阅读说明：本技术 包含依折麦布和瑞舒伐他汀的药物组合制剂 (Pharmaceutical combination preparation containing ezetimibe and rosuvastatin ) 是由 曹赫俊 金正贤 林昊泽 金用镒 于 2019-03-11 设计创作，主要内容包括：本发明涉及包含依折麦布和瑞舒伐他汀的药物组合制剂。所述药物组合制剂的水活度为0.40或更低。所述药物组合制剂还可以包含选自氨氯地平、氯沙坦、及其组合的一种或更多种成分,并且依折麦布分别与瑞舒伐他汀、氨氯地平和氯沙坦以物理分离的状态存在。(The present invention relates to a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin. The water activity of the pharmaceutical combination formulation is 0.40 or less. The pharmaceutical combination preparation may further comprise one or more ingredients selected from the group consisting of amlodipine, losartan, and a combination thereof, and ezetimibe is present in a physically separated state from rosuvastatin, amlodipine, and losartan, respectively.)

1. A pharmaceutical combination preparation comprising ezetimibe or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof,

wherein the water activity is 0.40 or less.

2. The pharmaceutical combination preparation according to claim 1,

wherein said ezetimibe or a pharmaceutically acceptable salt thereof and said rosuvastatin or a pharmaceutically acceptable salt thereof are present in a physically separated state.

3. The pharmaceutical combination preparation according to claim 2,

wherein said ezetimibe or a pharmaceutically acceptable salt thereof is present in the form of granules in admixture with said rosuvastatin or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical combination preparation according to claim 3,

wherein the particles comprising ezetimibe or a pharmaceutically acceptable salt thereof further comprise a solubilizer.

5. The pharmaceutical combination preparation according to claim 4,

wherein the solubilizer is sodium lauryl sulfate.

6. The pharmaceutical combination preparation according to claim 5,

wherein the weight ratio of sodium lauryl sulfate to ezetimibe in the particles comprising ezetimibe or a pharmaceutically acceptable salt thereof is from 0.15: 1 to 0.3: 1.

7. The pharmaceutical combination preparation according to claim 1,

wherein the pharmaceutical combination preparation further comprises one or more ingredients selected from the group consisting of: amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and combinations thereof.

8. The pharmaceutical combination preparation according to claim 7,

wherein the ezetimibe or a pharmaceutically acceptable salt thereof exists in a physically separated state from the rosuvastatin or a pharmaceutically acceptable salt thereof, the amlodipine or a pharmaceutically acceptable salt thereof, and the losartan or a pharmaceutically acceptable salt thereof, respectively.

9. The pharmaceutical combination preparation according to claim 8,

wherein the pharmaceutical combination formulation is present in the form of a bilayer tablet consisting of:

a first layer comprising the ezetimibe or a pharmaceutically acceptable salt thereof, the rosuvastatin or a pharmaceutically acceptable salt thereof, and the amlodipine or a pharmaceutically acceptable salt thereof; and

a second layer comprising the losartan or pharmaceutically acceptable salt thereof.

10. The pharmaceutical combination preparation according to claim 9,

wherein in the first layer, the ezetimibe or a pharmaceutically acceptable salt thereof is present in a mixture in the form of granules with the rosuvastatin or a pharmaceutically acceptable salt thereof, and the amlodipine or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical combination preparation according to claim 9,

wherein in the second layer the losartan or pharmaceutically acceptable salt thereof is present in the form of particles.

12. A method of preparing the pharmaceutical combination formulation of claim 1, comprising the steps of:

i) producing ezetimibe particles comprising ezetimibe or a pharmaceutically acceptable salt thereof;

ii) mixing the ezetimibe particles with rosuvastatin or a pharmaceutically acceptable salt thereof to produce a mixture;

iii) allowing the mixture to stand at a relative humidity of 15% to 25% to reduce the water activity to 0.40 or less; and

iv) tabletting the mixture with reduced water activity.

13. The method for preparing a pharmaceutical combination according to claim 12,

wherein in step ii) the rosuvastatin or a pharmaceutically acceptable salt thereof is mixed with the ezetimibe granule and amlodipine or a pharmaceutically acceptable salt thereof.

