WO2019177318A1 - Pharmaceutical formulation for solubilization comprising apixaban and its preparation method - Google Patents

Pharmaceutical formulation for solubilization comprising apixaban and its preparation method Download PDF

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Publication number
WO2019177318A1
WO2019177318A1 PCT/KR2019/002779 KR2019002779W WO2019177318A1 WO 2019177318 A1 WO2019177318 A1 WO 2019177318A1 KR 2019002779 W KR2019002779 W KR 2019002779W WO 2019177318 A1 WO2019177318 A1 WO 2019177318A1
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Prior art keywords
apixaban
pharmaceutical formulation
methylene chloride
formulation according
ethanol
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PCT/KR2019/002779
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French (fr)
Inventor
Seoung Youn Lee
Min Soo Kim
Shin Jung Park
Jong Lae Lim
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Chong Kun Dang Pharmaceutical Corp.
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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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, 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
    • A61K9/2004—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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the present invention relates to a pharmaceutical formulation with improved dissolution rate and bioavailability of a water insoluble drug, apixaban.
  • the present invention relates to a pharmaceutical formulation prepared according to a preparation method comprising the steps of: mixing apixaban and a water-soluble polymer; and wet kneading and vacuum drying.
  • apixaban is 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (CAS name) or 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (IUPAC name), having the structure of Formula I below.
  • Apixaban is disclosed in U.S. Patent Publication Nos. 2012/0087978 and 2013/0045245 and is used to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation and in patients following elective hip or knee surgery, which require the use of antithrombotic agents.
  • Apixaban is an anticoagulant and antithrombogenic factor Xa inhibitor developed by Bristol-Myers Squibb Co. for the prevention of various thromboembolism and paroxysmal atrial fibrillation and is currently available under the trade name Eliquis ® .
  • apixaban may be administered in the form of a pharmaceutical composition comprising apixaban and a pharmaceutically acceptable carrier, diluent or excipient. It is also disclosed that a pharmaceutical formulation for an oral administration may be in a form of a solution, suspension, tablet, pill, capsule, powder, or the like.
  • factor Xa inhibitors such as dabigatran, rivaroxaban, or apixaban are insoluble in water and are not well dissolved in organic solvents. As such, various problems are found when designing a formulation.
  • US Patent Publication No. 2013/0045245 discloses a composition with improved dissolution rate by using crystalline apixaban having D 90 equal to or less than 89 ⁇ m and a method for improving the dissolution rate of apixaban as a water insoluble drug by controlling the particle size distribution.
  • the method for improving the dissolution rate by reducing particle size has a problem that the drug distribution in vivo varies depending on the particle size variation
  • organic solvents such as methylene chloride are generally used for the solubilization of a water insoluble drug, apixaban.
  • highly volatile organic solvents such as methylene chloride are at high risk for explosion and fire when using a fluid bed granulator or a spray drying facility.
  • the present inventors attempted to develop a preparation method to provide a pharmaceutical formulation with improved dissolution rate and stability regardless of the particle size of apixaban, as well as to ensure safety even in case of the use of an organic solvent for the solubilization.
  • the present inventors have developed a preparation method for solubilizing a water insoluble drug, apixaban, in order to develop a formulation with improved dissolution rate and bioavailability regardless of the particle size of apixaban.
  • the inventors have attempted to reduce any side effects of apixaban by allowing a formulation comprising low dose of apixaban to exhibit equivalent or better dissolution rate and bioavailability.
  • the present inventors have also attempted to provide a safe preparation method in order to solve the safety problem due to an organic solvent used for the solubilization of a water insoluble drug.
  • the present invention relates to a preparation method comprising the steps of: (i) mixing apixaban and a water-soluble polymer to prepare a mixture; and (ii) wet kneading and vacuum drying of the mixture.
  • the present invention relates to a pharmaceutical formulation prepared according to said preparation method.
  • wet kneading and vacuum drying are carried out simultaneously to solve the problem due to volatile organic solvents such as methylene chloride. That is, the simultaneous process of wet kneading and vacuum drying can reduce the risk of explosion and fire by instantly removing organic solvents, and especially further reduce the risk of fire as vacuum drying does not increase a temperature.
