KR102042626B1 - PHARMACEUTICAL COMPOSITE CAPSULE FORMULATION COMPRISING IRBESARTAN AND HMG-CoA REDUCTASE INHIBITOR - Google Patents

Abstract

The present invention provides a composition comprising: 1) ibesaltan independent portion comprising ibesaltan 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, and relates to a pharmaceutical capsule complex preparation and a method for preparing the same. , The preparation according to the present invention can improve the bioavailability of the drug by improving the stability and dissolution rate by preventing the interaction of Ivesaltan and HMG-CoA reductase inhibitors, and can also increase the patient's medication compliance to hypertension and It can be usefully used as a therapeutic agent for hypercholesterolemia.

Description

PHARMACEUTICAL COMPOSITE CAPSULE FORMULATION COMPRISING IRBESARTAN AND HMG-CoA REDUCTASE INHIBITOR}

The present invention provides a composition comprising: 1) ibesaltan independent portion comprising ibesaltan 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 in a separated state, wherein the stability and dissolution rate are improved. It relates to a manufacturing method.

"Hyperlipidemia" refers to a condition in which lipids such as cholesterol or triglycerides are abnormally increased in plasma, and hyperlipidemia, particularly hypercholesterolemia, causes arterial thrombosis, which causes arteriosclerosis in which lipids thickly accumulate along blood vessels. This reduces blood flow and causes ischemic heart disease, angina and myocardial infarction. As such, hyperlipidemia and arteriosclerosis are closely related to each other, thereby treating atherosclerosis by treating hyperlipidemia.

HMG-CoA reductase inhibitors inhibit the production of mevalonate and interfere with cholesterol biosynthesis, and have been used in the treatment of hyperlipidemia by showing the effect of lowering total cholesterol and lowering LDL-cholesterol (Grundi SM, N Engl J Med 319 (1): 24-32, 25-26, 31 (1998).

Meanwhile, ibesaltan (Compound name: 2-butyl-3-({4- [2- (2H-1,2,3,4-tetrazol-5-yl) phenyl] phenyl} methyl) of Formula 1 1,3-diazaspiro [4.4] non-1-en-4-one, U.S. Patent No. 5,270,317) is a potent AT ₁ receptor blocker that binds AT ₁ to angiotensin-2, one of the sources of vasoconstriction It is a kind of angiotensin-2-receptor blocker which interferes with and exhibits a step-down effect. By selectively blocking the AT ₁ receptor but allowing angiotensin- _{2 to} bind to the AT ₂ receptor, there is an effect of inhibiting endothelial cell proliferation, vasoconstriction and tissue regeneration while maintaining vasodilation. These angiotensin-2-receptor blockers have been commercialized as antihypertensive drugs and have shown rapid growth, and their effects have been demonstrated in clinical trials (Jessica C. Song Pharm. D., C. Michael White Pharm. D., Pharmacotherapy , 20 (2): 130-139, 2000).

About 60% of hypertensive patients are hyperlipidemic patients, and hypertension and hyperlipidemia have proven to be closely related diseases. Therefore, in combination with angiotensin-2-receptor blocker and HMG-CoA reductase inhibitor in patients with cardiovascular disease, treatment of hypertension and hyperlipidemia, as well as treatment of hypertension and hyperlipidemia, are compared with each single agent. May be effective in the treatment of diabetes by increasing insulin sensitivity (Ceriello A, Assaloni R, Da Ros R, Maier A, Piconi L, Quagliaro L, et al., Circulation , 111: 2518-2524, May 2005 And Koh KK, Quon MJ, Han SH, et al., Circulation , 110: 3687-3692, Dec 2004).

Korean Unexamined Patent Publication Nos. 2009-0114328 and 2009-0114190 disclose a combination preparation of ibesaltan and atorvastatin, wherein the combination preparation is angiotensin receptor blocker (ARB) -based drug and IMG including ibesaltan. In fear of the interaction between the CoA reductase inhibitors, one of these drugs is delayed release for more than 2 hours. However, in the case of the delayed release combination formulation, a product designed for in vitro testing is not easy to manufacture a product that exhibits a constant release delay rate, and there is a difference in the gastrointestinal motility of each person. It is difficult to predict exactly.