14. The method for preparing a pharmaceutical combination according to claim 12,

wherein step iv) comprises compression into a bilayer tablet consisting of: the mixture having a reduced water activity as a first layer and the losartan granules having a reduced water activity as a second layer.

15. The method for preparing a pharmaceutical combination according to claim 14,

wherein the losartan granules having reduced water activity are prepared by the steps of:

a) producing granules of losartan comprising losartan or a pharmaceutically acceptable salt thereof; and

b) the resulting losartan granules are allowed to stand under conditions of 15% to 25% relative humidity to reduce the water activity to 0.40 or less.

Technical Field

The present invention relates to a pharmaceutical combination preparation comprising ezetimibe (ezetimibe) and rosuvastatin (rosuvastatin). More particularly, the present invention relates to a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin, wherein the water activity is 0.40 or less.

Background

Rosuvastatin or a pharmaceutically acceptable salt thereof is one of HMG-CoA reductase inhibitors which inhibit cholesterol synthesis to treat dyslipidemia. Guanzhituo tablets (Crestor Tab.) (rosuvastatin calcium salt, AstraZeneca) containing rosuvastatin as a main component are widely used for treatment of dyslipidemia and related diseases at home and abroad. In particular, studies have shown that rosuvastatin has not only an excellent effect of lowering blood LDL cholesterol level compared to atorvastatin (atorvastatin) or simvastatin (simvastatin) which are generally used as drugs having the same mechanism, but also an excellent effect of increasing HDL cholesterol level for physical benefit. Thus, there is an increasing interest in the formulation of rosuvastatin.

HMG-CoA reductase inhibitors are generally administered in combination with other therapeutic agents for dyslipidemia having other mechanisms to enhance the therapeutic effect. HMG-CoA reductase inhibitors have excellent interaction with ezetimibe (a drug that inhibits cholesterol reabsorption in the small intestine), and therefore, research into a combined preparation having two components is active. For example, proleg tablets (Vytorin Tab), which are a combination formulation of simvastatin and ezetimibe, have demonstrated excellent pharmacological effects and stability, and are therefore excellent for sale in commercial use.

The superiority of pharmacological effects when administered in combination with ezetimibe in the case of rosuvastatin has been demonstrated by many studies (see non-patent documents 1 and 2). Therefore, there is a need to develop a combined preparation having excellent pharmaceutical properties as a combination of rosuvastatin and ezetimibe whose pharmacological effects have been demonstrated. Furthermore, in order to effectively treat cardiovascular diseases, a combined preparation comprising amlodipine (amlodipine) and/or losartan (losartan) in addition to rosuvastatin and ezetimibe is required. There is also a need to develop a combined preparation having excellent pharmaceutical properties, which comprises a combined preparation of rosuvastatin, ezetimibe, amlodipine and losartan.

[ Prior art documents ]

[ non-patent document ]

(non-patent document 1) Brandon Ason et al, J Lipid Res.Apr 2011; 52(4): 679-687

(non-patent document 2) Torimoto et al, Lipids in Health and Disease 2013, 12: 137

Disclosure of Invention

Technical problem

The present inventors have aimed to provide a pharmaceutical combination preparation having improved stability of active ingredients due to inhibition of impurity production by experimentally determining the correlation between water activity and impurities in a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin as active ingredients and providing a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin in which water activity is 0.40 or less.

Technical scheme

According to a first aspect of the present invention,

the present invention provides a pharmaceutical combination preparation comprising ezetimibe or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof, wherein the water activity is 0.40 or less.

In one embodiment of the present invention, ezetimibe or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are present in a physically separated state.

In one embodiment of the invention, ezetimibe or a pharmaceutically acceptable salt thereof is present in a mixture in the form of granules and rosuvastatin or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, the particles comprising ezetimibe or a pharmaceutically acceptable salt thereof further comprise a solubilizer.

In one embodiment of the invention, the solubilizing agent is sodium lauryl sulfate.

In one embodiment of the invention, the weight ratio of sodium lauryl sulfate to ezetimibe in the particles comprising ezetimibe or a pharmaceutically acceptable salt thereof is from 0.15: 1 to 0.3: 1.

In one embodiment of the invention, the pharmaceutical combination preparation further comprises one or more ingredients selected from the group consisting of: amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and combinations thereof.

