KR102569271B1 - Pharmaceutical combination preparation comprising ezetimibe and rosuvastatin - Google Patents

Abstract

The present invention relates to a pharmaceutical combination preparation containing ezetimibe and rosuvastatin. The pharmaceutical combination formulation has a water activity of 0.40 or less. The pharmaceutical combination preparation may further include a component selected from the group consisting of amlodipine, losartan, or a combination thereof, and the ezetimibe exists in a physically separated state from rosuvastatin, amlodipine, and losartan, respectively. .

Description

Pharmaceutical combination preparation containing ezetimibe and rosuvastatin {PHARMACEUTICAL COMBINATION PREPARATION COMPRISING EZETIMIBE AND ROSUVASTATIN}

The present invention relates to a pharmaceutical combination preparation containing ezetimibe and rosuvastatin. More specifically, it relates to a pharmaceutical combination preparation containing ezetimibe and rosuvastatin and having a water activity of 0.40 or less.

Rosuvastatin or a pharmaceutically acceptable salt thereof is one of the HMG-CoA reductase inhibitors that treat dyslipidemia by inhibiting cholesterol synthesis. Crestor tablet (Rosuvastatin calcium salt, AstraZeneca), which contains rosuvastatin as a main ingredient, is widely used at home and abroad for the treatment of dyslipidemia and related diseases. In particular, research reports have shown that rosuvastatin is not only more effective in lowering blood LDL cholesterol than atorvastatin or simvastatin, which are commercially available as drugs with the same mechanism, but also has an excellent effect in increasing the concentration of beneficial HDL cholesterol in the body. There is a growing interest in suvastatin formulations.

HMG-CoA reductase inhibitors are generally administered in combination with other mechanisms of dyslipidemia treatment to enhance the therapeutic effect. Among them, because of its excellent interaction with Ezetimibe, a drug that inhibits cholesterol reabsorption in the small intestine, studies on complex formulations between the two components are active. For example, Vytorin, a combination formulation of simvastatin and ezetimibe, has already proven its pharmacological effect and stability, and is commercially available with excellent sales.

In the case of rosuvastatin, when used in combination with ezetimibe, the superiority of its pharmacological effect has been proven by many studies (Non-Patent Documents 1 and 2). Therefore, it is necessary to develop a combination preparation having excellent pharmaceutical properties for the combination of rosuvastatin and ezetimibe, the pharmacological effects of which have been proven as a combination preparation. Furthermore, in order to effectively treat cardiovascular diseases, a combination preparation in which amlodipine and/or losartan are added to rosuvastatin and ezetimibe is required, and a combination of such a combination of rosuvastatin, ezetimibe, amlodipine, and losartan is required. It is also necessary to develop a combination preparation having excellent pharmaceutical properties.

Brandon Ason et al., J Lipid Res. Apr 2011; 52(4): 679-687 Torimoto et al., Lipids in Health and Disease 2013, 12:137

The inventor of the present invention confirmed through experiments the correlation between water activity and related substances in a pharmaceutical combination formulation containing ezetimibe and rosuvastatin as active ingredients, and found a drug containing ezetimibe and rosuvastatin It is intended to provide a pharmaceutical combination preparation with improved stability of active ingredients by suppressing the production of related substances by providing a pharmaceutical combination preparation having a water activity of 0.40 or less.

According to the 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, and having a water activity of 0.40 or less.

In one embodiment of the present invention, the ezetimibe or a pharmaceutically acceptable salt thereof is physically separated from rosuvastatin or a pharmaceutically acceptable salt thereof.

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

In one embodiment of the present invention, the granules containing ezetimibe or a pharmaceutically acceptable salt thereof further include a solubilizing agent.

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

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

In one embodiment of the present invention, the pharmaceutical combination preparation further includes a component selected from the group consisting of amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and a combination thereof.

In one embodiment of the present invention, the ezetimibe or a pharmaceutically acceptable salt thereof is rosuvastatin or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof. It exists physically separated from each of the chemically acceptable salts.

In one embodiment of the present invention, the pharmaceutical combination preparation comprises ezetimibe or a pharmaceutically acceptable salt thereof, rosuvastatin or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof. A first layer comprising; and a second layer containing losartan or a pharmaceutically acceptable salt thereof.

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

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

According to the second aspect of the present invention,

The present invention comprises the steps of i) preparing ezetimibe granules containing ezetimibe or a pharmaceutically acceptable salt thereof; ii) preparing a mixture by mixing the ezetimibe granules with rosuvastatin or a pharmaceutically acceptable salt thereof; iii) reducing the water activity to 0.40 or less by leaving the mixture under a relative humidity condition of 15 to 25%; and iv) tableting the mixture having reduced water activity.

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

In one embodiment of the present invention, in step iv), the mixture with reduced water activity is used as a first layer, and losartan granules with reduced water activity are used as a second layer to form a two-layer tablet.

In one embodiment of the present invention, the losartan granules with reduced water activity can be obtained by a) preparing losartan granules containing losartan or a pharmaceutically acceptable salt thereof; and b) reducing the water activity to 0.40 or less by leaving the prepared losartan granules under a relative humidity condition of 15 to 25%.

The present invention provides a pharmaceutical combination preparation containing ezetimibe and rosuvastatin, by controlling the water activity to 0.40 or less, the production of related substances in the pharmaceutical combination preparation is suppressed, and thus the pharmaceutical combination preparation can improve the stability of active ingredients.

In addition, when providing a pharmaceutical combination preparation containing amlodipine and losartan in addition to ezetimibe and rosuvastatin, by physically separating ezetimibe from amlodipine, losartan, and rosuvastatin, respectively, pharmaceutical The stability and dissolution rate of the active ingredient of the combination preparation can be improved.

1 is a graph showing the measured bulk density and tap density of the products obtained in Examples 1 and 2, Examples 8 and 9, and Comparative Examples 1 to 4 immediately before tableting.
2 is a graph showing the measured hardness of the results immediately before tableting obtained in Examples 1 to 3, Examples 8 to 10, and Comparative Examples 1 to 6 according to tableting pressure.
3 is a graph showing the amount of related substances measured versus time in tablets according to Examples 3 and 10 and Comparative Examples 5 and 6 having different water activities.
Figure 4 is a graph showing the amlodipine dissolution rate versus time of tablets according to Examples 3 to 5, Comparative Examples 7 and 8, and Comparative Example 14 measured.
5 is a graph showing losartan dissolution rate versus time of tablets according to Examples 3 to 5, Comparative Examples 7 and 8, and Comparative Example 15 measured.
6 is a graph showing the dissolution rate of rosuvastatin versus time of tablets according to Examples 3 to 5, Comparative Examples 7 and 8, and Comparative Example 16 measured.
7 is a graph showing the dissolution rate of ezetimibe versus time of tablets according to Examples 3 to 5, Comparative Examples 7 and 8, and Comparative Example 17 measured.
8 is a graph showing the dissolution rate of ezetimibe versus time of tablets according to Examples 3, 6 and 7, Comparative Examples 12 and 13, and Comparative Example 17 measured.

