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
• • 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
  • 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
  • A61K9/2072—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
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
• • 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
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • 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
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—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
  • A61K9/14—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
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

• the present disclosure relates to an oral composite tablet including ezetimibe and rosuvastatin or a pharmaceutically acceptable salt thereof, having an improved initial dissolution rate of ezetimibe and improved productivity, and a method of preparing the oral composite tablet.
• Rosuvastatin or a pharmaceutically acceptable salt thereof is one of the HMG-CoA reductase inhibitors that inhibit the synthesis of cholesterol to treat dyslipidemia.
• Crestor tablets i.e., rosuvastatin calcium salts available from AstraZeneca
• rosuvastatin as a main ingredient
• HMG-CoA reductase inhibitors are generally used in combination with a therapeutic agent for dyslipidemia having a different mechanism from that of the HMG-CoA reductase inhibitors, in order to enhance therapeutic effects.
• a therapeutic agent for dyslipidemia having a different mechanism from that of the HMG-CoA reductase inhibitors, in order to enhance therapeutic effects.
• HMG-CoA reductase inhibitors and ezetimibe which is a drug which inhibits the re-absorption of cholesterol in the small intestine
• composite formulations 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, and is currently available on the market with noticeable sales performance.
• T max of ezetimibe is as short as less than about 1 hour, and thus rapid disintegration and dissolution of ezetimibe, when administered in the form of a tablet, are required for rapid absorption into the body to attain a desired therapeutic effect.
• ezetimibe is practically insoluble in water, and thus it is difficult to obtain a high dissolution rate and ensure sufficient bioavailability. Therefore, there is a need to develop a composite formulation of ezetimibe that ensures a high dissolution rate of ezetimibe and improved productivity and stability in terms of pharmaceutical aspects.
• the present disclosure provides an oral composite tablet of rosuvastatin and ezetimibe that may exhibit a high dissolution rate of ezetimibe and high productivity.
• the present disclosure provides a method of preparing the oral composite tablet of rosuvastatin and ezetimibe.
• an oral composite tablet including: an ezetimibe wet granule portion including ezetimibe; and a rosuvastatin mixture portion including rosuvastatin or a pharmaceutically acceptable salt thereof,
• the ezetimibe wet granule portion includes, as a binder, povidone having a weight average molecular weight of about 30,000 to about 50,000, and the rosuvastatin mixture portion includes a diluent including a water-soluble diluent and a water-insoluble diluent, the water-insoluble diluent having a particle size (d90) of about 98 ⁇ m to about 229 ⁇ m corresponding to 90% in a cumulative particle size distribution of total particles.
• a method of preparing the oral composite tablet including: preparing the ezetimibe wet granule portion by wet-granulating the ezetimibe together with a pharmaceutically acceptable additive including, as a binder, povidone having a weight average molecular weight of about 30,000 to about 50,000; and tableting the ezetimibe wet granule portion together with the rosuvastatin mixture portion including the rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive,
• the pharmaceutically acceptable additive includes a diluent including the water-soluble diluent and the water-insoluble diluent, the water-insoluble diluent having a particle size (d90) of about 98 ⁇ m to about 229 ⁇ m corresponding to 90% in a cumulative particle size distribution of total particles.
• an oral composite tablet including an ezetimibe wet granule portion and a rosuvastatin mixture portion may exhibit an improved initial dissolution rate and an improved angle of repose with respect to productivity by incorporating povidone having a weight average molecular weight of about 30,000 to about 50,000 as a binder in the ezetimibe wet granule portion.
• a water-insoluble diluent having a d90 of about 98 ⁇ m about 229 ⁇ m in the rosuvastatin mixture portion the d90 corresponding to an average particle size corresponding to the bottom 90% in a cumulative size distribution (cumulative 90% particle size), an increased initial dissolution rate of the ezetimibe and an appropriate flowability of a mixture of the ezetimibe wet granule portion and the rosuvastatin mixture portion may be ensured, compared with when a water-insoluble diluent having a relatively large particle size is used.
• a deviation in dissolution rate of the ezetimibe may be remarkably reduced, due to reduced deposition of the water-insoluble diluent in a dissolution vessel, and thus, an appropriate quality evaluation of the composite tablet may be ensured.