In one embodiment of the present invention, ezetimibe or a pharmaceutically acceptable salt thereof is present in a physically separated state from rosuvastatin or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, respectively.

In one embodiment of the present invention, the pharmaceutical combination formulation is present in the form of a bilayer tablet consisting of: a first layer comprising ezetimibe or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof; and a second layer comprising losartan or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, in the first layer, ezetimibe or a pharmaceutically acceptable salt thereof is present in a mixture in the form of granules with rosuvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, in the second layer, losartan or a pharmaceutically acceptable salt thereof is present in the form of particles.

According to a second aspect of the present invention,

the present invention provides a method for preparing a pharmaceutical combination preparation, comprising the steps of: i) producing ezetimibe particles comprising ezetimibe or a pharmaceutically acceptable salt thereof; ii) mixing ezetimibe particles with rosuvastatin or a pharmaceutically acceptable salt thereof to produce a mixture; iii) allowing the mixture to stand at a relative humidity of 15% to 25% to reduce the water activity to 0.40 or less; and iv) tableting the mixture having reduced water activity.

In one embodiment of the invention rosuvastatin or a pharmaceutically acceptable salt thereof is mixed with ezetimibe granules and amlodipine or a pharmaceutically acceptable salt thereof in step ii).

In one embodiment of the invention, step iv) comprises compression into a bilayer tablet consisting of: a mixture having a reduced water activity as a first layer and losartan granules having a reduced water activity as a second layer.

In one embodiment of the present invention, losartan granules having reduced water activity are prepared by the steps of: a) producing granules of losartan comprising losartan or a pharmaceutically acceptable salt thereof; and b) allowing the resulting losartan granules to stand under conditions of 15% to 25% relative humidity to reduce the water activity to 0.40 or less.

The invention has the advantages of

The present invention provides a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin, in which water activity is 0.40 or less, thereby inhibiting the generation of impurities in the pharmaceutical combination preparation and enabling to improve the stability of active ingredients in the pharmaceutical combination preparation.

In addition, when a pharmaceutical combination preparation including amlodipine and losartan in addition to ezetimibe and rosuvastatin is provided, the stability and dissolution rate of active ingredients in the pharmaceutical combination preparation may be improved by physically separating ezetimibe from amlodipine, losartan, and rosuvastatin, respectively.

Brief Description of Drawings

Fig. 1 is a graph showing the bulk density and tap density measured on the products obtained immediately before tableting in examples 1,2, 8 and 9 and comparative examples 1 to 4.

Fig. 2 is a graph showing the hardness measured according to the tableting pressure for the products obtained immediately before tableting in examples 1 to 3 and 8 to 10 and comparative examples 1 to 6.

Fig. 3 is a graph showing the amount of impurities measured according to purification time for products having different water activities obtained from examples 3 and 10 and comparative examples 5 and 6.

Fig. 4 is a graph showing the dissolution rate of amlodipine measured according to purification time of the products obtained from examples 3 to 5 and comparative examples 7, 8 and 14.

Fig. 5 is a graph showing the dissolution rate of losartan as measured according to purification time for the products obtained from examples 3 to 5 and comparative examples 7, 8 and 15.

Fig. 6 is a graph showing the dissolution rate of rosuvastatin measured according to purification time of the products obtained from examples 3 to 5 and comparative examples 7, 8 and 16.

Fig. 7 is a graph showing the dissolution rate of ezetimibe measured according to purification time for the products obtained from examples 3 to 5 and comparative examples 7, 8 and 17.

Fig. 8 is a graph showing the dissolution rate of ezetimibe measured according to purification time from the products obtained in examples 3, 6 and 7 and comparative examples 12, 13 and 17.

Best mode for carrying out the invention

All the embodiments provided according to the present invention can be realized by the following description. It is to be understood that the following description describes certain preferred embodiments of the present invention and that the present invention is not limited thereto.

The invention provides a pharmaceutical combination preparation containing ezetimibe or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof.

The pharmaceutical combination preparation according to the present invention comprises ezetimibe or a pharmaceutically acceptable salt thereof as a first active ingredient. Ezetimibe exerts a primary cholesterol absorption inhibiting effect to treat and prevent arteriosclerosis. The daily dose of ezetimibe or a pharmaceutically acceptable salt thereof is 5mg to 15 mg.

