KR20190084217A - PHARMACEUTICAL COMPOSITE CAPSULE FORMULATION COMPRISING IRBESARTAN AND HMG-CoA REDUCTASE INHIBITOR - Google Patents

Abstract

The present invention relates to: a pharmaceutical composite capsule formulation which contains 1) an irbesartan independent unit containing irbesartan or pharmaceutically acceptable salt thereof, and 2) an HMG-CoA reductase inhibitor independent unit containing an HMG-CoA reductase inhibitor or pharmaceutically acceptable salt thereof and an alkaline additive; and a manufacturing method thereof. According to the present invention, a formulation prevents the interaction of the irbesartan and the HMG-CoA reductase inhibitor for improving stability and an elution rate, thereby improving bio-availability of drugs and drug compliance of a patient. Therefore, the formulation can be usefully used as a therapeutic agent for high blood pressure and hypercholesteremia.

Description

TECHNICAL FIELD [0001] The present invention relates to a pharmaceutical capsule composition comprising ivesartan and an HMG-CoA reductase inhibitor,

The present invention relates to a pharmaceutical composition comprising 1) ivesartan independent comprising ivesartan or a pharmaceutically acceptable salt thereof; And 2) an HMG-CoA reductase inhibitor independent component comprising an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof and a basic additive. And a manufacturing method thereof.

"Hyperlipidemia" refers to a condition in which plasma lipids such as cholesterol and triglycerides are abnormally increased. Hyperlipidemia, particularly hypercholesterolemia, induces arterial thrombosis, resulting in arteriosclerosis, a thick lipid layer along the blood vessels , Which reduces blood flow to cause ischemic heart disease, angina and myocardial infarction. As such, hyperlipidemia and atherosclerosis are closely related to each other, so atherosclerosis can be prevented by treating hyperlipidemia.

The HMG-CoA reductase inhibitor inhibits the production of mevalonate and inhibits cholesterol biosynthesis, thereby lowering total cholesterol and lowering LDL-cholesterol, and has been used for the treatment of hyperlipidemia (Grundi SM, N Engl J Med , 319 (1): 24-32, 25-26, 31 (1998)).

On the other hand, when ivesartan (compound name: 2-butyl-3 - ({4- [2- (2H-1,2,3,4-tetrazol-5-yl) phenyl] Diazaspiro [4.4] non-1-en-4-one, U.S. Pat. No. 5,270,317) is a potent AT ₁ receptor blocker that binds angiotensin-2, one of the source materials causing vasoconstriction, to AT ₁ Receptor blockers that inhibit the action of angiotensin-2 receptor blockers. It selectively blocks AT ₁ receptors, but it inhibits endothelial cell proliferation, vasoconstriction, and tissue regeneration by allowing angiotensin- _{2 to} bind to the AT ₂ receptor, while maintaining the vasodilating action. These angiotensin-2 receptor blockers have been commercialized as a therapeutic agent for hypertension and have shown rapid growth, and their effects have been demonstrated in clinical trials (Jessica C. Song Pharm. D., C. Michael White Pharm. Pharmacotherapy , 20 (2): 130-139, 2000).

Approximately 60% of patients with hypertension are hyperlipidemia, and hypertension and hyperlipidemia are proven to be closely related diseases. Therefore, the combined use of angiotensin-2 receptor blocker and HMG-CoA reductase inhibitor in patients with cardiovascular disease improves the function of endothelial cells which plays a protective role of blood vessels, as well as treatment of hypertension and hyperlipidemia, (Ceriello A, Assaloni R, Da Ros R, Maier A, Piconi L, Quagliaro L, et al., Circulation , 111: 2518-2524, May 2005), and may be effective in the treatment of diabetes by increasing insulin sensitivity ; And Koh KK, Quon MJ, Han SH, et al., Circulation , 110: 3687-3692, Dec 2004).

Korean Patent Publication Nos. 2009-0114328 and 2009-0114190 disclose a combination preparation of ivesartan and atorvastatin, which comprises an angiotensin receptor blocker (ARB) -based drug including ibesartan and an HMG -COA reductase inhibitor, which causes delayed release of one of the two drugs over 2 hours. However, in the case of the delayed release combination preparation, it is not easy to produce a product exhibiting a constant release delay rate as a formulation designed mainly for in vitro test, and there is a difference in gastrointestinal motility for each person, Is difficult to predict accurately.

On the other hand, since ibesartan is mainly metabolized by 2C9 of cytochrome P450 as a liver metabolic enzyme, HMG-CoA reductase inhibitors are less likely to be metabolized by the liver and metabolized mainly by 3A4 of cytochrome P450, HMG-CoA reductase inhibitors are highly likely to lack pharmacological interactions with each other [Yoshihisa Shitaraa, Yuichi Sugiyamab , Pharmacology & Therapeutics , Vol. 112, Issue 1, October 2006. 71-105, and FDA Avapro label]. Therefore, in the case of two drugs which are expected to have no mutual interaction, it is considered that a quick-acting preparation which shows a drug effect within a short period of time is preferable.

In order to minimize adverse effects of physical or chemical interactions between the active ingredients, various preparations for drug-to-drug separation, such as preparing tablets containing double layer coated drugs and coated pellets, Are known. However, these methods can not achieve perfect separation because of possible contamination by incorporation of the principal components. For example, in the case of a two-layer structure, there is a structural disadvantage in that the granules are mixed with other parts due to factors such as pores in the tableting machine, vibration, vibration, and design problems in the tableting process and the shielding of the two components is not perfect . Also, even in the case of dual coating drugs, there is a high possibility of interlayer contamination due to abrasion and crushing of the product during coating.

 Korean Patent Publication No. 2011-0007602 discloses a polypylate containing acetylsalicylic acid, an HMG-CoA reductase inhibitor and an angiotensin converting enzyme (ACE) inhibitor, and a capsule preparation containing the same in a tablet form However, the preparation has a limited number of tablets, and there is no known effect of improving the stability and dissolution rate of each component.

Also, International Patent Publication No. WO 03/011283 discloses a combination preparation comprising atorvastatin calcium and amlodipine besylate, and improves the stability of atorvastatin calcium by adding an alkalizing agent that forms a pH of 5 or higher as a stabilizer . However, the use of such an alkalizing agent affects the stability of other active ingredients other than atorvastatin.

On the other hand, it is also known to separately produce granules of ibesartan and HMG-CoA reductase inhibitor. However, since the contact between the two active ingredients can not be fundamentally prevented, the stability of the active ingredient is lowered. The size and the volume become too large, so that the capsule filling is impossible or the compliance with medication is lowered.

