temperature, and a solvent is essentially introduced into the manufacturing process. If purified water is used as a solvent at this time, apixaban may be hydrolyzed and degradation of apixavan may be promoted by heat at high temperature drying.
  • the pharmaceutical formulation of the present invention is characterized in that it is prepared using a dry granulation method or a direct compression method in which a solvent is not used to suppress degradation of apixaban caused by moisture and heat and no drying process is performed.
  • the coating tablets of example 1 to 10 and comparative examples 1 and 2 were prepared by sequentially performing the granulation by the dry granulation method, the preparation of the tablet, and the coating process through the steps of:
  • the coating tablets of examples 11 to 15 were prepared by sequentially performing the preparation of the core tablet by the powder compression method and the coating process through the steps of:
  • the pharmaceutical formulations of comparative examples 3 and 4 were prepared by the following method.
  • the coating tablets of comparative examples 3 and 4 were prepared by sequentially performing the granulation by the wet granulation method, the preparation of the tablet, and the coating process through the steps of:
  • Test Example 1 in vivo dissolution test
  • the dissolution test was carried out in 900 mL of solvent medium at 37°C using a USP apparatus 2 (paddle) method at a rotation speed of 75 rpm in the same manner as in the method disclosed in the Korean Patent No. 10-1796300.
  • Samples were taken at 5, 10, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 420, 480 minutes after the start of the test, and were analyzed for apixaban at 280 nm by HPLC.
  • a medium for the dissolution test 0.05 M sodium phosphate at a pH 6.8 containing a 0.05 % by weight of sodium lauryl sulphate (SLS) solution was used.
  • SLS sodium lauryl sulphate
  • Drug lag time None None None More than 10 minutes More than 15 minutes More than 150 minutes More than 270 minutes _ 60% by weight release timeafter drug lag time _ _ _ Within20 minutes Within 30 minutes Within 60 minutes Within 60 minutes _
  • Example 6 Example 7
  • Example 8 Example 9
  • Example 10 5 9.4 0 0 0 0 10 50.6 7.8 0 9.9 0 15 76.7 61.1 42.2 58.1 0 30 88.8 83.6 66.3 85.6 0 45 91.0 81.0 95.9 0 60 92.1 85.4 96.1 26.6 90 89.5 98.6 72.4 120 89.9 180 90.2 210 93.5 Content of coating material to core tablet 2 wt. % 5 wt. % 10 wt. % 2 wt. % 10 wt. % Druglag time More than 5 minutes More than 10 minutes More than 10 minutes More than 10 minutes More than 45 minutes 60% by weight release timeafter drug lag time Within 10 minutes Within 20 minutes Within 35 minutes Within 20 minutes Within 45 minutes
  • the initial delayed release of the drugs did not occur in comparative examples 1 and 2 even when the content of the coating material was increased, but as the content of the coating material was increased, the release lag time (the time from zero to the last time point in minute at which the dissolution rate of apixaban is detected to be less than 10 % by weight) was increased in the examples and the fast release of more than 60% by weight within 60 minutes after the drug release lag time was shown.
  • the hygroscopicity was measured by putting the specimens prepared according to the examples and the comparative examples above in the stability test chamber and observing the change amount of the tablet weight under high temperature and high humidity conditions (40°C, 75 % relative humidity).
  • Test Example 4 In vivo test
  • Eliquis Tab.® 5 mg a commercially available formulation of apixaban, and the formulation of example 2 were crossover to 8 beagle dogs, which were divided into two groups, and then the pharmacokinetic parameters AUC, Cmax was calculated by measuring the concentration of apixaban in the blood and the results are shown in Table 8 below.

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Abstract

The present invention provides an apixaban pharmaceutical formulation for delayed release of drug, comprising: a core comprising at least one selected from the group consisting of an apixaban and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and a coated layer for the core, characterized in that a release lag time is from 5 to 360 minutes and 60% or more by weight of the apixaban dissolve within 60 minutes after the release lag time, wherein the release lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 10% by weight, as measured in 900 mL of dissolution medium at 37℃ using a USP Apparatus 2 at a rotation speed of 75 rpm; and a method for preparing the same.

Description

[Rectified under Rule 91, 14.06.2019] PHARMACEUTICAL FORMULATION COMPRISING APIXABAN AND METHOD FOR PREPARING THE SAME
The present invention relates to a pharmaceutical formulation comprising an apixaban and a method for preparing the same.
Apixaban is a known compound represented by the following chemical formula 1:
[Chemical Formula 1]
Figure PCTKR2019005795-appb-I000001
The chemical name for apixaban is 4,5,6,7-tetrahydro-l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidinyl)phenyl]-lH-pyrazolo[3,4-c]pyridine-3-carboxamide (CAS name) or l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide.
Apixaban is a factor Xa inhibitor disclosed in U.S. Patent No. 6,967,208, which discloses that it may be administrated in the form of a pharmaceutical formulation containing at least one pharmaceutically acceptable diluent or carrier.
Apixaban is a substance that has high water solubility in the drug itself, but is difficult to obtain a constant bioavailability according to the dosage form and is hydrolyzed when exposed to moisture (Sci Pharm. 2014(82)777-785).
In addition, the apixaban itself is a non-hygroscopic substance, but when it is stored under high temperature and high humidity conditions due to the additives contained for formulation into oral dosage form, the moisture of the tablet is increased and the apixaban is hydrolyzed accordingly. Thus, a decrease in content of apixaban by moisture, a decrease in therapeutic effect due to degraded apixaban, and an increase in side effects may occur.
