TW202224681A - Single dosage form of a pharmaceutical composition for the treatment or prevention of hypertension and hypercholesterolemia - Google Patents

Abstract

The present invention relates to a combined pharmaceutical formulation comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and this pharmaceutical composition may further comprises olmesartan medoxomil and amlodipine or a salt thereof. According to the present invention, a single dosage form of formulation is prepared by mixing a composition comprising drugs so as to minimize problems in regard to dissolution and absorption of drugs due to interaction between the drugs while ensuring stability and uniform dissolution rate of the drugs, whereby a formulation having biological equivalence as compared to the conventional single formulations can be obtained.

Description

Pharmaceutical composition in single dosage form for the treatment or prevention of hypertension and hypercholesterolemia

The present invention relates to a single-dosage pharmaceutical composition for treating hypertension and hypercholesterolemia.

Rosuvastatin is an HMG-CoA reductase inhibitor commonly used in the treatment of dyslipidemia and dyslipidemia-related diseases, such as hypercholesterolemia, hyperlipoproteinemia and atherosclerosis, and is currently Sold under the trade name Cresto Tablet ^(TM) . In order to improve the therapeutic effect of HMG-CoA reductase inhibitors on dyslipidemia, HMG-CoA reductase inhibitors are often used in combination with other therapeutic agents with mechanisms different from those described above.

Ezetimibe is a selective cholesterol absorption inhibitor and is marketed under the trade names EZETROL ^™ or ZETIA ^™ . Izetimibe has a mechanism of inhibiting cholesterol reabsorption in the small intestine and is known to exhibit beneficial therapeutic effects when used in combination with rosuvastatin, an HMG-CoA reductase inhibitor.

Therefore, rosuvastatin and ezetimibe are developed as a combination drug and Rosujet ^TM for the treatment of primary hypercholesterolemia is a representative product of the combination drug.

According to Korean Patent Publication No. 10-2014-0192374 (Patent Document 1), it is known that rosuvastatin is generally unstable in strong acid and thus is often designed as a pharmaceutical formulation together with an alkaline stabilizer. However, ezetimibe is unstable in a strong alkaline environment and generates many related substances, and therefore, it is said that it is difficult to ensure the stability of the active ingredient when manufacturing a combination drug of the above two drugs.

Meanwhile, many patients with dyslipidemia are also accompanied by hypertension, and thus, these patients generally receive treatment drugs for dyslipidemia and hypertension at the same time. Because it is advantageous for patients to receive a single dosage form of drug prescription, combination drugs have been actively developed for the treatment of both dyslipidemia and hypertension. For example, Caduet ^™ lozenge, which is a combination of atorvastatin and amlodipine as a combination formulation for the treatment of hypertension and hyperlipidemia, is typically prescribed to patients.

Drugs used as hypertension therapy may include, for example, olmesartan medoxomil and amlodipine.

Olmesartan medoxomil is an excellent angiotensin II receptor blocker (ARB) and is known to be useful as a medicine for the treatment or prevention of hypertension and heart disease. Olmesartan Medoxomil is currently marketed under the tradename Olmetech ^™ lozenges.

Amlodipine is a calcium channel blocker (CCB) and is known to be useful as a medicine for the treatment or prevention of hypertension and heart disease. Amlodipine is currently marketed under the tradename Novask ^™ .

Olmesartan medoxomil is an angiotensin II receptor blocker and is particularly useful in renin-dependent hypertension, while amlodipine has natriuretic effects and calcium channel prolongation such that it is useful in renin-independent hypertension . Accordingly, a combination drug of olmesartan medoxomil and amlodipine was developed to treat hypertension regardless of etiology, which is currently marketed under the trademark Sebica ^™ lozenges.

Meanwhile, the applicant of the present invention has disclosed a combined formulation comprising olmesartan medoxomil and rosuvastatin in Korean Patent Application No. 10-2013-0030734 (Patent Document 2). Currently, a combination drug comprising olmesartan medoxomil and rosuvastatin is marketed under the trade name Olostar Tablet ^(TM) .

In addition, the present applicant has disclosed a combined formulation comprising olmesartan medoxomil, amlodipine and rosuvastatin in Korean Patent Application No. 10-2019-0022739 (Patent Document 3). Currently, a combination drug comprising olmesartan medoxomil, amlodipine and rosuvastatin is marketed under the trade name Olomax Tablet ^(TM) .

When two or more drugs are used to make a combination drug, it is preferred that the combination drug have a dissolution and PK profile that is substantially equivalent to a control containing only the drugs.

Thus, a challenge in developing combination drugs has always been to achieve equivalence with reference drugs while maintaining the stability of two or more drugs. [Prior Art Literature] [Patent Literature]

Patent Document 1 - Korean Patent Publication No. 10-2014-0192374 Patent Document 2 - Korean Patent Application No. 10-2013-0030734 Patent Document 3 - Korean Patent Application No. 10-2019-0022739

[technical problem]

Accordingly, it is an object of the present invention to provide a combination formulation that minimizes the reduction in drug stability and drug interactions that occur during combination development, while ensuring equivalence with reference drugs. [Technical Solutions]

As a result of studying the formulation configuration of a combination drug comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, the inventors have found that by Particles of their salts and subsequent mixing of these particles with the outer phase of the particles to manufacture a pharmaceutical composition in a single dosage form can ensure the equivalence of each drug relative to a control drug while preventing damage to drug stability.

Accordingly, the present invention provides a single dosage form of a pharmaceutical composition ("pharmaceutical composition") comprising particles and an outer phase of the particles and comprising rosuvastatin or a salt thereof or ezetimibe or a salt thereof.

Specifically, the pharmaceutical composition of the present invention comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof may comprise rosuvastatin or a salt thereof and izetimibe or a salt thereof as active ingredients, wherein The active ingredient is contained in one or more of the particles and the outer phase of the particles.

Here, the term "particles" refers to granules or pellets prepared by micronizing all or part of a composition comprising a drug and additives. Additionally, the term "extra-particle phase" refers to the phase that exists outside the particles, ie, the post-mixed portion that is post-mixed with the pre-treated granules or pellets. In the present specification, "particles and external phase of particles" may also be interpreted as "particles and external phase of particles" or "pellets or external phase of pellets". In other words, when particles in the form of particles are used, particles and extra-particle phases refer to particles and extra-particle phases, respectively. Similarly, where pellet-type particles are used, the particle and the extra-particle phase refer to the pellet and the extra-pellet phase, respectively.

There is no particular limitation on whether rosuvastatin or a salt thereof and ezetimibe or a salt thereof are contained in the particle or the outer phase of the particle. The following descriptions are all included in the embodiments of the present invention.

when a portion of rosuvastatin or a salt thereof, and ezetimibe or a salt thereof are contained in the particle, and the remaining portion of the rosuvastatin or a salt thereof is contained in the outer phase of the particle;

when rosuvastatin or a salt thereof is contained in the particle and ezetimibe or a salt thereof is contained in the outer phase of the particle;

When a part of rosuvastatin or a salt thereof and a part of ezetimibe or a salt thereof are contained in the particles, and the rest of the rosuvastatin or its salt and the rest of the izetimibe or its salt are contained in the outer phase of the particles middle time

when ezetimibe or a salt thereof is contained in the particle and rosuvastatin or a salt thereof is contained in the outer phase of the particle;

when a portion of ezetimibe or a salt thereof is contained in the particles, and rosuvastatin or a salt thereof and the remaining portion of izetimibe or a salt thereof are contained in the outer phase of the particles;

Here, the sum of "part" and "remainder" represents the total amount of the corresponding drug contained in the pharmaceutical composition. For example, in the case where a part of the drug A is contained in the particle and the remaining part is contained in the outer phase of the particle, if the content of the drug A in the part is X parts by weight ("wt. parts"), when When the total amount of Drug A in the pharmaceutical composition is defined as 100 parts by weight, the content of the remainder of Drug A can be 100-X parts by weight. Similarly, in the case where a part of the drug B is contained in the particles and the remaining part is contained in the outer phase of the particles, if the content of the drug B in this part is Y parts by weight, when the total amount of the drug B in the pharmaceutical composition is When defined as 100 parts by weight, the content of the remainder of the drug B can be 100-Y parts by weight.

As described above, a pharmaceutical composition comprising a single dosage form of particles and an outer phase of the particles, rosuvastatin may be present only in the particles, however, may also be present in the outer phase of the particles.

In one embodiment, rosuvastatin or a salt thereof can be contained in both the particle and the extra-particle phase.

In one embodiment, the rosuvastatin or its salt contained in the particles may be 10 parts by weight or more based on a total of 100 parts by weight of the rosuvastatin or its salt contained in the pharmaceutical composition. For example, if the amount of rosuvastatin or its salt contained in the particles is 10 parts by weight based on 100 parts by weight of rosuvastatin or its salt contained in the pharmaceutical composition in total, the amount of rosuvastatin or its salt contained in the external phase of the particles is 10 parts by weight. The amount of suvastatin or a salt thereof may be 90 parts by weight based on a total of 100 parts by weight of rosuvastatin or a salt thereof contained in the pharmaceutical composition. On the other hand, if the amount of rosuvastatin or its salt contained in the particles is 90 parts by weight based on 100 parts by weight of rosuvastatin or its salt contained in the pharmaceutical composition in total, the amount of rosuvastatin or its salt contained in the external phase of the particles is 90 parts by weight. The amount of rosuvastatin or its salt contained may be 10 parts by weight based on 100 parts by weight of rosuvastatin or its salt contained in the pharmaceutical composition in total. The rosuvastatin or its salt contained in the particles may be present in an amount of 10 parts by weight or more, for example, 15, compared to 100 parts by weight of rosuvastatin or its salt contained in the pharmaceutical composition in total. parts by weight or more, 20 parts by weight or more, 25 parts by weight or more, 30 parts by weight or more, 35 parts by weight or more, 40 parts by weight or more, 45 parts by weight or more, 50 parts by weight parts by weight or more, 55 parts by weight or more, 60 parts by weight or more, 65 parts by weight or more, 70 parts by weight or more, 75 parts by weight or more, 80 parts by weight or more, 85 parts by weight or more, 90 parts by weight or more, 95 parts by weight or more, or 100 parts by weight.