In order to solve the above problems, the present inventors have developed a rapid capsule preparation capable of improving stability and dissolution rate by preventing physical contact by allowing ibasaltan and HMG-CoA reductase inhibitor to exist independently in capsules Respectively.

U.S. Patent No. 5,270,317 Korea Patent Publication No. 2009-0114328 Korea Patent Publication No. 2009-0114190 Korea Patent Publication No. 2011-0007602 International Patent Publication No. WO 03/011283

Grundi S. M., N Engl J Med, 319 (1): 24-32, 25-26, 31, 1998 Jessica C. Song Pharm. D., C. Michael White Pharm. D., Pharmacotherapy, 20 (2): 130-139, 2000 Ceriello, Assaloni R, Da Ros R, Maiera, Piconi L, Quagliaro L, et al., Circulation, 111: 2518-2524, May 2005 Koh KK, Quon MJ, Han SH, et al., Circulation, 110: 3687-3692, Dec 2004 Yoshihisa Shitaraa, Yuichi Sugiyamab, Pharmacology & Therapeutics, Vol. 112, Issue 1, 71-105, October 2006 FDA Avapro label

It is an object of the present invention to provide pharmaceutical preparations containing ibasaltan and an HMG-CoA reductase inhibitor exhibiting an improved dissolution rate and bioavailability.

Another object of the present invention is to provide a method for producing the above pharmaceutical preparation.

In order to achieve the above object,

1) ivesartan independent comprising ivesartan or a pharmaceutically acceptable salt thereof; And

2) an HMG-CoA reductase inhibitor independent part comprising an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and a basic additive

In a separate state.

To achieve these and other objects,

1) preparing ibasaltan granules or tablets comprising ivesartan or a pharmaceutically acceptable salt thereof;

2) preparing an HMG-CoA reductase inhibitor granule or tablet comprising an HMG-CoA reductase inhibitor, or a pharmaceutically acceptable salt thereof, and a basic additive;

3) filling the hard capsules with the ibasaltan granules or tablets prepared in step 1) and the HMG-CoA reductase inhibitor granules or tablets prepared in step 2) in separate states, A method for producing a combination preparation is provided.

The capsule combination preparation according to the present invention enables immediate release of a drug without deterioration of elution due to the interaction of ivesartan and HMG-CoA reductase inhibitor, thereby showing improved drug dissolution rate and bioavailability, The product stability according to the present invention is excellent and the content of the excipient can be greatly lowered, which can increase the patient's compliance with the dosage form due to the formulation size.

Figures 1 and 2 show the amounts of ivesartan and atorvastatin degradation products produced during long-term storage of the formulation of Example 5 and Comparative Examples 1 to 3, respectively.
Figures 3 and 4 show the dissolution rates of ivesartan and atorvastatin for the formulation of Example 5 and Comparative Examples 1 to 3, respectively.
Fig. 5 shows the results of comparing the saturation solubility of ivesartan with the formulation of Example 5 and Comparative Example 1. Fig.
Figure 6 compares the pharmacokinetic parameters of ivesartan for the formulation of Example 5 and Comparative Example 1.
Figure 7 shows a photograph of the preparation of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention relates to a pharmaceutical composition comprising 1) ivesartan independent comprising ivesartan or a pharmaceutically acceptable salt thereof; And 2) an HMG-CoA reductase inhibitor independent portion comprising an HMG-CoA reductase inhibitor, or a pharmaceutically acceptable salt thereof, and a basic additive, separately. FIG. 7 shows a photograph of the pharmaceutical capsule preparation according to the present invention.

The capsule preparation of the present invention is characterized in that the ibasalten independent part and the HMG-CoA reductase inhibitor independent part are each in the form of granules or tablets, wherein the capsules of the present invention contain ibasaltan granules or tablets and HMG-CoA reductase inhibitor Granules or tablets, of which at least one is in the form of tablets.

Thus, the capsule preparation of the present invention comprises 1) ivesartan granules or tablets comprising ivesartan or a pharmaceutically acceptable salt thereof; And 2) an HMG-CoA reductase inhibitor granule or tablet, which comprises an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and a basic additive, are separately packed in hard capsules. At this time, it is preferable that the diameters and thicknesses of the tablets are respectively mini-tablets of 3 mm or less. For more complete physical shielding, the two dosage units can be coated with conventional coating components.

According to one embodiment of the present invention, there is provided a tablet comprising ivesartan or a pharmaceutically acceptable salt thereof; And a capsule comprising the HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and a basic additive, wherein the tablet is filled in a hard capsule. The capsule preparation may be prepared, for example, by tableting tablets containing ivesartan or a pharmaceutically acceptable salt thereof, and separately therefrom tablets containing an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof and a basic additive , Followed by coating each, and filling them into capsules of appropriate size, for example, No. 1 capsules.

According to another embodiment of the present invention there is provided a pharmaceutical composition comprising granules comprising ivesartan or a pharmaceutically acceptable salt thereof; And a capsule comprising the HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and a basic additive, wherein the tablet is filled in a hard capsule.

According to another embodiment of the present invention, there is provided a tablet comprising ivesartan or a pharmaceutically acceptable salt thereof; And a granule comprising an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and a basic additive are packed in a hard capsule.

The ivesartan independent moiety according to the present invention comprises ivesartan or a pharmaceutically acceptable salt thereof as an active ingredient. Ivesartan or a pharmaceutically acceptable salt thereof is a potent long-acting angiotensin-2 receptor antagonist which binds to angiotensin receptor with high affinity to inhibit angiotensin-induced vasoconstriction, inhibit aldosterone secretion, Absorption can be suppressed and can be particularly useful for the treatment of cardiovascular diseases such as hypertension and heart failure. Pharmaceutically acceptable salts of ivesartan are all possible salts which those skilled in the art can readily use, including sodium, potassium, calcium, magnesium and ammonium salts.

The ivesartan or a pharmaceutically acceptable salt thereof according to the present invention may be contained in an amount of about 20 to about 70% by weight, preferably 40 to 70% by weight, based on the total weight of the ibasaltan granule or tablets, , For example, from 8 to 600 mg, preferably from about 100 to 200 mg, per unit dosage form, but is not limited thereto.

