BR112019010706A2 - oral composite tablet, and method of preparing the oral composite tablet - Google Patents

Abstract

An oral composite tablet and a method of preparing it are provided. The oral composite tablet includes: a portion of ezetimibe wet granules including ezetimibe; and a rosuvastatin mixture portion including rosuvastatin or a pharmaceutically acceptable salt thereof, wherein the wet granules portion of ezetimibe includes, as a binder, povidone with an average molecular weight of from 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 µm to about 229 µm corresponding to 90% in a cumulative particle size distribution of total particles.

Description

ORAL COMPOSITE TABLET AND METHOD OF PREPARING THE ORAL COMPOSITE TABLET

TECHNICAL FIELD [001] The present disclosure relates to an oral composite tablet including ezetimibe and rosuvastatin or a pharmaceutically acceptable salt thereof, which has a better rate of initial dissolution of ezetimibe and better productivity, and a method of preparing the composite tablet oral.

STATE OF THE TECHNIQUE [002] Rosuvastatin or a pharmaceutically acceptable salt thereof is one of the HMG-CoA reductase inhibitors that inhibit cholesterol synthesis to treat dyslipidemia. Crestor tablets (ie, rosuvastatin calcium salts available from AstraZeneca), including rosuvastatin as a main ingredient, have been widely used both domestically and internationally for the treatment of dyslipidemia and disorders related to dyslipidemia. In particular, research reports the excellent effects of rosuvastatin in lowering blood LDL cholesterol levels and increasing beneficial HDL cholesterol levels in the body, compared to the effects of atorvastatin or simvastatin, which are commercially available HMG-CoA reductase inhibiting drugs . Thus, there is a growing interest in formulations containing rosuvastatin.

[003] HMG-CoA reductase inhibitors are generally used in combination with a therapeutic agent for dyslipidemia having a different mechanism than HMG-CoA reductase inhibitors, in order to enhance the therapeutic effects. Among such combinations, due to the

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2/32 excellent drug interaction between HMG-CoA reductase inhibitors and ezetimibe, which is a drug that inhibits cholesterol reabsorption in the small intestine, composite formulations of these two ingredients are being actively studied. For example, Vytorin ™, which is a composite formulation of simvastatin and ezetimibe, has already shown good pharmacological effects and stability, and is currently available on the market with remarkable sales performance.

[004] Through much research, the combined administration of rosuvastatin and ezetimibe is also reported to have excellent pharmaceutical effects (non-patent documents 1 and 2). Thus, studies on a composite formulation of rosuvastatin and ezetimibe with excellent effectiveness and productivity are ongoing.

[005] The Tmax of ezetimibe is as short as less than about 1 hour and, therefore, rapid disintegration and dissolution of ezetimibe, when administered in the form of a tablet, are necessary for rapid absorption into the body to obtain the desired therapeutic effect. However, ezetimibe is practically insoluble in water and, therefore, 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 guarantees a high dissolution rate of ezetimibe and better productivity and stability in terms of pharmaceutical aspects.

[Previous document] [Non-patent document] [006] 1) Brandon Ason et al., J. Lipid Res., April 2011; 52 (4): 679 to 687.

[007] 2) Torimoto et al. , Lipids in Health and

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3/32

Disease, 2013, 12: 137

DISCLOSURE OF THE INVENTION

TECHNICAL PROBLEM [008] The present disclosure provides an oral composite tablet of rosuvastatin and ezetimibe that can exhibit a high dissolution rate of ezetimibe and high productivity.

[009] The present disclosure provides a method of preparing the oral composite tablet of rosuvastatin and ezetimibe.

TROUBLESHOOTING [010] In accordance with an aspect of the present invention, an oral composite tablet is provided including: a portion of wet granules of ezetimibe including ezetimibe; and a mixture portion of rosuvastatin including rosuvastatin or a pharmaceutically acceptable salt thereof, [011] wherein the wet granule portion of ezetimibe includes, as a binder, povidone with an average molecular weight of about 30,000 to about 50,000 , and the rosuvastatin mixing 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 pm to about 229 pm corresponding to 90 % in a cumulative particle size distribution of the total particles.

[012] According to another aspect of the present invention, there is provided a method of preparing the oral composite tablet, wherein the method includes: preparing the wet granule portion of ezetimibe by wet granulating ezetimibe together with a pharmaceutically additive

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4/32 acceptable including, as a binder, povidone with an average molecular weight of about 30,000 to about 50,000;

and the preparation in tablets with the portion of wet granules from ezetimiba in set with the portion mixing rosuvastatin including rosuvastatin or a salt pharmaceutically pharmaceutically acceptable acceptable, gives same and an additive

[013] wherein 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 pm to about 229 pm corresponding to 90% in a cumulative particle size distribution of the total particles.

ADVANTAGE EFFECTS OF THE INVENTION [014] As described above, according to one or more embodiments of the present disclosure, an oral composite tablet including a portion of wet granules of ezetimibe and a portion of rosuvastatin mixture may exhibit a better rate of initial dissolution and a better angle of rest in relation to productivity by incorporating povidone with an average molecular weight of about 30,000 to about 50,000 as a binder in the wet granule portion of ezetimibe.