More specifically, with respect to rosuvastatin or its salt contained in a total of 100 parts by weight of the pharmaceutical composition, the rosuvastatin or its salt contained in the particles may range from 10 to 100 parts by weight. In other words, the rosuvastatin or its salt contained in the particles can be in various numerical ranges within the range of 10 to 100 parts by weight to a total of 100 parts by weight of rosuvastatin or its salt contained in the pharmaceutical composition exist. Specifically, compared to 100 parts by weight of rosuvastatin or its salt contained in the pharmaceutical composition, the rosuvastatin or its salt contained in the particles may be present in, for example, 15 parts by weight or More to 100 parts by weight or less, 20 parts by weight or more to 95 parts by weight or less, 25 parts by weight or more to 90 parts by weight or less, 30 parts by weight or more to 90 parts by weight or less Less, 35 parts by weight or more to 90 parts by weight or less, 40 parts by weight or more to 100 parts by weight or less, 45 parts by weight or more to 100 parts by weight or less, 50 parts by weight or more to 100 parts by weight or less, 55 parts by weight or more to 95 parts by weight or less, 60 parts by weight or more to 90 parts by weight or less, 65 parts by weight or more to 95 parts by weight or less, 70 parts by weight or more to 100 parts by weight or less, 75 parts by weight or more to 100 parts by weight or less, 80 parts by weight or more to 100 parts by weight or less, 85 parts by weight or more to 100 Parts by weight or less, 90 parts by weight or more to 100 parts by weight or less, 95 parts by weight or more to 100 parts by weight, or 100 parts by weight.

In one embodiment of the present invention, a pharmaceutical composition comprising particles and an outer phase of the particles and comprising a single dosage form of rosuvastatin or a salt thereof and ezetimibe or a salt thereof, rosuvastatin or a salt thereof may comprise in the outer phase of the particle.

If rosuvastatin or its salt is contained in the outer phase of the particles, the amount of rosuvastatin or its salt contained in the outer phase of the particles is based on a total of 100 parts by weight of rosuvastatin or its salt in the pharmaceutical composition It may be 90 parts by weight or less.

Alternatively, with regard to a pharmaceutical composition comprising particles and an outer phase of the particles and comprising a single dosage form of rosuvastatin or a salt thereof and ezetimibe or a salt thereof, rosuvastatin or a salt thereof may only be included in the outer phase of the particles.

Likewise, with regard to a pharmaceutical composition comprising a single dosage form of particles and an outer phase of the particles, ezetimibe may be present only in the particles, however, may also be present in the outer phase of the particles.

In one embodiment of the present invention, a pharmaceutical composition comprising particles and an outer phase of the particles and comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof in a single dosage form may be included only in the particles and not in the outer phase of the particles Izetimibe or a salt thereof.

In another embodiment of the present invention, a pharmaceutical composition comprising particles and an outer phase of the particles and comprising rosuvastatin or a salt thereof and a single dosage form of ezetimibe or a salt thereof may comprise ezetimibe in the outer phase of the particles or its salt.

In one aspect of the invention, ezetimibe or a salt thereof may be contained in both the particle and the extra-particle phase.

In one embodiment, the ezetimibe or its salt contained in the particles may be 10 parts by weight or more based on a total of 100 parts by weight of the izetimibe or its salt contained in the pharmaceutical composition. For example, if the amount of ezetimibe or its salt contained in the particles is 10 parts by weight based on 100 parts by weight of izetimibe or its salt contained in the pharmaceutical composition in total, the ezetimibe or its salt contained in the external phase of the particles is 10 parts by weight. The amount of tilimibe or its salt may be 90 parts by weight based on 100 parts by weight of izetimibe or its salt contained in the pharmaceutical composition in total. On the other hand, if the amount of ezetimibe or its salt contained in the particles is 90 parts by weight based on 100 parts by weight of izetimibe or its salt contained in the pharmaceutical composition in total, the amount of izetimibe or its salt contained in the outer phase of the particles is 90 parts by weight The amount of ezetimibe or a salt thereof may be 10 parts by weight based on a total of 100 parts by weight of ezetimibe or a salt thereof contained in the pharmaceutical composition. The izetimibe or its salt contained in the particles may be present in an amount of 10 parts by weight or more, for example, 15, compared to 100 parts by weight of the izetimibe or its salt contained in the pharmaceutical composition in total. parts by weight or more, 20 parts by weight or more, 25 parts by weight or more, 30 parts by weight or more, 35 parts by weight or more, 40 parts by weight or more, 45 parts by weight or more, 50 parts by weight parts by weight or more, 55 parts by weight or more, 60 parts by weight or more, 65 parts by weight or more, 70 parts by weight or more, 75 parts by weight or more, 80 parts by weight or more, 85 parts by weight or more, 90 parts by weight or more, 95 parts by weight or more, or 100 parts by weight.

More particularly, with respect to izetimibe or its salt contained in a total of 100 parts by weight of the pharmaceutical composition, the izetimibe or its salt contained in the particles may range from 10 to 100 parts by weight. Izetimibe or a salt thereof contained in the particles may be present in various numerical ranges within the range of 10 to 100 parts by weight to a total of 100 parts by weight of ezetimibe or a salt thereof contained in the pharmaceutical composition. Specifically, compared to 100 parts by weight of ezetimibe or its salt contained in the pharmaceutical composition, the amount of ezetimibe or its salt contained in the particles may be, for example, 15 parts by weight or More to 100 parts by weight or less, 20 parts by weight or more to 95 parts by weight or less, 25 parts by weight or more to 90 parts by weight or less, 30 parts by weight or more to 90 parts by weight or less Less, 35 parts by weight or more to 90 parts by weight or less, 40 parts by weight or more to 100 parts by weight or less, 45 parts by weight or more to 100 parts by weight or less, 50 parts by weight or more to 100 parts by weight or less, 55 parts by weight or more to 95 parts by weight or less, 60 parts by weight or more to 90 parts by weight or less, 65 parts by weight or more to 95 parts by weight or less, 70 parts by weight or more to 100 parts by weight or less, 75 parts by weight or more to 100 parts by weight or less, 80 parts by weight or more to 100 parts by weight or less, 85 parts by weight or more to 100 Parts by weight or less, 90 parts by weight or more to 100 parts by weight or less, 95 parts by weight or more to 100 parts by weight, or 100 parts by weight.

In one embodiment of the present invention, a pharmaceutical composition comprising particles and an outer phase of the particles and comprising a single dosage form of rosuvastatin or a salt thereof and ezetimibe or a salt thereof, then ezetimibe or a salt thereof may comprise in the outer phase of the particle.

When ezetimibe or a salt thereof is contained in the outer phase of particles, the amount of ezetimibe or its salt contained in the outer phase of particles is based on a total of 100 parts by weight of ezetimibe or ezetimibe in the pharmaceutical composition. The salt thereof may be 90 parts by weight or less.

Alternatively, with regard to a pharmaceutical composition comprising particles and an outer phase of the particles and comprising a single dosage form of rosuvastatin or a salt thereof and ezetimibe or a salt thereof, izetimibe or a salt thereof may be included only in the outer phase of the particles.

The pharmaceutical composition of a single dosage form comprising particles and an extra-particle phase and comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof may be characterized as not comprising a co-solvent for ezetimibe or a salt thereof. Because izetimibe is an insoluble drug, co-solvents such as sodium lauryl sulfate have been used in izetimibe granules in the prior art. For example, Korean Patent Publication No. 10-2019-0109892 describes that when the amount of co-solvent used is 15 to 30 to 100 parts by weight of ezetimibe, the stability and desired dissolution of ezetimibe can be ensured Rate. However, since cosolvents such as sodium lauryl sulfate are surfactants, it is not advisable to use the above compounds in large quantities in medicine. The present invention does not use any co-solvent in the manufacture of particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, thereby ensuring advantages in terms of stability.

In one embodiment of the present invention, the pharmaceutical composition comprising particles and an outer phase of the particles and comprising a single dosage form of rosuvastatin or a salt thereof and ezetimibe or a salt thereof may additionally comprise one or more selected from the group consisting of Disintegrants of the group: crospovidone, sodium croscarmellose, sodium starch glycolate and low-substituted hydroxypropyl cellulose.

Although not limited thereto, regarding the pharmaceutical composition comprising particles and an outer phase of the particles and comprising a single dosage form of rosuvastatin or its salt and ezetimibe or its salt, the disintegrant is included in an amount based on a total of 100 parts by weight of the pharmaceutical composition The material may be 10 to 60 parts by weight, for example, 15 to 55 parts by weight, 20 to 50 parts by weight. More particularly, as a disintegrant, 3 to 15 parts by weight of crospovidone, 3 to 20 parts by weight of croscarmellose sodium, 3 to 15 parts by weight of crospovidone, 3 to 20 parts by weight of sodium starch glycolate, or 10 to 40 parts by weight of low-substituted hydroxypropyl cellulose.

Additionally, the pharmaceutical composition comprising particles and an extra-particle phase and comprising a single dosage form of rosuvastatin or a salt thereof and ezetimibe or a salt thereof may additionally comprise one or more binders selected from the group consisting of: Propylcellulose, povidone, copovidone and hypromellose. The binder may be included in an amount of 3 to 15 parts by weight to a total of 100 parts by weight of the pharmaceutical composition.

The pharmaceutical composition comprising particles and an outer phase of the particles and comprising a single dosage form of rosuvastatin or a salt thereof and ezetimibe or a salt thereof may additionally comprise calcium hydrogen phosphate hydrate, calcium phosphate anhydrous, calcium carbonate or mixtures thereof. When the pharmaceutical composition comprises calcium hydrogen phosphate hydrate, calcium phosphate anhydrous, calcium carbonate, or a mixture thereof, the stability of the formulation can be ensured.

In one embodiment, regarding a total of 100 parts by weight of a pharmaceutical composition comprising particles and an outer phase of the particles and comprising rosuvastatin or a salt thereof and ezetimibe or a single dosage form of a salt thereof, calcium hydrogen phosphate hydrate, anhydrous Calcium phosphate, calcium carbonate, or a mixture thereof may be included in an amount of 3 to 20 parts by weight, eg, 3 to 14 parts by weight, 3 to 10 parts by weight, and the like.

The pharmaceutical composition according to the present invention may additionally contain excipients, disintegrants, additives, and the like in addition to the corresponding drug.

Excipients can include, for example, lactose (including hydrates), dextrin, mannitol, sorbitol, starch, microcrystalline cellulose (eg, Celphere ^™ ), silicified microcrystalline cellulose (eg, Prosolv ^™ ), phosphoric acid Calcium hydrate, calcium phosphate anhydrous, calcium carbonate, sugar, or mixtures thereof.

