[go: up one dir, main page]

WO2015199356A1 - Formulation composite pour administration par voie orale comprenant de l'ézétimibe et de la rosuvastatine et procédé de préparation associé - Google Patents

Formulation composite pour administration par voie orale comprenant de l'ézétimibe et de la rosuvastatine et procédé de préparation associé Download PDF

Info

Publication number
WO2015199356A1
WO2015199356A1 PCT/KR2015/005779 KR2015005779W WO2015199356A1 WO 2015199356 A1 WO2015199356 A1 WO 2015199356A1 KR 2015005779 W KR2015005779 W KR 2015005779W WO 2015199356 A1 WO2015199356 A1 WO 2015199356A1
Authority
WO
WIPO (PCT)
Prior art keywords
ezetimibe
composite formulation
solid composite
rosuvastatin
fluid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2015/005779
Other languages
English (en)
Inventor
Yong Il Kim
Ha Young Jeong
Kyeong Soo Kim
Seung Jun Lee
Jae Hyun Park
Jong Soo Woo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
Original Assignee
Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=54938391&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2015199356(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Hanmi Pharmaceutical Co Ltd, Hanmi Pharmaceutical Industries Co Ltd filed Critical Hanmi Pharmaceutical Co Ltd
Priority to BR112016030111A priority Critical patent/BR112016030111A2/pt
Priority to SG11201610748RA priority patent/SG11201610748RA/en
Publication of WO2015199356A1 publication Critical patent/WO2015199356A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the present disclosure relates to a composite formulation for oral administration including ezetimibe and rosuvastatin (or a pharmaceutically acceptable salt thereof), and more particularly, to a composite formulation for oral administration having improved pharmaceutical characteristics, including improved dissolution rate and dissolution velocity of active ingredients, improved content uniformity, and improved productivity, and a method of preparing the solid composite formulation.
  • Rosuvastatin or a pharmaceutically acceptable salt thereof is one of HMG-CoA reductase inhibitors that inhibit the synthesis of cholesterol to treatment dyslipidemia.
  • Crestor tablets i.e., rosuvastatin calcium salts available from AstraZeneca
  • rosuvastatin as a main ingredient
  • research has been reporting on excellent effects of rosuvastatin of lowering LDL cholesterol levels in blood and increasing beneficial HDL cholesterol levels in the body, compared to the effects of atorvastatin or simvastatin, which is commercially available as a drug having the same mechanism as rosuvastatin. Accordingly, there is an increasing interest in rosuvastatin formulation.
  • HMG-CoA reductase inhibitors are generally used in a combination with a therapeutic agent for dyslipidemia having a different mechanism from that of the HMG-CoA reductase inhibitors to enhance therapeutic effects.
  • a composite formulation of these two ingredients are actively being studied.
  • Vytorin TM which is a composite formulation of simvastatin and ezetimibe, has already demonstrated good pharmacological effects and stability thereof, and is currently available in the market with a noticeable sales performance.
  • the present disclosure provides a solid composite formulation of rosuvastatin and ezetimibe for oral administration that may have improved pharmaceutical characteristics, in terms of dissolution rate and dissolution velocity of active ingredients and content uniformity, and that may be economically prepared with high productivity.
  • the present disclosure provides a method of preparing the composite formulation of rosuvastatin and ezetimibe for oral administration.
  • a solid composite formulation for oral administration including: an ezetimibe-wet granule portion including ezetimibe that is wet-granulated using a fluid-bed granulator; and a rosuvastatin mixture portion including rosuvastatin or a pharmaceutically acceptable salt thereof.
  • a method of preparing the solid composite formulation for oral administration including: preparing an ezetimibe-wet granule portion including ezetimibe by using a fluid-bed granulator; and formulating the ezetimibe-wet granule portion and a rosuvastatin mixture portion together, the rosuvastatin mixture portion including rosuvastatin or a pharmaceutically acceptable salt thereof.
  • a solid composite formulation of ezetimibe and rosuvastatin for oral administration may have a sufficiently improved dissolution rate and dissolution velocity of the active ingredients without using an excess of a disintegrant, and thus may ensure high bioavailability without the stability reduction of the active ingredients led to by the excessive disintegrant.
  • the solid composite formulation for oral administration may also have good content uniformity.
  • the solid composite formulation for oral administration may have good tableting characteristics, and may be prepared at a low internal temperature of a fluid-bed granulator, leading to high productivity.
  • the present inventors researched into the development of a solid composite formulation for oral administration that may have sufficient dissolution rate of active ingredients to ensure good pharmaceutical effects, and which may also be economically prepared with high productivity. As a result, they found that a solid composite formulation prepared as a mixture of ezetimibe-wet granules that are prepared by separate wet granulation using a fluid-bed granulator, with rosuvastatin or a pharmaceutically acceptable salt thereof may have high productivity and markedly improved pharmaceutical characteristics in terms of dissolution rate and dissolution velocity of active ingredients and content uniformity.
  • a solid composite formulation for oral administration including: an ezetimibe-wet granule portion including ezetimibe that is wet-granulated using a fluid-bed granulator; and a rosuvastatin mixture portion including rosuvastatin or a pharmaceutically acceptable salt thereof.