[015] Furthermore, by incorporating a water-insoluble diluent that has a d90 of about 98 pm to about 229 pm in the rosuvastatin mixing portion, the d90 corresponding to an average particle size corresponding to the lower 90% in a cumulative size distribution (particle size of 90% cumulative), a higher initial dissolution rate of ezetimibe and a fluidity

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A suitable mixture of the wet granule portion of ezetimibe and the rosuvastatin mixture portion can be guaranteed, compared to when a water insoluble diluent that has a relatively large particle size is used. In a dissolution test of the composite tablet according to any of the modalities, a deviation in the dissolution rate of ezetimibe can be noticeably reduced, due to reduced deposition of the water-insoluble diluent in a dissolution vessel and, therefore, an assessment of Proper quality of the composite tablet can be guaranteed.

[016] Therefore, an oral composite tablet, according to any of the modalities, can be a composite tablet of ezetimibe and rosuvastatin that can guarantee a better initial dissolution rate of ezetimibe and an appropriate quality assessment of the dissolution rate of ezetimibe , as well as a variety of pharmaceutical advantages, including improved productivity.

MODE FOR THE INVENTION [017] Unless otherwise defined, all terms (including technical and scientific terms) used in this document have the same meaning as commonly understood by a person of ordinary skill in the technique to which this invention belongs . Although exemplary methods or materials are listed in this document, similar or equivalent ones are also covered by the scope of the present invention. All numerical values mentioned in this document in connection with the modalities of this disclosure must be understood as approximate values, although not explicitly specified with the term as

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6/32 about. All publications disclosed as references in this document are incorporated in their entirety by reference.

[018] In accordance with one aspect of the present disclosure, an oral composite tablet includes: a portion of wet granules of ezetimibe including ezetimibe; and a mixture portion of rosuvastatin including rosuvastatin or a pharmaceutically acceptable salt thereof, wherein the portion of wet granules of ezetimibe includes, as a binder, povidone with an 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 pm to about 229 pm corresponding to 90% of the total particles in a cumulative particle size distribution.

[019] As used herein, the term d90 refers to an average particle size corresponding to 90% of the total particles in a cumulative size distribution, as is generally understood in the art. For example, when d90 is 100 pm, this may indicate that 90% or more of the active ingredient particles have an equivalent spherical volume diameter of about 100 pm or less, as measured using, for example, a Mastersizer (available from Malvern Instruments) or a HELOS particle size analyzer (available from Sympatec). However, the modalities are not limited to them, and other particle size analyzers can also be used.

[020] In one aspect pharmacokinetics as _Tm ax

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7/32 ezetimibe is as short as less than 1 hour, after administration in the form of a tablet, rapid disintegration and dissolution of the tablet are necessary for rapid absorption to obtain the desired therapeutic effect. To obtain a quick initial dissolution, granules containing the active ingredient can be prepared as bulky granules with a low density. However, such bulky granules can cause a problem such as capping during tablet formation or a large deviation of mass in the prepared tablets. On the other hand, when granules containing active ingredient are prepared without problems during the preparation of tablets, it can take a long time to disintegrate such granules, and a rapid rate of initial dissolution cannot be expected. Therefore, it may not be easy to prepare an ezetimibe tablet that has a high initial dissolution rate with better productivity.

[021] In the oral composite tablet, according to one or more modalities, the portion of wet granules of ezetimibe may include, as a binder, povidone with an average molecular weight of about 30,000 to about 50,000, thus ensuring a better initial dissolution rate of ezetimibe from the composite tablet while ensuring an angle of rest of the granules of about 35 ° to 40 ° in order to obtain appropriate fluidity of the wet granules of ezetimibe. In the oral composite tablet, according to one or more modalities, when the portion of wet granules of ezetimibe includes, as a binder, povidone with an average molecular weight of about 30,000 to about 50,000, as a result of a dissolution carried out according to Dissolution Method II in the Korean Pharmacopoeia at a

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8/32 blade rotation speed of about 75 rpm, it was observed that ezetimibe in the oral composite tablet had a dissolution rate of about 90% or more in about 30 minutes at a temperature of about 37.5 ° in a sodium acetate buffer solution with a pH of about 4.5 containing about 0.45% sodium lauryl sulfate (see Test Example 2 and Table 7). As a result of the evaluation of the physical properties of the wet granules of ezetimibe, it was observed that the wet granules of ezetimibe had an angle of rest in a range of about 35 ° to about 40 ° in which productivity is ensured during preparation tablets (see Test Example 1 and Table 5). Therefore, the oral composite tablet, according to one or more modalities, may have better pharmaceutical advantages, including a better rate of high initial dissolution and better productivity.

[022] In some embodiments, the wet granule portion of ezetimibe may include, as a binder, povidone with an average weight 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 ezetimibe.

[023] In the oral composite tablet, according to one or more modalities, the mixture portion of rosuvastatin may include a diluent including a water-soluble diluent and a water-insoluble diluent, the water-insoluble diluent having a d90 of about 98 pm to about 229 pm, thus ensuring that the ezetimibe of the oral composite tablet has a better rate of initial dissolution while ensuring an angle of rest in a range of about 35 ° to about 40 ° in relation to a final mixture of the wet granules portion of ezetimibe and the rosuvastatin mixture portion so

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9/32 that the final mixture can have appropriate fluidity during the preparation of tablets. In the oral composite tablet, according to one or more modalities, when the water-insoluble diluent of the rosuvastatin mixing portion has a d90 of about 98 pm to about 229 pm, as a result of a dissolution test carried out according to with the Korean Pharmacopoeia Dissolution Method II at a blade rotation speed of about 75 rpm, it was observed that ezetimibe in the oral composite tablet had a dissolution rate of about 90% or more in about 30 minutes at a temperature of about 37.5 ° in a sodium acetate buffer solution with 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 wet granule portion of ezetimibe and the mixture portion of rosuvastatin had an angle of rest in a range of about 35 ° to about 40 ° (see Test Example 1 and Table 4) . Thus, the oral composite tablet, according to one or more modalities, may have a better rate of initial resolution of ezetimibe and better productivity during tablet preparation when the composite tablet is prepared by incorporating a water-insoluble diluent that has a certain particle size range in the mixture portion of rosuvastatin.