Other additives may include, for example, binders, slip agents, colorants, and the like. Binders may include, for example, polyvinylpyrrolidone, povidone, gelatin, starch, sucrose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylcellulose Alkyl cellulose (eg hydroxypropyl methylcellulose) and mixtures thereof. Slip agents may include, for example, stearic acid, stearate salts (eg, magnesium stearate), talc, corn starch, carnauba wax, hardened anhydrous silicic acid, magnesium silicate, synthetic aluminum silicate, hardened oils , white wax, titanium dioxide, microcrystalline cellulose, macrogol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate and mixtures thereof.

A pharmaceutical composition comprising particles and an extra-particle phase and comprising a single dosage form of rosuvastatin or a salt thereof and ezetimibe or a salt thereof may have the dosage form of a lozenge. For example, the pharmaceutical composition described above may be a monolayer tablet formulation comprising granules and an extragranular phase and comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof.

Although not limited thereto, the above formulations can be obtained by preparing granules containing rosuvastatin and/or ezetimibe, mixing the granules with an extragranular phase, and then compressing the mixture using a tablet press. Rosuvastatin and/or ezetimibe-containing granules can be prepared by dry granulation or wet granulation by any conventional method. In one embodiment, granules comprising rosuvastatin or a salt thereof and/or ezetimibe or a salt thereof may be prepared by wet granulation. Since ezetimibe is an insoluble drug, it is preferable to use ethanol as the solvent for mixing, rather than water, during wet granulation. Also, a speed mixer is preferably used for the combination. This facilitates the dissolution and dispersion of ezetimibe.

Although not limited thereto, the mixture after inclusion of the particulate and extra-granular phase may meet conditions wherein the Hausner ratio is 1.34 or less, the compressibility index is 25% or less, and the angle of repose is 40° or less.

In another embodiment, a pharmaceutical composition according to the present invention comprising a dosage form of mini-lozenges can be prepared by preparing a mini-lozenge containing rosuvastatin or a salt and/or ezetimibe or a salt thereof, and then Manufactured by filling the capsules with the above mini lozenges together with the powder corresponding to the post-mix portion.

In another embodiment, the pharmaceutical composition of the pellet-containing capsule type according to the present invention can be prepared by preparing pellets containing rosuvastatin or a salt thereof and/or ezetimibe or a salt thereof, and then Manufactured by filling capsules with the above-mentioned pellets together with the powder corresponding to the post-mixed portion.

Herein, pellets comprising rosuvastatin or a salt thereof and/or ezetimibe or a salt thereof may be prepared by placing beads (eg, non-pareil) in a fluidized In a bed-type coating apparatus; dissolving rosuvastatin or its salt and/or ezetimibe or its salt, excipients (diluents), binders and disintegrants in a suitable solvent (such as ethanol and methanol) solvent mixture) to prepare a coating solution; and then coating the beads with the coating solution. Here, the viscosity of the coating solution is preferably from 5 mPa.s to 100 mPa.s.

If desired, a pharmaceutical composition comprising particles and an outer phase of the particles and comprising a single dosage form of rosuvastatin or a salt thereof and ezetimibe or a salt thereof may be coated with a coating agent. In one embodiment, the pharmaceutical composition may be a single-layer tablet coated with a coating. Coatings may include, for example, conventional polymers such as Opadry ^™ . Specifically, the film coating layer may include, for example, polyvinyl alcohol (PVA), polyvinyl alcohol copolymer, hydroxypropyl methylcellulose (HEMC), and the like. Examples of polyvinyl alcohol copolymers may include, but are not limited to, PVA/polyethylene glycol (macrogol) graft polymers. In one embodiment, the pharmaceutical composition of the present invention may be a single-layer tablet coated with polyvinyl alcohol or polyvinyl alcohol copolymer. The amount of film coating agent to be used is preferably the smallest amount that provides the optimum formulation size, but is not particularly limited.

On the other hand, according to the present invention, salts of rosuvastatin may include typical and pharmaceutically acceptable salts such as calcium salts, hydrochloride salts, hydrobromide salts, sulfate salts, phosphate salts, acetate salts, maleic acid salts salt, fumarate, lactate, tartrate, citrate, gluconate, besylate, camphorsulfonate, etc., preferably rosuvastatin calcium.

According to the present invention, salts of ezetimibe may include typical and pharmaceutically acceptable salts such as calcium, hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate acid salts, lactate salts, tartrate salts, citrate salts, gluconate salts, benzenesulfonate salts, camphorsulfonate salts, and the like.

Although not limited thereto, rosuvastatin or a salt thereof and ezetimibe or a salt thereof may have appropriately adjusted particle sizes.

When micronization of drug particle size is required, the particles can be pulverized using typical mills such as Z-mills, hammer mills, ball mills, fluid energy mills, and the like for micronization of drug particles. In addition, the particle size of the drug can be subdivided by a sieving method using a sieve or a size classification method such as air classification. Methods for adjusting the desired particle size are well known in the art. See, for example, the following: [Pharmaceutical dosage forms: volume 2, 2nd edition, Ed.: H.A. Lieberman, L. Lachman, J.B. Schwartz (Chapter 3: SIZE REDUCTION)].

In the present specification, the particle size of the drug may be expressed in terms of particle size distribution such as D(X)=Y (where X and Y are positive numbers). In d(X)=Y, when the particle size distribution of the drug obtained by measuring the particle size of the drug in the formulation is represented by a cumulative curve, Y represents the sum of the cumulative particle diameters in which the particle size of the drug is in the order of the smallest particle The result is the particle size at X% (% is calculated by number, volume or weight). For example, D(10) represents the particle size in which the particle size of the drug is accumulated in the order of the smallest particle and the result is 10%; D(50) represents the particle size in which the particle size of the drug is accumulated in the order of the smallest particle. The particle diameter when it becomes 50%; and D(90) represents the particle diameter when the particle diameter of the drug is 90% as a result of accumulating particle diameters in the order of the smallest particles.

Whether the particle size distribution d(X) represents the percentage of total accumulated particles by number, volume or weight may depend on the method used to measure the particle size distribution. Methods of measuring particle size distribution and the type of percentage (%) associated therewith are known in the art. For example, when the particle size distribution is measured by the well-known laser diffraction method, X in D(X) represents a percentage calculated as a volume average. It is well known to those skilled in the art that particle size distribution measurements obtained by a particular method can be correlated with results obtained from other techniques empirically through routine experimentation. For example, laser diffraction can provide a volume average particle size of the reactive particle volume that corresponds to the weight average particle size at constant density.

In the present invention, the measurement of the particle size distribution of the drug particles can be carried out by any commercially available device and the laser diffraction/scattering method according to the Mie theory. For example, the measurement is performed using a commercially available device such as the Mastersizer laser diffraction device manufactured by Malvern Instruments. The device is characterized in that when the particles are irradiated with a HeNe laser beam and a blue light emitting diode, scattering occurs and a light scattering pattern appears on the detector, and the particle size distribution is obtained by analyzing the above light scattering pattern according to Mie theory . The measurement method used here can be dry or wet.

Although not limited thereto, in the case of rosuvastatin or a salt thereof, D(90) may be 5 to 50 μm, preferably 15 to 40 μm, more preferably 20 to 35 μm. In addition, in the case of ezetimibe or a salt thereof, D(90) may be 5 to 60 μm, preferably 5 to 45 μm. When the particle sizes of rosuvastatin or a salt thereof or ezetimibe or a salt thereof are within the above ranges, respectively, it can be appropriately indicated that the degree of dissolution rate of the drug is equal to that of the control drug and/or the blood concentration compared with the control drug - Area under the curve over time (AUC) and maximum serum concentration ( _Cmax ) at bioequivalence.

The pharmaceutical composition comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof in a single dosage form comprising particles and an external phase of the particles can be used for the treatment or prevention of primary hypercholesterolemia.

A pharmaceutical composition comprising rosuvastatin or a salt thereof and izetimibe or a salt thereof in a single dosage form comprising particles and an external phase of the particles can be used in patients in need of simultaneous administration of rosuvastatin and izetimibe.

Compared to rosuvastatin or its salt contained in Cresto ^™ lozenges, a pharmaceutical composition comprising rosuvastatin or its salt and ezetimibe or its salt in a single dosage form comprising particles and an external phase of the particles can show The dissolution rate of rosuvastatin or its salts to an equivalent degree.

The rosuvastatin or its salt contained in the pharmaceutical composition exhibits substantial blood concentration-time area under the curve (AUC) and maximum serum concentration ( _Cmax ) compared to Cresto ^™ lozenges with the same active ingredient dose. to the bioequivalence level.

In addition, a pharmaceutical composition comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof in a single dosage form comprising particles and an extra-particle phase can be shown to be substantially equivalent to the ezetimibe contained in Ezetrol ^™ lozenges dissolution rate. In addition, ezetimibe in the pharmaceutical composition exhibited a substantially biologically equal area under the blood concentration-time curve (AUC) and maximum serum concentration ( _Cmax ) compared to Ezetrol ^™ lozenges with the same active ingredient dose degree of effectiveness.

Therefore, the pharmaceutical composition of the present invention is particularly useful for patients requiring simultaneous administration of rosuvastatin and ezetimibe.

Regarding the pharmaceutical composition of the present invention, active ingredients such as rosuvastatin or a salt thereof, ezetimibe, olmesartan medoxomil, amlodipine or a salt thereof, and the like may be used in a therapeutically effective amount thereof. A therapeutically effective amount may depend on the patient's symptoms, age, weight, disease severity, or the like.

Although not limited thereto, for example, rosuvastatin or a salt thereof may be used in an amount of about 2 mg to about 40 mg, preferably about 2.5 mg to about 20 mg, based on a unit formulation (ie, unit dosage form). Additionally, ezetimibe or a salt thereof may be used in an amount of about 5 mg to 20 mg, preferably about 10 mg, based on the unit formulation (ie, unit dosage form).

In one embodiment, the pharmaceutical composition of the present invention may include 40 mg of rosuvastatin or a salt thereof, and 20 mg of ezetimibe or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 40 mg of rosuvastatin or a salt thereof, and 10 mg of ezetimibe or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 40 mg of rosuvastatin or a salt thereof, and 5 mg of ezetimibe or a salt thereof.