The embodiments provided according to the present invention can all be achieved by the following description. The following description should be understood to describe preferred embodiments of the present invention, and it should be understood that the present invention is not necessarily limited thereto.

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

The pharmaceutical combination preparation according to the present invention contains ezetimibe or a pharmaceutically acceptable salt thereof as a first active ingredient. The ezetimibe mainly serves to inhibit cholesterol absorption for the treatment and prevention of atherosclerosis. The daily dose of ezetimibe or a pharmaceutically acceptable salt thereof is 5 mg to 15 mg.

The pharmaceutical combination preparation according to the present invention contains rosuvastatin or a pharmaceutically acceptable salt thereof as a second active ingredient. Examples of the pharmaceutically acceptable salt of rosuvastatin include calcium salts, magnesium salts, and strontium salts, and preferably rosuvastatin calcium salts, but are not limited thereto. The rosuvastatin inhibits HMG-CoA reductase, which is essential for the synthesis of cholesterol, thereby lowering the level of LDL-cholesterol in the blood and conversely increasing the level of HDL-cholesterol, thereby contributing to the treatment of dyslipidemia. The daily dose of the rosuvastatin or a pharmaceutically acceptable salt thereof is 10 mg to 20 mg.

In a pharmaceutical combination preparation containing ezetimibe and rosuvastatin as active ingredients, water activity may affect the production of related substances during storage of the pharmaceutical combination preparation. Since the water activity of these pharmaceutical combination preparations cannot be confirmed at all by measuring the water content or density of the combination preparation, the correlation between water activity and related substances is less predictable through other physical properties, and this correlation is effective. Considering that it can appear in a completely different form depending on the type of ingredient, water activity and related substance properties may be more important in the pharmaceutical combination preparation of the present invention. In addition, since it is difficult to satisfy the water activity standard required in the present invention according to the general pharmaceutical preparation method, a separate process for controlling the water activity is required. According to one embodiment of the present invention, the pharmaceutical combination preparation may have a water activity of 0.40 or less, preferably 0.35 or less, and more preferably 0.30 or less. Water activity refers to water availability (ie, free water) in a sample that can be used by microorganisms for growth. As described above, water activity is difficult to confirm 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 the water activity test, more precise measurement is required because the free water directly related to the stability of the main component, crystalline form, and movement of water is measured. , correlation with related substances can be confirmed only through the result of water activity measured in this way. Specifically, in the present specification, water activity was measured using a water activity meter (Labmaster, Novasina). According to the present invention, the pharmaceutical combination preparation containing ezetimibe and rosuvastatin increases the impurity due to a specific component as the water activity increases. An related substance that increases within a significant level according to an increase in water activity in the pharmaceutical combination preparation may be an EP related substance D derived from rosuvastatin. When the pharmaceutical combination preparation has a water activity of more than 0.40, it may easily exceed the related substance standard according to the ICH guidelines depending on the storage conditions, so it is necessary to evaluate the water content in general for the stability of the pharmaceutical combination preparation. The water activity should be adjusted to 0.40 or less by evaluation of the water activity. The method for controlling the water activity of the pharmaceutical combination preparation is not particularly limited, but the water activity of the pharmaceutical combination preparation according to the present invention can be obtained by leaving the pharmaceutical combination preparation under a certain level of relative humidity for a certain period of time. can be regulated. According to one embodiment of the present invention, in order to adjust the water activity of the pharmaceutical combination preparation to 0.40 or less, the pharmaceutical combination preparation is left under a relative humidity of 15 to 25% for 6 hours or more, preferably 8 to 15 hours. can do. When the water activity of the pharmaceutical combination preparation is adjusted according to the above conditions, the water activity can be effectively controlled while minimizing physical and chemical changes in the pharmaceutical combination preparation.

Ezetimibe and rosuvastatin, which are active ingredients in the pharmaceutical combination preparation, are formulated as a combination preparation due to the difference in mutually stable pH conditions. Problems can arise. For rosuvastatin, the major metabolite (3R,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan-2-yl)pyrimidine -5-yl]-3-hydroxy-5-oxo-hept-6-enoate calcium (hereinafter referred to as '5-Oxo analog'), or N-[4-(4-fluorophenyl)- 6-(1-methylethyl)-5-[(1E)-2-[(2S,4R)tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethenyl]-2- The production of related substances such as pyrimidinyl] -N-methylmethanesulfonamide (hereinafter referred to as 'lactone related substances') may increase. Accordingly, it may be preferable that the ezetimibe and rosuvastatin exist in a physically separated state. Here, the physically separated state is a state in which a standard active ingredient is subjected to a processing step to separate the standard active ingredient from other active ingredients, and the standard active ingredient is distinguished from other active ingredients in the final combination preparation obtained through this processing step. It refers to being maintained as, and it does not correspond to the case where the components themselves are mixed in the mixing process in advance without this processing step. The physically separated state may be exemplarily formed through physical separation using granule production, physical separation by dividing the layers into tablets, physical separation by tableting each other into tablets, and physical separation using a core-shell structure. . According to one embodiment of the present invention, in order to physically separate ezetimibe and rosuvastatin, ezetimibe may be processed into separate granules and then mixed with rosuvastatin. At this time, even after completion of the combination preparation, as in the processing step, in the case where the active ingredient (rosuvastatin) other than ezetimibe is not substantially present in the granule, even if each ezetimibe in the combination preparation Even though there is an interface in contact with rosuvastatin on the surface of the granules, ezetimibe can be said to be physically separated from rosuvastatin as described in the present invention in the combination preparation. Likewise, in another embodiment, after granulation processing of ezetimibe, rosuvastatin and amlodipine are mixed to obtain a combination preparation, wherein other active ingredients (rosuvastatin and amlodipine) are not substantially present in the granules of ezetimibe. In some cases, ezetimibe is physically separated from rosuvastatin and amlodipine.

The method for preparing the granules of ezetimibe is not particularly limited, but it may be preferable to prepare the granules in a wet state. Ezetimibe is a poorly soluble drug that shows a low saturation solubility of around 1 ppm in both acidic and weakly basic body fluid conditions. Saturation solubility and dissolution rate from the start of dissolution to saturation can be important indicators for evaluating the bioavailability of poorly soluble drugs. In the case of wet granules, saturation solubility can be reached at a faster rate, so It is possible to secure high bioavailability for Timibe. However, since wet granules may have high water activity, the water activity of the entire combination preparation may be adjusted by lowering the water activity of other ingredients.

The combined preparation of the present invention may further include at least one pharmaceutically acceptable additive required for formulation in addition to the active ingredient. Specifically, the ezetimibe wet granulation part or the rosuvastatin mixing part may contain at least one pharmaceutically acceptable additive selected from the group consisting of an excipient, a binder, a disintegrant, and a lubricant. According to one embodiment of the present invention, the granular part of ezetimibe and the mixing part of rosuvastatin contain 0.5 to 50 parts by weight of an excipient, 0.1 to 20 parts by weight of a binder, and 0.1 to 0.1 to 20 parts by weight of a disintegrant, based on 1 part by weight of ezetimibe. 10 parts by weight and 0.1 to 3 parts by weight of a lubricant may be further included.