• an oral composite tablet according to any of the embodiments may be a composite tablet of ezetimibe and rosuvastatin that may ensure an improved initial dissolution rate of the ezetimibe and an appropriate quality evaluation of the dissolution rate of the ezetimibe, as well as a variety of pharmaceutical advantages, including improved productivity.
• an oral composite tablet includes: an ezetimibe wet granule portion including ezetimibe; and a rosuvastatin mixture portion including rosuvastatin or a pharmaceutically acceptable salt thereof, wherein the ezetimibe wet granule portion includes, as a binder, povidone having a weight average molecular weight of about 30,000 to about 50,000, and the rosuvastatin mixture portion includes a diluent, wherein the diluent comprises a water-soluble diluent and a water-insoluble diluent, the water-insoluble diluent having a particle size (d90) of about 98 ⁇ m to about 229 ⁇ m corresponding to 90% of total particles in a cumulative particle size distribution.
• d90 particle size
• the term “d90” refers to an average particle size corresponding to 90% of total particles in a cumulative size distribution, as generally understood in the art. For example, when “d90 is 100 ⁇ m,” this may indicate that 90% or more of active ingredient particles have an equivalent spherical volume diameter of about 100 ⁇ m or less, as measured using, for example, a Mastersizer (available from Malvern Instruments) or a HELOS particle size analyzer (available from Sympatec). However, embodiments are not limited thereto, and other particle size analyzers may also be used.
• T max of ezetimibe is as short as less than 1 hour
• rapid disintegration and dissolution of the tablet are required for rapid absorption to attain a desired therapeutic effect.
• granules containing the active ingredient may be prepared as bulky granules having a small density.
• such bulky granules may cause a problem such as capping during tableting or a large mass deviation in the prepared tablets.
• active ingredient-containing granules are prepared without the occurrence of problems during tableting, it may take a long time to disintegrate such granules, and a rapid initial dissolution rate cannot be expected. Thus, it may not be easy to prepare a tablet of ezetimibe having a high initial dissolution rate with improved productivity.
• the ezetimibe wet granule portion may include, as a binder, povidone having a weight average molecular weight of about 30,000 to about 50,000, thereby ensuring an improved initial dissolution rate of the ezetimibe of the composite tablet while also securing an angle of repose of granules of about 35° to 40° so as to attain appropriate flowability of ezetimibe wet granules.
• the ezetimibe wet granule portion includes, as a binder, povidone having a weight average molecular weight of about 30,000 to about 50,000, as a result of a dissolution test performed according to Dissolution method II in the Korean Pharmacopoeia at a paddle rotation speed of about 75 rpm
• the ezetimibe in the oral composite tablet was found to have a dissolution rate of about 90% or greater in about 30 minutes at a temperature of about 37.5° in a sodium acetate buffer solution of a pH of about 4.5 containing about 0.45% sodium lauryl sulfate (see Test Example 2 and Table 7).
• the oral composite tablet according to one or more embodiments may have improved pharmaceutical advantages, including an improved high initial dissolution rate and improved productivity.
• the ezetimibe wet granule portion may include, as a binder, povidone having a weight average molecular weight of about 30,000 to about 50,000 in an amount of about 0.2 parts to about 0.6 parts by weight with respect to 1 part by weight of the ezetimibe.
• the rosuvastatin mixture portion may include a diluent including a water-soluble diluent and a water-insoluble diluent, the water-insoluble diluent having a d90 of about 98 ⁇ m to about 229 ⁇ m, thereby ensuring that the ezetimibe of the oral composite tablet has an improved initial dissolution rate while also securing an angle of repose in a range of about 35° to about 40° with respect to a final mixture of the ezetimibe wet granule portion and the rosuvastatin mixture portion such that the final mixture may have appropriate flowability during tableting.
• the ezetimibe in the oral composite tablet was found to have a dissolution rate of about 90% or greater in about 30 minutes at a temperature of about 37.5° in a sodium acetate buffer solution of a pH of about 4.5 containing about 0.45% sodium lauryl sulfate ( see Test Example 2 and Table 7), and the final mixture of the ezetimibe wet granule portion and the rosuvastatin mixture portion had an angle of repose in a range of about 35° to about 40° (see Test Example 1 and Table 4).