[024] The oral composite tablet, according to one or more modalities, can have a reduction effect on the deposition of the water-insoluble diluent in a dissolution vessel of a dissolution tester, thus significantly reducing a deviation in the rate of dissolution of ezetimibe, thus guaranteeing an adequate quality evaluation result for the oral composite tablet. The pill

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10/32 oral composite, according to one or more modalities, can include both a water-soluble diluent and a water-insoluble diluent. In general, during the 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 can delay the dissolution of ezetimibe, with ezetimibe being almost insoluble in water, in a dissolution medium during a dissolution test to evaluate the quality of the composite tablet, consequently leading to a increased deviation in the dissolution rate. In some embodiments, the rosuvastatin mixing 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 pm to about 229 pm, so the deposition of the water-insoluble diluent in a dissolution vessel can be remarkably reduced. Consequently, the dissolution rate of ezetimibe can be increased, with a reduced deviation in the dissolution rate (see Test Example 2, Table 6, Test Example 3 and Table 8). As described above, by including the water-insoluble diluent that has a certain particle size range in the rosuvastatin mixture portion, the oral composite tablet may have a higher initial dissolution rate for ezetimibe and a remarkably reduced deviation in the dissolution of ezetimibe in a dissolution test and therefore can be assessed as having adequate quality in terms of a dissolution rate of ezetimibe in the composite tablet.

[025] The water-insoluble diluent in the mixture portion of rosuvastatin, according to one or more modalities

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11/32 having a d90 of about 98 to about 229 pm, can be any diluent known in the art. For example, the water-insoluble diluent may include microcrystalline cellulose, pregelatinized starch starch, dicalcium phosphate (DCP, dicalcium phosphate), low substituted hydroxypropylcellulose, or any combination thereof. However, the modalities are not limited to that. In some embodiments, the water-insoluble diluents may be microcrystalline cellulose.

[026] In some embodiments, the water-insoluble diluent may be a water-insoluble diluent that has a d90 of about 98 pm to about 229 pm and a d50 of about 44 pm to about 108 pm, where d50 refers to a particle size corresponding to 50% in a cumulative particle size distribution. In some embodiments, the water-insoluble diluent that has a d90 of about 98 pm to about 229 pm can be microcrystalline cellulose that has a d90 of about 98 pm to about 229 pm, and a d50 of about 44 pm at about 108 pm.

[027] The water-insoluble diluent can be in an amount of about 2 parts to about 10 parts by weight relative to 1 part by weight of rosuvastatin.

[028] The water-soluble diluent can be any diluent known in the art. For example, the water-soluble diluent can be selected from the group consisting of lactose, mannitol, carboxymethylcellulose, and any combination thereof. However, the modalities are not limited to that.

[029] The water-soluble diluent can be in an amount of about 2 parts to about 10 parts by weight relative to 1 part by weight of rosuvastatin.

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12/32 [030] As used herein, the term wet granule portion may refer to a mixture of granules prepared in a wet condition, and the term mixing portion may refer to a simple mixture in a non-granular form. or a mixture of granules prepared using any method excluding wet granulation.

[031] In some embodiments, the mixture portion of rosuvastatin may be in the form of a simple mixture or a dry granular form. According to test results, when a mixture portion of rosuvastatin was prepared as a simple mixture or in a dry granular form without the use of water as in one or more modalities and then used to prepare a composite tablet, it was observed that the composite tablet included a noticeably reduced amount, for example, less than 1.5%, of rosuvastatin lactone-related compounds after storage under a stress condition, compared to a composite tablet obtained using a rosuvastatin blend portion prepared in a wet granular form using water (see Test Example 4 and Table 9). Therefore, the oral composite tablet, according to one or more modalities, can have remarkably better stability of rosuvastatin because it is produced through a process in which the exposure of rosuvastatin to water is minimized.

[032] In the oral composite tablet, according to one or more modalities, the wet granule portion of ezetimibe and the mixing portion of rosuvastatin may each additionally include a pharmaceutically acceptable additive selected from a binder, a disintegrant, a slider, and any combination of them.

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13/32 [033] The binder, ο disintegrant and the glidant can be selected from any known pharmaceutically acceptable additives commonly used in the art. For example, the binder can be selected from the group consisting of povidone, hypromellose, hydroxypropylcellulose, copovidone, and any combination thereof. However, the modalities are not limited to that. The disintegrant can be selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low substituted hydroxypropylcellulose, and any combination thereof. However, the modalities are not limited to that. The glidant can be selected from the group consisting of magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and any combination thereof. However, the modalities are not limited to that.

[034] In the oral composite tablet, according to one or more modalities, an amount of ezetimibe as a first active ingredient in the oral composite tablet can be from about 5 mg to about 20 mg, and in some other modalities, about 5 mg to about 10 mg, in a unit dosage form of the composite tablet.