Ivesaltan is a hepatic metabolizing enzyme that is mainly metabolized by 2C9 of cytochrome P450, whereas HMG-CoA reductase inhibitors are less likely to be metabolized by the liver and metabolized mainly by 3A4 of cytochrome P450. It is likely that HMG-CoA reductase inhibitors do not have pharmacological interactions with each other [Yoshihisa Shitaraa, Yuichi Sugiyamab , Pharmacology & Therapeutics , Vol. 112, Issue 1, October 2006. 71-105, and FDA Avapro label]. Therefore, for both drugs that are expected to have no interaction with each other, it is believed that immediate release preparations that exhibit medicinal effects in a short time are preferred.

In the case of physical or chemical interactions between the active ingredients, various formulations for the separation of drugs, such as the manufacture of tablets containing double-layered tablets, double layer coated drugs and coated pellets in order to minimize side effects The production method of is known. However, the above methods cannot achieve perfect separation because of the possibility of contamination by incorporation of the main components. For example, in the case of double-layered tablets, there are structural disadvantages in that tableting is refined with granules mixed into other parts due to voids, tremors, vibration, and device design problems in the tableting process, and the shielding of the two components is not perfect. . In addition, in the case of double coating drugs, there is a high possibility of interlayer contamination due to wear and fracture of the product during coating.

 In Korean Patent Application Publication No. 2011-0007602, a polyfill containing an acetylsalicylic acid, an HMG-CoA reductase inhibitor and an angiotensin converting enzyme (ACE) inhibitor, etc. It is disclosed, but the formulation is limited in the number of tablets, there is no known effect of improving the stability and dissolution rate of each component.

In addition, WO 03/011283 discloses a composite formulation comprising atorvastatin calcium and amlodipine besylate, and improves the stability of atorvastatin calcium by adding an alkalizing agent forming a pH of 5 or more as a stabilizer. Although the composition is intended to be disclosed, the use of such alkalizers affects the stability of the main ingredients other than atorvastatin.

On the other hand, there is also known a method for producing granules separately from the ibesaltan and the HMG-CoA reductase inhibitor, respectively, the contact between the two active ingredients can not fundamentally prevent the stability of the active ingredients, and the preparation of the formulation comprising such granules The size and volume become so large that capsule filling is impossible or medication compliance is low.

In order to solve the above problems, the present inventors have developed an immediate-release capsule formulation that can improve the stability and dissolution rate by preventing the physical contact by the presence of the Ivesaltan and HMG-CoA reductase inhibitors independently from each other in the capsule It was.

U.S. Patent 5,270,317 Republic of Korea Patent Publication No. 2009-0114328 Republic of Korea Patent Publication No. 2009-0114190 Republic of Korea Patent Publication No. 2011-0007602 International Patent Publication 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 A, Assaloni R, Da Ros R, Maier A, 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 a pharmaceutical formulation comprising ibesaltan and an HMG-CoA reductase inhibitor and exhibiting improved dissolution and bioavailability.

Another object of the present invention is to provide a method for preparing the pharmaceutical formulation.

The present invention to achieve the above object

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

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

It provides a pharmaceutical capsule composite formulation comprising a separated state.

The present invention to achieve the above other object

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

2) preparing a 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 ivesaltan granules or tablets prepared in step 1), and the HMG-CoA reductase inhibitor granules or tablets prepared in step 2) in a separated state. It provides a method for producing a composite formulation.

The capsule complex preparation according to the present invention enables rapid release of the drug without the dissolution deterioration phenomenon by the interaction of the ibesaltan and the HMG-CoA reductase inhibitor, thereby improving the dissolution rate and bioavailability of the drug, Product stability is excellent, and the content of excipients can be significantly lowered, thereby increasing patient compliance with the dosage form size.