• the oral composite tablet according to one or more embodiments may have an improved initial resolution rate of ezetimibe and improved productivity during tableting when the composite tablet is prepared by incorporating a water-insoluble diluent having a certain particle size range into the rosuvastatin mixture portion.
• the oral composite tablet according to one or more embodiments may have an effect of reducing deposition of the water-insoluble diluent in a dissolution vessel of a dissolution tester, thus remarkably reducing a deviation in dissolution rate of the ezetimibe, and accordingly ensuring a suitable quality evaluation result for the oral composite tablet.
• the oral composite tablet according to one or more embodiments may include both a water-soluble diluent and a water-insoluble diluent. In general, during a dissolution test of a composite tablet, a water-insoluble diluent tends to be deposited in a dissolution vessel and not dissolved.
• the deposition of the water-insoluble diluent in the dissolution vessel may delay dissolution of the ezetimibe, the ezetimibe being nearly insoluble in water, in a dissolution medium during a dissolution test for quality evaluation of the composite tablet, consequently leading to an increased deviation in dissolution rate.
• the rosuvastatin mixture portion of the oral composite tablet may include a water-soluble diluent and a water-insoluble diluent, the water-insoluble diluent having a d90 of about 98 ⁇ m to about 229 ⁇ m, so that deposition of the water-insoluble diluent in a dissolution vessel may be remarkably reduced.
• the dissolution rate of the ezetimibe may be increased, with a reduced deviation in the dissolution rate (see Test Example 2, Table 6, Test Example 3, and Table 8).
• the oral composite tablet may have an increased initial dissolution rate of the ezetimibe and a remarkably reduced deviation in dissolution of the ezetimibe in a dissolution test, and thus may be evaluated as having suitable quality in terms of a dissolution rate of ezetimibe in the composite tablet.
• the water-insoluble diluent in the rosuvastatin mixture portion may be any diluent known in the art.
• the water-insoluble diluent may include microcrystalline cellulose, starch, pregelatinized starch, dicalcium phosphate (DCP), low-substituted hydroxypropyl cellulose, or any combination thereof.
• DCP dicalcium phosphate
• embodiments are not limited thereto.
• the water-insoluble diluents may be microcrystalline cellulose.
• the water-insoluble diluent may be a water-insoluble diluent having a d90 of about 98 ⁇ m to about 229 ⁇ m and a d50 of about 44 ⁇ m to about 108 ⁇ m, wherein the d50 refers to a particle size corresponding to 50% in a cumulative particle size distribution.
• the water-insoluble diluent having a d90 of about 98 ⁇ m to about 229 ⁇ m may be microcrystalline cellulose having a d90 of about 98 ⁇ m to about 229 ⁇ m, and a d50 of about 44 ⁇ m to about 108 ⁇ m.
• the water-insoluble diluent may be in an amount of about 2 parts to about 10 parts by weight with respect to 1 part by weight of the rosuvastatin.
• the water-soluble diluent may be any diluent known in the art.
• the water-soluble diluent may be selected from the group consisting of lactose, mannitol, carboxymethyl cellulose, and any combination thereof.
• embodiments are not limited thereto.
• the water-soluble diluent may be in an amount of about 2 parts to about 10 parts by weight with respect to 1 part by weight of the rosuvastatin.
• wet granule portion may refer to a mixture of granules prepared in a wet condition
• mixture portion may refer to a simple mixture in a non-granular form or a mixture of granules prepared using any method excluding a wet granulation.
• the rosuvastatin mixture portion may be in the form of a simple mixture or a dry granular form. According to test results, when a rosuvastatin mixture portion was prepared as a simple mixture or in a dry granular form without using water as in one or more embodiments and then used to prepare a composite tablet, the composite tablet was found to include a remarkably reduced amount, for example, about less than 1.5%, of rosuvastatin lactone-related compounds after storage under a stressed condition, compared with a composite tablet obtained using a rosuvastatin mixture portion prepared in a wet granular form using water ( see Test Example 4 and Table 9). Thus, the oral composite tablet according to one or more embodiments may have remarkably improved stability of the rosuvastatin due to being produced through a process in which exposure of the rosuvastatin to water is minimized.