The pharmaceutical combination preparation according to the present invention comprises rosuvastatin or a pharmaceutically acceptable salt thereof as a second active ingredient. Examples of pharmaceutically acceptable salts of rosuvastatin include, but are not limited to, calcium, magnesium, strontium, and the like, and rosuvastatin calcium salt is preferred. Rosuvastatin inhibits HMG-CoA reductase required for cholesterol synthesis to lower blood LDL cholesterol levels while increasing HDL cholesterol levels, thereby contributing to treatment of dyslipidemia. The daily dose of rosuvastatin or pharmaceutically acceptable salt thereof is 10mg to 20 mg.

In a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin as active ingredients, the water activity may influence the production of impurities of the pharmaceutical combination preparation during storage. Since the water activity of a pharmaceutical combination formulation cannot be determined at all by measuring the water content or density of the pharmaceutical combination formulation, the correlation between water activity and impurities is less predictable by other physical properties, and such correlation may also be present in quite different forms depending on the kind of active ingredient. In view of these points, the characteristics of water activity and impurities may be more important in the pharmaceutical combination formulation of the present invention. In addition, since it is difficult for the general manufacturing method of the pharmaceutical combination preparation to satisfy the water activity standard required in the present invention, a separate method is required to control the water activity. According to one embodiment of the present invention, the water activity of the pharmaceutical combination formulation may be 0.40 or less, preferably 0.35 or less, more preferably 0.30 or less. Water activity refers to the availability of water (i.e., free water) in a sample (water availability), which can be used by microorganisms for growth. As described above, it is difficult to determine water activity by a general water content test. In the case of a general water content test, both free water and bound water are measured, whereas in the case of a water activity test, only free water directly related to stability, crystal form, moisture migration, and the like of the main ingredient is measured. Therefore, a more accurate measurement is required in the water activity test, and the correlation with impurities can be determined only by the water activity thus measured. Specifically, water activity herein is measured using a water activity meter (Labmaster, novasina). In the pharmaceutical combination preparation comprising ezetimibe and rosuvastatin according to the present invention, impurities attributed to specific ingredients increase with increasing water activity. The impurity that increases at a significant level with increasing water activity in the pharmaceutical combination formulation may be EP impurity D produced by rosuvastatin. If the water activity of the pharmaceutical combination formulation is greater than 0.40, it may easily exceed the ICH guidelines for impurities, depending on the storage conditions. Therefore, for the stability of the pharmaceutical combination formulation, the water activity should be controlled to 0.40 or less, which is evaluated by the water activity rather than the general water content. The method for controlling the water activity of the pharmaceutical combination formulation is not particularly limited, but the water activity of the pharmaceutical combination formulation according to the present invention may be controlled by allowing the pharmaceutical combination formulation to stand under the condition of a certain level of relative humidity for a certain period of time. According to an embodiment of the present invention, in order to control the water activity of the pharmaceutical combination formulation to 0.40 or less, the pharmaceutical combination formulation may be left to stand under the condition of 15% to 25% relative humidity for 6 hours or more, preferably 8 to 15 hours. When the water activity of the pharmaceutical combination preparation is controlled according to the above conditions, the water activity can be effectively controlled while minimizing physical and chemical changes of the pharmaceutical combination preparation.