  • the concentration of apixaban can be decreased by 25% or more and preferably 50% or more, compared with the commercial product comprising 5mg of apixaban. That is, the dissolution rate and bioavailability of a formulation is improved with less amount of apixaban to achieve equivalent efficacy.
  • the present invention relates to a preparation method comprising the steps of: (i) mixing apixaban and a water-soluble polymer to prepare a mixture wherein a binding solvent is added; and (ii) wet kneading and vacuum drying of the mixture, and a pharmaceutical formulation prepared according to said preparation method.
  • the binding solvent of the present invention may be ethanol, dimethyl sulfoxide, chloroform, acetone, methylene chloride, purified water, or a mixture thereof, and preferably, a mixed solvent of ethanol and methylene chloride, dimethyl sulfoxide, or methylene chloride, and most preferably, a mixed solvent of ethanol and methylene chloride.
  • the mixed solvent of ethanol and methylene chloride may comprise ethanol and methylene chloride in a weight ratio of preferably 1:1 to 1:7 and more preferably 1:3 to 1:5.
  • the water-soluble polymer may be one or more selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose, hydroxyethyl ethylcellulose, carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, polyvinylpyrrolidone, N-vinylpyrrolidone, vinyl acetate copolymer, vinyl propionate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and ethylene oxide-propylene oxide block copolymer.
  • the water-soluble polymer may be one or more selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose and hydroxyethyl ethylcellulose.
  • the present invention is related to a preparation method comprising the steps of:
  • the present invention relates to an oral pharmaceutical formulation comprising apixaban and further pharmaceutical excipients.
  • a pharmaceutically acceptable excipient may comprise fillers, binders, disintegrators, lubricants, and the like.
  • the formulation of the present invention not only has improved dissolution rate and bioavailability of a poorly soluble apixaban, but also has a superior effect of cost saving and reduced side effects by decreasing the concentration of apixaban in the formulation by 25% or more, and preferably by 50% or more, compared with the commercial product comprising 5mg of apixaban.
  • the processes of wet kneading and vacuum drying are simultaneously carried out to improve the safety problem due to an organic solvent.
  • Fig. 1 shows a graph of apixaban concentration in blood of an animal over time with respect to the tablets of Examples 1 to 3 and Comparative Example 1 (5 mg tablets of Eliquis).
  • a tablet comprising apixaban of the present invention was prepared based on the method as follows.
  • Apixaban, methylene chloride, and anhydrous ethanol were added to the container to completely dissolve them.
  • Hydroxypropyl methylcellulose (HPMC) and sodium lauryl sulfate (SLS) were added thereto and stirred to prepare a binding solution.
  • the binding solution was placed in a container, microcrystalline cellulose was added, and heating and stirring were followed in a water bath reactor to proceed with kneading and drying.
  • the mixture from process 2 was granulated and dried to obtain granules, which was then sized with a co-mil.
  • the granules from process 3 were blended with anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, and copolyvidone.
  • the mixture from process 4 was blended with sodium stearyl fumarate to prepare a final mixture, which was then compressed by using a tableting machine.
  • Opadry was added to purified water and stirred to prepare a coating solution.
  • the coating process was carried out with the above coating solution to obtain coated tablets.
  • Tablets of Examples 1 to 3 comprising the ingredients in amounts as shown in Table 1 below were prepared according to the above preparation method.
  • Example 1 Example 2
  • Example 3 mg/tablet mg/tablet mg/tablet Binding solution Apixaban 1.60 2.50 3.75 Sodium lauryl sulfate 4.95 4.95 4.95 Hydroxypropyl methylcellulose 3.75 3.75 3.75
  • Anhydrous ethanol 16.53 16.53 16.53 Methylene chloride 69.33 69.33 69.33 Kneading Microcrystalline cellulose 37.90 37.00 35.75
  • Mixing Anhydrous lactose 51.40 51.40 51.40 Microcrystalline cellulose 56.80 56.80 56.80 Sodium croscarmellose 6.00 6.00 6.00 Copolyvidone 15.00 15.00 15.00 Sodium stearyl fumarate 2.60 2.60 2.60
  • Example 2 showed AUC and C max values similar with those of Comparative Example 1 while Example 3 showed higher AUC and C max values than those of Comparative Example 1.