• the ezetimibe wet granule portion and the rosuvastatin mixture portion may each further include a pharmaceutically acceptable additive selected from a binder, a disintegrant, a glidant, and any combination thereof.
• the binder, the disintegrant, and the glidant may be selected from any known pharmaceutically acceptable additives commonly used in the art.
• the binder may be selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, copovidone, and any combination thereof.
• the disintegrant may be selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and any combination thereof.
• the glidant may be selected from the group consisting of magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and any combination thereof.
• embodiments are not limited thereto.
• an amount of the ezetimibe as a first active ingredient in the oral composite tablet may be from about 5 mg to about 20 mg, and in some other embodiments, about 5 mg to about 10 mg, in a unit dosage form of the composite tablet.
• the oral composite tablet according to one or more embodiments may include rosuvastatin or a pharmaceutically acceptable salt thereof as a second active ingredient.
• the rosuvastatin may be in the form of a free base or a pharmaceutically acceptable salt thereof.
• the pharmaceutically acceptable salt may be a calcium salt, a magnesium salt, a strontium salt, or the like.
• the rosuvastatin may be a rosuvastatin calcium salt.
• embodiments are not limited thereto.
• An amount of the rosuvastatin or a pharmaceutically acceptable salt thereof may be about 2.5 mg to about 40 mg, and in some embodiments, about 5 mg to about 20 mg, as a free base in a unit dosage form of the oral composite tablet according to one or more embodiments.
• the oral composite tablet may be any tablet form including the ezetimibe wet granule portion and the rosuvastatin mixture portion, for example, in the form of a single-layered tablet, a double-layered tablet, or a press-coated tablet.
• embodiments are not limited thereto.
• a dissolution rate of the ezetimibe may be about 90% or greater in about 30 minutes at a temperature of about 37.5°C in a sodium acetate buffer solution having a pH of about 4.5 containing about 0.45% sodium lauryl sulfate, as measured at a paddle rotation speed of about 75 rpm in a dissolution test of the oral composite tablet performed according to Dissolution method II in the Korean Pharmacopoeia.
• a dissolution rate of the ezetimibe may be about 20% or greater in about 30 minutes at a temperature of about 37.5°C in simulated gastric fluid (SGF) of a pH of about 1.2, as measured at a paddle rotation speed of about 50 rpm in a dissolution test of the oral composite tablet performed according to Dissolution method II in the Korean Pharmacopoeia.
• SGF simulated gastric fluid
• a total amount of rosuvastatin lactone-related compounds may be less than about 1.5%, as measured in a stress testing of the oral composite tablet under stressed conditions at a temperature of about 60°C for about 2 weeks.
• a method of preparing the oral composite tablet according to any of the embodiments includes: preparing the ezetimibe wet granule portion by wet-granulating the ezetimibe together with a pharmaceutically acceptable additive including, as a binder, povidone having a weight average molecular weight of about 30,000 to about 50,000; and tableting the ezetimibe wet granule portion together with the rosuvastatin mixture portion including the rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive as a diluent includes a water-soluble diluent and a water-insoluble diluent, the water-insoluble diluent having a particle size (d90) of about 98 ⁇ m to about 229 ⁇ m corresponding to 90% in a cumulative particle size distribution of total particles.
• a pharmaceutically acceptable additive including, as a binder, povidone having a weight average molecular weight of about 30,000
• the wet-granulating to prepare the ezetimibe wet granule portion may be performed using fluid-bed granulation, spray-drying, or a high-speed mixer.
• the rosuvastatin mixture portion including the rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive may be a simple mixture formed using simple mixing or a dry granule form prepared using dry granulation.
• the ezetimibe wet granule portion may be prepared so as to include, as a binder, the povidone having a weight average molecular weight of about 30,000 to about 50,000 in an amount of about 0.2 parts to about 0.6 parts by weight with respect to 1 part by weight of the ezetimibe.