Since ezetimibe and rosuvastatin, which are active ingredients in a pharmaceutical composition preparation, have different stable pH conditions, they may cause stability problems of the active ingredients, such as an increase in impurities of ezetimibe and rosuvastatin, when prepared into a pharmaceutical composition preparation. In the case of rosuvastatin, the production of impurities such as the following, which are the main metabolites, may be increased: (3R, 6E) -7- [4- (4-fluorophenyl) -2- (N-methylmethanesulfonylamino) -6- (prop-2-yl) pyrimidin-5-yl ] -3-hydroxy-5-oxo-hept-6-enoic acid calcium salt (hereinafter referred to as "5-oxo impurity") or N- [4- (4-fluorophenyl) -6- (1-methylethyl) -5- [ (1E) -2- [ (2S, 4R) -tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl ] vinyl ] -2-pyrimidinyl ] -N-methylmethanesulfonamide (hereinafter referred to as "lactone impurity"). Therefore, it may be preferable that ezetimibe and rosuvastatin exist in a physically separated state. Herein, the physically separated state means a state in which the reference active ingredient remains distinguished from other active ingredients in the final pharmaceutical combination preparation obtained by the processing steps performed to separate the reference active ingredient from other active ingredients. However, this does not include the case where the ingredients themselves are mixed into the mixing process in advance without performing this processing step. The state of physical separation can be achieved by, for example, physical separation using granulation, physical separation by multilayer tableting, physical separation by individually tableting each tablet, physical separation using a core-shell structure, and the like. According to one embodiment of the present invention, to physically separate ezetimibe from rosuvastatin, ezetimibe may be processed into a separate particle form and then mixed with rosuvastatin. At this time, in the case where a state in which the active ingredient (rosuvastatin) other than ezetimibe is substantially absent in the particles is maintained as in the processing step even after the completion of the pharmaceutical combination preparation, even if an interface where ezetimibe and rosuvastatin are in contact is present on the surface of each ezetimibe particle in the pharmaceutical combination preparation, it can be considered that ezetimibe and rosuvastatin are present in a physically separated state in the pharmaceutical combination preparation as described in the present invention. In another embodiment, the pharmaceutical combination preparation is obtained by mixing rosuvastatin and amlodipine with the produced ezetimibe granules after the granulation process of ezetimibe. At this time, in the case where other active ingredients (rosuvastatin and amlodipine) are substantially not present in the ezetimibe granule, it can be considered that ezetimibe is present in a physically separated state from rosuvastatin and amlodipine.

The method for producing the ezetimibe particles is not particularly limited, but the particles may preferably be produced in a wet state. Ezetimibe is a poorly soluble drug with a low saturation solubility of about 1ppm under acidic to weakly basic conditions (e.g., body fluids). Saturation solubility and dissolution rate from onset of dissolution to the saturation point can be important indicators for assessing the bioavailability of poorly soluble drugs. Since the wet granulation can reach saturation solubility at a faster rate, high bioavailability can be achieved for the poorly soluble drug ezetimibe. However, since the wet granulation may have a high water activity, the total water activity of the pharmaceutical combination formulation may be controlled by reducing the water activity of the other ingredients.

The pharmaceutical combination formulation of the present invention may contain, in addition to the active ingredient, one or more pharmaceutically acceptable additives required for the formulation. In particular, the ezetimibe wet granulate fraction or the rosuvastatin mixed fraction may comprise one or more pharmaceutically acceptable additives selected from excipients, binders, disintegrants and glidants. According to an embodiment of the present invention, each of the ezetimibe granule fraction and the rosuvastatin mixed fraction may further comprise 0.5 to 50 parts by weight of an excipient, 0.1 to 20 parts by weight of a binder, 0.1 to 10 parts by weight of a disintegrant, and 0.1 to 3 parts by weight of a glidant per 1 part by weight of ezetimibe.

The kind and content of such additives may be appropriately selected according to the type of specific formulation to be prepared by those skilled in the art. For example, excipients are selected from, but not limited to: lactose, starch, mannitol, microcrystalline cellulose, carboxymethyl cellulose, and combinations thereof; the binder is selected from, but not limited to: povidone, hypromellose, hydroxypropyl cellulose, copovidone, and combinations thereof; disintegrants are selected from, but not limited to: crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropylcellulose, and combinations thereof; and glidants selected from, but not limited to: magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof.

Since ezetimibe is a poorly soluble drug as described above, the ezetimibe particles may also comprise a solubilizing agent. Preferably, Sodium Lauryl Sulfate (SLS) may be used as a solubilizer. According to one embodiment of the invention, sodium lauryl sulfate may be used in a weight ratio of sodium lauryl sulfate to ezetimibe in the ezetimibe particles of 0.15: 1 to 0.3: 1. When the amount of sodium lauryl sulfate is used in a weight ratio of less than 0.15, the dissolution rate of ezetimibe is significantly reduced. On the other hand, when the amount of sodium lauryl sulfate is used in a weight ratio of more than 0.3, the effect of improving the dissolution rate of ezetimibe according to an increase in sodium lauryl sulfate is not significant. In addition, when the solubilizer is used in excess, the stability of the ezetimibe particles may be reduced.