  • wet granule portion refers to mixed granules prepared by wet granulation
  • mixture-part refers to a non-granulated mixture
  • the ezetimibe-wet granule portion may have a sufficiently high ezetimibe dissolution rate when prepared using a fluid-bed granulator and have high productivity in a tableting process due to good flowability of the wet granules. Accordingly, a solid composite formulation according to any embodiments may have high bioavailability and productivity. However, when the ezetimibe-wet granule portion is prepared using other wet granulation methods available in the pharmaceutical field, it may be difficult to ensure both high dissolution rate and productivity of the solid composite formulation (refer to Experimental Example 1).
  • the resulting solid composite formulation is shown to have a very low dissolution rate of less than about 50% in 10 minutes, as evaluated according to Dissolution method II of the Korean Pharmacopoeia (10 th edition). Though the dissolution rate may be increased with reduced amount of solvent used for the preparation, the dissolution rate of ezetimibe in 10 minutes may be still less than about 60%. In addition, the smaller the amount of solvent is, the lower the productivity may become.
  • the dissolution rate of ezetimibe in 10 minutes may be still less than about 70%.
  • the amount of disintegrant may be increased in a granulation process.
  • the disintegrant may affect the stability of active ingredients and negatively affect the quality of the medicine when used in excess.
  • the dissolution rate may be reduced with increased amount of the solvent used in the preparing process thereof.
  • the dissolution rate of ezetimibe in 10 minutes may be high enough as about 80% or greater even when the amount of the solvent is more than about 1 part by weight based on 1 part by weight of a total weight of the ingredients of the ezetimibe-wet granule portion, and the productivity may also be sufficiently high as 100,000 tablets per hour even with reduced amount of the solvent (Experimental Example 1).
  • the dissolution rate at early phase may be reduced when an amount of the solvent exceeds 0.5 parts by weight or more based on 1 part by weight of the ezetimibe-wet granule portion is used, due to hardening and increased density of the granules.
  • high dissolution rate may be ensured even when the amount of the solvent is as high as about 0.5 parts by weight or more. Rather, the productivity may be increased due to improved flowability of granules in a tableting process.
  • both high dissolution rate and productivity may be ensured without using an excessive amount of disintegrant, and consequently medicine with improved quality may be obtained.
  • This is an effect unexpectable in the art, in view that wet granulation using a fluid-bed granulator is conventionally known to reduce the productivity in a tableting process due to poor flowability of wet granules compared to wet granulation using a high-speed mixer.
  • the solvent may be any available solvent that may dissolve a binder to prepare a binder solution in wet granulation.
  • the solvent may include distilled water, ethanol, or any combination thereof, but is not limited thereto.
  • a solid composite formulation according to any embodiments of the present disclosure may have markedly improved content uniformity compared to a solid composite formulation including wet granules prepared using any other granulation methods not using a fluid-bed granulator (refer to Experimental Example 2). This is also an effect unexpectable in the art, in view that wet granulation using a fluid-bed granulator is conventionally known to reduce content uniformity compared to wet granulation using a high-speed mixer.
  • a solid composite formulation according to any embodiments of the present disclosure may reach the saturation solubility at a markedly high rate compared to a solid composite formulation including wet granules prepared using any other granulation methods not using a fluid-bed granulator.
  • Ezetimibe is known as a drug having poor solubility with a low saturation solubility of about 1 ppm or less in either acidic or weak alkali conditions as in the body fluid.
  • the saturation solubility and the dissolution velocity from a dissolution start point to saturation are important indices for bioavailability evaluations of drugs having poor solubility.
  • solid composite formulations according to embodiments of the present disclosures were found to reach the saturation solubility at a markedly high rate compared to a solid composite formulation including wet granules prepared using any other granulation methods not using a fluid-bed granulator, and thus to ensure improved bioavailability of ezetimibe as a drug having poor solubility (refer to Experimental Example 3).
  • the ezetimibe-wet granule portion of the solid composite formulation may be prepared using about 0.1 parts to about 2 parts by weight of the solvent based on 1 part by weight of a total weight of the ingredients of the ezetimibe-wet granule portion by using a fluid-bed granulator, and in some embodiments, about 0.2 parts to about 1 part by weight of the solvent.
  • a total weight of the ingredients of the ezetimibe-wet granule portion refers to a total weight of any active ingredients and additives, except for solvent, used to prepare the ezetimibe-wet granule portion.
  • the ezetimibe-wet granule portion may include about 0.1 parts to about 2 parts by weight of distilled water, and in some other embodiments, about 0.2 parts to about 1 part by weight, based on 1 part by weight of the total weight of the ingredients of the ezetimibe-wet granule portion.
  • the amount of ezetimibe as a first pharmacologically active ingredient in the solid composite formulation may be in a range of about 5 mg to about 20 mg in a unit dosage form, and in some embodiments, about 5 mg to about 10 mg in a unit dosage form.