In one embodiment, the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, and 20 mg of ezetimibe or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, and 10 mg of ezetimibe or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, and 5 mg of ezetimibe or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, and 20 mg of ezetimibe or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, and 10 mg of ezetimibe or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, and 5 mg of ezetimibe or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, and 20 mg of ezetimibe or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, and 10 mg of ezetimibe or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may comprise 5 mg of rosuvastatin or a salt thereof, and 5 mg of ezetimibe or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 2.5 mg of rosuvastatin or a salt thereof, and 20 mg of ezetimibe or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 2.5 mg of rosuvastatin or a salt thereof, and 10 mg of ezetimibe or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 2.5 mg of rosuvastatin or a salt thereof, and 5 mg of ezetimibe or a salt thereof.

The present invention can additionally provide a pharmaceutical composition in a single dosage form, comprising:

A compartment comprising particles and an extra-particle phase comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof; and a compartment comprising olmesartan medoxomil and amlodipine or a salt thereof, wherein the formulations are separated from each other Waiting room.

Compartments comprising particles and an extra-particle phase containing rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and the description of the individual drugs included in the particles and the extra-particle phase are substantially the same as those for containing rosuvastatin or its salt The salt is the same as the pharmaceutical composition of a single dosage form of ezetimibe or a salt thereof comprising particles and an external phase of the particles, and therefore, the description of overlapping subject matter will be omitted.

When making combination formulations of multiple drugs, it is difficult to ensure both dissolution rate and bioequivalence while avoiding drug-drug interactions. However, since the formulation is produced by separately manufacturing a compartment comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof comprising particles and an extra-particle phase, and another comprising olmesartan medoxomil and amlodipine or a salt thereof One compartment, the inventors have surprisingly obtained a compound that prevents interactions between individual drugs (i.e. rosuvastatin, ezetimibe, olmesartan medoxomil and amlodipine), presenting similarities to the control drugs formulations that are bioequivalent compared to some control drugs.

As mentioned above, "particles" refer to granules or pellets prepared by micronizing all or part of the composition comprising the drug and additives during formulation. Furthermore, "extra-particle phase" means the phase that exists outside the particles, ie the post-mixed portion that is post-mixed with the pre-treated granules or pellets. Thus, "particles and extra-particle phases" may also be interpreted as "particles and extra-granular phases" or "pellets or extra-pellet phases". In other words, when particles in the form of particles are used, particles and extra-particle phases refer to particles and extra-particle phases, respectively. Similarly, where pellet-type particles are used, the particle and the extra-particle phase refer to the pellet and the extra-pellet phase, respectively.

The compartment comprising the particle and the outer phase of the particle and comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof may comprise rosuvastatin or a salt thereof and izetimibe or a salt thereof as active ingredients, wherein these are effective. The ingredient may be included in one or more of the particle and the extra-particle phase.

In the compartment comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof comprising the particles and the outer phase of the particles, rosuvastatin may be present only in the particles, or may also be present in the outer phase of the particles.

Similarly, in a compartment comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof comprising particles and an extra-particle phase, izetimibe may be present only in the particles, or may also be present in the extra-particle phase .

The pharmaceutical compositions of the present invention may have individual compartment dosage forms such as bilayer lozenges, lozenges containing inner cores (tablet-in-tablet, "Tab-in-Tab"), mini-tablets doses, or capsules containing pellets, or the like.

According to one embodiment of the present invention, the pharmaceutical composition may be in the form of a bilayer lozenge consisting of: a layer comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof; and a layer comprising Another layer of olmesartan medoxomil and amlodipine or a salt thereof.

In one embodiment of the present invention, the pharmaceutical composition of the present invention may comprise: a Tab-in-Tab formulation having an inner core comprising rosuvastatin or a salt thereof and ezetimibe and a shell comprising olmesartan medoxomil and amlodipine or a salt thereof; or a lozenge-in-a-lozenge formulation having an inner core comprising olmesartan medoxomil and amlodipine or a salt thereof and a core comprising rosuvastatin or a salt thereof and The shell of ezetimibe or its salt.

In another embodiment, the pharmaceutical composition of the present invention may comprise: a capsule formulation comprising: a mini-lozenge comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and a capsule comprising olmesartan Esters and amlodipine or a mini-lozenge of a salt thereof; a capsule formulation comprising: a mini-lozenge comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and a mini-lozenge comprising olmesartan medoxomil and ammonia Pellets or powder of clodipine or a salt thereof; a capsule formulation comprising: mini-lozenges comprising olmesartan medoxomil and amlodipine or a salt thereof, and rosuvastatin or a salt thereof and ezetimibe pellets or powders thereof, or a salt thereof; or a capsule formulation comprising: pellets comprising olmesartan medoxomil and amlodipine or a salt thereof, and rosuvastatin or a salt thereof and ezetimibe or its Pellets of salt.

Although not limited thereto, according to one embodiment of the present invention, a pharmaceutical composition may include: a compartment comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof comprising granules and an extragranular phase; and a compartment comprising Compartment of olmesartan medoxomil and amlodipine or its salts. For example, the pharmaceutical composition can be a bilayer lozenge.

In addition, granules containing rosuvastatin or a salt thereof and ezetimibe or a salt thereof can be prepared by wet granulation using ethanol.

Although not limited thereto, the mixture after including the particulate and extra-granular phases may meet conditions wherein the Hausner ratio is 1.34 or less, the compressibility index (C.I.) is 25% or less, and the angle of repose is 40° or less.

According to one embodiment of the present invention, in a compartment comprising a particle and an extra-particle phase comprising rosuvastatin or a salt and ezetimibe or a salt thereof, the extra-particle phase may comprise rosuvastatin or a salt thereof.

Although not limited thereto, the included amount of rosuvastatin or a salt thereof in the particle external phase may be 25 to 90 parts by weight of rosuvastatin or a salt thereof included in a total of 100 parts by weight of the pharmaceutical composition, for example , 30 to 90 parts by weight, 40 to 90 parts by weight or 50 to 90 parts by weight.

In one embodiment of the present invention, rosuvastatin or a salt thereof may be included in the external phase of the particle in an amount of 25 to 90 parts by weight (for example) 60 to 85 parts by weight for a total of 100 parts by weight of the pharmaceutical composition Rosuvastatin or its salt included in it.

Similarly, in a compartment comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof comprising particles and an extra-particle phase, izetimibe may be present only in the particles, or may also be present in the extra-particle phase .

According to one aspect of the present invention, in the compartment comprising the particles and the outer phase of the particles containing rosuvastatin or a salt thereof and izetimibe or a salt thereof, izetimibe or a salt thereof may be included only in the particles But not included in the outer phase of the particle.

According to another aspect of the present invention, in a compartment comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof comprising particles and an outer phase of the particles, the outer phase of the particles may comprise ezetimibe or a salt thereof .

In one aspect of the invention, ezetimibe or a salt thereof may be included in both the particle and the extra-particle phase.

According to one aspect of the present invention, in a compartment comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof comprising a particle and an extra-particle phase, the outer phase of the particle may comprise ezetimibe or a salt thereof.

If ezetimibe or a salt thereof is included in the external phase of the particles, the amount of ezetimibe or a salt thereof included in the external phase of the particles is relative to a total of 100 parts by weight of ezetimibe or a salt thereof in the pharmaceutical composition It may be 90 parts by weight or less.

Although not limited thereto, the included amount of ezetimibe or a salt thereof in the particle external phase may be 25 to 90 parts by weight to a total of 100 parts by weight of ezetimibe or a salt thereof in the pharmaceutical composition, for example, 30 to 90 parts by weight, 40 to 90 parts by weight or 50 to 90 parts by weight.

Alternatively, in a compartment comprising rosuvastatin or a salt thereof and izetimibe or a salt thereof comprising particles and an extra-particle phase, izetimibe or a salt thereof may be included only in the extra-particle phase.

As described above, the compartment comprising the particles and the outer phase of the particles containing rosuvastatin or a salt thereof and ezetimibe or a salt thereof may not include a co-solvent for ezetimibe or a salt thereof.

In one aspect of the invention, the compartment comprising the particles and the extra-particle phase comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof may additionally comprise one or more selected from the group consisting of Disintegrants: crospovidone, croscarmellose sodium, sodium starch glycolate and low-substituted hydroxypropyl cellulose. Although not limited thereto, with respect to a total of 100 parts by weight of a compartment comprising particles and an extra-particle phase containing rosuvastatin or a salt thereof and ezetimibe or a salt thereof, the disintegrant included therein may be, for example, 3 To 15 parts by weight of crospovidone, 3 to 20 parts by weight of sodium croscarmellose, 3 to 20 parts by weight of sodium starch glycolate, or 10 to 40 parts by weight of low-substituted hydroxypropyl cellulose.

According to one aspect of the invention, the compartment comprising the particles and the extra-particle phase comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof may additionally comprise one or more binders selected from the group consisting of Agents: hydroxypropyl cellulose, povidone, hypromellose and copovidone.

Although not limited thereto, the included amount of the binder may be 3 to 15 parts by weight to a total of 100 parts by weight of the compartment including the particles and the outer phase of the particles containing rosuvastatin or a salt thereof and ezetimibe or a salt thereof. As shown in the following examples, if the above range is exceeded, it may not be desirable in terms of the dissolution rate of ezetimibe.

The compartment comprising the particles and the outer phase of the particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof may additionally comprise calcium hydrogen phosphate hydrate, calcium phosphate anhydrous, calcium carbonate or mixtures thereof. Formulation stability can be ensured when calcium hydrogen phosphate hydrate, anhydrous calcium phosphate, calcium carbonate, or mixtures thereof are included in the compartment.

In one embodiment, with respect to a total of 100 parts by weight containing rosuvastatin or a salt thereof and ezetimibe or a compartment thereof comprising particles and an extra-particle phase, calcium hydrogen phosphate hydrate, calcium phosphate anhydrous, carbonic acid Calcium or a mixture thereof may be included in an amount of 3 to 20 parts by weight, eg, 3 to 14 parts by weight, 3 to 10 parts by weight, and the like.

The compartment comprising the particles and the outer phase of the particles containing rosuvastatin or a salt thereof and ezetimibe or a salt thereof may additionally include excipients, disintegrants, additives, and the like in addition to the above-mentioned drugs.