Selection of the type and content of these additives can be appropriately selected according to the type of specific formulation to be prepared by a person skilled in the art. For example, the excipient is selected from the group consisting of lactose, starch, mannitol, microcrystalline cellulose, carboxymethylcellulose, and combinations thereof, and the binder is povidone, hypromellose, hydroxypropylcellulose, copovidone, and combinations thereof. selected from the group consisting of combinations, the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and combinations thereof, and the lubricant is stearic acid It may be selected from the group consisting of magnesium, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof, but is not limited thereto.

Since ezetimibe is a poorly soluble drug as described above, a solubilizing agent may be additionally included in the ezetimibe granules. As the solubilizing agent, sodium lauryl sulfate (SLS) may be preferably used. According to one embodiment of the present invention, sodium lauryl sulfate can be used within the range where the weight ratio of sodium lauryl sulfate and ezetimibe in ezetimibe granules is 0.15:1 to 0.3:1. When the amount of sodium lauryl sulfate is less than 0.15 in the above weight ratio, the dissolution rate of ezetimibe is significantly reduced, whereas, when the amount of sodium lauryl sulfate is greater than 0.3 in the above weight ratio, the dissolution rate of ezetimibe according to the increase in sodium lauryl sulfate improvement is insignificant. Also, when the solubilizing agent is used in an excessive amount, the stability of the ezetimibe granules may decrease.

The pharmaceutical combination preparation according to the present invention may further include a component 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 include amlodipine or a pharmaceutically acceptable salt thereof as a third active ingredient. Examples of pharmaceutically acceptable salts of amlodipine include hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate, lactate, tartrate, citrate, gluconate, besylate and camsylate. And, preferably, amlodipine besylate salt and camsylate salt may be mentioned, but it is not necessarily limited thereto. In addition, amlodipine of the present invention includes amlodipine racemate and (S)-amlodipine. Amlodipine is used to treat cardiovascular diseases such as angina pectoris, hypertension, and congestive heart failure by blocking calcium channels. The daily dose of amlodipine or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg as amlodipine.

The pharmaceutical combination preparation according to the present invention may include losartan or a pharmaceutically acceptable salt thereof as a fourth active ingredient. Examples of the pharmaceutically acceptable salt of losartan include, but are not limited to, losartan potassium salt. The losartan blocks the binding of angiotensin II, a vasoconstrictor, to its receptor, thereby treating hypertension and heart failure, treating ischemic peripheral circulatory disorders and myocardial ischemia (angina pectoris), preventing progression of heart failure after myocardial infarction, and diabetes It contributes to the treatment of sexual neuropathy and glaucoma. The daily dose of losartan or a pharmaceutically acceptable salt thereof is 45 mg to 100 mg.

Since ezetimibe can react not only with rosuvastatin but also with amlodipine or losartan to produce related substances, ezetimibe is physically separated from rosuvastatin, amlodipine, and losartan. exist. Here, the physically separated state follows the above description. According to one embodiment of the present invention, when the pharmaceutical combination preparation contains losartan, it may be preferable to prepare a two-layer tablet by separating a layer containing ezetimibe and rosuvastatin from a layer containing losartan. However, when it does not contain losartan, it may be formulated in more diverse forms.

When the pharmaceutical combination preparation contains all of ezetimibe, rosuvastatin, amlodipine and losartan as active ingredients, the pharmaceutical combination preparation includes the ezetimibe or a pharmaceutically acceptable salt thereof, rosuvastatin or a combination thereof A first layer comprising a pharmaceutically acceptable salt, and amlodipine or a pharmaceutically acceptable salt thereof; and a second layer containing losartan or a pharmaceutically acceptable salt thereof. In the first layer, ezetimibe or a pharmaceutically acceptable salt thereof is mixed with rosuvastatin or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt thereof in granular form. In the second layer, losartan or a pharmaceutically acceptable salt thereof is present in the form of granules. In the two-layer tablet, the first layer and the second layer may contain at least one pharmaceutically acceptable additive selected from the group consisting of an excipient, a binder, a disintegrant, and a lubricant.

The present invention provides a method for preparing 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 includes the steps of i) preparing ezetimibe granules containing ezetimibe or a pharmaceutically acceptable salt thereof; ii) preparing a mixture by mixing the ezetimibe granules with rosuvastatin or a pharmaceutically acceptable salt thereof; iii) reducing the water activity to 0.40 or less by leaving the mixture under a relative humidity condition of 15 to 25%; and iv) tableting the mixture with reduced water activity. In step ii), rosuvastatin or a pharmaceutically acceptable salt thereof may be mixed with amlodipine or a pharmaceutically acceptable salt thereof and ezetimibe granules. In the step iv), the mixture with reduced water activity may be used as a first layer and losartan granules with reduced water activity may be used as a second layer to form a two-layer tablet. Here, the losartan granules with reduced water activity can be prepared by a) preparing losartan granules containing losartan or a pharmaceutically acceptable salt thereof; and b) reducing the water activity to 0.40 or less by leaving the prepared losartan granules under a relative humidity condition of 15 to 25%. Specific details of the manufacturing method are supplemented through the above description and the following examples.

Hereinafter, preferred embodiments are presented to aid understanding of the present invention, but the following examples are provided to more easily understand the present invention, but the present invention is not limited thereto.

Example

Example One: Ezetimibe and with rosuvastatin Manufacture of tablets containing

According to the composition shown in Table 1 below, tablets containing ezetimibe and rosuvastatin as active ingredients were prepared.

Specifically, ezetimibe, lactose hydrate, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate were put into a fluid bed granulator and mixed for 3 minutes. Here, a binding solution in which Povidone was dissolved in water was added and assembled by uniting for about 50 minutes. The resulting product was dried in a fluidized bed dryer at 45° C., and then sieved through a sieve having an opening size of 0.6 mm to prepare ezetimibe granules.

The prepared ezetimibe granules were mixed with a mixture having the composition described in the mixing section of Table 1 in a mixer for 15 minutes, and then 4 mg of magnesium stearate was added as a lubricant and further mixed for 5 minutes. The resulting product was exposed for about 12 hours at 25 ° C. and a relative humidity of about 20%, and then a tablet having a hardness of about 13 kp was prepared by applying a pressure of about 950 kgf to the resulting product with a tablet press (Autotab-200TR, ichihashi seiki).

Example 2: Ezetimibe , Rosuvastatin and amlodipine Manufacture of tablets containing

According to the composition shown in Table 1 below, tablets containing ezetimibe, rosuvastatin and amlodipine as active ingredients were prepared.

Specifically, tablets were prepared in the same manner as in Example 1, except that amlodipine besilate was added to the mixing part in comparison with Example 1. The hardness of the prepared tablet was about 13 kp.

Example 3: Ezetimibe , Rosuvastatin , amlodipine and Rosatan Manufacture of a bi-layer tablet containing

According to the composition shown in Table 1 below, a two-layer tablet containing ezetimibe, rosuvastatin, amlodipine, and losartan as active ingredients was prepared.