  • the solid composite formulation according to any embodiment includes rosuvastatin as a second pharmacologically active ingredient.
  • the rosuvastatin may be in the form of free base or a pharmaceutically acceptable salt thereof.
  • Non-limiting examples of the pharmaceutically acceptable salt include a calcium salt, a magnesium salt, and a strontium salt.
  • the rosuvastatin may be in the form of calcium salt.
  • embodiments are not limited thereto.
  • Rosuvastatin or a pharmaceutically acceptable salt thereof may inhibit an HMG-CoA reductase, which is required for the synthesis of cholesterol, to lower LDL-cholesterol levels in blood and raise HDL-cholesterol levels in blood, thereby contributing to the treatment of dyslipidemia.
  • the amount of the rosuvastatin or a pharmaceutically acceptable salt thereof may be in a range of about 2.5 mg to about 40 mg, and in some embodiments, about 5 mg to about 20 mg, in a unit dosage form of the solid composite formulation.
  • the solid composite formulation may further include at least one pharmaceutically acceptable additive, in addition to the pharmacologically active ingredients.
  • the ezetimibe-wet granule portion or rosuvastatin mixture portion may include at least one additive selected from the group consisting of a diluent, a binder, a disintegrant, and a lubricant.
  • the ezetimibe-wet granule portion and the rosuvastatin mixture portion may each further include about 0.5 parts to about 50 parts of a diluent, about 0.1 parts to about 20 parts of a binder, about 0.1 parts to about 10 parts by weight of a disintegrant, and about 0.1 parts to about 3 parts by weight of a lubricant based on 1 part by weight of ezetimibe.
  • the diluent may be selected from the group consisting of lactose, starch, mannitol, microcrystalline cellulose, carboxymethyl cellulose, and any combinations thereof.
  • the binder may be selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, copovidone, and any combinations thereof.
  • the disintegrant may be selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and any combinations thereof.
  • the lubricant may be selected from the group consisting of magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and any combinations thereof. However, embodiments are not limited thereto.
  • the terms solid composite formulation for oral administration refers to a formulation prepared by molding or encapsulating drugs into a predetermined shape.
  • the solid composite formulation for oral administration may be formulated as, but not limited to, a pellet, a capsule, a tablet (including a single-layered tablet, a double-layered tablet, and a pressed core tablet), powder, or granules.
  • the solid composite formulation for oral administration may be in the form of a capsule, a single-layered tablet, or a double-layered tablet form.
  • the capsule may contain powder, granules, tablets, syrup, or pellets therein.
  • the ezetimibe-wet granule portion may include lactose, microcrystalline cellulose, sodium lauryl sulfate, povidone, and croscarmellose sodium
  • the rosuvastatin mixture portion may include microcrystalline cellulose, lactose, mannitol, crospovidone, and magnesium stearate.
  • the solid composite formulation may have an ezetimibe dissolution rate of about 85% or greater in 10 minutes, as evaluated in a buffer solution of about pH 4.5 containing about 0.45% of sodium lauryl sulfate at a paddle rotation speed of about 50 rpm according to Dissolution method II of the Korean Pharmacopoeia (10 th edition). Therefore, the solid composite formulation may have high bioavailability led to by the increased dissolution rate (refer to Experimental Example 1).
  • a method of preparing a solid composite formulation for oral administration including: preparing an ezetimibe-wet granule portion including ezetimibe by using a fluid-bed granulator; and formulating the ezetimibe-wet granule portion and a rosuvastatin mixture portion together, the rosuvastatin mixture portion including rosuvastatin or a pharmaceutically acceptable salt thereof.
  • the internal temperature of the fluid-bed granulator may be from about 20°C to about 40°C.
  • the internal temperature of the fluid-bed granulator refers to an internal temperature of the fluid-bed granulator that is measured when the temperature is maintained constant as a result of sufficient operational stabilization of the fluid-bed granulator, using an electronic thermometer equipped in the container of the fluid-bed granulator.
  • granulation is performed while maintaining the internal temperature of the fluid-bed granulator at a low temperature of about 30°C or less, the dissolution rate of active ingredients at early phase tends to be reduced due to increase in granule size and density.
  • the dissolution rate may nearly not be reduced. Accordingly, a solid composite formulation having a sufficiently high dissolution rate may be prepared at low temperatures.
  • the ezetimibe-wet granule portion may be prepared at a low internal temperature of the fluid-bed granulator of about 20°C to about 30°C. Accordingly, the source ingredient solution may be more rapidly transported to the fluid-bed granulator, so that the process time may be reduced and the productivity of the solid composite formulation may be increased.
  • a method of preparing a solid composite formulation for oral administration may include: i) preparing an ezetimibe-wet granule portion including ezetimibe by using a fluid-bed granulator; ii) preparing a rosuvastatin mixture portion including rosuvastatin or a pharmaceutically acceptable salt thereof; and iii) mixing the ezetimibe-wet granule portion of the step i) and the rosuvastatin mixture portion of the step ii) to obtain a mixture and forming a single-layered tablet of the mixture by using a common tableting method.