Examples of excipients may include lactose (including hydrates), dextrin, mannitol, sorbitol, starch, microcrystalline cellulose (eg, Celphere ^™ ), silicified microcrystalline cellulose (eg, Prosolv ^™ ), calcium phosphate Hydrate, anhydrous calcium phosphate, calcium carbonate, sugar, or mixtures thereof.

Examples of other additives may include binders, slip agents, colorants, and the like. Binders can include, for example, polyvinylpyrrolidone, povidone, gelatin, starch, sucrose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylalkyl Cellulose (eg hydroxypropyl methylcellulose) and mixtures thereof. Slip agents may include, for example, stearic acid, stearate salts (eg, magnesium stearate), talc, corn starch, carnauba wax, hardened anhydrous silicic acid, magnesium silicate, synthetic aluminum silicate, hardened oils , white wax, titanium dioxide, microcrystalline cellulose, macrogol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate and mixtures thereof.

Meanwhile, the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof may additionally comprise two or more disintegrants selected from the group consisting of: pregelatinized starch, croscarmellose Sodium, Crospovidone, Calcium Carmellose, Sodium Starch Glycolate, Copovidone and Combination Silicates.

Although not limited thereto, the disintegrant may be included in an amount of 5 to 60 parts by weight to a total of 100 parts by weight of the compartment including olmesartan medoxomil and amlodipine or a salt thereof.

Regarding a total of 100 parts by weight of the compartment including olmesartan medoxomil and amlodipine or a salt thereof, 4 to 40 parts by weight of pregelatinized starch, 1 to 10 parts by weight of croscarmellose sodium, Or 1 to 20 parts by weight of crospovidone.

On the other hand, the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof may comprise calcium hydrogen phosphate hydrate.

The included amount of the calcium hydrogen phosphate hydrate may be 1 to 30 parts by weight to a total of 100 parts by weight of the compartment including olmesartan medoxomil and amlodipine or a salt thereof.

In addition to the above-mentioned calcium hydrogen phosphate hydrate and disintegrant, the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof may additionally comprise suitable excipients and additives. Examples of excipients may include lactose (including hydrates), dextrin, mannitol, sorbitol, starch, microcrystalline cellulose (eg, Celphere ^™ ), silicified microcrystalline cellulose (eg, Prosolv ^™ ), calcium phosphate Hydrate, anhydrous calcium phosphate, calcium carbonate, sugar, or mixtures thereof. Other additives may include, for example, binders, slip agents, colorants, and the like. Binders can include, for example, polyvinylpyrrolidone, povidone, gelatin, starch, sucrose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylalkyl Cellulose (eg hydroxypropyl methylcellulose) and mixtures thereof. Slip agents may include, for example, stearic acid, stearate salts (eg, magnesium stearate), talc, corn starch, carnauba wax, hardened anhydrous silicic acid, magnesium silicate, synthetic aluminum silicate, hardened oils , white wax, titanium dioxide, microcrystalline cellulose, macrogol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate and mixtures thereof.

In one embodiment, the pharmaceutical composition of the present invention in the form of a bilayer lozenge can be prepared according to any conventional method by individually preparing particles and particles containing rosuvastatin or a salt thereof and ezetimibe or a salt thereof A mixture of the external phase and a mixture of olmesartan medoxomil and amlodipine or a salt thereof, and then, were produced by compressing the mixture using a bilayer tablet press.

Alternatively, each drug is first processed into granules and then compressed using a bilayer tablet press. For example, olmesartan medoxomil/amlodipine besylate granules and rosuvastatin/izetimibe granules can be produced by dry granulation or wet granulation, respectively, according to conventional methods.

If necessary, the resulting bilayer lozenge may be coated with a film coating such as Opadry ^(TM) .

Specifically, there is provided a pharmaceutical composition in a single dosage form, comprising: a compartment comprising particles and an extra-particle phase comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof; and a compartment comprising olmesartan medoxomil and amlodipine or a salt thereof, wherein the compartments are formulated in isolation from each other.

In another embodiment, the pharmaceutical composition in the form of a lozenge according to the present invention can be prepared by forming an inner core lozenge comprising particles and an outer phase of the particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof , if necessary, forming a film coating as described above, and then, using a single tablet press (EKO, Korsch) or the like, to compress the resulting inner core tablet together with olmesartan medoxomil and amlodipine or granules of its salt. Here, an inner core lozenge comprising particles and an outer phase of the particles containing rosuvastatin or a salt thereof and ezetimibe or a salt thereof is prepared by dry granulation or wet granulation, for example, comprising rosuvastatin or Its salt and granules of ezetimibe or its salt, the prepared granules are mixed with the outer phase of the granules, and then, produced using a continuous tablet press (Piccola D-8, RIVA) or the like containing the mixture. If necessary, the resulting lozenge-in-lozenge may be coated with a film coating such as Opadry ^™ or the like.

In another embodiment, a pharmaceutical composition comprising a dosage form of mini lozenges according to the present invention is manufactured by a method similar to that described above for the preparation of core lozenges comprising olmesartan medoxomil/aminochloride Mini lozenges of dipine or its salts and/or mini lozenges comprising rosuvastatin or its salts and ezetimibe or its salts, and then, with the mini lozenges prepared above together with rosuvastatin or its salts Mini lozenges, pellets or powders of salt and ezetimibe, or filled capsules with mini lozenges, pellets or powders containing olmesartan medoxomil/amlodipine or its salts.

In another embodiment, the pharmaceutical composition in the form of capsules containing pellets according to the present invention can be prepared by separately preparing olmesartan medoxomil/amlodipine besylate pellets and rosuvastatin/izetidine Mibe granules, and then filled with capsules of the pellets and granules prepared above are manufactured.

In another embodiment, the pharmaceutical composition in the form of a pellet-containing capsule according to the present invention can be prepared by separately preparing olmesartan medoxomil/amlodipine besylate granules and rosuvastatin/izetimibe Shell pellets were then manufactured by filling capsules with the granules and pellets prepared above.

In this case, the olmesartan medoxomil/amlodipine besylate pellets can be coated with olmesartan medoxomil by placing the beads (eg, non-pareil) in a fluid bed coater Tan ester, amlodipine, excipients (diluents), binders, and disintegrants are dissolved in an appropriate solvent (eg, a mixed solvent of water and methanol) to prepare a coating solution, and then, coated with the coating solution beads to form. The viscosity of the coating solution is preferably in the range of 5 mPa.s to 100 mPa.s.

When the pharmaceutical composition of the present invention is formed into a tablet, the tablet may be coated with a coating. In one embodiment, the pharmaceutical composition of the present invention may be a bilayer lozenge or a lozenge-in-lozenge. Coatings (eg, film coatings) may include typical polymers such as Opadry ^™ . Film coating agents used herein may include polyvinyl alcohol copolymers, hydroxypropyl methylcellulose (HPMC), and the like. Examples of polyvinyl alcohol copolymers may include, but are not limited to, PVA/polyethylene glycol (macrogol) graft polymers. In one embodiment, the pharmaceutical composition of the present invention may be a bilayer lozenge or a lozenge-in-lozenge coated with polyvinyl alcohol, polyvinyl alcohol copolymer. The amount of film-coating agent used is preferably the smallest amount that can achieve the optimum formulation size, and is not particularly limited.

Meanwhile, according to the present invention, rosuvastatin may include typical and pharmaceutically acceptable salts such as calcium salt, hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate salt, lactate, tartrate, citrate, gluconate, benzenesulfonate, camphorsulfonate, etc., preferably rosuvastatin calcium.

According to the present invention, salts of ezetimibe may include typical and pharmaceutically acceptable salts such as calcium, hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, rich Maleate, lactate, tartrate, citrate, gluconate, benzenesulfonate, camphorsulfonate, and the like.

In addition, according to the present invention, the salts of amlodipine can include pharmaceutically acceptable and common salts, for example, benzenesulfonate, hydrochloride, hydrobromide, fumarate, citrate, tartaric acid can be used salt, maleate, cancylate, lactate, mesylate, camphorsulfonate, gluconate, and the like. Preferably, amlodipine besylate is used.

Although not limited thereto, rosuvastatin or a salt thereof, ezetimibe or a salt thereof, olmesartan medoxomil, and amlodipine or a salt thereof may each have an appropriately adjusted particle size.

Although not limited thereto, rosuvastatin or a salt thereof may have a D(90) of 5 to 50 μm, preferably 15 to 40 μm, more preferably 20 to 35 μm. Likewise, ezetimibe or a salt thereof may have a D(90) of 5 to 60 μm. Olmesartan medoxomil may have a D(90) of 5 to 45 μm, preferably 5 to 30 μm. In addition, amlodipine or a salt thereof may have a D(90) of 5 to 100 μm, preferably 10 to 60 μm, more preferably 15 to 45 μm.

When rosuvastatin or a salt thereof, ezetimibe or a salt thereof, olmesartan medoxomil, and amlodipine or a salt thereof, respectively, had particle sizes within the above-mentioned ranges, each of these compounds was less than the control drug. The drug dissolution rate and/or the area under the blood concentration-time curve (AUC) and the maximum serum concentration ( _Cmax ) at substantially bioequivalent levels may be presented as appropriate.

A pharmaceutical composition in a single dosage form, comprising: a compartment comprising particles and an outer phase of particles comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof; and a compartment comprising olmesartan medoxomil and amlodipine or its Compartments of salt, wherein the compartments are formulated while being separated from each other.

The pharmaceutical composition of the present invention can be used for patients requiring simultaneous administration of rosuvastatin, ezetimibe, olmesartan medoxomil and amlodipine.

In fact, the combination drug of olmesartan medoxomil and amlodipine is currently used for essential hypertension, a disease in which blood pressure cannot be ideally regulated by monotherapy with amlodipine or olmesartan medoxomil. In addition, rosuvastatin is used for the treatment of hypercholesterolemia, hyperlipoproteinemia and/or atherosclerosis. In addition, ezetimibe is used for the treatment of primary hypercholesterolemia.

The combination of rosuvastatin and ezetimibe is also used to treat primary hypercholesterolemia. Information about individual drug applications is well known.

The present invention can provide a pharmaceutical composition in which rosuvastatin or a salt thereof has a dissolution rate at a bioequivalent level compared to the dissolution rate of rosuvastatin contained in Cresto ^™ lozenges. In this regard, whether the dissolution rate represents the degree of equivalence can be determined according to the management regulations of drug equivalence tests.