[035] The oral composite tablet, according to one or more modalities, may include rosuvastatin or a pharmaceutically acceptable salt thereof as a second active ingredient. Rosuvastatin can be in the form of a free base or a pharmaceutically acceptable salt thereof. For example, the pharmaceutically acceptable salt can be a calcium salt, a magnesium salt, a strontium salt or the like. For example, rosuvastatin can be a calcium salt of

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14/32 rosuvastatin. However, the modalities are not limited to that.

[036] An amount of rosuvastatin or a pharmaceutically acceptable salt thereof can 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 modalities.

[037] The oral composite tablet can be any tablet form that includes the wet granule portion of ezetimibe and the mixing portion of rosuvastatin, for example, in the form of a single layer tablet, a double layer tablet or a tablet compression coated. However, the modalities are not limited to that.

[038] In the oral composite tablet, according to one or more modalities, a dissolution rate of ezetimibe can be about 90% or more in about 30 minutes at a temperature of about 37.5 ° C in a solution of sodium acetate buffer with a pH of about 4.5 containing about 0.45% sodium lauryl sulfate, as measured with a paddle rotation speed of about 75 rpm in a composite tablet dissolution test oral performed according to the Dissolution Method II in the Korean Pharmacopoeia.

[039] In the oral composite tablet, according to one or more modalities, a dissolution rate of ezetimibe can be about 20% or more in about 30 minutes at a temperature of about 37.5 ° C in gastric fluid simulated (FGS) with a pH of about 1.2, as measured with a blade rotation speed of about 50 rpm in an oral composite tablet dissolution test performed in accordance with

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15/32 with the Dissolution Method II in the Korean Pharmacopoeia.

[040] In the oral composite tablet, according to one or more modalities, a total amount of rosuvastatin lactone-related compounds may be less than about 1.5%, as measured in a stress test of the oral composite tablet under conditions stress at a temperature of about 60 ° C for about 2 weeks.

[041] According to another aspect of the present disclosure, a method of preparing the oral composite tablet, according to any of the modalities, includes: the preparation of the wet granule portion of ezetimibe by wet granulation of ezetimibe together with an additive pharmaceutically acceptable including, as a binder, povidone with an average molecular weight of about 30,000 to about 50,000; and preparing tablets with the wet granule portion of ezetimibe together with the mixture portion of rosuvastatin including rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive as a diluent includes a diluent water-soluble and a water-insoluble diluent, the water-insoluble diluent having a particle size (d90) of about 98 pm to about 229 pm corresponding to 90% in a cumulative particle size distribution of the total particles.

[042] The above descriptions of the oral composite tablet, according to one or more modalities, may apply to modalities of the method of preparing the oral composite tablet.

[043] In some modalities of the method, the

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16/32 wet granulation for the preparation of the wet granule portion of ezetimibe can be carried out using fluid bed granulation, spray drying or a high speed mixer.

[044] In some embodiments of the method, the mixture portion of rosuvastatin including rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive may be a simple mixture formed using simple mixture or a form of dry granules prepared using dry granulation.

[045] In some embodiments of the method, the wet granule portion of ezetimibe can be prepared to include, as a binder, povidone with an average weight 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 ezetimibe.

[046] In some embodiments of the method, the wet granule portion of ezetimibe and the mixing portion of rosuvastatin may each additionally include about 0.5 parts to about 50 parts by weight of a diluent, about 0.1 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 in relation to to 1 part by weight of ezetimibe, or any combination thereof.

[047] In some embodiments, the method of preparing the oral composite tablet, according to any of the embodiments, may include: (1) preparing the wet granule portion of ezetimibe by wet granulation of ezetimibe together with a pharmaceutically additive

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17/32 acceptable including, as a binder, povidone with an average molecular weight of about 30,000 to about 50,000;

(11) preparing the mixture portion of rosuvastatin in the form of a simple mixture or dry granules, the mixture portion of rosuvastatin including rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and (iii) the preparation of single-layer tablets using a general method of preparing tablets from a final blend that includes the portion of wet granules of ezetimibe prepared in step (i) and the mixture portion of rosuvastatin prepared in step (ii).

[048] In some other embodiments, the method of preparing the oral composite tablet, according to any of the modalities, may include: (i) the preparation of the wet granule portion of ezetimibe by wet granulation of the ezetimibe together with an additive pharmaceutically acceptable including, as a binder, povidone with an average molecular weight of about 30,000 to about 50,000, and converting the wet granule portion of ezetimibe into a tablet; (ii) preparing the rosuvastatin mixing portion in the form of a simple mixture or dry granules the rosuvastatin mixing portion including rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive; and (iii) the preparation of a double layer tablet using a general method of preparing tablets with a double layer tablet machine, wherein the double layer tablet includes the tablet prepared in step (i) as a first layer and the mixture portion of rosuvastatin prepared in step (ii) as a

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18/32 second layer.

[049] In some embodiments, the preparation of the mixture portion of rosuvastatin as dry granules can be performed using a common method known in the art. In some embodiments, the preparation of the mixture portion of rosuvastatin as dry granules may include dry granulation of a simple mixture of 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.

MODE OF THE INVENTION [050] One or more modalities of the present disclosure will now be described in detail with reference to the following examples. However, these examples are for illustrative purposes only and are not intended to limit the scope of one or more modalities of this disclosure.