Specifically, Losartan potassium was put into a mixer with lactose hydrate, microcrystalline cellulose, and crospovidone and mixed for 20 minutes. The resulting product was compressed using a roller compactor (TF-1-A60, Freund vector) under conditions of hydraulic pressure of 2 MPa, feeder speed of 5 rpm, and roller speed of 1 rpm to form flakes, then 0.8 Losartan granules were prepared by sizing through a sieve having an opening size of mm.

3 mg of magnesium stearate was added to the prepared losartan granules and further mixed for 5 minutes in a mixer to prepare a mixture of the upper part of the two-layer tablet. In addition, the ezetimibe granules prepared in Example 1 were put into a mixer with the mixture of the composition described in the mixing part of Table 1 and mixed for 15 minutes, and then 4 mg of magnesium stearate was added and mixed for 5 minutes. was manufactured. The prepared upper mixed powder and lower mixed powder were exposed to a temperature of 25 ° C. and a relative humidity of about 20% for about 12 hours, and then a pressure of about 1,200 kgf was applied with a tableting machine to prepare a two-layer tablet having a hardness of about 20 kp.

Example 4: Ezetimibe , Rosuvastatin , amlodipine and Rosatan Manufacture of a bi-layer tablet containing

According to the composition shown in Table 1 below, a two-layer tablet containing ezetimibe, rosuvastatin, amlodipine, and losartan as active ingredients was prepared.

Specifically, in contrast to Example 3, a double-layer tablet was prepared in the same manner as in Example 3, except that ezetimibe granules were prepared in the same manner as in the method for preparing losartan granules in Example 3. The hardness of the prepared bi-layer tablet was about 20 kp.

Example 5: Ezetimibe , Rosuvastatin , amlodipine and Rosatan Preparation of capsules containing

According to the composition shown in Table 1 below, a two-layer tablet containing ezetimibe, rosuvastatin, amlodipine, and losartan as active ingredients was prepared.

Specifically, in order to fill the active ingredient in No. 0 capsule, the amount of excipients in the composition of Example 3 was reduced and applied. Ezetimibe granules and losartan granules were prepared as in Example 3. The prepared losartan granules and 1.5 mg of magnesium stearate were put into a mixer and mixed for 5 minutes, and then tablets having a hardness of about 13 kp were prepared using a tablet press. In addition, the components of the composition described in the mixing section of Table 1 below were placed in a mixer and mixed for 15 minutes, additionally 2 mg of magnesium stearate was added and mixed for 5 minutes, and the resulting product was kept for about 12 hours under a condition of about 20% relative humidity. After exposure, tablets having a hardness of about 7 kp were prepared using a tablet press. The two prepared tablets were filled into a No. 0 capsule together with ezetimibe granules to prepare a capsule.

Specific compositions of the pharmaceutical combination preparations according to Examples 1 to 5 are shown in Table 1 below.

ingredient Example One
(mg) Example 2
(mg) Example 3
(mg) Example 4
(mg) Example 5
(mg) Rosatan
granules losartan potassium - - 100.0 100.0 100.0 microcrystalline cellulose
(Avicel PH101) - - 125.0 125.0 62.5 Lactose monohydrate (#200) - - 60.0 60.0 30.0 Crospovidone (XL-10) - - 15.0 15.0 7.5 granule total mass - - 300.0 300.0 200.0 Ezetimibe
granules Ezetimibe 10.0 10.0 10.0 10.0 10.0 microcrystalline cellulose
(Avicel PH101) 90.0 90.0 90.0 90.0 44.0 Lactose monohydrate (#200) 35.0 35.0 35.0 35.0 17.5 Croscarmellose Sodium 15.0 15.0 15.0 15.0 7.5 sodium lauryl sulfate 2.0 2.0 2.0 2.0 2.0 Povidone (k-30) 5.0 5.0 5.0 5.0 2.5 Purified water (70.0) - - - (50.0) granule total mass 157.0 157.0 157.0 157.0 83.5 mixing part Amlodipine Besylate
(as amlodipine) - 6.94
(5.0) 6.94
(5.0) 6.94
(5.0) 6.94
(5.0) Rosuvastatin Calcium
(as rosuvastatin) 20.8
(20.0) 20.8
(20.0) 20.8
(20.0) 20.8
(20.0) 20.8
(20.0) Mannitol (SD200) 120.0 120.0 120.0 120.0 60.0 lactose hydration (supertab) 120.0 120.0 120.0 120.0 60.0 Microcrystalline cellulose (Avicel PH101) 30.0 30.0 30.0 30.0 15.0 Crospovidone (XL-10) 24.0 24.0 24.0 24.0 12.0 final mix magnesium stearate 4.0 4.0 3.0
(upper part) 3.0
(upper part) 1.5
(upper part) 4.0
(lower layer) 4.0
(lower layer) 2.0
(lower layer) tablet total mass 475.8 482.74 785.74 785.74 461.74

Example 6: Ezetimibe , Rosuvastatin , amlodipine and Rosatan Manufacture of a bi-layer tablet containing

According to the composition shown in Table 2 below, a two-layer tablet containing ezetimibe, rosuvastatin, and amlodipine as active ingredients was prepared.

Specifically, tablets were prepared in the same manner as in Example 3, except that the amount of microcrystalline cellulose in the ezetimibe granules was adjusted to 90.5 mg and the amount of sodium lauryl sulfate was adjusted to 1.5 mg in comparison with Example 3. did The hardness of the prepared tablet was about 20 kp.

Example 7: Ezetimibe , Rosuvastatin , amlodipine and Rosatan Manufacture of a bi-layer tablet containing

According to the composition shown in Table 2 below, a two-layer tablet containing ezetimibe, rosuvastatin, and amlodipine as active ingredients was prepared.

Specifically, tablets were prepared in the same manner as in Example 3, except that the amount of microcrystalline cellulose in the ezetimibe granules was adjusted to 89 mg and the amount of sodium lauryl sulfate was adjusted to 3 mg in comparison with Example 3. The hardness of the prepared tablet was about 20 kp.

Specific compositions of the pharmaceutical combination preparations according to Examples 6 and 7 are shown in Table 2 below.

ingredient Example 6
(mg) Example 7
(mg) Rosatan
granules losartan potassium 100.0 100.0 microcrystalline cellulose
(Avicel PH101) 125.0 125.0 Lactose monohydrate (#200) 60.0 60.0 Crospovidone (XL-10) 15.0 15.0 granule total mass 300.0 300.0 Ezetimibe
granules Ezetimibe 10.0 10.0 microcrystalline cellulose
(Avicel PH101) 90.5 89.0 Lactose monohydrate (#200) 35.0 35.0 Croscarmellose Sodium 15.0 15.0 sodium lauryl sulfate 1.5 3.0 Povidone (k-30) 5.0 5.0 Purified water (70.0) - granule total mass 157.0 157.0 mixing part Amlodipine Besylate
(as amlodipine) 6.94
(5.0) 6.94
(5.0) Rosuvastatin Calcium
(as rosuvastatin) 20.8
(20.0) 20.8
(20.0) Mannitol (SD200) 120.0 120.0 lactose hydration (supertab) 120.0 120.0 Microcrystalline cellulose (Avicel PH101) 30.0 30.0 Crospovidone (XL-10) 24.0 24.0 final mix magnesium stearate 3.0
(upper part) 3.0
(upper part) 4.0
(lower layer) 4.0
(lower layer) tablet total mass 785.74 785.74

Example 8: high water activity Ezetimibe and with rosuvastatin Manufacture of tablets containing

After final mixing obtained in Example 1, the resulting product was exposed to a relative humidity of about 20% for 8 hours, and then a tablet having a hardness of about 20 kp was prepared by applying a pressure of about 1,200 kgf with a tablet press.