  • the mixed solvent of methylene chloride and ethanol is most suitable for solubilizing apixaban.

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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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Abstract

The present invention relates to a pharmaceutical formulation with improved dissolution rate and bioavailability of water insoluble apixaban. Specifically, the present invention relates to a pharmaceutical formulation prepared according to a preparation method comprising the steps of: mixing apixaban and a water-soluble polymer to prepare a mixture; and wet kneading and vacuum drying of the mixture. The formulation of the present invention not only has improved dissolution rate and bioavailability of water insoluble apixaban, but also exerts a superior effect of cost saving and reduced side effects by decreasing the concentration of apixaban in the formulation by 25% or more, and preferably by 50% or more. In addition, in the preparation method of the present invention, the processes of wet kneading and drying are simultaneously carried out to improve the safety problem due to an organic solvent.

Description

PHARMACEUTICAL FORMULATION FOR SOLUBILIZATION COMPRISING APIXABAN AND ITS PREPARATION METHOD
The present invention relates to a pharmaceutical formulation with improved dissolution rate and bioavailability of a water insoluble drug, apixaban. Specifically, the present invention relates to a pharmaceutical formulation prepared according to a preparation method comprising the steps of: mixing apixaban and a water-soluble polymer; and wet kneading and vacuum drying.
The chemical name of apixaban is 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (CAS name) or 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (IUPAC name), having the structure of Formula I below.
[Formula I]
Figure PCTKR2019002779-appb-I000001
Apixaban is disclosed in U.S. Patent Publication Nos. 2012/0087978 and 2013/0045245 and is used to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation and in patients following elective hip or knee surgery, which require the use of antithrombotic agents.
Apixaban is an anticoagulant and antithrombogenic factor Xa inhibitor developed by Bristol-Myers Squibb Co. for the prevention of various thromboembolism and paroxysmal atrial fibrillation and is currently available under the trade name Eliquis®.
U.S. Patent No. 6,967,208 discloses that apixaban may be administered in the form of a pharmaceutical composition comprising apixaban and a pharmaceutically acceptable carrier, diluent or excipient. It is also disclosed that a pharmaceutical formulation for an oral administration may be in a form of a solution, suspension, tablet, pill, capsule, powder, or the like.
However, factor Xa inhibitors such as dabigatran, rivaroxaban, or apixaban are insoluble in water and are not well dissolved in organic solvents. As such, various problems are found when designing a formulation.
US Patent Publication No. 2013/0045245 discloses a composition with improved dissolution rate by using crystalline apixaban having D90 equal to or less than 89 μm and a method for improving the dissolution rate of apixaban as a water insoluble drug by controlling the particle size distribution. However, the method for improving the dissolution rate by reducing particle size has a problem that the drug distribution in vivo varies depending on the particle size variation
In addition, organic solvents such as methylene chloride are generally used for the solubilization of a water insoluble drug, apixaban. However, highly volatile organic solvents such as methylene chloride are at high risk for explosion and fire when using a fluid bed granulator or a spray drying facility.
Accordingly, the present inventors attempted to develop a preparation method to provide a pharmaceutical formulation with improved dissolution rate and stability regardless of the particle size of apixaban, as well as to ensure safety even in case of the use of an organic solvent for the solubilization.
The present inventors have developed a preparation method for solubilizing a water insoluble drug, apixaban, in order to develop a formulation with improved dissolution rate and bioavailability regardless of the particle size of apixaban. At the same time, the inventors have attempted to reduce any side effects of apixaban by allowing a formulation comprising low dose of apixaban to exhibit equivalent or better dissolution rate and bioavailability.