In the present invention, the ivesartan-independent portion, specifically the ivesartan granule or tablet, is a pharmaceutically acceptable salt selected from the group consisting of pharmaceutically acceptable binders, disintegrants, lubricants, diluents, colorants, antiadhesives, But it is not limited thereto. In addition, a surfactant may be further included to improve the hydrophobic nature of ibesartan, which may improve aqueous granulation, facilitate release of the tablet after compression, and accelerate dissolution of the pharmacologically active ingredient .

Binders usable in the present invention may be selected from the group consisting of sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, povidone and mixtures thereof, But is not limited thereto. The binder may be used in an amount ranging from about 2 to about 20 weight percent, preferably from about 2 to about 10 weight percent, based on the total weight of the granule or tablet.

The disintegrant which can be used in the present invention may be selected from the group consisting of corn starch, crospovidone, croscarmellose sodium, carboxymethylcellulose calcium, sodium starch glycolate, low substituted hydroxypropylcellulose and mixtures thereof, It is not. The disintegrant may be used in an amount ranging from about 1 to about 20% by weight, preferably from about 1 to about 15% by weight, based on the total weight of the granule or tablet.

Lubricants usable in the present invention include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, cured vegetable oil, Polyethylene glycol, sodium benzoate, talc, and mixtures thereof, but is not limited thereto. The glidant may be used in an amount ranging from about 0.2 to about 5% by weight, preferably from about 0.5 to about 4% by weight, based on the total weight of the granule or tablet.

Surfactants usable in the present invention may be selected from the group consisting of sodium lauryl sulfate, poloxamer, polyethylene glycol, and mixtures thereof, and poloxamers are preferred, but are not limited thereto. According to one embodiment of the present invention, the surfactant is preferably present only in the ivesartan-independent portion in order to improve stability, but is not limited thereto.

In one preferred embodiment, the ivesartan granules according to the present invention comprise 20 to 70% by weight (for example 50% by weight) of ibasaltan, (b) (D) from 1 to 20% by weight of a disintegrant, (e) from 0.1 to 5% by weight of an anti-sticking agent, (f) from 0.2 to 5% by weight of a lubricant, and g) 2% by weight or less (for example, 0.1 to about 1% by weight) of a coloring agent.

Meanwhile, the HMG-CoA reductase inhibitor independent part according to the present invention comprises, as an active ingredient, an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and a basic additive.

The HMG-CoA reductase inhibitor may be selected from the group consisting of rosuvastatin (US Pat. No. 4,231,938), lovastatin, atorvastatin, pravastatin (U.S. Patent Nos. 4,346,227 and 4,410,629) (Such as fluvastatin, pitavastatin, velostatin, simvastatin (U.S. Patent Nos. 4,448,784 and 4,450,171), rivastatin, cerivastatin, valostatin, mevastatin (US Patent No. 3,983,140), pharmaceutically acceptable salts thereof, precursors, and mixtures thereof, preferably atorvastatin calcium, but is not limited thereto .

The HMG-CoA reductase inhibitor according to the present invention or a pharmaceutically acceptable salt thereof is used in an amount of about 5 to about 20% by weight, preferably 5 to 10% by weight (based on the total weight of the HMG-CoA reductase inhibitor granule or tablet) About 8% by weight), and may be included in a therapeutically effective amount, for example, 0.5 to 100 mg, more preferably 2.5 to 80 mg, most preferably 5 to 80 mg per unit dosage form , But is not limited thereto.

The basic additive according to the present invention is present only in the same layer as the HMG-CoA reductase inhibitor, thereby improving the stability of the HMG-CoA reductase inhibitor and providing a basic microenvironment condition for ivesartan, thereby improving the solubility of ibesartan To ultimately increase the bioavailability of ibesartan.

The basic additives include basic inorganic substances such as NaHCO ₃ , CaCO ₃ , MgCO ₃ , KH ₂ PO ₄ , K ₂ HPO ₃ and calcium trichloro phosphate, arginine, lysine, histidine, meglumine, aluminum magnesium silicate, aluminum magnesium metasilicate, A salt thereof, and a mixture thereof, preferably NaHCO ₃ , CaCO ₃ , MgCO _3, or a mixture thereof, but is not limited thereto. The basic additive may be used in an amount of 2 to 10 parts by weight based on 1 part by weight of the HMG-CoA reductase inhibitor and may be included in an amount of about 8 to about 65% by weight based on the total weight of the HMG-CoA reductase inhibitor granule or tablet .

In the present invention, the HMG-CoA reductase inhibitor independent moiety, specifically, the HMG-CoA reductase inhibitor granule or tablet is a pharmaceutically acceptable diluent, disintegrant, binder, carrier, filler, lubricant, And may further comprise pharmaceutically acceptable additives selected from the group consisting of wetting agents, solubilizers, colorants, pH adjusting agents, surfactants, emulsifiers, coatings, and mixtures thereof.

The aqueous diluent may be selected from the group consisting of mannitol, sucrose, lactose, sorbitol, xylitol, glucose, and mixtures thereof, but is not limited thereto.

Examples of the disintegrant include hydroxypropylcellulose, crospovidone, sodium starch gluconate, sodium croscarmellose, and the like, and they can be appropriately selected from commonly used disintegrants. Examples of the binder include povidone, copovidone, and cellulose. Examples of the lubricant include magnesium stearate, stearyl sodium fumarate, talc, glyceryl fatty acid esters, glycerol dibehenate, and the like, and they can be appropriately selected from commonly used lubricants. Examples of the coating agent include polyvinyl alcohol, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, and the like, and they can be appropriately selected from commonly used coating agents.

In a preferred embodiment, the HMG-CoA reductase inhibitor independent part of the present invention comprises (a) 5 to 20% by weight of an HMG-CoA reductase inhibitor, (b) (C) from 0.5 to 2% by weight of a lubricant or coating, and (d) from 8 to 65% by weight of a basic additive.

Tablets constituting the ibasalant-independent moiety or the HMG-CoA reductase inhibitor independent moiety according to the present invention may each further comprise a coating layer. The coating layer may be coated on the surface of one or more of the tablets of each tablet to completely separate the ibalsartan and the HMG-CoA reductase inhibitor to improve stability and dissolution characteristics.

In the present invention, the coating process can improve the quality of the capsule filling process and the final product by increasing the mechanical strength of mini-tablets having diameters and thicknesses of less than 3 mm which are filled into capsules. In addition, the coating of mini tablets can have a significant impact on the speed of production of the final product. For example, a coated mini tablet having a property of suitable mechanical strength or higher may be fed to the hopper and feeder This makes it possible to prevent damage to the pump.