1 and 2 show the amounts of ibesaltan and atorvastatin degradation products produced during long term storage of the formulations of Examples 5 and Comparative Examples 1 to 3, respectively.
3 and 4 show the dissolution rates of ibesaltan and atorvastatin for the formulations of Example 5 and Comparative Examples 1 to 3, respectively.
5 is a result of comparing the saturated solubility of ibesaltan for the formulations of Example 5 and Comparative Example 1.
FIG. 6 shows the results of comparing the pharmacokinetic parameters of ibesaltan for the formulations of Example 5 and Comparative Example 1. FIG.
Figure 7 shows a photograph of the formulation of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention provides a composition comprising: 1) ibesaltan independent portion comprising ibesaltan 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. 7 shows a photograph of the pharmaceutical capsule combination preparation according to the present invention.

The capsule formulation of the present invention is characterized in that the independent portion of the ibesaltan independent portion and the HMG-CoA reductase inhibitor, respectively, in the form of granules or tablets. Granules or tablets, wherein at least one of them is in the form of tablets.

Thus, the capsule formulation of the present invention comprises 1) ibesaltan granules or tablets comprising ibesaltan or a pharmaceutically acceptable salt thereof; And 2) a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and a capsule formulation filled in a hard capsule with granules or tablets of HMG-CoA reductase inhibitor comprising a basic additive separated from each other. In this case, the diameter and thickness of the tablets are preferably mini tablets of 3 mm or less, respectively, and the two formulation units may be coated with conventional coating components for more complete physical shielding.

According to one embodiment of the invention, the present invention provides a tablet comprising Ivesaltan or a pharmaceutically acceptable salt thereof; And a tablet containing a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and a basic additive, in a hard capsule. The capsule formulation may, for example, tablet a tablet comprising Ivesaltan or a pharmaceutically acceptable salt thereof, and separately tablets comprising a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof and basic additives. After tableting, each of the coatings may be applied to prepare them in a capsule of a suitable size, for example, No. 1 capsule.

According to another embodiment of the present invention, the present invention provides granules comprising ibesaltan or a pharmaceutically acceptable salt thereof; And a tablet containing a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and a basic additive, in a hard capsule.

According to another embodiment of the invention, the present invention provides a tablet comprising Ivesaltan or a pharmaceutically acceptable salt thereof; And a granule comprising a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and a basic additive, in a hard capsule.

Ivesaltan independent portion according to the present invention comprises Ivesaltan or a pharmaceutically acceptable salt thereof as an active ingredient. The ibesaltan or its pharmaceutically acceptable salts are potent long-acting angiotensin-2-receptor antagonists that bind with angiotensin receptors with high affinity to inhibit angiotensin-induced vasoconstriction, inhibit aldosterone secretion, and rehydrate water and sodium Absorption can be suppressed, which makes it particularly useful for the treatment of cardiovascular diseases such as hypertension and heart failure. The pharmaceutically acceptable salt of ibesaltan can be any salt that can be easily used by those skilled in the art, including sodium salts, potassium salts, calcium salts, magnesium salts and ammonium.

Ivesaltan or a pharmaceutically possible salt thereof according to the present invention may be included in an amount of about 20 to about 70% by weight, preferably 40 to 70% by weight, based on the total weight of the Ivesaltan granules or tablets, It may be included in an effective amount, for example, 8 to 600 mg, preferably about 100 to 200 mg per unit dosage form, but is not limited thereto.

In the present invention, the ibesaltan independent portion, specifically, the ibesaltan granule or tablet, is a pharmaceutically acceptable binder selected from the group consisting of pharmaceutically acceptable binders, disintegrants, lubricants, diluents, colorants, anti-sticking agents, and mixtures thereof. The additive may further include, but is not limited thereto. In addition, surfactants may be further included to improve the hydrophobic properties of ibesaltan, which may improve aqueous granulation, facilitate the release of tablets after compression, and accelerate dissolution of pharmacologically active ingredients. .

The binder usable in the present invention may be selected from the group consisting of sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, gelatin, povidone and mixtures thereof. It is not limited. 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 granules or tablets.

Disintegrants usable in the present invention may be selected from the group consisting of corn starch, crospovidone, croscarmellose sodium, carboxymethyl cellulose calcium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and mixtures thereof, but is not limited thereto. 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 granules or tablets.