  • a method of preparing a solid composite formulation for oral administration may include: i) preparing an ezetimibe-wet granule portion including ezetimibe by using a fluid-bed granulator and tableting the ezetimibe-wet granule portion to obtain a tablet; ii) preparing a rosuvastatin mixture portion including rosuvastatin or a pharmaceutically acceptable salt thereof; and iii) forming a double-layered tablet by using a common double-layered tablet formation method with a tablet press for double-layered tablets, the double-layered tablet including the tablet prepared in the step i) as a first layer, and the rosuvastatin mixture portion of the step ii) as a second layer.
  • a method of preparing a solid composite formulation for oral administration may include: i) preparing an ezetimibe-wet granule portion including ezetimibe by using a fluid-bed granulator; ii) preparing a rosuvastatin mixture portion including rosuvastatin or a pharmaceutically acceptable salt thereof; iii) mixing the ezetimibe-wet granule portion prepared in the step i) and the rosuvastatin mixture portion prepared in the step ii) to obtain a mixture; and iv) encapsulating the mixture to form a capsule according to a common capsulation method.
  • Composite formulations were prepared as follows according to the compositions in Table 1, in which used ingredients and amounts thereof are shown. Povidone was dissolved in distilled water to prepare a binder solution. Ezetimibe, lactose hydrate, microcrystalline cellulose, sodium lauryl sulfate, and croscarmellose sodium were mixed and the mixture was put into a chamber of a high-speed mixer (P/VAC60, available from Diosna), and then the binder solution above was injected into the chamber while working the high-speed mixer at an agitator speed of about 100 rpm and a chopper speed of about 3000 rpm for about 3 minutes in total to granulate the mixture, followed by drying the resulting granules in a fluid bed dryer.
  • P/VAC60 available from Diosna
  • the dried granules were then passed through a sieve having a mesh size of 20.
  • the sieved granules were mixed with a rosuvastatin mixture portion as a mixture of the ingredients in amounts as listed in Table 1, and then the mixture was pressed into tablets having a hardness of 10 kp using a rotary tablet press (MRC-45N, available from Sejong Pharmatech Co., Ltd., Korea).
  • Composite formulations were prepared as follows according to the compositions in Table 1, in which used ingredients and amounts thereof are shown. Povidone was dissolved in distilled water to prepare a binder solution. Ezetimibe, lactose hydrate, microcrystalline cellulose, sodium lauryl sulfate, and croscarmellose sodium were mixed and the mixture was put into a container of a fluid-bed granulator (GRETC-30, available from GR-ENG) and then the binder solution above was injected into the container by spraying while working the fluid-bed granulator at an internal temperature of about 30C, a spray pressure of about 1.2 bar, and a spray speed of about 10 rpm to granulate the mixture until all the binder solution was injected, followed by drying the resulting granules in a fluid bed dryer.
  • GRETC-30 fluid-bed granulator
  • the dried granules were then passed through a sieve having a mesh size of 20.
  • the sieved granules were mixed with a rosuvastatin mixture portion as a mixture of the ingredients in amounts as listed in Table 1, and then the mixture was pressed into tablets having a hardness of 10 kp using a rotary tablet press (MRC-45N, available from Sejong Pharmatech Co., Ltd.).
  • Composite formulations were prepared as follows according to the compositions in Table 1, in which used ingredients and amounts thereof are shown. Povidone was dissolved in distilled water to prepare a binder solution. Ezetimibe, lactose hydrate, microcrystalline cellulose, sodium lauryl sulfate, and croscarmellose sodium were mixed and the mixture was put into a feeder of a ConsiGma (Consigma-1, available from GEA) while working the ConsiGma at a screw speed of about 700 rpm for about 3 minutes in total to granulate the mixture, followed by drying the resulting granules in a fluid bed dryer. The dried granules were then passed through a sieve having a mesh size of 20.
  • ConsiGma ConsiGma
  • the sieved granules were mixed with a rosuvastatin mixture portion as a mixture of the ingredients in amounts as listed in Table 1, and then the mixture was pressed into tablets having a hardness of 10 kp using a rotary tablet press (MRC-45N, available from Sejong Pharmatech Co., Ltd.).
  • the dissolution rate evaluation was performed using tablets of Examples 1 to 6 and Comparative Examples 1 to 12 under the conditions as described below.
  • the productivity of each composite formulation was evaluated as a total number of tablets produced per hour which was shown as a total weight (g) / an average weight (g/tablet) of when the tablets were prepared under the condition of a rotary tablet press (MRC-45N, available from Sejong Pharmatech Co., Ltd., able to press 45 tablets per revolution and produce 108,000 tablets per hour at a rotation speed of 40 rpm) that is in common use in the art, at a maximum rotation speed that was adjusted to press good tablets having a hardness of about 10 or greater without tableting defects such as capping, sticking, laminating, or the like.
  • MRC-45N available from Sejong Pharmatech Co., Ltd.
  • Dissolution method II (paddle method) according to the Korean Pharmacopoeia (10 th edition)
  • Dissolution medium 0.45% sodium lauryl sulfate solution in a 0.025M sodium dihydrogen phosphate (NaH 2 PO 4 2H 2 O) buffer (pH 4.5) (obtained by dissolving 3.9 g of sodium dihydrogen phosphate in 900 mL of water, adjusting the pH to 4.5 with 50%(w/w) sodium hydroxide solution or phosphoric acid, filling it with water up to a total volume of 1,000 mL, and then thoroughly mixing the solution)
  • NaH 2 PO 4 2H 2 O sodium dihydrogen phosphate