In the coating layer of the tablet according to the present invention, a conventional polymer can be used as a coating agent. For example, methylcellulose, ethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose and the like may be used, but the present invention is not limited thereto. The amount of the coagulant to be used is preferably kept at a minimum to provide an optimal formulation size and effective production, and is preferably in the range of 1 to 20% by weight, preferably 2 to 10% by weight, based on the total weight of the tablet .

In the capsule preparation of the present invention, the capsules may be any of ordinary hard capsules used in medicine. The base of the hard capsules usable in the present invention may be, for example, gelatin, hypromellose, pullulan (Capsugel, NP caps, etc.) or polyvinyl alcohol.

The size of the hard capsule that can be used in the capsule preparation of the present invention may be a general capsule size used in medicine. The size of the capsule has various internal volumes according to the size of the capsule. The capsule has 0.95ml, 0.68ml, 0.47ml, 0.37ml, 0.27ml, No. 4 capsule is known as 0.20ml (Seoheung capsules website). The size of the capsules is preferably small considering the convenience of medicines of the patient taking the formulation of the present invention. However, in the present invention, due to the mass limit of the contents to be filled in capsules, the size of the capsules is preferably 0, 1, 2, A capsule may be used, preferably capsules of No. 1, No. 2 and No. 3.

The present invention also relates to a method for the production of ivesartan granules or tablets comprising the steps of: 1) preparing ivesartan granules or tablets comprising ivesartan or a pharmaceutically acceptable salt thereof; 2) preparing an HMG-CoA reductase inhibitor granule or tablet comprising an HMG-CoA reductase inhibitor, or a pharmaceutically acceptable salt thereof, and a basic additive; 3) filling the hard capsules with the ibasaltan granules or tablets prepared in step 1) and the HMG-CoA reductase inhibitor granules or tablets prepared in step 2) in separate states, A method for producing a combination preparation is provided.

Specifically, the method comprises the steps of i) granulating ivesartan or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive, or tableting the granules; ii) granulating the HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and a basic additive with a pharmaceutically acceptable additive, or tableting the granules; iii) coating the ibasaltan granules or tablets prepared in step i) and the HMG-CoA reductase inhibitor granules or tablets prepared in step ii); And iii) charging the ibasaltan granules or tablets prepared in step i) and the HMG-CoA reductase inhibitor granules or tablets prepared in step ii) to form separate isolated parts in the hard capsule.

The various processes involved in the preparation of the combination preparation according to the present invention can be carried out based on conventional processes. In the above step i) or ii), when tablets are prepared by tabletting, granules may be prepared using a tablet machine according to a conventional tablet production method, and the tablets prepared may have an appropriate hardness, for example, in the range of 1 to 30 kp It is preferable that the average hardness is shown. The measurement of the average hardness can be performed before forming any film coating layer on the tablet. It may further comprise the step of coating the tablets when the tablets are prepared in step i) or ii) above.

In step iii), the hard capsule is filled with the ibasaltan granule or tablet and the HMG-CoA reductase inhibitor granule or tablet so as to form a separated independent part, and at least one of them is filled in the capsule in the form of tablet.

The capsule preparation of the present invention may be administered orally, buccally, or sublingually, and may be administered orally or parenterally such as a hypertension, hypercholesterolemia, hyperlipidemia, myocardial infarction, stroke, angioplasty and chronic stable angina ≪ / RTI >

The capsule preparation according to the present invention can completely separate the two active ingredients by including ibasalten and HMG-CoA reductase inhibitor in the form of separate from each other in the hard capsule. Accordingly, it is possible to maximize the therapeutic effect by minimizing the reactivity between the active ingredients and the product stability due to the change over time, and also to provide a method for analyzing the stability of the product, There are advantages to use.

In view of the fact that the basic additive stabilizing the HMG-CoA reductase inhibitor affects the stability of ibesartan in the immediate-release pharmaceutical preparations comprising ibecartan and HMG-CoA reductase inhibitor in the present invention, The formulation was prepared. According to the present invention, granules containing each of the main ingredients are separately prepared, followed by tableting with mini tablets each having a diameter and a thickness of 3 mm or less, filling the hard capsules with the tablets if necessary, Since the content of the excipient can be greatly lowered, the problems due to the size of the final pharmaceutical composition can be solved, and thus a combined preparation having improved convenience for patients in oral administration can be obtained. Further, when the capsules are packed in the form of physically separated mini-tablets, the ivesartan and HMG-CoA reductase inhibitors enable immediate release of the drug without interfering with dissolution of the drug (ivesartan or its pharmaceutical , And an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, respectively, at 80% or more in 30 minutes, preferably 80% or more in 15 minutes), the initial dissolution rate can be increased, Thereby increasing the bioavailability and improving the therapeutic effect of the patient.

[Example]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1: Preparation of capsules containing rosuvastatin mini-tablet and ibesartan granules- (1)

(HPC-L, Nisso, Japan) and Poloxamer (Japan) were prepared by mixing ibasaltan (Hanmi Precision, Korea), lactose, pregelatinized starch and crospovidone using the composition described in Example 1 below. 188 (BASF, Germany) was combined with a binding solution dissolved in water, dried and sieved through a 30-mesh sieve to prepare wet granules. Thereafter, talc was added and finally mixed to prepare ibegaarten granules.

Meanwhile, rosuvastatin calcium, lactose, crospovidone and sodium monohydrogen carbonate were mixed using the composition described in Example 1 in the following Table 1, and hydroxypropylcellulose (HPC-L) and polysorbate 80 (Croda, USA) was combined with a binding solution dissolved in water, dried, and sieved with a 30 mesh sieve to prepare wet granules. Then, rosuvastatin calcium granules were prepared by adding sodium croscarmellose sodium, mixing and adding magnesium stearate and final mixing. The rosuvastatin calcium granules prepared above were tableted with mini-tablets and then coated. For tableting mini-tablet, rotary tablet machine (Sejung, GRC-18) was used and tablet diameter and thickness were 2mm. The prepared mini tablet was coated with hydroxypropylmethylcellulose using a topcoat coating method using a fluid bed coater (Dalton, NQ-160).

The above-prepared ibasaltan granules and rosuvastatin mini tablets were taken respectively by the total weight shown in the following Table 1 and filled into No. 1 hard capsules using a capsule filling machine (GKF-2500, Bosch).