Accordingly, various attempts have been made to provide stable oral formulation, and various prior art techniques for controlling release patterns have been disclosed.
Korean Patent Application Laid-Open No. 10-2012-0029428 discloses a bilayer osmotic controlled release dosage form of apixaban. Said application discloses that the dosage form can minimize the number of drug doses and can provide a controlled release dosage form regardless of a meal.
Korean Patent Laid-Open No. 10-2014-0046395 discloses a pharmaceutical composition for oral administration, comprising a factor Xa inhibitor and heavy chain fatty acid or an enhancer having a carbon chain length of from 4 to 20 carbon atoms. Said application discloses that a water-in-oil microemulsion composition provides a reproducible and predictable bioavailability.
Korean Patent Laid-Open No. 10-2016-0098508 discloses a formulation wherein a factor Xa inhibitor including an apixaban is micronized and a solubilizer is adsorbed on the surface.
In addition, Korean Patent Laying-Open No. 10-2009-0052346 discloses that a pharmaceutical composition comprising a plurality of small tablets containing an Xa inhibitor including apixaban as a pharmaceutical composition capable of having modified release.
Korean Patent No. 10-1796300 also discloses a pharmaceutical formulation comprising a crystalline apixaban particle having a limited maximum size. Said application discloses how to use apixaban particles having a particle size of a certain value or less to provide a pharmaceutical composition that does not impose limitations on solubility and bioavailability.
However, since the above prior arts are designed to release the drug immediately without the delayed release upon administration of the formulation, the short-term fluctuation in gastric pH by food and co-administered drug is likely to exhibit an abnormal drug release pattern, which is not preferable.
Therefore, there is a need for the development of an improved apixaban formulation to overcome the above problems.
[Prior Art Pefferences]
Korean Patent Application Laid-Open No. 10-2012-0029428
Korean Patent Application Laid-Open No. 10-2014-0046395
Korean Patent Application Laid-Open No. 10-2016-0098508
Korean Patent Application Laid-Open No. 10-2009-0052346
Korean Patent No. 10-1796300
The present invention has been devised to solve the above problems of the prior arts, and
it is an object of the present invention to provide an apixaban pharmaceutical formulation, which is capable of stably dissolving apixaban and providing its excellent bioavailability by its immediate-release property after the initial delayed release, even when short-term fluctuation of pH occurs in the stomach upon oral administration of the drug.
Specifically, it is an object of the present invention to provide an apixaban pharmaceutical formulation, which is capable of being formulated into a form which is hardly affected by the digestion process of food by its immediate-release property after the initial delayed release even when it is taken with meals or after meals to be very convenient to take and have more excellent therapeutic effect; and which is capable of being formulated into a form which is hardly affected by other drugs even when taken along with other drugs to be very convenient to take and have more excellent therapeutic effect.
It is another object of the present invention to provide an apixaban pharmaceutical formulation, which effectively prevents moisture from penetrating into the formulation to inhibit the hydrolysis of apixaban and the generation of impurities, thereby improving the storage stability of the formulation.
It is further object of the present invention to provide a method for preparing an apixaban pharmaceutical formulation, which can efficiently impart the above characteristics to the formulation.
The present invention provides
a pharmaceutical formulation for delayed release of drug, comprising: a core comprising at least one selected from the group consisting of an apixaban and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and a coated layer for the core,
characterized in that a lag time is from 5 to 360 minutes and 60% or more by weight of the apixaban dissolve within 60 minutes after the lag time, wherein the lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 10% by weight, as measured in 900 mL of dissolution medium at 37℃ using a USP Apparatus 2 at a rotation speed of 75 rpm.
In addition, the present invention provides a method for preparing a pharmaceutical formulation of the present invention, comprising the steps of:
(a) mixing at least one selected from the group consisting of an apixaban and a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier;
(b) compressing the mixture from step (a) by a direct compression method to produce a core tablet, or dry-granulating and compressing the mixture from step (a) to produce a core tablet; and
(c) coating the produced core tablet from step (b).
An apixaban pharmaceutical formulation provides the effect of stably dissolving apixaban and providing its excellent bioavailability by having its immediate-release function after the initial delayed release by a coated layer, even when short-term fluctuation of pH occurs in the stomach upon administration of the drug.
Specifically, the pharmaceutical formulation of the present invention can be formulated into a form which is hardly affected by the digestion process of food even when it is taken with meals or after meals to provide excellent convenience of taking as well as provide more excellent therapeutic effect; and can be formulated into a form which hardly affected by other drugs even when taken along with other drugs to provide excellent convenience of taking as well as provide more excellent therapeutic effect.
Further, the apixaban pharmaceutical formulation of the present invention prevents moisture from penetrating into the formulation by a coated layer to prevent the hydrolysis of apixaban and the production of impurities, thereby providing the excellent storage stability.
Furthermore, the method for preparing a pharmaceutical formulation of the present invention provides a method for efficiently preparing an apixaban pharmaceutical formulation having the above effects.
Fig. 1 is a graph showing apixaban dissolution profiles of apixaban pharmaceutical formulations of example 2 and comparative example 1.
Fig. 2 is a graph showing apixaban dissolution profiles of apixaban pharmaceutical formulations of examples 1 to 5.
Fig. 3 is a graph showing the blood apixaban concentration profile in a beagle dog of a commercially available Eliquis Tab. 5 mg and a pharmaceutical preparation of example 2.
Fig. 4 is a graph showing a relationship between a lag time of apixaban drug and 60% by weight of a release time after initial delayed release according to the content of Eudragit E as a coating material.