In addition, the present invention can provide a pharmaceutical composition in which ezetimibe or a salt thereof has a dissolution rate at a bioequivalent level compared to the dissolution rate of ezetimibe contained in Ezetrol ^™ lozenges.

In addition, the present invention can provide a pharmaceutical composition in which rosuvastatin or a salt thereof has a dissolution rate at a bioequivalent level compared to the dissolution rate of rosuvastatin contained in Rosujet ^™ lozenges.

In addition, the present invention can provide a pharmaceutical composition in which ezetimibe or a salt thereof has a dissolution rate at a bioequivalent level compared to the dissolution rate of izetimibe contained in Rosujet ^™ lozenges.

In addition, the present invention can provide a pharmaceutical composition in which olmesartan medoxomil has a dissolution rate at a bioequivalent level compared to the dissolution rate of olmesartan medoxomil contained in a Sebica ^™ lozenge.

In addition, the present invention can provide a pharmaceutical composition in which amlodipine or a salt thereof has a dissolution rate at a bioequivalent level compared to the dissolution rate of amlodipine or a salt thereof contained in a Sebica ^™ lozenge.

The ezetimibe and rosuvastatin calcium salts in the pharmaceutical composition of the present invention are characterized by exhibiting substantially bioequivalent levels of blood compared to Cresto ^™ lozenges and Ezetrol ^™ lozenges having the same active ingredient doses Area under the concentration-time curve (AUC) and maximum serum concentration ( _Cmax ).

The ezetimibe and rosuvastatin calcium salts in the pharmaceutical composition of the present invention are characterized by blood concentration-time profiles that exhibit a substantially bioequivalent degree compared to Rosujet ^™ lozenges with the same active ingredient dose Lower area (AUC) and maximum serum concentration ( _Cmax ).

Olmesartan medoxomil and amlodipine or salts thereof in the pharmaceutical composition of the present invention are characterized by exhibiting a substantially bioequivalent degree of blood concentration-time as compared to Sebica ^™ lozenges having the same active ingredient dose. Area under the curve (AUC) and maximum serum concentration ( _Cmax ).

Therefore, the pharmaceutical composition of the present invention is particularly useful for patients who require simultaneous administration of a combination drug of amlodipine and olmesartan medoxomil and a combination drug of rosuvastatin and ezetimibe.

Regarding the pharmaceutical composition of the present invention, the active ingredient (ie, rosuvastatin or a salt thereof, ezetimibe, olmesartan medoxomil, amlodipine or a salt thereof, etc.) may be used in a therapeutically effective amount. A therapeutically effective amount may depend on the patient's symptoms, age or weight, the severity of the disease, or the like.

Although not limited thereto, for example, based on a unit formulation (ie, unit dosage form), rosuvastatin or a salt thereof may be used in an amount of about 2 mg to about 40 mg, preferably about 2.5 mg to about 20 mg, and ezetimibe The usage amount of the salt thereof may be about 5 mg to 20 mg, preferably about 10 mg. Additionally, olmesartan medoxomil may be used in an amount of about 5 mg to about 80 mg, preferably about 10 mg to about 40 mg, based on the unit formulation (ie, unit dosage form). Additionally, amlodipine or a salt thereof may be used in an amount of about 2.5 mg to about 10 mg based on the unit formulation (ie, unit dosage form).

In one embodiment, the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 20 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 10 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.

In another embodiment, the pharmaceutical composition of the present invention may include 2.5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof .

In another embodiment, the pharmaceutical composition of the present invention may include 2.5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof .

In another embodiment, the pharmaceutical composition of the present invention may include 2.5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof .

In another embodiment, the pharmaceutical composition of the present invention may include 2.5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof .

In another embodiment, the pharmaceutical composition of the present invention may include 2.5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof .

In another embodiment, the pharmaceutical composition of the present invention may include 2.5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof .

The pharmaceutical composition of the present invention can be orally administered once a day, but is not limited thereto. [Beneficial effect]

As described above, according to the present invention, stability and uniform dissolution rate can be ensured by mixing the drug-containing compositions and then formulating the mixture into a single dosage form, while solving the problems of dissolution and absorption due to interactions between drugs This is minimized, thereby obtaining formulations that are biologically equivalent compared to conventional single formulations.

[Best Mode] [Example]

Hereinafter, the present invention will be illustrated in more detail in the following examples. However, the following examples are only intended to illustrate the content of the present invention, and are not intended to limit or limit the scope of the present invention. Those skilled in the art that can easily infer from the detailed description and examples of the present invention are deemed to belong to the scope of the present invention.

[Preparation example] Preparation Examples 1 to 7: Preparation of Granules Containing Rosuvastatin and Izetimibe

Each of the pharmaceutical compositions comprising rosuvastatin calcium/izetimibe was prepared according to any conventional method with the constituent compositions in Table 1 below. Additionally, the formulations in the Preparation Examples were prepared with varying levels of rosuvastatin calcium in the post-mix section as follows. Wet granules were prepared and ground according to the constituent compositions of the granule fraction shown in Table 1. Film-coated tablets are produced by mixing the milled granules and the post-mix portion, obtaining a post-mix, compressing, and then film-coating with Opadry ^™ .

[Experimental example] Experimental Example 1: Measurement of Physical Properties of Particulate Parts Containing Rosuvastatin/Izetimibe or Its Salt

Regarding the post-mixtures including particles and extra-particle phases obtained in Preparations 1 to 7, particle size distribution, density and angle of repose were measured.

The measurement results are shown in Table 2 below.

From the above test results, it was confirmed that even if the ratio of rosuvastatin in the post-mixed portion was increased, similar particle physical properties were observed without significant effects on particle size distribution, density and angle of repose. To ensure productivity during ingot pressing, the Hausner ratio ranges from 1 to 1.34, the compression index (C.I.) is 25% or less, and the angle of repose ranges from about 35 to 40°. In this regard, since all of Preparations 1 to 7 showed a Hausner ratio of 1.34 or less, a C.I. of 25% or less, and an angle of repose of 40°, it was confirmed that the products of the above-mentioned preparations achieved excellent productivity.

Experimental Example 2: Dissolution Test

Comparative dissolution tests were performed on the formulations prepared in the present preparations under the following dissolution test conditions.

As control drugs used in the comparative dissolution test, 20 mg of Cresto Tablet ^TM (rosuvastatin), 10 mg of Ezetrol Tablet ^TM (izetimibe), 10/40 mg of Sebica Tablet ^TM (amlodipine besylate) salt/olmesartan medoxomil), and 10/20 mg of Rosujet Tablet ^™ (ezetimibe/rosuvastatin calcium).

Cresto Tablet( ^TM) , Sebica Tablet ^(TM) , and Rosujet Tablet ^(TM) each have a film-coated single tablet form, while Ezetrol Tablet ^(TM) is an open-cell form.

Cresto Tablet ^™ contains microcrystalline cellulose, lactose hydrate, tricalcium phosphate, crospovidone and magnesium stearate as excipients and additionally contains hypromellose, triacetin , titanium dioxide and iron oxide as film coating agents.

Ezetrol Tablet ^™ contains lactose hydrate, magnesium stearate, povidone, microcrystalline cellulose, sodium lauryl sulfate and croscarmellose sodium as excipients.

Sebica Tablet ^™ contains silicified microcrystalline cellulose, pregelatinized starch, croscarmellose sodium and magnesium stearate as excipients, and additionally contains polyvinyl alcohol, macrogol/polyethylene Diol 3350, titanium dioxide, talc and iron oxide were used as film coating agents.

In addition, Rosujet Tablet ^TM contains lactose hydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate, D-mannitol, crospovidone and magnesium stearate as excipients. excipients, and other hypromellose, polyethylene glycol 6000, talc, iron oxide and titanium dioxide as film coating agents.

[Dissolution test conditions]

Dissolution Solution: Water, pH 6.8, Solution 1 + 0.5% Polysorbate 80, in Korean Pharmacopoeia Disintegration Test Method

Olmesartan medoxomil, amlodipine besylate: water

Rosuvastatin calcium: pH 6.8

Izetimibe: Solution 1, pH 1.2 + 0.5% Polysorbate 80

Temperature: 37 ± 0.5 °C

Test method: Korean Pharmacopoeia Dissolution Test Method No. 2 (paddle method)

Blade speed: 50 rpm

Analysis method: UPLC method

(*) UPLC operating conditions

Column: ACQUITY UPLC BEH C18 (2.1 × 50 mm 1.7 μm)

Detector: UV Absorption Photometer (249 nm)

Flow rate: 0.3 mL/min

Analysis time: 10 minutes

Mobile phase: Phosphate buffer/acetonitrile = 60/40

Dissolution test results for the formulations are shown in the table below.

All formulations in Preparations 1 to 7 showed that when the post-mix ratio of rosuvastatin calcium was increased, the dissolution rate at 5 minutes increased, and the dissolution rate was generally higher than that of the control drug, while the dissolution rate was substantially equivalent to degree. In addition, it was confirmed that the ratio of rosuvastatin calcium contained in the izetimibe particle fraction had little effect on the dissolution of izetimibe, and the dissolution rate was substantially equivalent to that of the control drug.

For the determination of similarity in the comparative dissolution test, refer to Article 21 of Chapter 3 of the Ministry of Food and Drug Safety Notice No. 2017-28 (Ministry of Food and Drug Safety Notice No. 2017-28, Chapter 3, Article 21). If when the mean dissolution rate of the control drug is 85% or greater, the deviation is within ±15%, otherwise when the mean dissolution rate of the control drug is 85% or greater, close to the 60% or 85% dissolution rate region , the deviation is within ±15%, it can be judged as equivalent.

Preparation Examples 8 to 14: Preparation of Film-Coated Bilayer Lozenges Comprising Olmesartan/Amlodipine Composition and Rosuvastatin/Izetimibe Composition Separately

A pharmaceutical composition comprising olmesartan medoxomil/amlodipine besylate and a pharmaceutical composition comprising rosuvastatin calcium/izetimibe were prepared respectively using the constituent compositions and according to conventional methods, followed by lamination of two layers Tablet press to form bilayer lozenges. Thereafter, the formed tablet is processed by a coating device to produce a film-coated tablet.

In Preparation Examples 8 to 14, after preparing granules containing olmesartan medoxomil and amlodipine besylate and granules containing rosuvastatin calcium/izetimibe, respectively, the two granules were permeated through tableting A bilayer tablet is formed, followed by a film coating method.

The results of dissolution testing of the above formulations are shown in the table below.