Example 2: Preparation of capsules containing rosuvastatin mini tablets and ibesartan granules- (2)

(HPC-L, Nisso, Japan) and lauryl (L-glutamic acid) were mixed after mixing Ibetalane (Hanmi Precision, Korea), lactose, pregelatinized starch and crospovidone using the composition described in Example 2 below. Sodium sulfate was combined with a binding solution dissolved in water, dried and sieved in a 30 mesh sieve to prepare wet granules. Thereafter, talc was added and finally mixed to prepare ibegaarten granules.

On the other hand, rosuvastatin calcium, microcrystalline cellulose, crospovidone and sodium monohydrogen carbonate were mixed using the composition described in Example 2 in the following Table 1, and hydroxypropylcellulose (HPC-L) and polysorbate 80 , USA) was combined with a binding solution dissolved in water, dried, and sieved with a 30 mesh sieve to prepare wet granules. Then, rosuvastatin calcium granules were prepared by adding sodium croscarmellose sodium, mixing and adding magnesium stearate and final mixing. The rosuvastatin calcium granules prepared above were tableted with mini-tablets and then coated. For tableting mini-tablet, rotary tablet machine (Sejung, GRC-18) was used and tablet diameter and thickness were 2mm. The prepared mini tablet was coated with hydroxypropylmethylcellulose using a topcoat coating method using a fluid bed coater (Dalton, NQ-160).

The above-prepared ibasaltan granules and rosuvastatin mini tablets were taken respectively by the total weight shown in the following Table 1 and filled into No. 1 hard capsules using a capsule filling machine (GKF-2500, Bosch).

Ingredients and content of hard capsules containing ibesartan granules and rosuvastatin mini tablets (unit: mg) division Example 1 Example 2 Ibesartan granule Granule Yves Saltan 150 150 Lactose 30 20 Pregelatinized starch 23 23 Crospovidone 12 6 Hydroxypropylcellulose 9 6 Poloxamer 188 12  - Sodium lauryl sulfate  - 9 Final mixing Talc 4 4.5 Total weight of ibesartan granule 240 218.5 Rosuvastatin
Calcium mini tablet Granule Rosuvastatin calcium 10.4 10.4 Lactose 15  - Microcrystalline cellulose  - 16 Crospovidone 7 7 NaHCO ₃ 60 40 Hydroxypropylcellulose 4 5 Polysorbate 80 0.6 0.6 mix Croscarmellose sodium 3 3 Final mixing Magnesium stearate 1.25 1.25 Tableting coating Hydroxypropylmethylcellulose 2 2 　
　 Rosuvastatin calcium
Mini Tablet Gross Weight 103.25 85.25 Capsule filling Total weight (excluding capsules) 343.25 303.75

Example 3: Preparation of capsules containing atorvastatin granules and ivesartan mini tablet - (1)

Povidone (BASF, Germany) and Poloxamer 188 (BASF, Germany) were mixed after mixing the iveartan (Hanmi Precision, Korea), mannitol, pregelatinized starch and crospovidone using the composition described in Example 3 below. Dried with a binding solution dissolved in water, and sieved with 30 mesh sieve to prepare wet granules. Thereafter, mannitol, silicon dioxide and crospovidone were added and mixed, and magnesium stearate was added and finally mixed to prepare ibesartan granules. The tablets were tableted with mini tablets and then coated. For tableting mini-tablet, rotary tablet machine (Sejung, GRC-18) was used and tablet diameter and thickness were 2mm. The mini-tablets thus prepared were coated with hydroxypropylmethylcellulose using a top-spray coating method using a fluid bed coater (Dalton, NQ-160).

Meanwhile, atorvastatin calcium (TEVA, India), lactose, croscarmellose sodium and sodium monohydrogen carbonate were mixed using the composition described in Example 3 in the following Table 2, povidone and polysorbate 80 (Croda, USA) Dried with a binding solution dissolved in water, and sieved with 30 mesh sieve to prepare wet granules. Then, magnesium stearate was added and finally mixed to prepare atorvastatin calcium granules.

The above-prepared ibasaltarmin tablets and atorvastatin granules were each taken to the total weight given in Table 2 below and filled into No. 1 hard capsules using a capsule filling machine (GKF-2500, Bosch).

Example 4: Preparation of capsules containing atorvastatin granules and ivesartan mini tablet - (2)

After mixing with atorvastatin calcium (TEVA, India), lactose, sodium croscarmellose sodium and magnesium carbonate (Tomita, Japan) using the composition described in Example 4 in Table 2 below, povidone and polysorbate 80 (Croda, USA) Was combined with a binding solution dissolved in water, dried, and sieved through a 30-mesh sieve to prepare wet granules. Then, magnesium stearate was added and finally mixed to prepare atorvastatin calcium granules.

The ibasaltarmin tablets and atorvastatin granules prepared in the same manner as in Example 3 were taken respectively by the total weight as shown in Table 2 below and filled into No. 1 hard capsules using a capsule filling machine (GKF-2500, Bosch) .

Ingredients and content of hard capsules containing ibesartan mini tablet and atorvastatin granules (unit: mg) division Example 3 Example 4 Ibesartan mini tablets Granule Yves Saltan 150 Mannitol 15 Pregelatinized starch 20 Crospovidone 6 Povidone 8 Poloxamer 188 9 mix Mannitol 28.5 Silicon dioxide 10 Crospovidone 6 Final mixing Magnesium stearate 2.5 Tableting coating Hydroxypropylmethylcellulose 2 Ivesartan mini tablet Total weight 257 257 Atorvastatin
Calcium granule Granule Atorvastatin calcium 10.36 10.36 Lactose 20 20 Croscarmellose sodium 10 10 Povidone 5 5 Polysorbate 80 0.6 0.6 Magnesium carbonate  - 57 NaHCO ₃ 57  - Final mixing Magnesium stearate 1.25 1.25 　
　 Atorvastatin calcium mini tablet Total weight 104.21 104.21 Capsule filling Total weight (excluding capsules) 361.21 361.21

Example 5: Preparation of capsules containing atorvastatin mini tablet and ivesartan mini tablet

Mannitol, pregelatinized starch and croscarmellose sodium (DMV international) were mixed using povidone (BASF, Germany) and Poloxamer 188 (BASF, Germany) using the compositions described in Table 3 below, ) Was combined with a binding solution dissolved in water, dried, and sieved through a 30-mesh sieve to prepare wet granules. Thereafter, mannitol, silicon dioxide and croscarmellose sodium were added and mixed, and magnesium stearate was added and finally mixed to prepare ibacartan granules.