Fig. 5 is a graph showing a relationship between a lag time of apixaban drug and 60% by weight of a release time after initial delayed release according to the content of EC;PVA as a coating material.
Fig. 6 is a graph showing a relationship between a lag time of apixaban drug and 60% by weight of a release time after initial delayed release according to the content of EC;HPMC as a coating material.
The present invention relates to an apixaban pharmaceutical formulation for delayed release of drug, comprising: a core comprising at least one selected from the group consisting of an apixaban and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and a coated layer for the core, characterized in that
a release lag time is from 5 to 360 minutes and 60% or more by weight of the apixaban dissolve within 60 minutes after the release lag time, wherein the release lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 10% by weight, as measured in 900 mL of dissolution medium at 37℃ using a USP Apparatus 2 at a rotation speed of 75 rpm.
In the case where an apixaban pharmaceutical formulation is designed to release the drug from the start after the administration of the formulation without the delayed release of a certain period of time as in the prior arts, a change in the drug release pattern due to short-term fluctuation in gastric pH by food and co-administered drug may occur, and furthermore apixaban may be degraded by food and co-administered drug and decreased absorption due to competitive absorption and increased absorption by lipid materials may occur.
For example, the gastric pH is between 1 and 2 on fasting but increases to 3.5 to 5.0 on meals, and this short-term rise in pH has a large effect on the absorption of the drug according to the pH-partition theory (Kor. J. Clin. Pharm 16(2) 2006 147-154).
The abnormal drug release, degradation, and absorption rate fluctuation of apixaban by food and co-administered drug as described above are not preferable for the therapeutic effect, and thus the present inventors have devised the present invention to solve the above problems.
Therefore, the pharmaceutical formulation of the present invention has an important technical feature that a release lag time is from 5 to 360 minutes and 60% or more by weight of the apixaban is controlled to dissolve within 60 minutes after the release lag time. That is, the pharmaceutical formulation of the present invention has immediate-release property after the initial delayed release.
The release lag time is defined as a time at which the dissolution rate of apixaban is detected to be less than 10% by weight or it may be defined as a time from zero to the last time point in minute at which the dissolution rate of apixaban is detected to be less than 10% by weight.
In the case where the drug lag time becomes too long, the apixaban passes through the stomach and small intestine to be released in the large intestine where the water is relatively small, and thus the drug may not be sufficiently dissolved due to a small amount of water and absorption may not be smooth.
Thus, in consideration of the transit time from the administration of the drug to the small intestine (about 6 hours, see Pharm Tech 51-68 (July, 2003)), the drug release lag time is appropriately from 5 to 360 minutes.
In the case of widely used enteric coating formulations or sustained-release formulations, the enteric coated layer is collapsed due to short-term fluctuation of gastric pH to be able to result in unwanted drug release, and there is a possibility that the dissolution of the drug is changed due to the pH change to be able to change the drug release rate of the sustained release formulations, and thus the effect of the present invention is not obtained.
In the pharmaceutical preparation of the present invention, the drug release lag time is from 5 to 360 minutes and the apixaban may dissolve by 70 % or more within 60 minutes after the release lag time.
In addition, the drug release lag time is from 10 to 150 minutes and the apixaban may dissolve 77 % or more by weight within 60 minutes after the release lag time.
The pharmaceutical formulation of the present invention is characterized in that the release lag time is from 5 to 360 minutes and 60 % or more by weight of the apixaban dissolve within 60 minutes after the release lag time, wherein the release lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 1 % by weight, as measured in 900 mL of dissolution medium at 37℃ using a USP Apparatus 2 at a rotation speed of 75 rpm.
Further, the pharmaceutical formulation of the present invention is characterized in that the release lag time is from 30 to 150 minutes and 70 % or more by weight of the apixaban dissolve within 60 minutes after the release lag time, wherein the release lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 3 % by weight, as measured in 900 mL of dissolution medium at 37℃ using a USP Apparatus 2 at a rotation speed of 75 rpm.
From the above, it may be more preferable that the apixaban dissolves 70 % or more by weight within 30 minutes after the release lag time.
Furthermore, the pharmaceutical formulation of the present invention is characterized in that the lag time is from 30 to 150 minutes and 70 % or more by weight of the apixaban dissolve within 60 minutes after the release lag time, wherein the release lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 1 % by weight, as measured in 900 mL of dissolution medium at 37℃ using a USP Apparatus 2 at a rotation speed of 75 rpm.
From the above, it may be more preferable that the apixaban dissolves 70 % or more by weight within 30 minutes after the release lag time.
The pharmaceutical formulation having the above-described release lag time of 30 to 150 minutes may be taken in the form which is hardly affected by the digestion process of food even when it is taken with meals or after meals to be very convenient to take and have more improved therapeutic effect accordingly, and thus it may be a very desirable form.
In addition, the pharmaceutical formulation may be taken a form which is hardly affected by other drugs even when co-administered with other drugs to be very convenient to take and have more improved therapeutic effect accordingly, and thus it may be a very desirable form.
In the case where an apixaban pharmaceutical formulation is designed to release the drug from the beginning after the administration of the formulation without the delayed release of a certain period of time as in the prior arts, a change in the drug release pattern due to short-term fluctuation in gastric pH by food and co-administered drug may occur, and furthermore apixaban may be degraded by food and co-administered drug and decreased absorption due to competitive absorption and increased absorption by lipid materials may occur.
According to the technical features of the present invention as described above, a stable in vivo dissolution and bioavailability of apixaban may be obtained. Therefore, the present invention may be said to overcome the limitations of the prior arts as described above.