Example 9: high water activity Ezetimibe , Rosuvastatin and amlodipine Manufacture of tablets containing

After final mixing obtained in Example 2, the resulting product was exposed to a relative humidity of about 20% for 8 hours, and then a tablet having a hardness of about 13 kp was prepared by applying a pressure of about 950 kgf with a tablet press.

Example 10: high water activity Ezetimibe , Rosuvastatin , amlodipine and Rosatan Manufacture of a bi-layer tablet containing

After final mixing obtained in Example 3, the product was exposed to a relative humidity of about 20% for 8 hours, and then a tablet having a hardness of about 13 kp was prepared by applying a pressure of about 950 kgf with a tablet press.

comparative example 1: high water activity Ezetimibe and with rosuvastatin Manufacture of tablets containing

After final mixing obtained in Example 1, the resulting product was exposed to a relative humidity of about 20% for 4 hours, and then a tablet having a hardness of about 20 kp was prepared by applying a pressure of about 1,200 kgf with a tableting machine.

comparative example 2: high water activity Ezetimibe and with rosuvastatin Manufacture of tablets containing

After final mixing obtained in Example 1, a tablet having a hardness of about 20 kp was prepared by applying a pressure of about 1,200 kgf to the resulting product with a tablet press.

comparative example 3: high water activity Ezetimibe , Rosuvastatin and amlodipine Manufacture of tablets containing

After final mixing obtained in Example 2, the resulting product was exposed to a relative humidity of about 20% for 4 hours, and then a tablet having a hardness of about 13 kp was prepared by applying a pressure of about 950 kgf with a tablet press.

comparative example 4: high water activity Ezetimibe , Rosuvastatin and amlodipine Manufacture of tablets containing

After final mixing obtained in Example 2, a tablet having a hardness of about 13 kp was prepared by applying a pressure of about 950 kgf to the resulting product.

comparative example 5: high water activity Ezetimibe , Rosuvastatin , amlodipine and Rosatan Manufacture of a bi-layer tablet containing

After final mixing obtained in Example 3, the resulting product was exposed to a relative humidity of about 20% for 4 hours, and then a tablet having a hardness of about 13 kp was prepared by applying a pressure of about 950 kgf with a tablet press.

comparative example 6: high water activity Ezetimibe , Rosuvastatin , amlodipine and Rosatan Manufacture of a bi-layer tablet containing

After final mixing obtained in Example 3, a tablet having a hardness of about 13 kp was prepared by applying a pressure of about 950 kgf to the resulting product.

comparative example 7: Ezetimibe , Rosuvastatin , amlodipine and Rosatan Manufacture of single-layer tablets containing

After preparing ezetimibe granules and losartan granules as in Example 3, the prepared ezetimibe granules and losartan granules were mixed with a mixture of the composition described in the mixing section of Example 3 in Table 1 above in a mixer for 15 minutes did After adding 7 mg of magnesium stearate thereto and mixing for 5 minutes, a tablet having a hardness of about 20 kp was prepared by a tableting machine.

comparative example 8: Ezetimibe , Rosuvastatin , amlodipine and Rosatan Manufacture of a bi-layer tablet containing

After preparing ezetimibe granules and losartan granules as in Example 3, the prepared ezetimibe granules and losartan granules were mixed in a mixer for 15 minutes. 3 mg of magnesium stearate was added thereto and further mixed for 5 minutes in a mixer to prepare a mixture of the upper layer of the two-layer tablet. 4 mg of magnesium stearate was added to the mixture of the composition described in the mixing section of Example 3 in Table 1 and further mixed for 5 minutes in a mixer to prepare a mixed powder for the lower layer of the two-layer tablet. A two-layer tablet having a hardness of about 20 kp was prepared by applying a pressure of about 1,200 kgf to the prepared upper mixed powder and lower mixed powder using a tablet press.

comparative example 9: Ezetimibe , Rosuvastatin , amlodipine and Rosatan Manufacture of a bi-layer tablet containing

According to the composition shown in Table 3 below, a double-layer tablet containing ezetimibe, rosuvastatin, amlodipine, and losartan was prepared.

Specifically, in contrast to Example 3, a double-layer tablet was prepared in the same manner as in Example 3, except that amlodipine besylate and rosuvastatin calcium were added to the ezetimibe granules instead of the mixing part. The hardness of the prepared bi-layer tablet was about 20 kp.

comparative example 10: Ezetimibe , Rosuvastatin , amlodipine and Rosatan Manufacture of a bi-layer tablet containing

According to the composition shown in Table 3 below, a double-layer tablet containing ezetimibe, rosuvastatin, amlodipine, and losartan was prepared.

Specifically, in contrast to Example 3, a two-layer tablet was prepared in the same manner as in Example 3, except that amlodipine besilate was added to the ezetimibe granules instead of the mixing part. The hardness of the prepared bi-layer tablet was about 20 kp.

comparative example 11: Ezetimibe , Rosuvastatin , amlodipine and Rosatan Manufacture of a bi-layer tablet containing

According to the composition shown in Table 3 below, a double-layer tablet containing ezetimibe, rosuvastatin, amlodipine, and losartan was prepared.

Specifically, in contrast to Example 3, a two-layer tablet was prepared in the same manner as in Example 3, except that rosuvastatin calcium was added to the ezetimibe granules instead of the mixing part. The hardness of the prepared bi-layer tablet was about 20 kp.

Specific compositions of the pharmaceutical combination preparations according to Comparative Examples 9 to 11 are shown in Table 3 below.

ingredient comparative example 9
(mg) comparative example 10
(mg) comparative example 11
(mg) Rosatan
granules losartan potassium 100.0 100.0 100.0 microcrystalline cellulose
(Avicel PH101) 125.0 125.0 125.0 Lactose monohydrate (#200) 60.0 60.0 60.0 Crospovidone (XL-10) 15.0 15.0 15.0 granule total mass 300.0 300.0 300.0 Ezetimibe
granules Ezetimibe 10.0 10.0 10.0 Amlodipine Besylate
(as amlodipine) 6.94
(5.0) 6.94
(5.0) - Rosuvastatin Calcium (as Rosuvastatin) 20.8
(20.0) - 20.8
(20.0) Microcrystalline cellulose (Avicel PH101) 90.0 90.0 90.0 Lactose monohydrate (#200) 35.0 35.0 35.0 Croscarmellose Sodium 15.0 15.0 15.0 sodium lauryl sulfate 2.0 2.0 2.0 Povidone (k-30) 5.0 5.0 5.0 Purified water (70.0) - - granule total mass 184.74 163.94 177.8 mixing part Amlodipine Besylate
(as amlodipine) - - 6.94
(5.0) Rosuvastatin Calcium
(as rosuvastatin) - 20.8
(20.0) - Mannitol (SD200) 120.0 120.0 120.0 lactose hydration (supertab) 120.0 120.0 120.0 Microcrystalline cellulose (Avicel PH101) 30.0 30.0 30.0 Crospovidone (XL-10) 24.0 24.0 24.0 final mix magnesium stearate 3.0
(upper part) 3.0
(upper part) 3.0
(upper part) 4.0
(lower layer) 4.0
(lower layer) 4.0
(lower layer) tablet total mass 785.74 785.74 785.74

comparative example 12: Ezetimibe , Rosuvastatin , amlodipine and Rosatan Manufacture of a bi-layer tablet containing

According to the composition shown in Table 4 below, a double-layer tablet containing ezetimibe, rosuvastatin, amlodipine, and losartan was prepared.