Preparation Example 1: Preparation of composite tablet using rosuvastatin mixture portion prepared using different methods [Preparation of wet granules of ezetimibe] [051] Wet granules of ezetimibe were prepared by mixing ezetimibe with lactose hydrate, microcrystalline cellulose, lauryl sulfate sodium and croscarmellose sodium, according to the compositions shown in Table 1. The resulting mixture was placed in a fluidized bed granulator, and then an agglutinating solution (a solution of 4 mg of povidone dissolved in 90 mg of water) was injected by spraying while the fluid bed granulator was operated at an inlet temperature of about

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19/32 at 50 ° C, a spray pressure of about 100 kPa (1.0 bar) and a spray speed of about 10 rpm to granulate the mixture. The operating conditions of the fluidized bed granulator were kept constant while the binder solution was injected. After granulation, 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 with a mesh size of about 841 microns (20 mesh), preparing thus, wet granules of ezetimibe.

Example 1: Preparation of simple rosuvastatin mixture and composite tablet [052] The wet granules of ezetimibe prepared as a portion of wet granules of ezetimibe were mixed with a simple mixture of additives for a portion of the mixture of rosuvastatin as shown in Table 1. The resulting product was converted into tablets with a tablet machine, thereby preparing composite tablets.

Example 2: Preparation of dry rosuvastatin granule and composite tablet [053] A mixture of the additives for a rosuvastatin mixture portion as shown in Table 1 was sieved, mixed, dry granulated with a roller compactor and then divided into dry granules , and sieved using an oscillator. The dried rosuvastatin granules obtained were mixed with the wet granules of ezetimibe prepared as described above, and the resulting mixture was then converted into tablets using a tablet machine, thereby preparing composite tablets.

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20/32

Comparative Example 1: Preparation of wet rosuvastatin granules using high speed mixer, and preparation of composite tablet [054] A mixture of the additives for a rosuvastatin mixture portion as shown in Table 1, excluding water, was mixed with 50 mg of water using a high speed mixer under the following conditions: agitator speed of 150 rpm, agitator pressure of 1.6A and mincer speed of 3000 rpm, dried and then sieved through a sieve with a mesh size of about 841 microns (20 mesh), thus preparing moist granules of rosuvastatin. The obtained rosuvastatin wet granules were mixed with the wet ezetimibe granules prepared as described above, and the resulting mixture was then converted into tablets using a tablet machine, thereby preparing composite tablets.

Comparative Example 2: Preparation of wet rosuvastatin granules using fluidized bed granulator, and preparation of composite tablet [055] A mixture of the additives for a mixture portion of rosuvastatin as shown in Table 1, excluding water, was added to a granulator of fluidized bed, and then 50 mg of water were injected into it by spraying while the fluidized bed granulator was operated at an inlet temperature of about 50 ° C, a spray pressure of about 100 kPa (1.0 bar) and a spray speed of about 10 rpm, thus granulating the mixture. The operating conditions of the fluidized bed granulator were kept constant while the water was injected. After granulation, the inlet temperature was

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21/32 decreased to about 45 ° C, and the resulting granules were dried at the reduced inlet temperature and sieved through a sieve with a mesh size of about 841 microns (20 mesh), thus preparing wet granules of rosuvastatin. The resulting wet granules of rosuvastatin were mixed with the wet granules of ezetimibe prepared as described above, and the resulting mixture was then converted into tablets using a tablet machine, thereby preparing composite tablets.

[Table 1] Preparation of composite tablets using different methods of forming the mixture portion of rosuvastatin

Example Method of preparing the rosuvastatin mixing portion Types and quantities of additives for the portion of mix of rosuvastatin (mg) Types and amounts of additives for the wet granule portion of ezetimibe (mg) Example 1 Simple mixing (simple mixing) Rosuvastatin calcium (20 as Rosuvastatin) Microcrystalline cellulose 50 Hydrate lactose 100 Mannitol 100 Crospovidone 3 Stearate magnesium 4 Ezetimibe 10 Hydrate lactose 30 Microcrystalline cellulose 90 Sodium lauryl sulfate 2 Povidone 4 Croscarmellose sodium 10 Water (90) Example 2 Dry granules (Compaction) Comparative Example 1 Wet granules (mixer High velocity) Rosuvastatin calcium (Rosuvastatin 20) Microcrystalline cellulose 50 Example Granules

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22/32

Comparative 2 damp (Bed granulator fluidized) Hydrate lactose 100 Mannitol 100 Crospovidone 3 Stearate Magnesium 4 Water (50)

[056] (Microcrystalline cellulose in the mixture portion of rosuvastatin: Comprecel M101D +) [057] (Povidone in the portion of wet granules of ezetimibe: PVP K-30 (average molecular weight: 30,000))

Preparation Example 2: Preparation of composite tablet using rosuvastatin blend portion that includes different diluents with different particle sizes [058] Composite tablets were prepared in the same manner as in Example 1, except that, as shown in Table 2, different types microcrystalline cellulose with different particle sizes were used as diluents for mixing portions of rosuvastatin, respectively. After wet granules of ezetimibe were prepared in the same manner as in Example 1, the wet granules of ezetimibe were mixed with a simple mixture of rosuvastatin, and the resulting mixture was then converted into tablets, thus preparing composite tablets (Examples 3 and 4 and

Comparative Examples 3 and 4).