The present inventors have also attempted to provide a safe preparation method in order to solve the safety problem due to an organic solvent used for the solubilization of a water insoluble drug.
The present invention relates to a preparation method comprising the steps of: (i) mixing apixaban and a water-soluble polymer to prepare a mixture; and (ii) wet kneading and vacuum drying of the mixture.
The present invention relates to a pharmaceutical formulation prepared according to said preparation method.
In said preparation method, wet kneading and vacuum drying are carried out simultaneously to solve the problem due to volatile organic solvents such as methylene chloride. That is, the simultaneous process of wet kneading and vacuum drying can reduce the risk of explosion and fire by instantly removing organic solvents, and especially further reduce the risk of fire as vacuum drying does not increase a temperature.
Through the preparation method of the present invention, the concentration of apixaban can be decreased by 25% or more and preferably 50% or more, compared with the commercial product comprising 5mg of apixaban. That is, the dissolution rate and bioavailability of a formulation is improved with less amount of apixaban to achieve equivalent efficacy.
The present invention relates to a preparation method comprising the steps of: (i) mixing apixaban and a water-soluble polymer to prepare a mixture wherein a binding solvent is added; and (ii) wet kneading and vacuum drying of the mixture, and a pharmaceutical formulation prepared according to said preparation method.
The binding solvent of the present invention may be ethanol, dimethyl sulfoxide, chloroform, acetone, methylene chloride, purified water, or a mixture thereof, and preferably, a mixed solvent of ethanol and methylene chloride, dimethyl sulfoxide, or methylene chloride, and most preferably, a mixed solvent of ethanol and methylene chloride.
Further, the mixed solvent of ethanol and methylene chloride may comprise ethanol and methylene chloride in a weight ratio of preferably 1:1 to 1:7 and more preferably 1:3 to 1:5.
The water-soluble polymer may be one or more selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose, hydroxyethyl ethylcellulose, carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, polyvinylpyrrolidone, N-vinylpyrrolidone, vinyl acetate copolymer, vinyl propionate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and ethylene oxide-propylene oxide block copolymer.
Preferably, the water-soluble polymer may be one or more selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose and hydroxyethyl ethylcellulose.
The present invention is related to a preparation method comprising the steps of:
(i) mixing apixaban and a water-soluble polymer to prepare a mixture wherein a binding solvent is added;
(ii) wet kneading and vacuum drying of the mixture wherein the wet kneading and vacuum drying are carried out simultaneously;
(iii) granulating and sizing; and
(iv) adding excipients, final blending, and tableting
and a pharmaceutical formulation prepared according to the preparation method.
The present invention relates to an oral pharmaceutical formulation comprising apixaban and further pharmaceutical excipients. In the present invention, a pharmaceutically acceptable excipient may comprise fillers, binders, disintegrators, lubricants, and the like.
The formulation of the present invention not only has improved dissolution rate and bioavailability of a poorly soluble apixaban, but also has a superior effect of cost saving and reduced side effects by decreasing the concentration of apixaban in the formulation by 25% or more, and preferably by 50% or more, compared with the commercial product comprising 5mg of apixaban.
In addition, in the preparation method of the present invention, the processes of wet kneading and vacuum drying are simultaneously carried out to improve the safety problem due to an organic solvent.
Fig. 1 shows a graph of apixaban concentration in blood of an animal over time with respect to the tablets of Examples 1 to 3 and Comparative Example 1 (5 mg tablets of Eliquis).
Hereinafter, the present invention will be more detailed through the following examples. However, the examples are merely provided for a better understanding of the present invention for the purpose of illustration, but are not to be construed as the limitation of the claimed scope.
[Preparation Example]
Preparation of a tablet comprising solubilization steps of apixaban
A tablet comprising apixaban of the present invention was prepared based on the method as follows.
1. Preparation of a binding solution
Apixaban, methylene chloride, and anhydrous ethanol were added to the container to completely dissolve them. Hydroxypropyl methylcellulose (HPMC) and sodium lauryl sulfate (SLS) were added thereto and stirred to prepare a binding solution.