Specifically, tablets were prepared in the same manner as in Example 3, except that the amount of microcrystalline cellulose in the ezetimibe granules was adjusted to 92.0 mg and the amount of sodium lauryl sulfate was adjusted to 0 mg in comparison with Example 3. . The hardness of the prepared tablet was about 20 kp.

comparative example 13: Ezetimibe , Rosuvastatin , amlodipine and Rosatan Manufacture of a bi-layer tablet containing

According to the composition shown in Table 4 below, a double-layer tablet containing ezetimibe, rosuvastatin, amlodipine, and losartan was prepared.

Specifically, tablets were prepared in the same manner as in Example 3, except that the amount of microcrystalline cellulose in the ezetimibe granules was adjusted to 91.0 mg and the amount of sodium lauryl sulfate was adjusted to 1.0 mg in comparison with Example 3. did The hardness of the prepared tablet was about 20 kp.

Specific compositions of the pharmaceutical combination preparations according to Comparative Examples 12 to 13 are shown in Table 4 below.

ingredient comparative example 12
(mg) comparative example 13
(mg) Rosatan
granules losartan potassium 100.0 100.0 microcrystalline cellulose
(Avicel PH101) 125.0 125.0 Lactose monohydrate (#200) 60.0 60.0 Crospovidone (XL-10) 15.0 15.0 granule total mass 300.0 300.0 Ezetimibe
granules Ezetimibe 10.0 10.0 microcrystalline cellulose
(Avicel PH101) 92.0 91.0 Lactose monohydrate (#200) 35.0 35.0 Croscarmellose Sodium 15.0 15.0 sodium lauryl sulfate 0.0 1.0 Povidone (k-30) 5.0 5.0 Purified water (70.0) - granule total mass 157.0 157.0 mixing part Amlodipine Besylate
(as amlodipine) 6.94
(5.0) 6.94
(5.0) Rosuvastatin Calcium
(as rosuvastatin) 20.8
(20.0) 20.8
(20.0) Mannitol (SD200) 120.0 120.0 lactose hydration (supertab) 120.0 120.0 Microcrystalline cellulose (Avicel PH101) 30.0 30.0 Crospovidone (XL-10) 24.0 24.0 final mix magnesium stearate 3.0
(upper part) 3.0
(upper part) 4.0
(lower layer) 4.0
(lower layer) tablet total mass 785.74 785.74

comparative example 14: Control drug Ⅰ

As a control drug, Norvasc tablets containing amlodipine besylate were used.

comparative example 15: Control drug Ⅱ

As a control, Koza tablets containing Rosatan potassium were used.

comparative example 16: Control drug Ⅲ

As a control drug, Crestor tablets containing rosuvastatin calcium were used.

comparative example 17: Control drug IV

As a control drug, Easytrol tablets containing ezetimibe were used.

test example

test example One: Example 1 to 3; Example 8 to 10, and comparative example Moisture content determination from 1 to 6

The moisture content of the tablets obtained in Examples 1 to 3, Examples 8 to 10, and Comparative Examples 1 to 6 was measured using a moisture content meter (MA45, sartorius). The results are shown in Table 5 below.

Sample Moisture content (%) Sample Moisture content (%) Sample Moisture content (%) Example 1 2.81 Example 2 2.63 Example 3 2.94 Example 8 3.19 Example 9 2.63 Example 10 3.16 Comparative Example 1 2.84 Comparative Example 3 2.76 Comparative Example 5 3.06 Comparative Example 2 3.26 Comparative Example 4 2.94 Comparative Example 6 2.92

In Table 5, Comparative Examples 2, 4, and 6 were not left under a relative humidity condition of about 20%, Comparative Examples 1, 3, and 5 each for 4 hours, Examples 8, 9, and 10 each for 8 hours, Examples 1, 2 and 3 were left under the above conditions for 12 hours each. According to Table 5, it can be seen that the water content is 2.76 to 3.06% at 4 hour exposure, 2.63 to 3.19% at 8 hour exposure, and 2.63 to 2.94% at 12 hour exposure.

As a result, when the resulting product was left at a relative humidity of about 20% after final mixing, the moisture content of the tablet was not significantly affected by the standing time.

test example 2: Example 1 to 3; Example 8 to 10, and comparative example Measurement of water activity from 1 to 6

The water activity of the tablets obtained in Examples 1 to 3 and 8 to 10 and Comparative Examples 1 to 6 was measured using a water activity meter (Labmaster, Novasina). Specifically, 4 tablets were pulverized into a particle size smaller than No. 20 sieve in a cylindrical container with a diameter of 4 cm and a height of 13 mm at 25 ° C., and the change in value was observed using a water activity meter. When the change in value stays at ±0.001 level for about 1 minute, the value is measured and shown in Table 6 below.

Sample water activity Sample water activity Sample water activity Example 1 0.196 Example 2 0.204 Example 3 0.208 Example 8 0.338 Example 9 0.341 Example 10 0.349 Comparative Example 1 0.419 Comparative Example 3 0.411 Comparative Example 5 0.428 Comparative Example 2 0.471 Comparative Example 4 0.472 Comparative Example 6 0.481

In Table 6, Comparative Examples 2, 4, and 6 were not left under a relative humidity condition of about 20%, Comparative Examples 1, 3, and 5 each for 4 hours, Examples 8, 9, and 10 each for 8 hours, Examples 1, 2 and 3 were left under the above conditions for 12 hours each. According to Table 6, it can be seen that the water activity ranges from 0.411 to 0.428 for 4 hours of exposure, 0.338 to 0.349 for 8 hours of exposure, and 0.196 to 0.208 for 12 hours of exposure.

As a result, when the product was left at a relative humidity of about 20% after final mixing, the water activity of the tablet decreased as the standing time increased.

test example 3: Example 1 and 2; Example 8 and 9, and comparative example Density measurements from 1 to 4

In order to compare the granular properties of each product immediately before tableting according to the water activity, the bulk density (bulk density, g/ml) of the products obtained in Examples 1 and 2, Examples 8 and 9, and Comparative Examples 1 to 4 were obtained immediately before tableting. ) and tapped density (g/ml) were measured and shown in FIG. 1 below. Here, the bulk density was calculated by measuring the mass of about 5 to 10 g of the granules, carefully putting the granules into a 50 mL measuring cylinder and measuring the volume in the bulk state. In addition, the tap density was calculated by measuring the volume of granules in a compacted state by tapping the measuring cylinder 100 times.