The pharmaceutical formulation of the present invention is characterized by:
(1) satisfying the following formula when the drug release lag time of apixaban is more than 5 minutes to 10 minutes or less:
60 % by weight release time after a drug release lag time (minute) = drug release lag time (minute) Х (rational number 1.5 to 2.5);
(2) satisfying the following formula when the drug release lag time of apixaban is more than 10 minutes to 15 minutes or less:
60 % by weight release time after a drug release lag time (minute) = drug lag time (minute) Х (rational number 1.5 to 3);
wherein the 60 % by weight release time after a drug release lag time of apixaban is within 35 minutes after the release lag time;
(3) satisfying the following formula when the drug release lag time of apixaban is more than 15 minutes to 45 minutes or less:
60 % by weight release time after a drug release lag time (minute) = drug release lag time (minute) Х (rational number 0.8 to 2.5);
wherein the 60 % by weight release time after a drug release lag time of apixaban is within 40 minutes after the release lag time;
(4) satisfying the following formula when the drug release lag time of apixaban is more than 45 minutes to 360 minutes:
60 % by weight release time after a drug release lag time (minute) = drug release lag time (minute) Х (rational number 1/3 to 1/6),
wherein the 60 % by weight release time after a drug release lag time of apixaban is within 60 minutes after the release lag time.
The characteristics of the present invention as described above indicate the features of the present invention as immediate-release after initial delayed release and that it is possible to provide a formulation capable of having faster immediate-release when the release lag time is short.
In the pharmaceutical formulation of the present invention, the core may comprise at least one selected from the group consisting of 1 to 10 % by weight of an apixaban and a pharmaceutically acceptable salt thereof, with 90 to 99 % by weight of a pharmaceutically acceptable carrier, based on the total weight of the core.
The pharmaceutically acceptable carrier may include fillers, binders, disintegrators, surfactants, lubricants, and the like.
The filler includes starch, lactose, anhydrous lactose, microcrystalline cellulose, silicified microcrystalline cellulose, silicic anhydride, calcium phosphate, calcium phosphate anhydrous, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium silicate, dextrin, dextrose, dextrates, mannitol, maltose, sorbitol, sucrose, and the like, and these may be used alone or in combination of two or more.
The binding agent includes povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, xanthan gum, and the like, and these may be used alone or in combination of two or more.
The disintegrator includes crospovidone, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, low-substituted hydroxypropyl cellulose, grain starch, and the like, and these may be used alone or in combination of two or more.
The surfactant is generally used to help wet the hydrophobic drug and include, for example, sodium lauryl sulfate, sodium stearate, polysorbate 80, poloxamer, and the like, and these may be used alone or in combination of two or more.
The lubricant includes magnesium stearate, stearic acid, talc, silicon dioxide, sodium stearyl fumarate, sodium lauryl sulfate, poloxamer, and the like, and these may be used alone or in combination of two or more.
The pharmaceutical formulation of the present invention may comprise a disintegrator, as the pharmaceutically acceptable carrier, from 1 to 40 % by weight, preferably from 2 to 20 % by weight, more preferably from 5 to 10 % by weight, based on the total weight of the core. In the case where the disintegrator is included in the above-mentioned range, it is preferable since immediate-release of apixaban can be effectively performed at the time of immediate-release after initial delayed release.
The pharmaceutical formulation of the present invention may comprise one or more filler selected from the group consisting of microcrystalline cellulose, anhydrous lactose, and silicified microcrystalline cellulose, as the pharmaceutically acceptable carrier, from 10 to 80 % by weight, preferably from 30 to 60 % by weight, more preferably from 40 to 50 % by weight, based on the total weight of the core. In the case where the filler is included in the above-mentioned range, it is preferable since immediate-release of apixaban can be effectively performed after initial delayed release.
The pharmaceutical formulation of the present invention relates to a pharmaceutical formulation for delayed release of drug, comprising: a core comprising at least one selected from the group consisting of an apixaban and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and a coated layer for the core; and also provides an in vitro drug release rate capable of securing pharmacokinetic parameters similar to those of a commercially available formulation (Eliquis Tab.®), while effectively inhibiting the increase in moisture in the core by the coated layer.
As the coating material for forming the coated layer, at least one selected from the group consisting of hypromellose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, polyvinyl alcohol, povidone, ethylcellulose, methylcellulose, methyl methacrylate-ethyl acrylate copolymer, ethyl methacrylate-chlorotrimethyl ammonium ethyl methacrylate copolymer, and the like may be used.
In the pharmaceutical formulation of the present invention, the coated layer may comprise the coating material in an amount of 1 to 30 parts by weight, preferably 2 to 15 parts by weight, more preferably 2 to 10 parts by weight, based on 100 parts by weight of the core.
If the weight ratio of the coated layer is too small, moisture permeation becomes easy, and thus there is a problem that moisture increment becomes large. If the weight ratio of the coated layer is too large, it is effective to prevent moisture permeation, but it may slow the drug release lag time and drug release rate to adversely affect bioavailability.
In particular, if the amount of the coating material is more than 30% by weight, the release of the drug become too delayed or the release rate of the drug become too lower, and thus the drug is released after about 6 hours, which is the transit time to the small intestine of a human, to be undesirable in terms of absorption of the drug.
Among the coating materials, at least one selected from the group consisting of ethyl cellulose and methyl methacrylate-ethyl acrylate copolymer is preferably used in consideration of the digestion environment of the formulation.