  • pH 4.5 obtained by dissolving 3.9 g of sodium dihydrogen phosphate in 900 mL of water, adjusting the pH to 4.5 with 50%(w/w) sodium hydroxide solution or phosphoric acid, filling it with water up to a total volume of 1,000 mL, and then thoroughly mixing the solution
  • the composite formulations of Comparative Examples 7 to 11 prepared using ConsiGma had improved dissolution rates compared to those of Comparative Examples 1 to 4. However, the dissolution rates did not significantly achieve 85% or more ensuring high bioavailability.
  • the solid composite formulation of Comparative Example 11 had high productivity, but an excessively low dissolution rate.
  • the solid composite formulations of Examples 1 to 6 prepared using fluid-bed granulator had improved dissolution rates compared to those prepared using any other methods.
  • the composite formulations of Examples 1 to 5 were found to have a high dissolution rate of about 85% or more after 10 minutes.
  • the solid composite formulations of Examples 1 to 6 had improved productivity due to good flowabiliity of granules, particularly, the solid composite formulations of Examples 1 to 5 had a significantly high productivity of about 100,000 tablets per hour.
  • a content uniformity test was performed on the composite formulations of Examples 1 to 6 and Comparative Examples 1 to 12 according to the content uniformity test method among general test methods in the Korean Pharmacopoeia (10 th edition).
  • the resulting test values (a smaller content uniformity value is desired; quality is generally ensured at 15 or less) are shown in Table 3.
  • the concentration of ezetimibe detected at each sampling time was represented in ppm, and the concentration measured at a certain sampling time was regarded as being saturated whenever the difference between said concentration and a concentration measured at a subsequent sampling time was 0.05 ppm or less.
  • the sampling time at which the concentration of ezetimibe was saturated is represented by a dissolution velocity (time), and the concentration of ezetimibe at said sampling time is represented by a saturation solubility (ppm).
  • Test method Dissolution method II (paddle method) according to the Korean Pharmacopoeia (10 th edition)
  • Example 1 prepared using a fluid-bed granulator was found to have improved saturation solubility and about 3 to 6 times higher dissolution velocity, which is defined as the time taken to reach saturation solubility, compared to the solid composite formulations of Comparative Examples 1 and 7 prepared using the same amount of distilled water as in Example 1 but different wet granulation methods. Therefore, the solid composite formulation of Example 1 may also have improved bioavailability due to such increased saturation solubility and dissolution velocity of ezetimibe.
  • Composite formulations were prepared as follows according to the compositions in Table 5, in which used ingredients and amounts thereof are shown. Povidone was dissolved in distilled water to prepare a binder solution. Ezetimibe, lactose hydrate, microcrystalline cellulose, sodium lauryl sulfate, and croscarmellose sodium were mixed and the mixture was put into a container of fluid-bed granulator (GRETC-30, available from GR-ENG), and the internal temperature fluid-bed granulator was set as shown in Table 5.
  • GRETC-30 fluid-bed granulator
  • the binder solution was injected into the container by spraying at a spray pressure of about 1.2 bar and a spray speed of about 10 rpm while working the fluid-bed granulator to granulate the mixture, followed by drying the resulting granules in a fluid bed dryer.
  • the dried granules were then passed through a sieve having a mesh size of 20.
  • the sieved granules were mixed with a rosuvastatin mixture portion as a mixture of the ingredients in amounts as listed in Table 5, and then the mixture was pressed into tablets having a hardness of 10 kp using a rotary tablet press (MRC-45N, available from Sejong Pharmatech Co., Ltd.).
  • This internal temperature indicates an internal temperature of the fluid-bed granulator that was measured when the temperature is maintained constant as a result of sufficient operational stabilization of the fluid-bed granulator, using an electronic thermometer equipped in the container of the fluid-bed granulator.
  • Example 3 the solid composite formulations of Example 3 and Examples 7 to 11 were all found to have improved ezetimibe dissolution rate, productivity, and content uniformity, particularly when the Internal temperature of the fluid-bed granulator was in the range of about 20°C to about 40°C.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Obesity (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une formulation composite solide pour administration par voie orale qui comprend une partie sous forme de granulés comprenant de l'ézétimibe qui a été soumis à une granulation par voie humide à l'aide d'un granulateur à lit fluidisé, et une partie mélange de rosuvastatine comprenant de la rosuvastatine ou un sel pharmaceutiquement acceptable de celle-ci.
PCT/KR2015/005779 2014-06-25 2015-06-09 Formulation composite pour administration par voie orale comprenant de l'ézétimibe et de la rosuvastatine et procédé de préparation associé Ceased WO2015199356A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
BR112016030111A BR112016030111A2 (pt) 2014-06-25 2015-06-09 formulação compósita sólida para administração oral, e método de preparação da formulação compósita sólida para administração oral
SG11201610748RA SG11201610748RA (en) 2014-06-25 2015-06-09 Composite formulation for oral administration comprising ezetimibe and rosuvastatin and a process for the preparation thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020140078388A KR101977785B1 (ko) 2014-06-25 2014-06-25 에제티미브 및 로수바스타틴을 포함하는 경구용 복합제제 및 그 제조방법
KR10-2014-0078388 2014-06-25