The evaluation of physical properties of the granules of Test Example 3 is performed for the purpose of confirming whether a specific issue occurs during the production of a semi-finished product (granule or final mixture) produced during the process, not after the production of the formulation is completed in the pharmaceutical field. According to FIG. 1 below, when the resultant product is left at a relative humidity of about 50%, the density of the resultant product is not significantly affected by the standing time. In other words, it can be confirmed that the change in water activity during the production process is difficult to confirm by the density measurement method.

test example 4: Example 1 to 3; Example 8 to 10, and comparative example Hardness measurement from 1 to 6

In order to compare the tableting properties of the granules according to the water activity, the hardness by compression pressure of the results immediately before tableting obtained in Examples 1 to 3, Examples 8 to 10, and Comparative Examples 1 to 6 were measured using a hardness meter (TBH 425, Erweka ) was measured and shown in FIG. 2 below.

The evaluation of the compressibility of Test Example 4 is conducted for the purpose of confirming whether a specific issue occurs during tablet production. According to FIG. 2 below, when the resulting product was left in a condition of about 50% relative humidity and then compressed into tablets, the hardness of the tablet was not significantly affected by the standing time. In other words, it can be confirmed that the change in water activity during the production process is difficult to confirm by the hardness measurement method.

test example 5: Example 1 to 3; Example 8 to 10, and comparative example 1 to 6 related substances measurement

The tablets of Examples 1 to 3, Examples 8 to 10, and Comparative Examples 1 to 6 were packed in HDPE bottles, respectively, and stored under harsh conditions at 60° C. for 5 days and 10 days, and related substances were analyzed as follows. Conditions were analyzed and the results of rosuvastatin EP related substance D are shown in Table 7 below.

- Analytical conditions -

Column: A column filled with 3 μm octadecylsilylated silica gel for liquid chromatography in a stainless steel tube with an inner diameter of about 4.6 mm and a length of 25 cm.

Mobile phase: *7mM sodium hexanesulfonate/0.05% (v/v) phosphoric acid: acetonitrile (66:34, v/v)

(*7mM sodium hexanesulfonate/0.05% (v/v) phosphoric acid: Take 1.45g of sodium 1-hexanesulfonate monohydrate, put it in a 1L flask, and carefully add 0.5mL of phosphoric acid. Add purified water to dissolve. After dilution, mix well.)

Detector: UV absorbance photometer (measurement wavelength 239 nm)

Flow Rate: 1.0 mL/min

Injection volume: 10 μL

Column temperature: 40 ℃

Sample water activity Early harsh 5 days harsh 10 days Example 1 0.196 0.02 0.12 0.19 Example 8 0.338 0.02 0.24 0.38 Comparative Example 1 0.419 0.02 0.36 0.64 Comparative Example 2 0.471 0.02 0.47 0.80 Example 2 0.204 0.02 0.13 0.20 Example 9 0.341 0.02 0.24 0.39 Comparative Example 3 0.411 0.02 0.37 0.62 Comparative Example 4 0.472 0.02 0.47 0.80 Example 3 0.208 0.02 0.13 0.20 Example 10 0.349 0.02 0.25 0.40 Comparative Example 5 0.428 0.02 0.38 0.65 Comparative Example 6 0.481 0.02 0.48 0.82

When the tablets of Examples 1 to 3, Examples 8 to 10, and Comparative Examples 1 to 6 were each stored under harsh conditions, related substances derived from amlodipine, losartan, and ezetimibe were less than LOQ (0.1%) at all time points. confirmed as Among the related substances derived from rosuvastatin, except for the EP related substance D, the remaining related substances also showed similar patterns irrespective of the types of Examples and Comparative Examples. In contrast, EP related substance D, which is a related substance derived from rosuvastatin, showed a pattern in which the related substance increased as the water activity increased. Considering that the related substance standard according to the ICH guideline is 0.5%, Comparative Examples 1, 3, and 5 having a water activity of about 0.41 to 0.43 exceeded the standard on day 10, and Comparative Example 2 having a water activity of about 0.47 to 0.48; 4 and 6 were identified as results close to the criterion on the 5th day of severity.

In order to find out the correlation between water activity and related substance D, the results of Examples 3 and 10 and Comparative Examples 5 and 6 in Table 7 are shown graphically in FIG. 3 . 3, it was confirmed that the amount of related substance D increased with a steep slope under harsh conditions in tablets having high water activity.

test example 6: Example 3 to 5; comparative example 7 and 8, and comparative example Dissolution test of 14 to 16 (amlodipine, Rosatan , Rosuvastatin )

As the tablets produced in Examples 3 to 5 and Comparative Examples 7 and 8 and control drugs, Comparative Example 14 (control drug of amlodipine), Comparative Example 15 (control drug of losartan), and Comparative Example 16 (control drug of rosuvastatin) Control drug) was evaluated for dissolution rates of amlodipine, losartan, and rosuvastatin over time under the following dissolution conditions and analysis conditions, and the results are shown in FIGS. 4 to 6.

-Elution conditions-

Eluate: pH 6.8, 900mL

Apparatus: USP paddle method, 50 rpm

Temperature: 37±0.5℃

- Analytical conditions -

Column: A column filled with 3 μm octadecylsilylated silica gel for liquid chromatography in a stainless steel tube with an inner diameter of about 4.6 mm and a length of 25 cm.

Mobile phase: *9mM sodium hexanesulfonate/0.05% (v/v) phosphoric acid: acetonitrile (52:48, v/v)

(*9mM sodium hexanesulfonate/0.13% (v/v) phosphoric acid: Take 1.86g of sodium 1-hexanesulfonate monohydrate, put it in a 1L flask, and carefully add 1.3mL of phosphoric acid. Add purified water to dissolve. After dilution, mix well.)

Detector: Ultraviolet absorbance photometer (measurement wavelength 254 nm)

Flow rate: 1.3 mL/min

Injection volume: 10 μL

Column temperature: 45°C

According to FIGS. 4 to 6, amlodipine and rosuvastatin of Examples 3 to 5 and Comparative Example 8 had different dissolution rates from losartan. However, amlodipine and rosuvastatin of Comparative Example 7, in which all components were mixed, showed a slow dissolution phenomenon similar to that of Rosatan under the influence of Rosatan, which is also different from the control drug of each component (Comparative Examples 14 and 16). A large difference in dissolution was observed.

test example 7: Example 3 to 7; comparative example 7 and 8; comparative example 12 and 13, and comparative example Dissolution test of 17 ( Ezetimibe )

In the case of ezetimibe, a poorly soluble drug, the dissolution rate was less than about 10%, and the dissolution of ezetimibe was confirmed under different dissolution conditions from Test Example 6.

The tablets produced in Examples 3 to 7, Comparative Examples 7 and 8, and Comparative Examples 12 and 13 and Comparative Example 17 (control drug of ezetimibe) as a control drug were subjected to the following elution conditions and the analysis conditions of Test Example 6 over time. The dissolution rate of ezetimibe was evaluated and the results are shown in FIGS. 7 and 8.