In particular, the ethyl cellulose may be used in admixture with at least one selected from hypromellose and polyvinyl alcohol in order to control the release delay performance. In this case, it is preferable that the ethyl cellulose and at least one selected from hypromellose and polyvinyl alcohol are mixed in a weight ratio of 1.5 to 50:1 in order to easily satisfy the requirement according to the digestion environment of the formulation.
The coating materials make it easy to prepare the formulation such that the drug release lag time is 5 to 360 minutes and the apixaban dissolves 60 % or more by weight within 60 minutes after the lag time. In particular, even when the coating materials are used in a small amount such as 2 to 5 parts by weight or 2 to 3 parts by weight, based on 100 parts by weight of the core, the coating materials may be preferably used to achieve delayed release and immediate-release after the release lag time as described above.
The pharmaceutical formulation of the present invention is characterized by:
(1') satisfying the following formula when the content of the coating material is 2 to 3 parts by weight, based on 100 parts by weight of the core:
60 % by weight release time after a drug release lag time (minute) = content of a coating material Х (rational number 8 to 11);
(2') satisfying the following formula when the content of the coating material is more than 3 parts by weight to 10 parts by weight, based on 100 parts by weight of the core:
60 % by weight release time after a drug release lag time (minute) = content of a coating material Х (rational number 3.5 to 7),
wherein the 60 % by weight release time after a drug release lag time of apixaban is within 60 minutes after the release lag time;
(3') satisfying the following formula when the content of the coating material is more than 10 parts by weight to 15 parts by weight, based on 100 parts by weight of the core:
60 % by weight release time after a drug release lag time (minute) = content of a coating material Х (rational number 3 to 6),
wherein the 60 % by weight release time after a drug release lag time of apixaban is within 60 minutes after the release lag time.
The above conditions indicate that the pharmaceutical formulation of the present invention can appropriately control the release time of 60% by weight after the drug release lag time within 60 minutes despite the increase or decrease of the used amount of the coating material.
In the pharmaceutical formulation of the present invention, the coating composition for forming the coated layer may further comprise conventional fillers such as plasticizers (polyethylene glycol, triacetin, lactose, and the like), and pigments (titanium oxide, iron oxide, titanium, and the like) together with the coating material.
The coating composition for forming the coated layer may comprise 40 to 100% by weight of the coating material and 0 to 60% by weight of the filler, based on the total weight of the composition. Wherein, 0 % by weight represents the case where no filler is comprised.
Additionally, a secondary coating may be provided for aesthetic purposes or to facilitate identification of the tablet.
In the pharmaceutical formulation of the present invention, the dissolution rate of apixaban may be the result of performing the dissolution test in vitro in accordance with the following dissolution standards.
That is, the dissolution test may be carried out at 900 mL of dissolution medium at 37℃ using a USP Apparatus 2 (paddle) method at a rotation speed of 75 rpm. After a period of time from the start of the test, the sample is removed and analyzed for apixaban at 280 nm by HPLC. 0.05 M sodium phosphate at a pH 6.8 with 0.05% by weight SLS solution as the dissolution medium may be used.
The dissolution test may be carried out with reference to the method disclosed in Korean Patent No. 10-1796300.
The apixaban pharmaceutical formulations of the present invention may be used for the treatment or prevention of thromboembolic disorders. The thrombotic disorders include deep vein thrombosis, acute coronary syndrome, apoplexy, pulmonary embolism, and the like.
The amount of apixaban included in the pharmaceutical formulation of the present invention may be generally from 2.5 to 5 mg, and the apixaban may be usually administered orally twice a day, but may be used for treatment in amounts outside of the range and other administration frequency depending on the condition of the patient and the like.
In addition, the present invention relates to
a method for preparing a pharmaceutical formulation of the present invention, comprising the steps of:
(a) mixing at least one selected from the group consisting of an apixaban and a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier;
(b) compressing the mixture from step (a) by a direct compression method to produce a core tablet, or dry-granulating and compressing the mixture from step (a) to produce a core tablet; and
(c) coating the produced core tablet from step (b).
The pharmaceutical formulation of the present invention is characterized in that it is prepared without using moisture except for the film coating process in order to suppress the hydrolysis of apixaban by moisture exposure during the manufacturing process.
That is, a wet granulation method, a dry granulation method, and a direct compacting method are usually used for preparing a solid preparation for oral use. Among them, the wet granulation method is a manufacturing method in which granulation is carried out after combining raw materials using a solvent and drying them at a high temperature, and a solvent is essentially introduced into the manufacturing process. If purified water is used as a solvent at this time, apixaban may be hydrolyzed and degradation of apixavan may be promoted by heat at high temperature drying.
Therefore, the pharmaceutical formulation of the present invention is characterized in that it is prepared using a dry granulation method or a direct compression method in which a solvent is not used to suppress degradation of apixaban caused by moisture and heat and no drying process is performed.
Hereinafter, the present invention will be described in more detail with reference to the examples. However, the following examples are intended to further illustrate the present invention, and the scope of the present invention is not limited by the examples. The following examples may be appropriately modified and changed by those skilled in the art within the scope of the present invention.
Examples 1 to 10 and Comparative Examples 1 and 2: Preparation of apixaban pharmaceutical formulations
The pharmaceutical formulations of example 1 to 10 and comparative examples 1 and 2 were prepared by the following method:
The coating tablets of example 1 to 10 and comparative examples 1 and 2 were prepared by sequentially performing the granulation by the dry granulation method, the preparation of the tablet, and the coating process through the steps of:
(1) blending the granulating raw materials (inter granules) shown in Tables 1 and 2 below before granulation;
(2) compressing the blend of (1) to produce dry granules;
(3) sieving a compressed material of (2);
(4) blending a sieved product of (3) with magnesium stearate (outer granules);
(5) compressing the blended product of (4) to obtain a core tablet; and
(6) film-coating the core tablets of (5) with coating compositions shown in Tables 1 and 2.