When using croscarmellose as the disintegrant and hydroxypropyl cellulose as the binder as shown in Preparation 8, the dissolution was most similar to the control. In addition, it was confirmed that all the dissolutions in Preparation Examples 8 to 12 were substantially equivalent to the control drug. On the other hand, it was proved that ezetimibe in Preparation Example 13 was not equivalent to the control drug, while Preparation Example 14 showed that the initial dissolution of the two components was lower due to the increased disintegration time of the lozenge, thus confirming that the dissolution rate was not equal to degree of effectiveness.

Olmesartan medoxomil in Preparation Examples 8 to 14 showed a higher dissolution rate than the control drug. Additionally, amlodipine besylate dissolves by 85% or greater within 15 minutes, demonstrating that dissolution is similar to the control drug.

Preparation Examples 15 to 18: Preparation of film-coated bilayer tablets, changing the binder solvent and additives according to the composition in Preparation Example 8

Using the constituent compositions in Table 10 and according to conventional methods, a pharmaceutical composition comprising olmesartan medoxomil/amlodipine besylate and a pharmaceutical composition comprising rosuvastatin calcium/izetimibe were prepared, respectively, A bilayer tablet press is then pressed to form a bilayer tablet. Thereafter, the formed tablet is processed by a coating device to produce a film-coated tablet.

The results of dissolution testing and stability testing of the above formulations are shown below.

As in Preparation Example 8 and Preparation Examples 16 to 18, in the case where ethanol was used as the binder solvent, it was confirmed that the dissolution rate of the above two components was substantially equivalent to that of the control drug. In addition, acceptable results were obtained in stability tests. Furthermore, when calcium phosphate hydrate was added to the constituent composition, acceptable results were confirmed in the stability test.

Experimental Example 3: Bioequivalence Test

The formulation of Preparation Example 5 was subjected to a pharmacokinetic test (PK test) to evaluate its bioequivalence with a control drug.

Specifically, 24 test subjects (participants) were divided into 2 groups with 12 people in each group, wherein the first group was orally administered with the lozenge of Preparation Example 5, while the second group received oral administration of 20 mg of Cresto lozenge ( rosuvastatin) in combination with a 10 mg lozenge of Ezetrol. Blood was collected at 0, 0.33, 0.67, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 48, and 72 hours after administration and rosuva was quantified, respectively Blood concentrations of statins and izetimibe. After quantification, AUC and Cmax of rosuvastatin and izetimibe at the time of administration of control drug (combination administration) and test drug, respectively, were statistically processed to assess bioequivalence between formulations.

The results of the bioequivalence assessment performed above are shown in Table 14 below. In Table 14, the T/R ratio is calculated by dividing the geometric mean of the evaluation items of the test formulation by the geometric mean of the evaluation items of the control formulation (ie, T/R ratio=geometric mean of the evaluation items ( Geometric mean (control) of test formulation)/assessed item] is obtained. If the T/R ratio is higher than 1, it means that the mean absorption of the test drug is greater than that of the control drug, or that the maximum serum concentration of the test drug is on average higher On the contrary, if the T/R ratio is less than 1, it means that the absorption of the test drug is on average lower than that of the control drug, or that the blood concentration of the test drug is on average lower than that of the control drug. In other words, as T The /R ratio is getting further and further away from 1, with a high probability of being determined to be biologically non-equivalent. As shown in Table 14, Preparation Example 5 is close to a T/R ratio of 1 and thus determined to be biologically equivalent.

Experimental Example 4: Bioequivalence Test

The formulation of Preparation Example 8 was subjected to a pharmacokinetic test (PK test) to evaluate its bioequivalence with a control drug.

Specifically, the 24 test subjects were divided into 2 groups of 12 people in each group, wherein the first group was orally administered the lozenge of Preparation Example 8, while the second group received the oral administration of 10/20 mg of Sebica lozenge (ammonium chloride) orally. Dipine besylate/olmesartan medoxomil) in combination with Rosujet lozenges of 10/20 mg. Blood was collected at 0, 0.33, 0.67, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 48, and 72 hours after administration and olmesartan was quantified, respectively , amlodipine, rosuvastatin, and ezetimibe blood concentrations. After quantification, the AUC and Cmax of olmesartan, amlodipine, rosuvastatin and izetimibe at the time of administration of the control drug (combination administration) and the test drug, respectively, were statistically processed to assess the performance of the formulations. bioequivalence between.

The results of the bioequivalence assessment performed above are shown in Table 15 below. In Table 15, the T/R ratio was calculated by dividing the geometric mean of the evaluation items for the test formulation by the geometric mean of the evaluation items for the control formulation (ie, T/R ratio=geometric mean of the evaluation items ( Geometric mean (control) of test formulation)/assessed item] obtained. If the T/R ratio is greater than 1, it means that the mean absorption of the test drug is greater than that of the control drug, or that the maximum serum concentration of the test drug is greater than the mean Control drug. On the contrary, if the T/R ratio is less than 1, it means that the absorption of the test drug is on average lower than that of the control drug, or that the blood concentration of the test drug is on average lower than that of the control drug. In other words, with T/R The R ratio is getting further and further away from 1, with a high probability of being determined to be biologically non-equivalent. As shown in Table 15, Preparation 8 is close to a T/R ratio of 1 and thus determined to be biologically equivalent.

[ FIG. 1 ] illustrates the results of the bioequivalence test on rosuvastatin calcium salt comparing the formulation in Preparation Example 5 with a control drug. [ FIG. 2 ] illustrates the results of the bioequivalence test on ezetimibe comparing the formulation in Preparation Example 5 with the control drug.

Claims (66)