2. Wet kneading and vacuum drying
The binding solution was placed in a container, microcrystalline cellulose was added, and heating and stirring were followed in a water bath reactor to proceed with kneading and drying.
3. Granulation and sizing
The mixture from process 2 was granulated and dried to obtain granules, which was then sized with a co-mil.
4. Blending
The granules from process 3 were blended with anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, and copolyvidone.
5. Final blending and tableting
The mixture from process 4 was blended with sodium stearyl fumarate to prepare a final mixture, which was then compressed by using a tableting machine.
6. Coating
Opadry was added to purified water and stirred to prepare a coating solution. The coating process was carried out with the above coating solution to obtain coated tablets.
[Examples 1 to 3]
Tablets of Examples 1 to 3 comprising the ingredients in amounts as shown in Table 1 below were prepared according to the above preparation method.
Ingredient Name Example 1 Example 2 Example 3
mg/tablet mg/tablet mg/tablet
Binding solution Apixaban 1.60 2.50 3.75
Sodium lauryl sulfate 4.95 4.95 4.95
Hydroxypropyl methylcellulose 3.75 3.75 3.75
Anhydrous ethanol 16.53 16.53 16.53
Methylene chloride 69.33 69.33 69.33
Kneading Microcrystalline cellulose 37.90 37.00 35.75
Sub-total weight 48.20 48.20 48.20
Mixing Anhydrous lactose 51.40 51.40 51.40
Microcrystalline cellulose 56.80 56.80 56.80
Sodium croscarmellose 6.00 6.00 6.00
Copolyvidone 15.00 15.00 15.00
Sodium stearyl fumarate 2.60 2.60 2.60
Sub-total weight 180.00 180.00 180.00
Coating Opadry 10.00 10.00 10.00
Purified water 66.67 66.67 66.67
Total Weight of Tablet 190.00 190.00 190.00
[Test Example 1]
PK tests in animals
For the tablets of Examples 1 to 3 and Comparative Example 1 (5 mg tablets of Eliquis), PK tests were performed as following.
- Test design: 4X4 crossover
- Test species: Beagle dog, male
- Blood sampling time: 0, 0.5, 1, 1.5, 2, 3, 4, 5, 7, 10, and 24 hours (11 points)
The test results are shown in Tables 2 and 3 below and Fig.1.
AUC (h*ng/mL) Cmax (ng/mL)
Comparative Example 1 5247 715
Example 1 4332 559
Example 2 5022 691
Example 3 5814 902
Concentration (ng/mL) 0.5h 1h 1.5h 2h 3h 4h 5h 7h 10h 24h
Comparative Example 1 372 616 656 692 631 576 448 262 143 60
Example 1 341 468 535 529 494 443 381 266 131 31
Example 2 444 646 655 644 582 533 451 287 137 39
Example 3 383 747 860 858 759 679 498 308 150 38
Example 2 showed AUC and Cmax values similar with those of Comparative Example 1 while Example 3 showed higher AUC and Cmax values than those of Comparative Example 1.
Thus, it was found that the tablets of Examples 2 and 3 comprising 2.5 and 3.75 mg of apixaban exhibited similar or more improved dissolution rates and bioavailabilities when compared to Comparative Example 1 comprising 5 mg of apixaban.
[Test Example 2]
Solubilizing solvent of apixaban
Experiments were conducted to select a solubilizing solvent for the solubilization of apixaban as a poorly soluble drug, from which the results are shown in Table 4 below.
Volume of solvent required for dissolving 5 mg of apixaban (mL) Volume of solvent required per batch (100,000 tablets) (L) Result
Ethanol 1000.00 100 Insoluble
50% Ethanol 2000.00 200 Insoluble
Dimethyl sulfoxide 277.78 27.8 Soluble
Chloroform 0.50 0.05 Sparingly soluble
Acetone 500.00 50 Practically insoluble
2000.00 200 Practically insoluble
4000.00 400 Slightly soluble
8000.00 800 Soluble
Methylene chloride 125.00 12.5 Practically insoluble
175.00 17.5 Practically insoluble
250.00 25 Soluble
Methylene chloride + Ethanol 85.86(69.33+16.53) 8.59 Soluble
Purified water 1000 (SLS 73g added) 100 Soluble
73637.70 7363.8 Practically insoluble
As shown in Table 4 above, it was confirmed that when dimethyl sulfoxide, acetone, methylene chloride, purified water (SLS 73 g added) and a mixed solvent of methylene chloride and ethanol were used, apixaban was dissolved.