Classification Comparative Example (mg) Example (mg)
1 2 1 2 3 4 5
Inter granules Apixaban 5 5 5 5 5 5 5
Anhydrous lactose 88.5 88.5 88.5 88.5 88.5 88.5 88.5
Microcrystalline cellulose 82 82 82 82 82 82 82
Croscarmellose sodium 20 20 20 20 20 20 20
Sodium lauryl sulfate 2 2 2 2 2 2 2
Magnesium stearate 1 1 1 1 1 1 1
Outer granules Magnesium stearate 1.5 1.5 1.5 1.5 1.5 1.5 1.5
Core tablet weight 200 200 200 200 200 200 200
Film coat Coating material Hypromellose 4 20
Polyvinyl alcohol
Ethylcellulose
Eudragit E
4 6 10 20 30
Plasticizer Polyethylene glycol 4000 0.8 1.2 2 4 6
Triacetin 0.8 4
Pigment Talc 1.2 1.8 3 6 9
Titanium oxide 4 20
Sum 8.8 44 6 9 15 30 45
Amount of coating material compared to core tablet (% by weight) 2wt. % 10 wt. % 2wt. % 3wt. % 5wt. % 10 wt. % 15 wt. %
Classification Example (mg)
6 7 8 9 10
Inter granules Apixaban 5 5 5 5 5
Anhydrous lactose 98.5 98.5 98.5 98.5 98.5
Microcrystalline cellulose 82 82 82 82 82
Croscarmellose sodium 10 10 10 10 10
Sodium lauryl sulfate 2 2 2 2 2
Magnesium stearate 1 1 1 1 1
Outer granules Magnesium stearate 1.5 1.5 1.5 1.5 1.5
Core tablet weight 200 200 200 200 200
Film coat Coating material Hypromellose 0.4 1 2
Polyvinyl alcohol 0.4 2
Ethylcellulose 3.6 9 18 3.6 18
Eudragit E
Plasticizer Polyethylene glycol 4000
Triacetin 0.08 0.1 0.2
Pigment Talc
Titanium oxide 0.4 1 2
Sum 4.48 11.1 22.2 4 20
Amount of coating material compared to core tablet (% by weight) 2wt. % 5wt. % 10 wt. % 2wt. % 10 wt. %
Examples 11 to 15 and Comparative Examples 3 and 4: Preparation of apixaban pharmaceutical formulations
The pharmaceutical formulations of example 11 to 15 were prepared by the following method.
The coating tablets of examples 11 to 15 were prepared by sequentially performing the preparation of the core tablet by the powder compression method and the coating process through the steps of:
(1) blending the raw materials shown in Table 3 below;
(2) compressing the blended product of (1) to obtain a core tablet; and
(3) film-coating the core tablets of (2) with coating compositions shown in Table 3.
The pharmaceutical formulations of comparative examples 3 and 4 were prepared by the following method.
The coating tablets of comparative examples 3 and 4 were prepared by sequentially performing the granulation by the wet granulation method, the preparation of the tablet, and the coating process through the steps of:
(1) blending the granulating raw materials shown in Table 3 below before granulation;
(2) adding a solvent to the blend of (1) and combining them to produce wet granules (Water is used as a solvent in comparative example 3 and ethanol is used as a solvent in comparative example 4);
(3) drying a combination of (2) with hot air at 60℃ for 2 hours;
(4) blending the combination of (3) with magnesium stearate;
(5) compressing the blend product of (4) to obtain a core tablet; and
(6) film-coating the core tablets of (5) with coating compositions shown in Table 2.
Classification Comparative Example (mg) Example (mg)
3 4 11 12 13 14 15
In case of granules,inter granules Apixaban 5 5 5 5 5 5 5
Anhydrous lactose 88.5 88.5 88.5 88.5 88.5 98.5 98.5
Microcrystalline cellulose 82 82 82 82 82 82 82
Croscarmellose sodium 20 20 20 20 20 10 10
Sodium lauryl sulfate 2 2 2 2 2 2 2
Magnesium stearate 1 1 1 1 1 1 1
In case of granules,outer granules Magnesium stearate 1.5 1.5 1.5 1.5 1.5 1.5 1.5
Core tablet weight 200 200 200 200 200 200 200
Film coat Coating material Hypromellose 0.4
Polyvinyl alcohol 0.4
Ethylcellulose 3.6 3.6
Eudragit E 6 6 4 6 10
Plasticizer Polyethylene glycol 4000 1.2 1.2 0.8 1.2 2
Triacetin 0.08
Pigment Talc 1.8 1.8 1.2 1.8 3
Titanium oxide 0.4
Sum 9 9 6 9 15 4.48 4
Amount of coating material compared to core tablet (% by weight) 3 wt. % 3 wt. % 2 wt. % 3 wt. % 5 wt. % 2 wt. % 2 wt. %
Test Example 1: in vivo dissolution test
In order to confirm the release rate of the drug to have a sufficient bioavailability for therapeutic effect, the dissolution test was carried out in 900 mL of solvent medium at 37℃ using a USP apparatus 2 (paddle) method at a rotation speed of 75 rpm in the same manner as in the method disclosed in the Korean Patent No. 10-1796300. Samples were taken at 5, 10, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 420, 480 minutes after the start of the test, and were analyzed for apixaban at 280 nm by HPLC. As a medium for the dissolution test, 0.05 M sodium phosphate at a pH 6.8 containing a 0.05 % by weight of sodium lauryl sulphate (SLS) solution was used. The test results are shown in Tables 4 and 5 below.