• the ezetimibe wet granule portion and the rosuvastatin mixture portion may each further include about 0.5 parts to about 50 parts by weight of a diluent, about 0.1 parts to about 20 parts by weight of a binder, about 0.1 parts to about 40 parts by weight of a disintegrant, about 0.1 parts to about 3 parts by weight of a glidant, each with respect to 1 part by weight of the ezetimibe, or any combination thereof.
• the method of preparing the oral composite tablet according to any of the embodiments may include: (i) preparing the ezetimibe wet granule portion by wet-granulating the ezetimibe together with a pharmaceutically acceptable additive including, as a binder, povidone having a weight average molecular weight of about 30,000 to about 50,000; (ii) preparing the rosuvastatin mixture portion in the form of a simple mixture or dry granules, the rosuvastatin mixture portion including the rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and (iii) preparing single-layered tablets using a general tablet preparation method from a final mixture including the ezetimibe wet granule portion prepared in step (i) and the rosuvastatin mixture portion prepared in step (ii).
• the method of preparing the oral composite tablet according to any of the embodiments may include: (i) preparing the ezetimibe wet granule portion by wet-granulating the ezetimibe together with a pharmaceutically acceptable additive including, as a binder, povidone having a weight average molecular weight of about 30,000 to about 50,000, and tableting the ezetimibe wet granule portion into a tablet; (ii) preparing the rosuvastatin mixture portion in the form of a simple mixture or dry granules, the rosuvastatin mixture portion including the rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and (iii) preparing a double-layered tablet using a general tableting method with a double-layer tableting machine, the double-layered tablet including the tablet prepared in step (i) as a first layer and the rosuvastatin mixture portion prepared in step (ii) as a second layer.
• a pharmaceutically acceptable additive including
• the preparing of the rosuvastatin mixture portion as dry granules may be performed using a common method known in the art.
• the preparing of the rosuvastatin mixture portion as dry granules may include dry-granulating a simple mixture of the rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive using a roller compactor, and then sieving the resulting dry granules using an oscillator.
• Ezetimibe-wet granules were prepared by mixing ezetimibe with lactose hydrate, microcrystalline cellulose, sodium lauryl sulfate, and croscarmellose sodium, according to the compositions represented in Table 1.
• the resulting mixture was put into a fluid-bed granulator, and then a binder solution (a solution of 4 mg of povidone dissolved in 90 mg of water) was injected thereinto by spraying while working the fluid-bed granulator at an inlet temperature of about 50°C, a spray pressure of about 1.0 bar, and a spray speed of about 10 rpm to granulate the mixture.
• the working conditions of the fluid-bed granulator were maintained constant while the binder solution was injected.
• the inlet temperature was lowered to about 45°C, and the resulting granules were dried at the reduced inlet temperature and sieved through a sieve having a mesh size of about 20, thereby preparing ezetimibe wet-granules.
• Example 1 Preparation of simple rosuvastatin mixture and composite tablet
• the prepared ezetimibe wet granules as an ezetimibe wet granule portion were mixed with a simple mixture of additives for a rosuvastatin mixture portion as represented in Table 1.
• the resulting product was tableted with a tableting machine, thereby preparing composite tablets.
• a mixture of the additives for a rosuvastatin mixture portion as represented in Table 1 was sieved, mixed, dry-granulated with a roller compactor, and then broken down into dry granules, and sieved using an oscillator.
• the obtained rosuvastatin dry-granules were mixed with the ezetimibe wet granules prepared as described above, and the resulting mixture was then tableted using a tableting machine, thereby preparing composite tablets.
• Comparative Example 1 Preparation of rosuvastatin wet-granules using high-speed mixer, and preparation of composite tablet
• the obtained rosuvastatin wet-granules were mixed with the ezetimibe wet-granules prepared as described above, and the resulting mixture was then tableted using a tableting machine, thereby preparing composite tablets.
• Comparative Example 2 Preparation of rosuvastatin wet-granules using fluid-bed granulator, and preparation of composite tablet
• the working conditions of the fluid-bed granulator were maintained constant while the water was injected.