Glidants 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 oils, Polyethylene glycol, sodium benzoate, talc, and mixtures thereof, but is not limited thereto. The glidants may be used in amounts 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 granules or tablets.

The surfactant usable in the present invention may be selected from the group consisting of sodium lauryl sulfate, poloxamer, polyethylene glycol and mixtures thereof, with poloxamer being preferred, but not limited thereto. According to one embodiment of the present invention, the surfactant is preferably present only in the independent portion of the ibesaltan for stability improvement, but is not limited thereto.

In a preferred embodiment, the Ivesaltan granules according to the present invention, based on the total weight of the Ivesaltan granules or tablets (a) 20 to 70% by weight (eg 50% by weight), (b) diluent 1 To 70 weight percent, (c) 2 to 20 weight percent binder, (d) 1 to 20 weight percent disintegrant, (e) 0.1 to 5 weight percent anti-sticking agent, (f) 0.2 to 5 weight percent lubricant, and ( g) colorants up to 2% by weight (for example from 0.1 to about 1% by weight).

On the other hand, the HMG-CoA reductase inhibitor independent part according to the present invention includes an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and basic additives as active ingredients.

The HMG-CoA reductase inhibitor is rosuvastatin (US Pat. No. 4,231,938), lovastatin, atorvastatin, pravastatin (US Pat. Nos. 4,346,227 and 4,410,629), fluva Statin (fluvastatin), pitavastatin, velostatin, simvastatin (US Pat. Nos. 4,448,784 and 4,450,171), rivastatin, cerivastatin, cerivastatin, velostatin velostatin), mevastatin (US Pat. No. 3,983,140), pharmaceutically acceptable salts, precursors thereof, and mixtures thereof, preferably atorvastatin calcium, but not limited thereto. .

The HMG-CoA reductase inhibitor or pharmaceutically possible salt thereof according to the present invention is about 5 to about 20% by weight, preferably 5 to 10% by weight (eg, based on the total weight of the HMG-CoA reductase inhibitor granules or tablets) For example, about 8% by weight), and may be contained in a therapeutically effective amount, such as 0.5 to 100 mg, more preferably 2.5 to 80 mg, most preferably 5 to 80 mg per unit dosage form. However, the present invention 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, while providing basic microenvironmental conditions for ibesaltan, thereby improving the solubility of ibesaltan. And ultimately increase the bioavailability of Ivesaltan.

The basic additives include basic minerals such as NaHCO ₃ , CaCO ₃ , MgCO ₃ , KH ₂ PO ₄ , K ₂ HPO ₃ and calcium trichloride, arginine, lysine, histidine, meglumine, aluminum magnesium silicate, aluminum magnesium metasilicate, It may be selected from the group consisting of salts thereof, and mixtures thereof, preferably NaHCO ₃ , CaCO ₃ , MgCO ₃ or mixtures 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 granules or tablets. Can be.

In the present invention, the HMG-CoA reductase inhibitor independent portion, specifically, the HMG-CoA reductase inhibitor granule or tablet is a pharmaceutically acceptable water-soluble diluent, disintegrant, binder, carrier, filler, glidant, flow regulator, delay crystallization It may further include a pharmaceutically acceptable additive selected from the group consisting of a solubilizer, a colorant, a pH adjuster, a surfactant, an emulsifier, a coating agent, and mixtures thereof.

The water soluble 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 hydroxypropyl cellulose, crospovidone, sodium gluconate starch, croscarmellose sodium, and the like, and can be appropriately selected from disintegrants generally used. Examples of the binder are povidone, copovidone, celluloses, and the like. Examples of the glidants include magnesium stearate, stearyl fumarate sodium, talc, glyceryl fatty acid esters, and glycerol dibehenate, and can be appropriately selected from commonly used glidants. Examples of the coating agent include polyvinyl alcohol, hydroxypropylmethyl cellulose, methyl cellulose and ethyl cellulose, and can be appropriately selected from coating agents generally used.

In one preferred embodiment, the HMG-CoA reductase inhibitor independent portion according to the invention based on the total weight of the HMG-CoA reductase inhibitor granules or tablets (a) 5 to 20% by weight of the HMG-CoA reductase inhibitor (b) pharmaceutical Alternatively acceptable diluents, disintegrants and binders from 2 to 70 weight percent, (c) from 0.5 to 2 weight percent of glidants or coatings, and (d) from 8 to 65 weight percent of basic additives.