On the other hand, after mixing the atorvastatin calcium (TEVA, India), mannitol, microcrystalline cellulose, sodium croscarmellose sodium and magnesium carbonate (Tomita, Japan) using the composition shown in the following Table 3, HPC and polysorbate 80 ) Was combined with a binding solution dissolved in water, dried, and sieved through a 30-mesh sieve to prepare wet granules. The atorvastatin calcium granules were then prepared by adding sodium croscarmellose sodium and adding magnesium stearate and final mixing.

The ibasalten granules and atorvastatin calcium granules prepared above were each tableted with mini-tablets and then coated. For tableting mini-tablet, rotary tablet machine (Sejung, GRC-18) was used and tablet diameter and thickness were 2mm. Each of the mini-tablets thus prepared was coated with a fluidized bed coater (Dalton, NQ-160) using Opaque II 85F18422 white using a top spray coating method.

The above-prepared Ivesartan mini and atorvastatin mini tablets were each taken to the total weight listed in Table 3 below and filled into No. 1 hard capsules using a capsule filling machine (GKF-2500, Bosch).

Ingredients and content of hard capsules containing ibesartan and atorvastatin mini tablets (unit: mg) division Example 5 Comparative Example 1 Ivesartan tablets Granule Yves Saltan 150 150 Mannitol 15 15 Pregelatinized starch 23 23 Croscarmellose sodium 6 6 Povidone 8 8 Poloxamer 188 9 9 mix Mannitol 28.5 28.5 Silicon dioxide 10 10 Croscarmellose sodium 6 6 Final mixing Magnesium stearate 2.5 2.5 Tableting Mini tablets Mini tablets coating Opadry II 85F18422 white 4 4  Gross weight 262 262 Atorvastatin calcium tablets Granule Atorvastatin calcium 10.36 10.36 Mannitol 10 10 Microcrystalline cellulose 6 6 Croscarmellose sodium 7 7 Magnesium carbonate 57 - HPC 5 5 Polysorbate 80 0.6 0.6 mix Croscarmellose sodium 3 3 Final mixing Magnesium stearate 1.25 1.25 Tableting Mini tablets Mini tablets coating Opadry II 85F18422 white 2 2  Gross weight 102.21 45.21 Capsule filling Total weight (excluding capsules) 364.21 307.21

Comparative Example 1: Preparation of capsules containing atorvastatin and ibesartan mini tablet without basic additives

A capsule was prepared in the same manner as described in Example 5, except that magnesium carbonate was not used as a basic additive, using the composition described in Table 3 above.

Comparative Example 2: Preparation of Hard Capsules Containing Tablets of Atorvastatin and Ivesartan

Ivesartan and atorvastatin calcium granules were respectively prepared in the same manner as described in Example 5 above. The tablet was then tableted with two tablets of ibesartan granules and one tablets of atorvastatin granules using a rotary tablet machine (Sejung, GRC-18). At this time, the diameter of the tablets was adjusted to be 5 mm in order to fill the capsule, which is larger than the size of the mini tablet tableted in the embodiment of the present invention.

The single tablet prepared above was coated with a pan coater (Sejung, SFC-30) using Opadry II 85F18422 white, and filled into hard capsule No. 0 in the same manner as in Example 5. [

Comparative Example 3: Manufacture of two-layered definition comprising atorvastatin and ibesartan mini tablet

(Hanmi Precision, Korea) granules and atorvastatin calcium (TEVA, India) granules were prepared according to the method described in Example 5 using the compositions shown in Table 4 below. The above-prepared ibasalten granules and atorvastatin calcium granules were compressed into two-layer tablets using a two-layer tablet machine. Next, Opadry II 85F18422 white was coated using a fan coater (Sejung, SCF-30).

Components and contents of two-layer definition including ivesartan and atorvastatin (unit: mg) division Comparative Example 3 Granule Yves Saltan 150 Mannitol 47 Pregelatinized starch 23 Croscarmellose sodium 12 Povidone 8 Poloxamer 188 9 Final mixing Magnesium stearate 4 Granule Atorvastatin calcium 10.85 Lactose 120 Microcrystalline cellulose 65.6 Cross Carmelo Ossusium 36 Magnesium carbonate 57 HPC 3 Polysorbate 80 1.2 Final mixing Magnesium stearate 3 Tableting Mini tablets coating Opadry II 85F18422 white 2 Gross weight 551.65

≪ Experimental Example 1 >

To evaluate the stability of the preparations prepared in Example 5 and Comparative Examples 1 to 3, each preparation was packed in an HDPE bottle with 1 g of silica gel, stored under long-term conditions (25 ° C. and 60% RH) (RRT 1.81) was measured after 3, 6, 9, 12, 18, 24 and 36 months after the administration of atorvastatin.

≪ Conditions for analysis of atorvastatin '

(1) Detector: Ultraviolet absorptiometer (measuring wavelength 254 nm)

(2) Column: A column or similar column (eg, Kromasil 100-5, C18) filled with 5 μm C ₁₈ in a stainless steel tube with an internal diameter of about 4.6 mm and a length of about 250 mm,

(3) mobile phase: mobile phase A: acetonitrile: tetrahydrofuran: buffer 1 (31: 9: 60) (v / v)

- Buffer 1; The pH is adjusted with 0.05M NH ₄ H ₂ PO ₄ (pH 5.0, aqueous ammonia.

- mobile phase B: acetonitrile: buffer 2 (75: 25) (v / v)

(Buffer 2: Buffer 1: THF (60: 9) (v / v))

(4) Diluent: acetonitrile: tetrahydrofuran: water (60: 5: 35) (v / v)

(5) Injection amount: 10 uL

(6) Temperature: 35 DEG C

(7) Flow rate: 1.8 mL / min

Each formulation was also stored under accelerated conditions (40 ° C and 75% RH) and the amount of decomposed product (RRT 0.8) of ibesartan after 1, 3 and 6 months after the start of the test was determined.

<Flexible Substance Analysis Condition of Ivecaltan>

(1) Detector: Ultraviolet absorptiometer (measuring wavelength 220 nm)

(2) Column: a column or the like filled in a stainless column tube of internal diameter of about 4.6 mm, about 250 mm long by 5 ㎛ C ₁₈

(3) mobile phase: acetonitrile: phosphate buffer (60:40) (v / v)

(Phosphoric acid buffer = 5.5 mL of phosphoric acid dissolved in 1 L of purified water (pH 5.0, pH adjusted with triethylamine)

(4) Diluent: Methanol

(5) Amount of injection: 15 uL

(6) Temperature: 30 DEG C

(7) Flow rate: 1.2 mL / min

The results are shown in Tables 5 and 6, and Figs. 1 and 2.