In case of acetone and purified water (SLS 73 g added), it was confirmed that they are not suitable as a solubilizing solvent since more than 1000 mL of solvent is required. Particularly, in case of purified water (SLS 73 g added), it resulted in exceeding the maximum daily dose of SLS (30 mg /day).
It was also confirmed that in case of the mixed solvent of methylene chloride and ethanol, it exhibited more improved solubilization than in case of each use of dimethyl sulfoxide or methylene chloride.
Therefore, it was confirmed that the mixed solvent of methylene chloride and ethanol is most suitable for solubilizing apixaban.

Claims (11)

  1. A pharmaceutical formulation comprising apixaban, wherein the formulation is prepared according to a preparation method comprising the steps of:
    mixing apixaban and a water-soluble polymer to prepare a mixture; and
    wet kneading and vacuum drying of the mixture.
  2. The pharmaceutical formulation according to Claim 1, characterized in comprising 3.75 mg or less of apixaban.
  3. The pharmaceutical formulation according to Claim 2, characterized in comprising 2.50 mg or less of apixaban.
  4. The pharmaceutical formulation according to Claim 1, characterized in that the wet kneading and vacuum drying are carried out simultaneously.
  5. The pharmaceutical formulation according to Claim 1, characterized in that a binding solvent is added in the step of mixing apixaban and the water-soluble polymer.
  6. The pharmaceutical formulation according to Claim 5, characterized in that the binding solvent is a mixed solvent of methylene chloride and ethanol, dimethyl sulfoxide, or methylene chloride.
  7. The pharmaceutical formulation according to Claim 6, characterized in that the binding solvent is a mixed solvent of methylene chloride and ethanol.
  8. The pharmaceutical formulation according to Claim 7, characterized in that the weight ratio of ethanol to methylene chloride in the mixed solvent of methylene chloride and ethanol is 1:1 to 1:7.
  9. The pharmaceutical formulation according to Claim 8, characterized in that the weight ratio of ethanol to methylene chloride in the mixed solvent of methylene chloride and ethanol is 1:3 to 1:5.
  10. The pharmaceutical formulation according to Claim 1, characterized in that the water-soluble polymer is one or more selected from the group consisting of methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose, hydroxyethyl ethylcellulose, carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, polyvinylpyrrolidone, N-vinylpyrrolidone, vinyl acetate copolymer, vinyl propionate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and ethylene oxide-propylene oxide block copolymer.
  11. The pharmaceutical formulation according to Claim 10, characterized in that the water-soluble polymer is one or more selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methylcellulose, and hydroxyethyl ethylcellulose.
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WO2022115052A1 (en) 2020-11-27 2022-06-02 Santa Farma Ilac Sanayii A.S. Improved wet granulation processes for apixaban comprising formulations
WO2022115051A1 (en) 2020-11-27 2022-06-02 Santa Farma Ilac Sanayii A.S. Direct compression method for non-micronised apixaban formulations
JP7520351B2 (en) 2020-08-14 2024-07-23 日医工株式会社 Apixaban-containing pharmaceutical composition

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Publication number Priority date Publication date Assignee Title
JP7520351B2 (en) 2020-08-14 2024-07-23 日医工株式会社 Apixaban-containing pharmaceutical composition
WO2022115052A1 (en) 2020-11-27 2022-06-02 Santa Farma Ilac Sanayii A.S. Improved wet granulation processes for apixaban comprising formulations
WO2022115051A1 (en) 2020-11-27 2022-06-02 Santa Farma Ilac Sanayii A.S. Direct compression method for non-micronised apixaban formulations

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