Tablets constituting the Ivesaltan independent portion or HMG-CoA reductase inhibitor independent portion according to the present invention may further include a coating layer, respectively. The coating layer may be coated on the surface of one or more tablets of each tablet to completely separate the ibesaltan and the HMG-CoA reductase inhibitor to improve stability and dissolution properties.

In the present invention, the coating process may improve the capsule filling process and the quality of the final product by increasing the mechanical strength of the mini-tablets having a diameter and thickness of less than 3mm filled in the capsule. In addition, the coating of the mini tablets can have a significant effect on the speed of production of the final product, for example, coated mini tablets with properties above the appropriate mechanical strength, hoppers and transfers in the capsule filling machine which will stand by during capsule filling. This prevents breakage in the pump.

In the coating layer of the tablet according to the present invention can be used a conventional polymer as a coating base. For example, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and the like may be used, but is not limited thereto. The amount of the coating base is preferably kept to a minimum in order to provide an optimum formulation size and effective preparation, in an amount ranging from 1 to 20% by weight, preferably 2 to 10% by weight, based on the total weight of the tablet. Can be used as

In the capsule formulation of the present invention, the capsule may be used as long as it is a general hard capsule used in medicine. The base of the hard capsule usable in the present invention may be, for example, gelatin, hypromellose, pullulan (NP caps ™, Capsugel, etc.) or polyvinyl alcohol.

The size of the hard capsules usable in the capsule formulations of the present invention may be any size of the general capsules used in medicine. The size of capsule has various internal volume depending on the number of capsules.The number 00 capsule is 0.95ml, the number 0 capsule is 0.68ml, the number 1 capsule is 0.47ml, the number 2 capsule is 0.37ml, the number 3 capsule is 0.27ml, Capsule No. 4 is known as 0.20ml (Seoheung Capsule homepage). The size of the capsule is more preferably smaller considering the convenience of the patient taking the formulation of the present invention, but in the present invention 0, 1, 2, 3 and 4 due to the mass limitation of the contents filled in the capsule Arc capsules may be used, preferably No. 1, No. 2 and No. 3 capsules.

In another aspect, the present invention, 1) preparing ibesaltan granules or tablets comprising ibesaltan or a pharmaceutically acceptable salt thereof; 2) preparing a 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 ivesaltan granules or tablets prepared in step 1), and the HMG-CoA reductase inhibitor granules or tablets prepared in step 2) in a separated state. It provides a method for producing a composite formulation.

Specifically, the preparation method comprises the steps of: i) granulating by mixing ibesaltan or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive, or by tableting the granules; ii) granulating the HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and basic additives with a pharmaceutically acceptable additive, or granulating or tableting the granules; iii) coating the ibesaltan granules or tablets prepared in step i) and the HMG-CoA reductase inhibitor granules or tablets prepared in step ii); And iii) filling the ibesaltan granules or tablets prepared in step i), and the HMG-CoA reductase inhibitor granules or tablets prepared in step ii) to form isolated portions in the hard capsule.

Various processes involved in the preparation of the composite preparation according to the present invention can be carried out based on conventional processes. In the above step i) or ii), the tablet may be prepared by tableting the granules according to a conventional method for preparing tablets, and the prepared tablets may have a suitable hardness, for example, in the range of 1 to 30 kp. It is preferable to show the average hardness. The measurement of the average hardness can be carried out before forming any film coating layer on the tablet. In addition, if the tablet is prepared in step i) or ii) it may further comprise the step of coating the tablet.

In step iii), the Ivesaltan granules or tablets and the HMG-CoA reductase inhibitor granules or tablets are filled into hard capsules to form separate independent portions, at least one of which is filled into the capsules in the form of tablets.

The capsule formulation of the present invention prepared above may be administered by oral, oral, sublingual, and the like, and is selected from the group consisting of hypertension, hypercholesterolemia, hyperlipidemia, myocardial infarction, stroke, angiogenesis and chronic stable angina. It can be used for the prevention or treatment of.