Time (minute) Eliquis Tab.ⓡ Comparative Example 1 Comparative Example 2 Example 1 Example 2 Example 3 Example 4 Example 5
5 36.7 41.4 33.7 0 0 0 0 0
10 71.8 81.6 66.8 7.2 0 0 0 0
15 89.1 96.9 93.5 33.5 0.7 0 0 0
30 97.8 100.2 101.0 79.0 44.5 0 0 0
45 99.3 94.5 78.9 0 0 0
60 99.5 96.8 85.8 0 0 0
90 100.6 97.4 96.5 0 0 0
120 100.2 0 0 0
150 2.3 0 0
180 24.6 0 0
210 80.0 0 0
240 97.9 0 0
270 98.5 7.1 0
300 100.8 53.0 0
330 72.8 0
360 82.4 0
420 98.9 21.8
480 82.4
Content of coating material to core tablet - 2wt. % 10 wt. % 2wt. % 3wt. % 5wt. % 10wt. % 15 wt. %
Drug lag time None None None More than 10 minutes More than 15 minutes More than 150 minutes More than 270 minutes _
60% by weight release timeafter drug lag time _ _ _ Within20 minutes Within 30 minutes Within 60 minutes Within 60 minutes _
Note) Unit: % by weight
Time (minute) Example 6 Example 7 Example 8 Example 9 Example 10
5 9.4 0 0 0 0
10 50.6 7.8 0 9.9 0
15 76.7 61.1 42.2 58.1 0
30 88.8 83.6 66.3 85.6 0
45 91.0 81.0 95.9 0
60 92.1 85.4 96.1 26.6
90 89.5 98.6 72.4
120 89.9
180 90.2
210 93.5
Content of coating material to core tablet 2 wt. % 5 wt. % 10 wt. % 2 wt. % 10 wt. %
Druglag time More than 5 minutes More than 10 minutes More than 10 minutes More than 10 minutes More than 45 minutes
60% by weight release timeafter drug lag time Within 10 minutes Within 20 minutes Within 35 minutes Within 20 minutes Within 45 minutes
Note) Unit: % by weight
As confirmed from Tables 4 and 5 above, the initial delayed release of the drugs did not occur in comparative examples 1 and 2 even when the content of the coating material was increased, but as the content of the coating material was increased, the release lag time (the time from zero to the last time point in minute at which the dissolution rate of apixaban is detected to be less than 10 % by weight) was increased in the examples and the fast release of more than 60% by weight within 60 minutes after the drug release lag time was shown.
Test Example 2: Hygroscopicity test
The hygroscopicity was measured by putting the specimens prepared according to the examples and the comparative examples above in the stability test chamber and observing the change amount of the tablet weight under high temperature and high humidity conditions (40℃, 75 % relative humidity).
Weight increase rate at the time of comparison to initial weight (% by weight) Comparative Example Example
1 2 3 4 6 7 8 9 12
1 hour 1.27 1.12 0.92 0.57 1.13 1.08 0.83 0.48 1.11
3 hours 2.68 2.45 2.06 1.36 2.55 2.19 2.04 1.38 2.47
6 hours 3.43 3.15 2.78 1.91 3.24 3.00 2.62 1.89 3.13
Moisture increase rate (% by weight) after 6 hourscompared to comparative example 1 - 0.92 0.81 0.56 0.94 0.87 0.76 0.55 0.91
Amount of coating materialcompared to core tablet 3 wt. % 3 wt. % 5 wt. % 10 wt. % 2 wt. % 3 wt. % 5 wt. % 10 wt. % 3 wt. %
As shown in Table 6 above, as a result of the hygroscopicity measurement, it was confirmed that the pharmaceutical formulations of the examples had a moisture increase rate after storage for 6 hours under high temperature and high humidity conditions (40℃, 75 % relative humidity) as low as at least 6 % by weight (example 6) to at most 45% by weight (example 9), compared with comparative example 1.
Test Example 3: Impurity test
The specimens prepared according to the examples and the comparative examples above were put in the stability test chamber, the content and the change amount of the impurities in the tablets were observed under high temperature and high humidity conditions (40℃, 75 % relative humidity), and the results are shown in Table 7 below.
Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Example 2 Example 4 Example 8
InitialImpurity (% byweight) 0.03 0.02 0.04 0.05 0.02 0.03 0.02
After 12 weeksImpurity (% by weight) 0.28 0.25 0.47 0.53 0.19 0.14 0.15
As shown in Table 7 above, it was confirmed that the formulations in the examples of the present invention were significantly lower in the generation amount of the impurities as compared with the formulations of the comparative examples.
In addition, among the comparative examples, it was confirmed that, in the formulations of comparative examples 3 and 4 prepared by the wet granulation method, the generation amount of the impurities was relatively larger than that of the formulations of comparative examples 1 and 2.
Test Example 4: In vivo test
In order to calculate the pharmacokinetic parameters for the in vivo blood concentration of apixaban, Eliquis Tab.® 5 mg, a commercially available formulation of apixaban, and the formulation of example 2 were crossover to 8 beagle dogs, which were divided into two groups, and then the pharmacokinetic parameters AUC, Cmax was calculated by measuring the concentration of apixaban in the blood and the results are shown in Table 8 below.