Publications (1)

Publication Number Publication Date
WO2015199356A1 true WO2015199356A1 (fr) 2015-12-30

Family

ID=54938391

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2015/005779 Ceased WO2015199356A1 (fr) 2014-06-25 2015-06-09 Formulation composite pour administration par voie orale comprenant de l'ézétimibe et de la rosuvastatine et procédé de préparation associé

Country Status (10)

Country Link
KR (1) KR101977785B1 (fr)
AR (1) AR100977A1 (fr)
BR (1) BR112016030111A2 (fr)
CL (1) CL2016003283A1 (fr)
EC (1) ECSP16096477A (fr)
JO (1) JOP20150154B1 (fr)
SG (2) SG11201610748RA (fr)
TW (1) TWI700100B (fr)
UY (1) UY36190A (fr)
WO (1) WO2015199356A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018041281A1 (fr) 2016-09-05 2018-03-08 Zentiva, K.S. Composition pharmaceutique comprenant de la rosuvastatine et de l'ézétimibe et son procédé de préparation
WO2018041282A1 (fr) 2016-09-05 2018-03-08 Zentiva, K.S. Composition pharmaceutique comprenant de la rosuvastatine et de l'ézétimibe et son procédé de préparation
EP3437636A1 (fr) * 2017-08-02 2019-02-06 Adamed sp. z o.o. Composition pharmaceutique comprenant de l'ézétimibe
WO2021019499A1 (fr) 2019-07-31 2021-02-04 TECNIMEDE - Sociedade Técnico-medicinal, SA Compositions solides orales à libération immédiate à unités multiples, procédés et utilisations de celles-ci
CN113747885A (zh) * 2019-04-18 2021-12-03 韩美药品株式会社 包含依泽替米贝和氯沙坦的药物组合制剂