Atorvastatin degradation products (RRT 1.81) after long-term storage (25 ° C and 60% RH) Long term condition (months) division 0 3 6 9 12 18 24 36 Amount of Atorvastatin Decomposition (%) Example 5 0.07 0.09 0.09 0.11 0.12 0.14 0.16 0.18 Comparative Example 1 0.12 0.13 0.15 0.17 0.18 0.23 0.28 0.45 Comparative Example 2 0.1 0.1 0.09 0.12 0.13 0.14 0.17 0.19 Comparative Example 3 0.08 0.06 0.1 0.12 0.14 0.17 0.19 0.26

(RRT 0.8) after storage under accelerated conditions (40 ° C and 75% RH) Acceleration condition (months) division 0 3 6 Yves Saltan
Decomposition products (%) Example 5 0.031 0.042 0.072 Comparative Example 1 0.031 0.035 0.062 Comparative Example 2 0.028 0.031 0.073 Comparative Example 3 0.044 0.073 0.161

As can be seen from Tables 5 and 6, it can be seen that the amounts of atorvastatin degradation products (RRT 1.81) and ibasal cleansing products (RRT 0.8) increase over time. According to the ICH Guidelines, the release of ibasaltan and atorvastatin degradation products should not be more than 0.2% for accelerated 6 months or 24 to 36 months. The formulation according to the present invention was able to specifically improve the stability of atorvastatin by including a basic additive and showed the most stable results as compared with the preparations of Comparative Examples 1 to 3, .

<Experimental Example 2> Evaluation of dissolution of ibesartan

The results of the dissolution test were shown in Example 5, Comparative Examples 1 to 3, and 150 mg of Aflobel (sanofi-aventis) as a control agent according to the following dissolution test conditions. The results are shown in Fig.

&Lt; Dissolution test conditions >

(1) Elution test apparatus: PTWS-1210 (Pharmatest, Germany)

(2) Elution solution: 0.1 mol / L hydrochloric acid solution

(3) Temperature of eluent: 37 ° C ± 0.5 ° C

(4) Amount of eluent: 1000 ml

(5) Rotation speed: 50 rpm

(6) Sampling: The eluate was taken every 5, 10, 15, 30 and 45 minutes and filtered through a 0.45 μm membrane filter and used as the sample solution. After taking the eluate, a new eluant of the same amount was replenished to the elution test apparatus.

<Analysis method>

(1) Analytical instrument: high performance liquid chromatography (HPLC)

(2) mobile phase: acetonitrile: tetrahydrofuran: buffer 1 = 31: 9: 60

(Buffer _{1 = 0.05M NH 4 H 2 PO} 4, pH5.0, adjusting the pH with aqueous ammonia)

(3) Detector: Ultraviolet absorbance photometer (244 nm)

(4) Column: Column with an inner diameter of about 4.6 and a length of about 150 mm filled with octadecyl silylated 5 탆 silica gel

(5) Flow rate: 1.8 ml / min

<Experimental Example 3> Evaluation of dissolution of atorvastatin calcium

20 mg of Lipitor (reference drug, Pfizer) as Example 5, Comparative Examples 1 to 3, and a control agent were subjected to a dissolution test of atorvastatin calcium by the analytical method and the method of Experimental Example 2 according to the following dissolution test conditions, The results are shown in Fig.

&Lt; Dissolution test conditions >

(1) Elution test apparatus: PTWS-1210 (Pharmatest, Germany)

(2) Effluent: purified water

(3) Temperature of eluent: 37 ° C ± 0.5 ° C

(4) Amount of eluent: 900 ml

(5) Rotation speed: 50 rpm

(6) Sampling: The eluate was taken every 5, 10, 15, 30 and 45 minutes and filtered through a 0.45 μm membrane filter and used as the sample solution. After taking the eluate, a new eluant of the same amount was replenished to the elution test apparatus.

As can be seen from Figs. 3 and 4, the capsules containing the tablets of greater than 3 mm (Comparative Example 2) but not the mini tablets had a low 5-minute initial dissolution rate and a similar dissolution profile of the control after 10 minutes I could. It was observed that gelatin capsules had a lag time before disintegration of external gelatin capsules before internal tablet elution and gelatin affects disintegration of internal tablets. In addition, in the case of the capsule containing no basic stabilizer (Comparative Example 1), the dissolution rate of atorvastatin was low even in the latter half.

On the other hand, the capsule preparation according to the present invention (Example 5) exhibited rapid disintegration by including a mini tablet. Specifically, disintegration was initiated immediately by the eluate introduced into the pores produced by the partial disintegration of the gelatin capsule, and it was found that the small particle size quickly eluted out of the capsule. In addition, the results of analysis of the active ingredients showed the same level of dissolution rate as that of each control.

In addition, the capsule preparation according to the present invention exhibited a dissolution rate equivalent to that of the two-layer tablet (Comparative Example 3) even when the total weight of the preparation was small, showing excellent dissolution effect. Therefore, the capsule preparation according to the present invention is expected to improve the stability and dissolution rate as well as reduce the amount of the excipient, thereby increasing the compliance of patients with the medicament.

Experimental Example 4 Evaluation of saturation solubility of ibesartan

The saturation solubility of ibesartan was confirmed with respect to the preparation prepared in Example 5 and Comparative Example 1. 10 tablets of each sample were subjected to the USP elution method 2 (Paddle method) using 1000 mL of water and 1000 mL of pH 6.8 solution as the eluent at a rotation speed of 50 rpm, and then 12 hours after the test, the sample solution was taken and the saturation solubility Respectively. The results are shown in Fig.

As can be seen from FIG. 5, the formulation of the present invention showed a significant increase in saturation solubility in water and pH 6.8 solution as compared with the formulation of Comparative Example 1, which did not contain a basic additive. It was found that the additive enhances the solubility of ivezartan, which is poor in water solubility.

EXPERIMENTAL EXAMPLE 4 Evaluation of bioavailability of ibesartan

The bioavailability of ibesartan was confirmed in the beagle dogs of the preparation prepared in Example 5 and Comparative Example 1. The experimental methods are as shown in Table 7 below.