Eliquis Tab. 5 mg Example 2
Average Deviation Average Deviation
AUC(ng·hr/mL) 9023 2869.153 11833 3459.012
Cmax(ng/ml) 974.4 398.4456 1184 368.8621
As shown in Table 8 above, it was confirmed that the formulation of example 2 of the present invention exhibited similar pharmacokinetic parameters to commercially available Eliquis Tab.

Claims (14)

  1. An apixaban pharmaceutical formulation for delayed release of drug, comprising: a core comprising at least one selected from the group consisting of an apixaban and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and a coated layer for the core, characterized in that
    a release lag time is from 5 to 360 minutes and 60 % or more by weight of the apixaban dissolve within 60 minutes after the release lag time, wherein the lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 10 % by weight, as measured in 900 mL of dissolution medium at 37℃ using a USP Apparatus 2 at a rotation speed of 75 rpm.
  2. The apixaban pharmaceutical formulation according to claim 1, characterized in that the release lag time is from 5 to 360 minutes and 70 % or more by weight of the apixaban dissolve within 60 minutes after the release lag time, wherein the release lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 1 % by weight, as measured in 900 mL of dissolution medium at 37℃ using a USP Apparatus 2 at a rotation speed of 75 rpm.
  3. The apixaban pharmaceutical formulation according to claim 1, characterized in that the release lag time is from 30 to 150 minutes and 70 % or more by weight of the apixaban dissolve within 60 minutes after the lag time, wherein the release lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 3 % by weight, as measured in 900 mL of dissolution medium at 37℃ using a USP Apparatus 2 at a rotation speed of 75 rpm.
  4. The apixaban pharmaceutical formulation according to claim 1, characterized in that the release lag time is from 30 to 150 minutes and 70 % or more by weight of the apixaban dissolve within 30 minutes after the release lag time, wherein the release lag time is defined as the time at which the dissolution rate of apixaban is detected to be less than 1 % by weight, as measured in 900 mL of dissolution medium at 37℃ using a USP Apparatus 2 at a rotation speed of 75 rpm.
  5. The apixaban pharmaceutical formulation according to claim 1, characterized in that the dissolution medium is 0.05 M sodium phosphate at a pH 6.8 containing a 0.05 % by weight of sodium lauryl sulphate (SLS) solution.
  6. The apixaban pharmaceutical formulation according to claim 1, characterized in that the pharmaceutical formulation comprises a disintegrator, as the pharmaceutically acceptable carrier, from 2 to 20 % by weight, based on the total weight of the core.
  7. The apixaban pharmaceutical formulation according to claim 1, characterized in that the pharmaceutical formulation comprises a disintegrator, as the pharmaceutically acceptable carrier, from 5 to 10 % by weight, based on the total weight of the core.
  8. The apixaban pharmaceutical formulation according to claim 1, characterized in that the pharmaceutical formulation comprises one or more fillers selected from the group consisting of microcrystalline cellulose, anhydrous lactose, and silicified microcrystalline cellulose, as the pharmaceutically acceptable carrier, from 10 to 80 % by weight, based on the total weight of the core.
  9. The apixaban pharmaceutical formulation according to claim 1, characterized in that the pharmaceutical formulation comprises one or more fillers selected from the group consisting of microcrystalline cellulose, anhydrous lactose, and silicified microcrystalline cellulose, as the pharmaceutically acceptable carrier, from 40 to 50 % by weight, based on the total weight of the core.
  10. The apixaban pharmaceutical formulation according to claim 1, characterized in that a coating material for forming the coated layer comprises at least one selected from the group consisting of polyvinyl alcohol, ethyl cellulose, and methyl methacrylate-ethyl acrylate copolymer.
  11. The apixaban pharmaceutical formulation according to claim 1, characterized in that a coating material for forming the coated layer comprises a mixture of ethyl cellulose and at least one selected from hypromellose and polyvinyl alcohol, in a weight ratio of 1.5 to 50:1.
  12. The apixaban pharmaceutical formulation according to claim 1, characterized in that a coating material included in the coated layer is comprised in an amount of 1 to 30 parts by weight, based on 100 parts by weight of the core.
  13. The apixaban pharmaceutical formulation according to claim 1, characterized in that the pharmaceutical formulation is used for the treatment or prevention of thromboembolic disorders.
  14. A method for preparing a pharmaceutical formulation according to any one of claims 1 to 13, comprising the steps of:
    (a) mixing at least one selected from the group consisting of an apixaban and a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier;
    (b) compressing the mixture from step (a) by a powder compression method to produce a core tablet, or dry-granulating and compressing the mixture from step (a) to produce a core tablet; and
    (c) coating the produced core tablet from step (b).
PCT/KR2019/005795 2018-05-14 2019-05-14 Pharmaceutical formulation comprising apixaban and method for preparing the same WO2019221488A1 (en)

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CN113577035A (en) * 2021-09-07 2021-11-02 山东仁和制药有限公司 Apixaban tablet and preparation method thereof
WO2022115051A1 (en) * 2020-11-27 2022-06-02 Santa Farma Ilac Sanayii A.S. Direct compression method for non-micronised apixaban formulations
WO2024144207A1 (en) * 2022-12-26 2024-07-04 Rexpharmtech Co., Ltd Sustained-release tablet comprising apixaban

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WO2024144207A1 (en) * 2022-12-26 2024-07-04 Rexpharmtech Co., Ltd Sustained-release tablet comprising apixaban

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