The capsule preparation according to the present invention can completely separate the two active ingredients by including the ibesaltan and the HMG-CoA reductase inhibitor in a form separated from each other inside the hard capsule. Accordingly, the reactivity between the active ingredients is minimized to maximize the therapeutic effect due to excellent product stability according to changes over time, and the existing single agent analysis method does not need to be developed separately for evaluating the stability according to the change of the product over time. There is an advantage to use.

In the present invention, the capsule complex of the present invention focuses on the fact that the basic additive for stabilizing the HMG-CoA reductase inhibitor affects the stability of the ibesaltan in a rapid-release pharmaceutical preparation including an Ivesaltan and an HMG-CoA reductase inhibitor. The formulation was prepared. According to the present invention, by preparing granules containing each main ingredient separately and tableting each into mini tablets having a diameter and thickness of 3 mm or less, and then filling the hard capsules after coating the tablets if necessary, the stability is excellent for long-term storage It is possible to significantly reduce the content of excipients can solve the problems caused by the size of the final pharmaceutical composition can be obtained a combination formulation of the patient's convenience in taking oral administration. Furthermore, when the Ivesaltan and HMG-CoA reductase inhibitors are filled into capsules in the form of physically separated mini-tablets, they allow immediate release of the drug without interactional elution (Ivesaltan or its pharmaceuticals). And at least 80% at 30 minutes, preferably at least 80% at 15 minutes) of the acceptable salts, and each of the HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, may increase the initial dissolution rate, Administration can increase bioavailability and at the same time improve 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 only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1 Preparation of Capsules Containing Rosuvastatin Minitablets and Ivesaltan Granules- (1)

Ibesaltan (Hanmi Precision, South Korea), lactose, pregelatinized starch and crospovidone were mixed using the composition described in Example 1 below, followed by hydroxypropylcellulose (HPC-L, Nisso, Japan) and poloxamer 188 (BASF, Germany) was combined with a binder solution dissolved in water, dried, and sieved through a 30 mesh sieve to prepare wet granules. Thereafter, the ibesaltan granules were prepared by adding talc and final mixing.

Meanwhile, after mixing rosuvastatin calcium, lactose, crospovidone and sodium hydrogen carbonate using the composition shown in Example 1 in Table 1, hydroxypropyl cellulose (HPC-L) and polysorbate 80 (Croda, USA) was combined with a solution dissolved in water, dried and sieved through a 30 mesh sieve to prepare wet granules. Subsequently, rosuvastatin calcium granules were prepared by adding and mixing croscarmellose sodium, and finally mixing with magnesium stearate. The rosuvastatin calcium granules prepared above were compressed into mini tablets and then coated. Rotary tablet press (Sejung, GRC-18) was used for the tablet tablet mini, tablet diameter and thickness was 2mm tableting. The prepared mini tablets were coated using a hydroxypropylmethylcellulose with a top spray coating method with a fluidized bed coater (Dalton, NQ-160).

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

Example 2 Preparation of Capsules Containing Rosuvastatin Minitablets and Ivesaltan Granules- (2)

Ibesaltan (Hanmi Precision, Korea), lactose, pregelatinized starch and crospovidone were mixed using the composition described in Example 2 below, followed by hydroxypropyl cellulose (HPC-L, Nisso, Japan) and lauryl Sodium sulfate was combined with a binder solution dissolved in water, dried, and sieved through a 30-mesh sieve to prepare wet granules. Thereafter, the ibesaltan granules were prepared by adding talc and final mixing.

Meanwhile, after mixing rosuvastatin calcium, microcrystalline cellulose, crospovidone and sodium hydrogen carbonate using the composition shown in Example 2 in Table 1, hydroxypropyl cellulose (HPC-L) and polysorbate 80 (Croda , USA) was combined with a solution dissolved in water, dried and sieved through a 30-mesh sieve to prepare wet granules. Subsequently, rosuvastatin calcium granules were prepared by adding and mixing croscarmellose sodium, and finally mixing with magnesium stearate. The rosuvastatin calcium granules prepared above were compressed into mini tablets and then coated. Rotary tablet press (Sejung, GRC-18) was used for tablet tablet mini- tableting, and the tablet diameter and thickness were tableted with 2mm. The prepared mini tablets were coated using a hydroxypropylmethylcellulose with a top spray coating method with a fluidized bed coater (Dalton, NQ-160).