Evaluation method of bioavailability of ibesartan title Biomedical pharmacokinetic study after single administration of ivesartan composition in beagle dog purpose Evaluation of bioavailability enhancement effect of ivesartan composition with increased solubility Test system Animals used: Beagle dogs
Sex: Male
Number of animals used: 6 rats per group, randomized cross-over study Test group Test group: Use of formulation of Example 5
Control group: Use of formulation of Comparative Example 1 Test Methods 1) Maintain fasting state before 12 hours, supply only water
2) Oral administration of the preparation of Example 5 or Comparative Example 1
3) Blood collection after 0, 0.33, 0.66, 1, 2, 3, 8, 12,
4) Measurement of ivesartan concentration using LC / MS Statistical processing The pharmacokinetic parameters are measured using a data processing program (KE-Test).

The results are shown in Table 8 and FIG. Figure 6 shows the arithmetic mean plasma concentration of ibesartan (ng / ml) versus time (hr) on a linear scale.

The pharmacokinetic parameter of ivesartan Yves Saltan parameter Example 1 Comparative Example 1 AUC _0-48 (ng · hr / mL) 20136.4 ± 4835.7 9956.0 + - 6859.6 C _max (ng / mL) 13856.4 ± 5746.5 6493.4 + 3349.8 T _max (hr) 1.3 ± 0.7 0.8 ± 0.6

As can be seen in Table 8 and FIG. 6, the formulation of the present invention showed a higher bioavailability compared to the formulation of Comparative Example 1, which did not contain a basic additive, so that the basic additive increased the bioavailability of ivesartan I was able to know Sikim.

Claims (21)

1) ivesartan independent comprising ivesartan or a pharmaceutically acceptable salt thereof; And
2) an HMG-CoA reductase inhibitor independent part comprising an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and a basic additive
In a separated state,
The basic additive is included only in the HMG-CoA reductase inhibitor independent part,
Wherein the ivesartan independent moiety or the HMG-CoA reductase inhibitor independent moiety is in the form of a granule or tablet, wherein at least one of the ibalsartan independent moiety or the HMG-CoA reductase inhibitor moiety is in the form of a tablet, Or less, the thickness of the tablet is 3 mm or less, the tablet further comprises a coating layer,
Wherein the HMG-CoA reductase inhibitor is atorvastatin calcium. The method according to claim 1,
Wherein the coating agent used in the coating layer is selected from the group consisting of methylcellulose, ethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, and mixtures thereof. Compound preparation. 3. The method of claim 2,
Characterized in that the coating agent is used in an amount of 1 to 20% by weight based on the total weight of the tablet. The method according to claim 1,
Wherein the capsule is a hard capsule. The method of claim 4, wherein
Wherein the base of the capsule is selected from the group consisting of hypromellose, pullulan, gelatin and polyvinyl alcohol. The method according to claim 1,
The basic additive is _{NaHCO 3, CaCO 3, MgCO 3} , KH 2 PO 4, K 2 HPO 3, phosphorus trichloride, calcium, arginine, lysine, histidine, meglumine phosphate, magnesium aluminum silicate, magnesium aluminum metasilicate, a salt thereof, and &Lt; / RTI &gt; or a mixture thereof. The method according to claim 6,
Wherein the basic additive is NaHCO ₃ , MgCO ₃ or a mixture thereof. The method according to claim 1,
Wherein the basic additive is contained in an amount of 2 to 10 parts by weight based on 1 part by weight of the HMG-CoA reductase inhibitor. The method according to claim 1,
Wherein the ivesartan independent component further comprises a component selected from the group consisting of a pharmaceutically acceptable binder, a disintegrant, a lubricant, a diluent, a colorant, an anti-sticking agent, a surfactant and mixtures thereof. Compound preparation. 10. The method of claim 9,
Characterized in that the binding agent is selected from the group consisting of sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, povidone and mixtures thereof. Capsule combination preparation. 10. The method of claim 9,
Wherein the disintegrant is selected from the group consisting of corn starch, crospovidone, croscarmellose sodium, carboxymethylcellulose calcium, sodium starch glycolate, low substituted hydroxypropylcellulose, and mixtures thereof. Formulation. 10. The method of claim 9,
Wherein the lubricant is selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, cured vegetable oil, polyethylene glycol, sodium benzoate , Talc, and mixtures thereof. &Lt; RTI ID = 0.0 &gt; 15. &lt; / RTI &gt; 10. The method of claim 9,
Wherein said surfactant is selected from the group consisting of sodium lauryl sulfate, poloxamer, polyethylene glycol, and mixtures thereof. The method according to claim 1,
Wherein said HMG-CoA reductase inhibitor independent component is selected from the group consisting of aqueous diluents, disintegrants, binders, carriers, fillers, lubricants, flow control agents, crystallization retarders, solubilizers, colorants, pH adjusters, surfactants, emulsifiers, &Lt; / RTI &gt; further comprising a pharmaceutically acceptable additive selected from the group consisting of pharmaceutically acceptable excipients. 15. The method of claim 14,
Wherein the aqueous diluent is selected from the group consisting of mannitol, sucrose, lactose, sorbitol, xylitol, glucose, and mixtures thereof. The method according to claim 1,
Wherein the combination agent comprises ivesartan or a pharmaceutically acceptable salt thereof in an amount of 8 mg to 600 mg per unit dosage form. The method according to claim 1,
Wherein the combination agent comprises an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof in an amount of 5 mg to 80 mg per unit dosage form. The method according to claim 1,
Wherein the combination agent releases 80% or more of ibesartan and HMG-CoA reductase inhibitor in 30 minutes, respectively. 19. The method of claim 18,
Wherein the combination agent releases 80% or more of ibesartan and HMG-CoA reductase inhibitor in 15 minutes, respectively. The method according to claim 1,
Wherein the combination is used for the prevention or treatment of diseases selected from the group consisting of hypertension, hypercholesterolemia, hyperlipidemia, myocardial infarction, stroke, angioplasty and chronic stable angina pectoris. 1) preparing ibasaltan granules or tablets comprising ivesartan or a pharmaceutically acceptable salt thereof;
2) preparing an HMG-CoA reductase inhibitor granule or tablet comprising an HMG-CoA reductase inhibitor, or a pharmaceutically acceptable salt thereof, and a basic additive;
3) filling the hard capsules with the ibasaltan granules or tablets prepared in step 1), and the HMG-CoA reductase inhibitor granules or tablets prepared in step 2, separately,
The basic additive is included only in the HMG-CoA reductase inhibitor independent part,
Wherein the product produced in step 1) or step 2) is in the form of a tablet, the diameter of the tablet is 3 mm or less, the thickness of the tablet is 3 mm or less,
And coating the tablets,
The method according to claim 1, wherein the HMG-CoA reductase inhibitor is atorvastatin calcium.

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