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102206535B1 (ko) * 2016-11-29 2021-01-22 한미약품 주식회사 에제티미브 및 로수바스타틴을 포함하는 경구용 복합정제
KR20200137243A (ko) 2019-05-29 2020-12-09 콜마파마(주) 로수바스타틴 및 에제티미브를 포함하는 복합제의 제조방법
MX2023002403A (es) * 2020-08-25 2023-03-22 Daewoong Pharmaceutical Co Ltd Composicion farmaceutica en forma de dosificacion individual para tratar o prevenir hipertension e hipercolesterolemia.
KR20250096941A (ko) 2023-12-20 2025-06-30 안국약품 주식회사 피타바스타틴 및 에제티미브를 포함하는 단일 정제 형태의 약학 조성물 및 이의 제조방법

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009024889A2 (fr) * 2007-08-21 2009-02-26 Ranbaxy Laboratories Limited Composition pharmaceutique comprenant un inhibiteur de réductase hmg-coa et un ézétimibe
WO2011012912A2 (fr) * 2009-07-28 2011-02-03 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Nouveau procédé de granulation et granulé ainsi préparé
WO2011019326A2 (fr) * 2009-07-02 2011-02-17 Mahmut Bilgic Formulation pharmaceutique permettant d'augmenter la solubilité et la stabilité
WO2013166117A1 (fr) * 2012-05-01 2013-11-07 Althera Life Sciences, Llc Formulation de comprimé oral constituée d'une combinaison fixe de rosuvastatine et d'ézétimibe pour le traitement de l'hyperlipidémie et de maladies cardiovasculaires
US20130338131A1 (en) * 2010-12-22 2013-12-19 Lek Pharmaceuticals D.D. Process for the preparation of a pharmaceutical composition comprising a low soluble pharmaceutically active ingredient

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100907144B1 (ko) * 2007-09-05 2009-07-09 박재섭 이동부재를 이용한 골프 클럽

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009024889A2 (fr) * 2007-08-21 2009-02-26 Ranbaxy Laboratories Limited Composition pharmaceutique comprenant un inhibiteur de réductase hmg-coa et un ézétimibe
WO2011019326A2 (fr) * 2009-07-02 2011-02-17 Mahmut Bilgic Formulation pharmaceutique permettant d'augmenter la solubilité et la stabilité
WO2011012912A2 (fr) * 2009-07-28 2011-02-03 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Nouveau procédé de granulation et granulé ainsi préparé
US20130338131A1 (en) * 2010-12-22 2013-12-19 Lek Pharmaceuticals D.D. Process for the preparation of a pharmaceutical composition comprising a low soluble pharmaceutically active ingredient
WO2013166117A1 (fr) * 2012-05-01 2013-11-07 Althera Life Sciences, Llc Formulation de comprimé oral constituée d'une combinaison fixe de rosuvastatine et d'ézétimibe pour le traitement de l'hyperlipidémie et de maladies cardiovasculaires

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018041281A1 (fr) 2016-09-05 2018-03-08 Zentiva, K.S. Composition pharmaceutique comprenant de la rosuvastatine et de l'ézétimibe et son procédé de préparation
WO2018041282A1 (fr) 2016-09-05 2018-03-08 Zentiva, K.S. Composition pharmaceutique comprenant de la rosuvastatine et de l'ézétimibe et son procédé de préparation
JP2019526591A (ja) * 2016-09-05 2019-09-19 サノフイＳａｎｏｆｉ ロスバスタチン及びエゼチミブを含む医薬組成物並びにその調製方法
CN110418637A (zh) * 2016-09-05 2019-11-05 赛诺菲 包含瑞舒伐他汀和依泽替米贝的药物组合物及其制备方法
JP7094944B2 (ja) 2016-09-05 2022-07-04 サノフイ ロスバスタチン及びエゼチミブを含む医薬組成物並びにその調製方法
IL265172B (en) * 2016-09-05 2022-09-01 Sanofi Sa A pharmaceutical composition comprising rosuvastatin and ezetimibe and a preparation method thereof
US11786526B2 (en) 2016-09-05 2023-10-17 Sanofi Pharmaceutical composition comprising rosuvastatin and ezetimibe and a preparation method thereof
EP3437636A1 (fr) * 2017-08-02 2019-02-06 Adamed sp. z o.o. Composition pharmaceutique comprenant de l'ézétimibe
WO2019025512A1 (fr) * 2017-08-02 2019-02-07 Adamed Pharma S.A. Comprimé comprenant de l'ézétimibe
CN113747885A (zh) * 2019-04-18 2021-12-03 韩美药品株式会社 包含依泽替米贝和氯沙坦的药物组合制剂
CN113747885B (zh) * 2019-04-18 2023-08-15 韩美药品株式会社 包含依泽替米贝和氯沙坦的药物组合制剂
WO2021019499A1 (fr) 2019-07-31 2021-02-04 TECNIMEDE - Sociedade Técnico-medicinal, SA Compositions solides orales à libération immédiate à unités multiples, procédés et utilisations de celles-ci