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

Ingredients and content (mg) of hard capsules containing ibesaltan granules and rosuvastatin mini tablets division Example 1 Example 2 Ibesaltan granules Granules Ibersaltan 150 150 Lactose 30 20 Pregelatinized starch 23 23 Crospovidone 12 6 Hydroxypropyl cellulose 9 6 Poloxamer 188 12  - Sodium Lauryl Sulfate  - 9 Final mixing Talc 4 4.5 Ivesaltan Granule Gross Weight 240 218.5 Rosuvastatin
Calcium Mini Tablet Granules Rosuvastatin Calcium 10.4 10.4 Lactose 15  - Microcrystalline cellulose  - 16 Crospovidone 7 7 NaHCO ₃ 60 40 Hydroxypropyl cellulose 4 5 Polysorbate 80 0.6 0.6 mix Croscarmellose sodium 3 3 Final mixing Magnesium stearate 1.25 1.25 Tableting coating Hydroxypropyl methylcellulose 2 2 　
　 Rosuvastatin Calcium
Mini tablet gross weight 103.25 85.25 Capsule Filling Total weight (without capsules) 343.25 303.75

Example 3 Preparation of Capsules Containing Atorvastatin Granules and Ivesaltan Minitablets- (1)

Ibesaltan (Hanmi Precision, South Korea), mannitol, pregelatinized starch and crospovidone were mixed using the composition described in Example 3 below, and then povidone (BASF, Germany) and poloxamer 188 (BASF, Germany) were mixed. It was combined with a binder solution dissolved in water, dried and sieved through a 30-mesh sieve to prepare wet granules. Thereafter, mannitol, silicon dioxide, and crospovidone were added and mixed, and magnesium stearate was added to the final mixture to prepare ivesaltan granules. Ivesaltan granules prepared above were compressed into mini tablets and then coated. Rotary tablet press (Sejung, GRC-18) was used for tablet tablet mini- tableting, and the tablet diameter and thickness were tableted with 2mm. Then, the prepared mini tablets were coated using a hydroxypropyl methylcellulose using a top spray coating method with a fluidized bed coater (Dalton, NQ-160).

Meanwhile, after mixing atorvastatin calcium (TEVA, India), lactose, croscarmellose sodium and sodium hydrogen carbonate using the composition described in Example 3 in Table 2, povidone and polysorbate 80 (Croda, USA) were mixed. It was combined with a binder solution dissolved in water, dried and sieved through a 30-mesh sieve to prepare wet granules. Next, atorvastatin calcium granules were prepared by adding magnesium stearate and final mixing.

The ibesaltan mini tablets and atorvastatin granules prepared above were taken in the total weights shown 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 Ivesaltan Minitablets- (2)

After mixing atorvastatin calcium (TEVA, India), lactose, croscarmellose sodium and magnesium carbonate (Tomita, Japan) using the composition described in Example 4 below, povidone and polysorbate 80 (Croda, USA) It was combined with a binder solution dissolved in water, dried, and sieved through a 30 mesh sieve to prepare wet granules. Next, atorvastatin calcium granules were prepared by adding magnesium stearate and final mixing.

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

Ingredients and content of hard capsules containing Ivesaltan mini tablets and atorvastatin granules in mg division Example 3 Example 4 Ivesaltan Mini Tablets Granules Ibersaltan 150 Mannitol 15 Pregelatinized starch 20 Crospovidone 6 Povidone 8 Poloxamer188 9 mix Mannitol 28.5 Silicon dioxide 10 Crospovidone 6 Final mixing Magnesium stearate 2.5 Tableting coating Hydroxypropyl methylcellulose 2 Ivesaltan Mini Tablets Gross Weight 257 257 Atorvastatin
Calcium granules Granules 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 Tablets Gross Weight 104.21 104.21 Capsule Filling Total weight (without capsules) 361.21 361.21

Example 5 Preparation of Capsules Containing Atorvastatin Mini Tablets and Ivesaltan Mini Tablets

After mixing ibesaltan (Hanmi Precision, Korea), mannitol, pregelatinized starch and croscarmellose sodium (DMV international) using the composition shown in Table 3, povidone (BASF, Germany) and poloxamer 188 (BASF, Germany) ) Was combined with a binder 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 to the final mixture to prepare the ivesaltan granules.