• the inlet temperature was lowered to about 45°C, and the resulting granules were dried at the reduced inlet temperature and sieved through a sieve having a mesh size of about 20, thereby preparing rosuvastatin wet-granules.
• the resulting rosuvastatin wet granules were mixed with the ezetimibe wet granules prepared as described above, and the resulting mixture was then tableted using a tableting machine, thereby preparing composite tablets.
• Preparation Example 2 Preparation of composite tablet using rosuvastatin mixture portion including different diluents having different particle sizes
• Composite tablets were prepared in the same manner as in Example 1, except that, as represented in Table 2, different types of microcrystalline cellulose having different particle sizes were used as diluents for rosuvastatin mixture portions, respectively.
• ezetimibe wet granules were prepared in the same manner as in Example 1, the ezetimibe wet granules were mixed with a simple rosuvastatin mixture, and the resulting mixture was then tableted, thereby preparing composite tablets (Examples 3 and 4 and Comparative Examples 3 and 4).
• Composite tablets were prepared in the same manner as in Example 1, except that, as represented in Table 3, povidones having different weight average molecular weights were used as binders for ezetimibe wet granules, respectively. After the ezetimibe wet granules were prepared in the same manner as in Example 1, the ezetimibe wet granules were mixed with each simple rosuvastatin mixture, and the resulting mixture was then tableted, thereby preparing composite tablets(Example 5 and Comparative Examples 5, 6, and 7).
• Example Method of forming rosuvastatin mixture portion Weight average molecular weight of binder (povidone) Types and amounts of additives for ezetimibe wet granule portion (mg) Types and amounts of additives for rosuvastatin mixture portion (mg) Comparative Example 5 Simple mixing 10,000 Ezetimibe 10Lactose hydrate 30Microcrystalline cellulose 90Sodium lauryl sulfate 2Povidone 4Croscarmellose sodium 10Water (90) Rosuvastatin calcium (20 as Rosuvastatin)Microcrystalline cellulose 50Lactose hydrate 100Mannitol 100Crospovidone 3Magnesium stearate 4 Example 1 30,000 Example 5 50,000 Comparative Example 6 400,000 Comparative Example 7 1,000,000
• Test Example 1 Physical property measurement of mixture of ezetimibe wet granules and rosuvastatin simple mixture
• Dissolution method II Dissolution method II (paddle method) according to the Korean Pharmacopoeia
• UV-absorption detector Measurement wavelength: 250 nm
• Dissolution rate comparison of composite tablets with respect to weight average molecular weights of povidones used in ezetimibe wet granules Example 5-min dissolution rate (%) 30-min dissolution rate (%) Average Standard deviation Average Standard deviation Control formulation: Ezetrol® Tablet (available from MSD) 56.2 5.2 90.6 3.4 Comparative Example 5 68.2 3.7 98.1 2.4 Example 1 61.5 4.8 93.5 3.3 Example 5 58.3 5.1 91.0 3.3 Example 6 55.1 4.2 89.7 3.7 Comparative Example 7 51.0 4.4 85.1 4.2
• Test method Dissolution method II (paddle method) according to the Korean Pharmacopoeia
• SGF Simulated gastric fluid
• UV-absorption detector Measurement wavelength: 250 nm
• the composite tablets of Comparative Example 3 including a water-insoluble diluent having a relatively small particle size in the rosuvastatin mixture portion, had an improved dissolution rate, but poor flowability due to a relatively large angle of repose. Flowability affects tableting properties of granules, and low flowability may lead to a large deviation in mass among tablets and low production efficiency, which would thereby render such mixtures unsuitable for mass production.
• the composite tablets of Comparative Example 4 including a water-insoluble diluent having a relatively large particle size in the rosuvastatin mixture portion were found to have good flowability but a large deviation in dissolution rate.
• the composite tablets of Comparative Example 4 were found to exhibit a profile of delayed dissolution in simulated gastric fluid, relative to the composite tablets of the other examples.
• the initial dissolution rate i.e., the release of ezetimibe in gastric juice
• the composite tablets of Comparative Example 4 are expected to have a low bioavailability in practice due to their low initial dissolution rate.
• UV-absorption detector Measurement wavelength: 250 nm

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• 2016
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