[Table 2]

Example Types of microcrystalline cellulose in portion of rosuvastatin mixture d50 (pm) d90 (pm) Types and quantities of additives for the wet granule portion of ezetimibe (mg) Types and quantities of additives for the mixing portion of rosuvastatin (mg) Example Avicel PH105 23 50 Ezetimibe 10 Rosuvastatin

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Comparative 3 Hydrate lactose 30 Microcrystalline cellulose 90 Lauryl sulfate sodium 2 Povidone 4 Croscarmellose sodium 10 Water (90) calcium (20 as Rosuvastatin) Microcrystalline cellulose 50 Hydrate lactose 100 Mannitol 100 Crospovidone 3 Magnesium stearate 4 Example 1 Comprecel M101D + 44 98 Example 3 Avicel PH101 53 116 Example 4 Avicel PH102 108 229 Comparative Example 4 Vivapur 12 195 379

[059] Povidone in the wet granule portion of ezetimibe: PVP K-30 (average molecular weight: 30,000) [060] d50 = median diameter of the particle distribution

Preparation Example 3: Preparation of composite tablet using povidones with different average weight molecular weights in wet granule of ezetimibe [061] Composite tablets were prepared in the same manner as in Example 1, except that, as shown in Table 3, povidones with different weights molecular weight averages were used as binders for wet granules of ezetimibe, respectively. After the wet granules of ezetimibe were prepared in the same manner as in Example 1, the wet granules of ezetimibe were mixed with each simple mixture of rosuvastatin, and the resulting mixture was then converted into tablets, thus preparing composite tablets (Example 5 and Comparative Examples 5, 6 and 7).

[Table 3]

Example Method of forming the mixing portion Average molecular weight of Types and amounts of additives for the Types and amounts of additives for the

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from rosuvastatin binder (povidone) wet granules of ezetimibe (mg) mix of rosuvastatin (mg) Comparative Example 5 Simple mixing 10,000 Ezetimibe 10 Hydrate lactose 30 Microcrystalline cellulose 90 Sodium lauryl sulfate 2 Povidone 4 Croscarmellose sodium 10 Water (90) Rosuvastatin calcium (20 as Rosuvastatin) Microcrystalline cellulose 50 Hydrate lactose 100 Mannitol 100 Crospovidone 3 Stearate magnesium 4 Example 1 30,000 Example 5 50,000 Comparative Example 6 400,000 Comparative Example 7 1,000,000

Test Example 1: Measurement of physical properties of the mixture of wet granules of ezetimibe and simple mixture of rosuvastatin [062] The densities and angles of rest of the final mixtures of wet granules of ezetimibe and simple mixtures of rosuvastatin, obtained in the Preparation Example 2, were measured, and the Hausner ratios (as a ratio between the compacted density and the apparent density) of the final mixtures were calculated. The results are shown in Table 4. As a reference, an angle of rest at which productivity is guaranteed in the preparation of tablets can be about 35 ° to about 40 °.

[Table 4]

Example Compare -tive 3 Example 1 Example 3 Example 4 Example Comparative -4 Density e (g / mL) Apparent 0.40 0.38 0.39 0.37 0.32 Compactad a 0.56 0.47 0.46 0.44 0.37 Hausner reason 1.40 1.24 1.18 1.19 1, 16 Poor Reasonable 1 Good Reasonable 1 Good

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Rest angle (°) 46 38 38 37 32

[063] The densities and resting angles of the final mixtures of the wet granules of ezetimibe and the simple mixtures of rosuvastatin in relation to the average weight molecular weights of povidone in the wet granules of ezetimibe obtained in Preparation Example 2, were measured, and the Hausner's ratios (as a ratio between the compacted density and the apparent density) of the final mixtures were calculated. The results are shown in Table 5.

[Table 5] Physical properties of wet granules of ezetimibe in relation to the average weight molecular weights of povidones used in wet granules of ezetimibe

Example Compare -tive 5 Example 1 Example 5 Example Comparative-6 Example Comparative-7 Density e (g / mL) Apparent 0.42 0.38 0.37 0.36 0.37 Compactad a 0.57 0.46 0.44 0.41 0.41 Hausner reason 1.36 1.21 1.19 1, 14 1, 11 Poor Reasonable 1 Reasonable 1 Good Good Rest angle (°) 42 36 38 32 33 Test Example 2: Test of this] _uction (1)

[064] A dissolution test was performed on the composite tablet of Example 1; in the composite tablets of Examples 3 and 4 and Comparative Examples 3 and 4, obtained in Preparation Example 2; and the composite tablets of Examples 1, 5 and Comparative Examples 5, 6 and 7, obtained in Preparation Example 3, under the following conditions.

[065] c Dissolution test conditions>

[066] 1) Dissolution method: Dissolution method

II (paddle method) according to the Korean Pharmacopoeia

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[067] 2) Dissolution medium: acetate buffer sodium pH 4.5 + 0.45 SLS% [068] 3) Dissolution medium quantity: 500 mL [069] 4) Dissolution device temperature: 37.5 ° C [070] 5) Paddle speed: 75 rpm [071] 6) Number of test samples for each group

experimental: 6 [072] 7) Sampling time: 5 min and 30 min [073] <Sample analysis conditions>

[074] Detector: UV absorption detector (Measurement wavelength: 250 nm) [075] Column: 150 mm ODS-2, C18 column [076] Flow rate: 1.5 mL / min [077 ] Column temperature: 40 ° C [078] Analysis time: 20 min [079] <Test results>

[Table 6] Comparison of the dissolution rates of composite tablets in relation to the particle size of diluents used in the rosuvastatin mixture portion

Example Dissolution rate in 5 min (%) Dissolution rate in 30 min (%) Average Detour pattern Average Detour pattern Comparative Example 3 63.2 7.4 93.7 5, 1 Example 1 61.5 4.8 93.5 3.3 Example 3 59.7 5.2 92, 9 3, 1 Example 4 57.0 8, 6 93, 1 5.3 Comparative Example 4 56, 6 15, 1 92.7 12.8

[Table 7] Comparison of dissolution rates for

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27/32 tablets composites in relation to the average molecular weight of the povidones used in the wet granules of ezetimibe

Example Dissolution rate in 5 min (%) Dissolution rate in 30 min (%) Average Detour pattern Average Detour pattern 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 Example 3: Dissolution test (2) [080] A dissolution test was performed on the composite tablet of Example 1 and on the composite tablets of Examples 3 and 4 and Comparative Examples 3 and 4, obtained in Preparation Example 2, under the following conditions.