-Elution conditions-

Eluent: 0.1% polysorbate 80, 900mL

Apparatus: USP paddle method, 75 rpm

Temperature: 37±0.5℃

As in Test Example 6, based on the results of FIG. 7, ezetimibe dissolution patterns according to whether or not mixed with Rosatan were compared. Ezetimibe of Examples 3 to 7 showed a different dissolution pattern from losartan. However, ezetimibe of Comparative Example 7 in which all components were mixed and ezetimibe in Comparative Example 8 in which losartan was mixed showed a slow dissolution phenomenon similar to that of losartan under the influence of losartan. Comparative Example 17) also showed a large difference in dissolution.

As a result of Test Examples 6 and 7, when developing a pharmaceutical combination formulation including amlodipine, losartan, rosuvastatin, and ezetimibe, amlodipine, rosuvastatin, and ezetimibe were physically separated from losartan. Confirmed that it should exist.

In addition, as a result of confirming the dissolution result of ezetimibe according to the amount of sodium lauryl sulfate widely used as a solubilizer, when the amount of sodium lauryl sulfate was 1.5 to 3 mg, the dissolution pattern was similar to that of Comparative Example 17, which is a control drug. It is determined that a certain amount or more of sodium lauryl sulfate is required as a solubilizing agent for the dissolution rate of ezetimibi, which is a poorly soluble drug.

test example 8: Example 3 to 5, and comparative example 7 to 11 related substances measurement

The tablets of Examples 3 to 5 and Comparative Examples 7 to 11 were packed in HDPE bottles, respectively, and stored under harsh conditions at 60° C. for 5 days and 10 days, and then related substances were analyzed under the analysis conditions of Test Example 5. The results are shown in Tables 8 to 11 below.

amlodipine
Related substance II Example 3 Example 4 Example 5 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Early ND ND ND ND ND ND ND ND harsh 5 days ND ND ND 0.07 ND 0.07 0.06 ND harsh 10 days ND ND ND 0.18 ND 0.16 0.14 ND

Rosatan
total related substances Example 3 Example 4 Example 5 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Early ND ND ND ND ND ND ND ND harsh 5 days ND ND ND ND 0.05 ND ND ND harsh 10 days ND ND ND 0.08 0.16 ND ND ND

Rosuvastatin
Related substance D Example 3 Example 4 Example 5 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Early ND ND ND ND ND ND ND ND harsh 5 days 0.13 0.11 0.12 0.16 0.13 0.61 0.13 0.45 harsh 10 days 0.20 0.17 0.16 0.28 0.20 1.64 0.20 1.34

Ezetimibe
total related substances Example 3 Example 4 Example 5 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Early ND ND ND ND ND ND ND ND harsh 5 days ND ND ND 0.21 0.17 ND ND ND harsh 10 days ND ND ND 0.34 0.27 ND ND ND

In the case of amlodipine and rosuvastatin, the base related substances produced the most were compared, and in the case of losartan and ezetimibe, an unknown peak was generated, so the total related substances were compared.

In the case of amlodipine, Comparative Example 7 prepared by mixing all four components together and Comparative Examples 9 to 10 prepared by granulating together with ezetimibe had poor stability. In the case of amlodipine, reactivity with ezetimibe is expected, and separate manufacturing is required to ensure stability.

In the case of losartan, Comparative Example 7 prepared by mixing all four components together and Comparative Example 8 prepared by granulating together with ezetimibe had poor stability. Rosatan is also expected to be reactive with ezetimibe, and separate manufacturing is required to ensure stability.

In the case of rosuvastatin, an increase in related substances was confirmed in Comparative Example 7, Comparative Example 9, and Comparative Example 11. In particular, in Comparative Example 9 and Comparative Example 11 prepared by granulating with ezetimibe, an increase in related substances was evident. Rosuvastatin is also expected to be reactive with ezetimibe, and separate manufacturing is required to ensure stability.

In the case of ezetimibe, an increase in related substances was confirmed in Comparative Examples 7 to 8, and separate preparation from losartan is required to secure stability.

In summary of the above results, in order to ensure stability, ezetimibe needs to be physically separated from amlodipine, losartan, and rosuvastatin.

All simple modifications or changes of the present invention belong to the scope of the present invention, and the specific protection scope of the present invention will be clarified by the appended claims.

Claims (15)

Ezetimibe or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof;
The ezetimibe or a pharmaceutically acceptable salt thereof is present in a granular form in a mixture with rosuvastatin or a pharmaceutically acceptable salt thereof,
A pharmaceutical combination preparation having water activity reduced to 0.40 or less by leaving it under a relative humidity condition of 15 to 25%. delete delete The method of claim 1,
The granules containing ezetimibe or a pharmaceutically acceptable salt thereof further comprise a solubilizing agent, a pharmaceutical combination formulation. The method of claim 4,
The solubilizing agent is a pharmaceutical combination preparation, characterized in that sodium lauryl sulfate. The method of claim 5,
A pharmaceutical combination preparation, characterized in that the weight ratio of sodium lauryl sulfate and ezetimibe in the granules containing ezetimibe or a pharmaceutically acceptable salt thereof is 0.15: 1 to 0.3: 1. The method of claim 1,
The pharmaceutical combination preparation further comprises a component 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 method of claim 7,
The ezetimibe or a pharmaceutically acceptable salt thereof is physically compatible with rosuvastatin or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, respectively. A pharmaceutical combination preparation characterized in that it exists in a separated state. The method of claim 8,
The pharmaceutical combination formulation,
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 pharmaceutical combination preparation characterized in that it exists in the form of a two-layer tablet consisting of a second layer containing the losartan or a pharmaceutically acceptable salt thereof. The method of claim 9,
In the first layer, ezetimibe or a pharmaceutically acceptable salt thereof is mixed with rosuvastatin or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt thereof in granular form. Pharmaceutical combination preparations. The method of claim 9,
In the second layer, losartan or a pharmaceutically acceptable salt thereof is present in the form of granules. As a method for producing a pharmaceutical combination preparation according to claim 1,
i) preparing ezetimibe granules containing ezetimibe or a pharmaceutically acceptable salt thereof;
ii) preparing a mixture by mixing the ezetimibe granules with rosuvastatin or a pharmaceutically acceptable salt thereof;
iii) reducing the water activity to 0.40 or less by leaving the mixture under a relative humidity condition of 15 to 25%; and
iv) A method for preparing a pharmaceutical combination formulation comprising the step of tableting a mixture having reduced water activity. The method of claim 12,
In step ii), rosuvastatin or a pharmaceutically acceptable salt thereof is mixed with ezetimibe granules together with amlodipine or a pharmaceutically acceptable salt thereof. The method of claim 12,
In step iv), tableting into a double-layered tablet is performed by using the mixture with reduced water activity as a first layer and losartan granules with water activity reduced to 0.40 or less as a second layer,
The losartan granules having the water activity reduced to 0.40 or less,
a) preparing losartan granules comprising losartan or a pharmaceutically acceptable salt thereof; and
b) A method for preparing a pharmaceutical combination preparation, which is characterized in that it is prepared through the step of reducing the water activity to 0.40 or less by leaving the prepared losartan granules under a relative humidity condition of 15 to 25%. delete