Also Published As

Publication number Publication date
TWI700100B (zh) 2020-08-01
TW201625223A (zh) 2016-07-16
JOP20150154B1 (ar) 2021-08-17
KR101977785B1 (ko) 2019-05-14
SG11201610748RA (en) 2017-01-27
AR100977A1 (es) 2016-11-16
CL2016003283A1 (es) 2017-07-28
KR20160000762A (ko) 2016-01-05
ECSP16096477A (es) 2017-01-31
SG10201811586YA (en) 2019-02-27
BR112016030111A2 (pt) 2017-08-22
UY36190A (es) 2015-10-30

Similar Documents

Publication Publication Date Title
WO2015199356A1 (fr) Formulation composite pour administration par voie orale comprenant de l'ézétimibe et de la rosuvastatine et procédé de préparation associé
JP6084161B2 (ja) ７−［４−（４−ベンゾ［ｂ］チオフェン−４−イル−ピペラジン−１−イル）ブトキシ］−１Ｈ−キノリン−２−オン又はその塩を含む錠剤
KR101840182B1 (ko) 4-아미노-5-플루오로-3-[6-(4-메틸피페라진-1-일)-1ｈ-벤즈이미다졸-2-일]-1ｈ-퀴놀린-2-온 락테이트 일수화물을 포함한 제약 조성물
EP2815752B1 (fr) Composition pharmaceutique orale
CA2601955A1 (fr) Composition pharmaceutique comprenant une diphenyluree substituee par un omega-carboxyaryle pour le traitement du cancer
TW202112376A (zh) 一種含有布魯頓氏酪胺酸激酶抑制劑的口服固體錠劑及其製備方法
US9730932B2 (en) Pharmaceutical composition containing crystalline macitentan
JP2020518611A (ja) 水溶解度及びバイオアベイラビリティが改善された組成物
TWI774159B (zh) 含有托格列淨（Tofogliflozin）之固體製劑及其製造方法
JP2018177657A (ja) レベチラセタム含有医薬組成物及びその製造方法
WO2016003091A1 (fr) Composition pharmaceutique solide contenant une base libre de l'oséltamivir
WO2011155728A2 (fr) Composition destinée à prévenir ou à traiter l'ostéoporose, et procédé de fabrication de celle-ci
JP2013544272A5 (fr)
JP5461084B2 (ja) 崩壊遅延が抑制されたパロキセチン塩酸塩水和物の経口投与用医薬組成物
US20130085145A1 (en) Imatinib mesilate pharmaceutical tablet
JPH1121236A (ja) ロキソプロフェン・ナトリウム固形製剤
US9775832B2 (en) Pharmaceutical composition for oral administration
JP2018065752A (ja) シロドシン含有医薬組成物とその製造方法
WO2018101681A1 (fr) Comprimé composite oral comprenant de l'ézétimibe et de la rosuvastatine
US20120058185A1 (en) Stable pharmaceutical compositions of olanzapine and process for their preparation
CN104000821B (zh) 含有替米沙坦和苯磺酸氨氯地平的口服双层片剂及其制备方法
KR20200002486A (ko) 습식과립 조성물, 이를 함유하는 정제 및 정제의 제조 방법
KR20110130872A (ko) 결정형 염산 네비볼롤을 포함하는 약학 조성물 및 제조방법
WO2014038895A1 (fr) Forme posologique orale solide contenant du valsartan et son procédé de préparation
JP6558530B2 (ja) アリピプラゾール医薬品製剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15811319

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112016030111

Country of ref document: BR

122 Ep: pct application non-entry in european phase

Ref document number: 15811319

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 112016030111

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20161221