[081] c Dissolution test conditions>

[082] 1) Test method: Dissolution method II (paddle method) according to the Korean Pharmacopoeia [083] 2) Dissolution medium: Simulated gastric fluid (FGS), prepared by dissolving 2.0 g of chloride sodium and 3.2 g of purified pepsin in 1,000 ml of water containing 7.0 ml of hydrochloric acid.

[084] 3) Amount of dissolution medium: 900 mL [085] 4) Temperature of the dissolution apparatus:

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37.5 ° C

[086] 5) Blade speed: 50 rpm [087] 6) Number of samples of test for each group experimental: 6 [088] 7) Time to sampling: 5 min and 30 min [089] < Conditions analysis < of samples>

[090] Detector: UV absorption detector (Measurement wavelength: 250 nm) [091] Column: 150 mm ODS-2, C18 column [092] Flow rate: 1.5 mL / min [093 ] Column temperature: 40 ° C [094] Analysis time: 20 min [095] <Test results>

[Table 8] Comparison of the dissolution rates of composite tablets in relation to the particle size of the diluent used in the rosuvastatin mixture portion

Example Dissolution rate in 5 min (%) Dissolution rate in 30 min (%) Average Detour pattern Average Detour pattern Comparative Example 3 4.7 1, 1 29.7 1.8 Example 1 3, 9 0.8 25.5 1.8 Example 3 3, 6 1.4 26.1 2.1 Example 4 2.7 1.2 23.5 2, 6 Comparative Example 4 1, 6 1.2 15.3 3.2

[096] With reference to Tables 4 and 6, the composite tablets of Comparative Example 3, including a water-insoluble diluent with a relatively small particle size in the mixture portion of rosuvastatin, had a better dissolution rate, but poor fluidity due

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29/32 at a relatively large angle of rest. Flowability affects the tabletting properties of granules, and low flowability can lead to a large deviation of the mass between tablets and low production efficiency, which would then make such mixtures unsuitable for mass production. The compositional tablets of Comparative Example 4, including a water-insoluble diluent with a relatively large particle size in the rosuvastatin mixing portion, were observed to have good fluidity, but a large deviation in the dissolution rate. This is attributed to the fact that the water-insoluble diluent with a relatively large particle size in the rosuvastatin mixture portion is deposited in a dissolution vessel during the dissolution test, inhibiting the release of the active ingredient ezetimibe. The United States Pharmacopoeia (USP) prescribes that an acceptable range of dissolution rates deviation in the dissolution test is within 20% within 10 minutes or within 10% after 10 minutes (see USP 1092). With reference to Table 6, the quality of the composite tablets of Comparative Example 4 could not be properly assessed due to a large standard deviation in the dissolution rate.

[097] With reference to Tables 4 and 8, it was observed that the composite tablets of Comparative Example 4 exhibit a delayed dissolution profile in simulated gastric fluid, compared to the composite tablets of the other examples. In the case of ezetimibe that has a T _m max of less than 1 hour, the initial dissolution rate, that is, the release of ezetimibe in gastric juice, may have an important influence on the bioavailability of ezetimibe. Thus, it is expected that the composite tablets of Comparative Example 4 will have a

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30/32 low bioavailability in practice due to its low rate of initial dissolution.

[098] With reference to the results of Tables 5 and 7, the wet granules of ezetimibe from Comparative Examples 6 and 7 prepared using povidones with large average molecular weights as binders had good fluidity, while it was observed that the composite tablets of Comparative Examples 6 and 7 including wet granules of ezetimibe had lower initial dissolution rates, compared to the control formulation, due to the delayed dissolution of ezetimibe according to the dissolution test. Considering the importance of the initial resolution rate of ezetimibe in relation to bioavailability, it was observed that the use of povidones with large average molecular weight to prepare wet granules of ezetimibe as in Comparative Examples 6 and 7 was undesirable in terms of the dissolution rate of ezetimibe. On the contrary, it was observed that the composite tablets of Comparative Example 5 prepared using povidone with a relatively low average molecular weight, had a better initial ezetimibe resolution rate, but poor fluidity of the wet ezetimibe granules and, consequently, lower productivity tablets and are therefore inadequate in terms of productivity.