A single dosage form pharmaceutical composition comprising Particles and extra-particle phases and comprise rosuvastatin or a salt thereof and ezetimibe or a salt thereof. The pharmaceutical composition of claim 1, wherein the content of rosuvastatin or a salt thereof contained in the particles is 10 parts by weight based on a total of 100 parts by weight of rosuvastatin or a salt thereof in the pharmaceutical composition ( "parts by weight (wt. parts)") or more. The pharmaceutical composition according to claim 1, wherein the content of rosuvastatin or a salt thereof contained in the particles ranges from 10 parts by weight to 100 parts by weight of rosuvastatin or a salt thereof in the pharmaceutical composition in total. 100 parts by weight. The pharmaceutical composition of claim 1, wherein the particle outer phase contains rosuvastatin or a salt thereof. The pharmaceutical composition according to claim 4, wherein the content of rosuvastatin or a salt thereof contained in the outer phase of the particles is 90 parts by weight or less. The pharmaceutical composition of claim 1, wherein the particle outer phase contains ezetimibe or a salt thereof. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition does not contain a cosolvent for ezetimibe or a salt thereof. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises one or more disintegrants selected from the group consisting of: crospovidone, sodium croscarmellose croscarmellose), sodium starch glycolate and low-substituted hydroxypropyl cellulose. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises 3 to 15 parts by weight of crospovidone, 3 to 20 parts by weight of crospovidone as a disintegrant based on a total of 100 parts by weight of the pharmaceutical composition Sodium carboxymethyl cellulose, 3 to 20 parts by weight of sodium starch glycolate, and 10 to 40 parts by weight of low-substituted hydroxypropyl cellulose. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises one or more binders selected from the group consisting of hydroxypropylcellulose, povidone, copovidone, and Hydroxypropyl methylcellulose (hypromellose). The pharmaceutical composition of claim 10, wherein the pharmaceutical composition comprises 3 to 15 parts by weight of hydroxypropyl cellulose, povidone, copovidone and hydroxypropyl cellulose as a binder based on a total of 100 parts by weight of the pharmaceutical composition propyl methylcellulose. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in the form of a lozenge. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a single-layer tablet coated with a coating agent. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is a single-layer tablet coated with polyvinyl alcohol, polyvinyl alcohol copolymer or hydroxypropyl methylcellulose (HPMC). The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has the dosage form of a monolayer lozenge comprising granules and an extragranular phase and comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof. The pharmaceutical composition of claim 15, wherein the granules comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof are prepared by wet granulation using ethanol. The pharmaceutical composition of claim 15, wherein the mixture after including the granules and the extragranular phase meets the conditions wherein the Hausner ratio is 1.34 or less, the compressibility index is 25% or less, and the angle of repose is 40° or less. The pharmaceutical composition of claim 1, wherein the salt of rosuvastatin is rosuvastatin calcium salt. The pharmaceutical composition of claim 1, wherein rosuvastatin or a salt thereof has a D(90) in the range of 5 to 50 μm. The pharmaceutical composition of claim 1, wherein ezetimibe or a salt thereof has D(90) in the range of 5 to 60 μm. The pharmaceutical composition of claim 1, wherein the particles are granules or pellets. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in the form of a monolayer tablet, or a capsule containing granules-, pellet- and/or mini-lozenges. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is used for the treatment or prevention of primary hypercholesterolemia. The pharmaceutical composition of claim 1, wherein rosuvastatin or a salt thereof in the pharmaceutical composition exhibits a dissolution rate equivalent to that of rosuvastatin in Cresto ^™ lozenges. The pharmaceutical composition of claim 1, wherein the rosuvastatin or a salt thereof in the pharmaceutical composition exhibits a blood concentration-time in a bioequivalent degree compared to a Cresto ^™ lozenge having the same active ingredient dose The area under the curve (AUC) and the maximum serum concentration ( _Cmax ). The pharmaceutical composition of claim 1, wherein the ezetimibe in the pharmaceutical composition has a dissolution rate equivalent to that of the izetimibe in Ezetrol ^™ lozenges. The pharmaceutical composition of claim 1, wherein the ezetimibe in the pharmaceutical composition exhibits a blood concentration-time curve at a bioequivalent level compared to Ezetrol ^™ lozenges having the same active ingredient dose Area (AUC) and maximum serum concentration ( _Cmax ). The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises the following amounts of rosuvastatin and ezetimibe based on the unit dosage form: 40 mg of rosuvastatin or a salt thereof and 20 mg of ezetimibe; 40 mg of rosuvastatin or its salt and 10 mg of ezetimibe; 40 mg of rosuvastatin or its salt and 5 mg of ezetimibe; 20 mg of rosuvastatin or a salt thereof and 20 mg of ezetimibe; 20 mg of rosuvastatin or its salt and 10 mg of ezetimibe; 20 mg of rosuvastatin or its salt and 5 mg of ezetimibe; 10 mg of rosuvastatin or its salt and 20 mg of ezetimibe; 10 mg of rosuvastatin or its salt and 10 mg of ezetimibe; 10 mg of rosuvastatin or a salt thereof and 5 mg of ezetimibe; 5 mg of rosuvastatin or its salt and 20 mg of ezetimibe; 5 mg of rosuvastatin or its salt and 10 mg of ezetimibe; 5 mg of rosuvastatin or its salt and 5 mg of ezetimibe; 2.5 mg of rosuvastatin or a salt thereof and 20 mg of ezetimibe; 2.5 mg of rosuvastatin or a salt thereof and 10 mg of izetimibe; or 2.5 mg of rosuvastatin or a salt thereof and 5 mg of ezetimibe. A single dosage form of a pharmaceutical composition comprising: A compartment comprising a particle and an outer phase of the particle and comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof; and a compartment comprising olmesartan medoxomil and amlodipine or a salt thereof compartments, wherein the compartments are formulated while being separated from each other. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is in the form of a bilayer lozenge, a lozenge containing an inner core, or a capsule containing mini lozenges and/or pellets. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is in the form of a bilayer lozenge, comprising: a layer comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof; and a layer comprising A layer of olmesartan medoxomil and amlodipine or a salt thereof. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition has a dosage form selected from the group consisting of: a tablet-in-tablet formulation comprising rosuvastatin or a salt thereof and ezetimibe an inner core and a shell comprising olmesartan medoxomil and amlodipine or a salt thereof; or a tablet-in-tablet formulation having an inner core comprising olmesartan medoxomil and amlodipine or a salt thereof and A shell containing rosuvastatin or a salt thereof and ezetimibe or a salt thereof. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition has a dosage form selected from the group consisting of: a capsule comprising: a mini-lozenge comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and a capsule comprising Mini lozenges of olmesartan medoxomil and amlodipine or a salt thereof; a capsule comprising: a mini lozenge comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, and a mini lozenge comprising olmesartan medoxomil and a salt thereof Pellets or powder of amlodipine or a salt thereof; a capsule comprising: mini-lozenges comprising olmesartan medoxomil and amlodipine or a salt thereof, and rosuvastatin or a salt thereof and ezetimibe or Pellets or powder of salts thereof; or a capsule comprising: pellets comprising olmesartan medoxomil and amlodipine or salts thereof, and pellets comprising rosuvastatin or salts thereof and ezetimibe or salts thereof grain. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition comprises: a compartment comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof, comprising granules and an extragranular phase; and comprising olmesartan medoxomil and Compartment of amlodipine or its salts. The pharmaceutical composition of claim 34, wherein the granules comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof are prepared by wet granulation using ethanol. The pharmaceutical composition of claim 34, wherein the mixture after including the granules and the extragranular phase meets the conditions wherein the Hausner ratio is 1.34 or less, the compressibility index is 25% or less, and the angle of repose is 40° or less. The pharmaceutical composition of claim 29, wherein the particle outer phase comprises rosuvastatin or a salt thereof. The pharmaceutical composition of claim 37, wherein the content of rosuvastatin or a salt thereof contained in the particle outer phase is 25 to 90 weight parts based on a total of 100 parts by weight of rosuvastatin or a salt thereof in the pharmaceutical composition share. The pharmaceutical composition of claim 37, wherein the content of rosuvastatin or a salt thereof contained in the particle outer phase is 60 to 85 weight parts based on a total of 100 parts by weight of rosuvastatin or a salt thereof in the pharmaceutical composition share. The pharmaceutical composition of claim 29, wherein the particle external phase comprises ezetimibe or a salt thereof. The pharmaceutical composition of claim 29, wherein the compartment comprising particles and an extra-particle phase and comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof does not include a cosolvent for ezetimibe or a salt thereof . The pharmaceutical composition of claim 29, wherein the particles and the outer phase of the particles are included and the compartment comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof additionally comprises one or more selected from the group consisting of Disintegrants: crospovidone, croscarmellose sodium, sodium starch glycolate and low-substituted hydroxypropyl cellulose. The pharmaceutical composition of claim 42, wherein the compartment comprising particles and an extra-particle phase and comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof based on a total of 100 parts by weight as a disintegrant is 3 to 15 parts by weight of crospovidone, 3 to 20 parts by weight of croscarmellose sodium, 3 to 20 parts by weight of sodium starch glycolate, and 10 to 40 parts by weight of low-substituted hydroxypropyl fibers white. The pharmaceutical composition of claim 29, wherein the particles and the outer phase of the particles are included and the compartment comprising rosuvastatin or a salt thereof and ezetimibe or a salt thereof additionally comprises one or more selected from the group consisting of Binders: hydroxypropyl cellulose, povidone, hydroxypropyl methyl cellulose and copovidone. The pharmaceutical composition of claim 44, wherein hydroxypropyl cellulose, povidone, copovidone, and hydroxypropyl methyl cellulose as binders are included in an amount based on a total of 100 parts by weight including particles and an outer phase of particles and The compartment containing rosuvastatin or a salt thereof and ezetimibe or a salt thereof is 3 to 15 parts by weight. The pharmaceutical composition of claim 29, wherein the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof additionally comprises calcium hydrogen phosphate hydrate. The pharmaceutical composition of claim 46, wherein the calcium hydrogen phosphate hydrate is contained in an amount of 1 to 30 parts by weight to a total of 100 parts by weight of the compartment containing olmesartan medoxomil and amlodipine or a salt thereof. The pharmaceutical composition of claim 29, wherein the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof further comprises two or more disintegrants selected from the group consisting of: pregelatinized starch , croscarmellose sodium, crospovidone, sodium carboxymethyl cellulose, sodium starch glycolate, copovidone and combined silicates. The pharmaceutical composition of claim 48, wherein the disintegrant is contained in an amount of 5 to 60 parts by weight to a total of 100 parts by weight of the compartment containing olmesartan medoxomil and amlodipine or a salt thereof. The pharmaceutical composition of claim 48, comprising 4 to 40 parts by weight of pregelatinized starch, 1 to 10 parts by weight based on a total of 100 parts by weight of the compartment comprising olmesartan medoxomil and amlodipine or a salt thereof of croscarmellose sodium and 1 to 20 parts by weight of crospovidone. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is a bilayer tablet or a tablet containing an inner core coated with a coating agent. The pharmaceutical composition of claim 51, wherein the pharmaceutical composition is a bilayer tablet or a tablet containing an inner core coated with polyvinyl alcohol, polyvinyl alcohol copolymer or hydroxypropyl methylcellulose (HPMC). The pharmaceutical composition of claim 29, wherein the salt of amlodipine is amlodipine besylate. The pharmaceutical composition of claim 29, wherein the salt of rosuvastatin is rosuvastatin calcium salt. The pharmaceutical composition of claim 29, wherein rosuvastatin or a salt thereof has a D(90) in the range of 5 to 50 μm. The pharmaceutical composition of claim 29, wherein ezetimibe or a salt thereof has D(90) in the range of 5 to 60 μm. The pharmaceutical composition of claim 29, wherein olmesartan medoxomil has a D(90) in the range of 5 to 45 μm. The pharmaceutical composition of claim 29, wherein amlodipine or a salt thereof has D(90) in the range of 5 to 100 μm. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is used for the treatment or prevention of hypertension and hypercholesterolemia. The pharmaceutical composition of claim 29, wherein the dissolution rate of amlodipine or a salt thereof in the pharmaceutical composition is equivalent to the dissolution rate of amlodipine or a salt thereof in the Sebica ^TM lozenge. The pharmaceutical composition of claim 29, wherein the dissolution rate of rosuvastatin or its salt in the pharmaceutical composition is equivalent to the dissolution rate of rosuvastatin or its salt in Rosujet ^™ lozenge. The pharmaceutical composition of claim 29, wherein the dissolution rate of ezetimibe or a salt thereof in the pharmaceutical composition is equivalent to the dissolution rate of ezetimibe in Rosujet ^™ lozenges. The pharmaceutical composition of claim 29, wherein olmesartan ^medoxomil and amlodipine or a salt thereof in the pharmaceutical composition exhibit a bioequivalent degree of Area under the blood concentration-time curve (AUC) and maximum serum concentration ( _Cmax ). The pharmaceutical composition of claim 29, wherein the rosuvastatin calcium salt in the pharmaceutical composition exhibits a bioequivalent level of blood concentration-time in comparison to Rosujet ^™ lozenges having the same active ingredient dose Area under the curve (AUC) and maximum serum concentration ( _Cmax ). The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is administered to the need for simultaneous administration of a combination drug comprising amlodipine and olmesartan medoxomil and another combination drug comprising rosuvastatin and ezetimibe of patients. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition comprises the following amounts of rosuvastatin, ezetimibe, olmesartan medoxomil, and amlodipine based on the unit dosage form: 20 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 10 mg of amlodipine or its salt; 20 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 5 mg of amlodipine or its salt; 20 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 10 mg of amlodipine or its salt; 20 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 5 mg of amlodipine or its salt; 20 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 10 mg of amlodipine or its salt; 20 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 5 mg of amlodipine or its salt; 10 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 10 mg of amlodipine or its salt; 10 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 5 mg of amlodipine or its salt; 10 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 10 mg of amlodipine or its salt; 10 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 5 mg of amlodipine or its salt; 10 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 10 mg of amlodipine or its salt; 10 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 5 mg of amlodipine or its salt; 5 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 10 mg of amlodipine or its salt; 5 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 5 mg of amlodipine or its salt; 5 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 10 mg of amlodipine or its salt; 5 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 5 mg of amlodipine or its salt; 5 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 10 mg of amlodipine or its salt; 5 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 5 mg of amlodipine or its salt; 2.5 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 40 mg of olmesartan medoxomil, and 10 mg of amlodipine or its salt; 2.5 mg of rosuvastatin or its salt, 10 mg of izetimibe, 40 mg of olmesartan medoxomil, and 5 mg of amlodipine or its salt; 2.5 mg of rosuvastatin or its salt, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 10 mg of amlodipine or its salt; 2.5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 20 mg of olmesartan medoxomil, and 5 mg of amlodipine or its salt; 2.5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 10 mg of amlodipine or a salt thereof; and 2.5 mg of rosuvastatin or a salt thereof, 10 mg of ezetimibe, 10 mg of olmesartan medoxomil, and 5 mg of amlodipine or a salt thereof.

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