The pharmaceutical combination preparation according to the present invention may further comprise one or more ingredients selected from the group consisting of amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and a combination thereof.

The pharmaceutical combination preparation according to the present invention may comprise amlodipine or a pharmaceutically acceptable salt thereof as a third active ingredient. Examples of pharmaceutically acceptable salts of amlodipine include, but are necessarily limited to: hydrochloride, hydrobromide, sulphate, phosphate, acetate, malate, fumarate, lactate, tartrate, citrate, gluconate, besylate and camphorsulfonate, preferably amlodipine besylate and amlodipine camphorsulfonate. In addition, amlodipine of the present invention includes amlodipine racemate and (S) -amlodipine. Amlodipine blocks calcium channels and is therefore useful in the treatment of cardiovascular diseases such as angina, hypertension and congestive heart failure. The daily dose of amlodipine or a pharmaceutically acceptable salt thereof is 5mg to 20 mg.

The pharmaceutical combination preparation according to the present invention may comprise losartan or a pharmaceutically acceptable salt thereof as a fourth active ingredient. Examples of pharmaceutically acceptable salts of losartan include, but are not limited to, the potassium salt of losartan. Losartan blocks the binding of angiotensin II, which is a vasoconstrictor substance, to a receptor, thereby contributing to the treatment of hypertension and heart failure; treatment of ischemic peripheral circulatory disorders and myocardial ischemia (angina pectoris); preventing the development of heart failure after myocardial infarction; and in the treatment of diabetic neuropathy, glaucoma, and the like. The daily dose of losartan or a pharmaceutically acceptable salt thereof is 45mg to 100 mg.

Since ezetimibe may also react with amlodipine or losartan and rosuvastatin to generate impurities, ezetimibe exists in a physically separated state from rosuvastatin, amlodipine and losartan, respectively. Wherein the physically separated state follows the above description. According to an embodiment of the present invention, when the pharmaceutical combination preparation comprises losartan, a bilayer tablet consisting of a layer comprising ezetimibe and rosuvastatin and a layer comprising losartan can be preferably prepared. However, when the pharmaceutical combination preparation does not contain losartan, it can be formulated in a more diversified form.

When the pharmaceutical combination preparation contains all of ezetimibe, rosuvastatin, amlodipine, and losartan as active ingredients, the pharmaceutical combination preparation may exist in the form of a bilayer tablet consisting of: a first layer comprising ezetimibe or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof; and a second layer comprising losartan or a pharmaceutically acceptable salt thereof. In the first layer, ezetimibe or a pharmaceutically acceptable salt thereof is present in a mixture in granular form with rosuvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof. In the second layer, losartan or a pharmaceutically acceptable salt thereof is present in the form of particles. The first and second layers in a bilayer tablet may comprise one or more pharmaceutically acceptable additives selected from excipients, binders, disintegrants and glidants.

The present invention provides a process for the preparation of a pharmaceutical combination preparation comprising ezetimibe or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.

The method for preparing a pharmaceutical combination preparation according to the present invention comprises the steps of: i) producing ezetimibe particles comprising ezetimibe or a pharmaceutically acceptable salt thereof; ii) mixing ezetimibe particles with rosuvastatin or a pharmaceutically acceptable salt thereof to produce a mixture; iii) allowing the mixture to stand at a relative humidity of 15% to 25% to reduce the water activity to 0.40 or less; and iv) tableting the mixture having reduced water activity. Rosuvastatin or a pharmaceutically acceptable salt thereof may be mixed with ezetimibe granules and amlodipine or a pharmaceutically acceptable salt thereof in step ii). Step iv) may comprise compression into a bilayer tablet consisting of: a mixture having a reduced water activity as a first layer and losartan granules having a reduced water activity as a second layer. Wherein the losartan particles having reduced water activity can be prepared by the following steps: a) producing granules of losartan comprising losartan or a pharmaceutically acceptable salt thereof; and b) allowing the resulting losartan granules to stand under conditions of 15% to 25% relative humidity to reduce the water activity to 0.40 or less. The details of the preparation process are supplemented by the above description and the following examples.

Detailed Description

Hereinafter, some preferred embodiments will be described to facilitate understanding of the present invention. However, the following examples are not provided to limit the present invention, but to facilitate understanding thereof.