Test Example 4: Related compound test [099] After the composite tablets prepared in Examples 1 and 2 and Comparative Examples 1 and 2 were wrapped in aluminum-aluminum blister packs (AluAlu) and subjected to stress conditions (about 60 ° C) for 2 weeks, lactone-related compounds were

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[0100] <Test conditions>

[0101] <Sample analysis conditions>

[0102] Detector: UV absorption detector (Measurement wavelength: 250 nm) [0103] Column: ODS-2, C18, 150 mm column [0104] Flow rate: 1.0 mL / min [0105 ] Column temperature: 45 ° C [0106] Analysis time: 70 min [Table 9] Generation of lactone-related compounds from composite tablets according to methods of preparing the rosuvastatin mixture portion

Example Start 60 ° C for 2 weeks (packing blister Alu-Alu) Example 1 0.03 0.26 Example 2 0.04 0.29 Comparative Example 1 0.04 2.44 Comparative Example 2 0.03 1.97 [0107] With reference to the test results of

Table 9, it was observed that the composite tablets of Comparative Examples 1 and 2, including wet granules of rosuvastatin, included markedly increased lactone-related compounds after being left for 2 weeks for testing. Therefore, it has been observed that composite tablets with better rosuvastatin stability can be obtained by preparing the rosuvastatin mixture portion as a simple mixture or dry granules without the use of water.

[0108] It should be understood that the exemplary modalities described in this document should be considered in a descriptive sense only and not for

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32/32 purposes of limitation. Descriptions of characteristics or aspects within each modality should typically be considered to be available for other characteristics or similar aspects in other modalities. Although one or more embodiments of the present invention have been described with reference to the figures, it will be understood by those of ordinary skill in the art that various changes in shape and details can be made in this document without departing from the spirit and scope of the present invention as defined by following claims.

Claims (14)

1. ORAL COMPOSITE TABLET, characterized by comprising: a portion of wet granules of ezetimibe including ezetimibe; and a mixture portion of rosuvastatin including rosuvastatin or a pharmaceutically acceptable salt thereof, wherein the portion of wet granules of ezetimibe includes, as a binder, povidone with an average molecular weight of about 30,000 to about 50,000, and a rosuvastatin blend 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 pm to about 229 pm corresponding to 90% in one cumulative particle size distribution of total particles. 2. TABLET according to claim 1, characterized in that the amount of the water-insoluble diluent is from about 2 parts to about 10 parts by weight with respect to 1 part by weight of rosuvastatin. 3. TABLET according to claim 1, characterized in that the wet granule portion of ezetimibe and the rosuvastatin mixture portion each additionally include a pharmaceutically acceptable additive selected from a binder, a disintegrant, a glidant and any combination of the same. 4. TABLET according to claim 3, characterized in that the binder is selected from the group consisting of povidone, hypromellose, hydroxypropylcellulose, copovidone and Petition 870190048896, of 05/24/2019, p. 42/98 2/4 any combination thereof, the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low substituted hydroxypropylcellulose, and any combination thereof, and the glidant is selected from the group consisting of stearate magnesium, talc, light anhydrous silicic acid, sodium stearyl fumarate and any combination thereof. 5. TABLET according to claim 1, characterized in that the water-insoluble diluent is selected from the group consisting of microcrystalline cellulose, starch, pregelatinized starch, dicalcium phosphate (DCP), low substituted hydroxypropylcellulose, and any combination thereof . 6. TABLET according to claim 1, characterized in that the water-soluble diluent is selected from the group consisting of lactose, mannitol, carboxymethylcellulose and any combination thereof. TABLET according to claim 1, characterized in that the mixture portion of rosuvastatin is in the form of a simple mixture or dry granules. 8. TABLET according to claim 1, characterized in that the oral composite tablet is in the form of a single-layer tablet, a double-layer tablet or a compression-coated tablet. 9. TABLET according to claim 1, characterized in that the dissolution rate of ezetimibe is about 90% or more in about 30 minutes at a temperature of about 37.5 ° C in a solution of acetate buffer sodium with a pH of about 4.5 containing about 0.45% lauryl Petition 870190048896, of 05/24/2019, p. 43/98 3/4 sodium sulfate, as measured with a paddle rotation speed of about 75 rpm in an oral composite tablet dissolution test performed according to Dissolution Method II in the Korean Pharmacopoeia. 10. TABLET according to claim 1, characterized in that the dissolution rate of ezetimibe is about 20% or more in about 30 minutes at a temperature of about 37.5 ° C in simulated gastric fluid (FGS) with a pH of about 1.2, as measured with a blade rotation speed of about 50 rpm in an oral composite tablet dissolution test performed according to Korean Pharmacopoeia Dissolution Method II. 11. TABLET according to claim 7, characterized in that a total amount of rosuvastatin lactone-related compounds is less than about 1.5%, as measured in an oral composite tablet stress test under stress conditions at a temperature of about 60 ° C for about 2 weeks. 12. TABLET according to claim 1, characterized in that an amount of ezetimibe is in the range of about 5 mg to about 20 mg in a unit dosage form. 13. TABLET according to claim 1, characterized in that an amount of rosuvastatin or a pharmaceutically acceptable salt thereof is in a range of about 2.5 mg to about 40 mg as a free base in a form of unit dosage. 14. METHOD OF PREPARING THE ORAL COMPOSITE TABLET, as defined in any one of claims 1 to 13, characterized by the method comprising: Petition 870190048896, of 05/24/2019, p. 44/98 4/4 preparing the wet granule portion of ezetimibe by wet granulating ezetimibe together with a pharmaceutically acceptable additive including, as a binder, povidone with an average molecular weight of about 30,000 to about 50,000; and preparing tablets with the wet granule portion of ezetimibe together with the mixing portion of rosuvastatin including rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive comprises a diluent that includes the water-soluble diluent and water-insoluble diluent, the water-insoluble diluent having a particle size (d90) of about 98 pm to about 229 pm corresponding to 90% in a cumulative particle size distribution of the total particles.