Meanwhile, atorvastatin calcium (TEVA, India), mannitol, microcrystalline cellulose, croscarmellose sodium and magnesium carbonate (Tomita, Japan) were mixed using the composition shown in Table 3, followed by HPC and polysorbate 80 (Croda, USA). ) Was combined with a binder solution dissolved in water, dried, and sieved through a 30-mesh sieve to prepare wet granules. Subsequently, atorvastatin calcium granules were prepared by adding croscarmellose sodium, adding magnesium stearate and finally mixing.

The ibesaltan granules and atorvastatin calcium granules prepared above were compressed into mini tablets, and then coated. Rotary tablet press (Sejung, GRC-18) was used for tablet tablet mini- tableting, and the tablet diameter and thickness were tableted with 2mm. Each of the prepared mini tablets were then coated using a fluid spray coating machine (Dalton, NQ-160) using Opadry II 85F18422 white using a top spray coating method.

The ibesaltan minitablet and atorvastatin minitablet prepared above were each taken by the total weight shown in Table 3 and filled into No. 1 hard capsules using a capsule filling machine (GKF-2500, Bosch).

Ingredients and content (in mg) of hard capsules containing ibesaltan and atorvastatin mini tablets division Example 5 Comparative Example 1 Ibesaltan tablets Granules Ibersaltan 150 150 Mannitol 15 15 Pregelatinized starch 23 23 Croscarmellose sodium 6 6 Povidone 8 8 Poloxamer188 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 Tablet Mini Tablet coating Opadry II 85F18422 white 4 4  Gross weight 262 262 Atorvastatin calcium tablets Granules 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 Tablet Mini Tablet coating Opadry II 85F18422 white 2 2  Gross weight 102.21 45.21 Capsule Filling Total weight (without capsules) 364.21 307.21

Comparative Example 1 Preparation of Capsules Containing Atorvastatin and Ivesaltan Mini Tablets Without Basic Additives

Capsules were prepared in the same manner as described in Example 5 using the compositions shown in Table 3 above, except that magnesium carbonate was not used as the basic additive.

Comparative Example 2: Preparation of Hard Capsules Comprising Purification of Atorvastatin and Ivesaltan

Ivesaltan and atorvastatin calcium granules were prepared in the same manner as described in Example 5, above. Then, using a rotary tablet press (Sejung, GRC-18) was compressed into two tablets in the case of ibesaltan granules, one tablet in the case of atorvastatin granules. At this time, the tablet was filled with a diameter of 5mm for filling the capsule, which shows a larger size than the tablet mini tablet 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 then filled into No. 0 hard capsules in the same manner as in Example 5.

Comparative Example 3: Preparation of Bilayer Tablet Containing Atorvastatin and Ivesaltan Mini Tablets

Ivesaltan (Hanmi Precision, Korea) granules and atorvastatin calcium (TEVA, India) granules were prepared according to the manner described in Example 5 using the composition shown in Table 4 below. The ibesaltan granules and atorvastatin calcium granules prepared above were compressed into bilayer tablets using a bilayer tablet press. Then, using Opadry II 85F18422 white was coated using a fan coater (Sejung, SCF-30).

Composition and Content of Bilayer Tablets Containing Ivesaltan and Atorvastatin (Unit: mg) division Comparative Example 3 Granules Ibersaltan 150 Mannitol 47 Pregelatinized starch 23 Croscarmellose sodium 12 Povidone 8 Poloxamer188 9 Final mixing Magnesium stearate 4 Granules Atorvastatin calcium 10.85 Lactose 120 Microcrystalline cellulose 65.6 Cross Chamelos Sodium 36 Magnesium carbonate 57 HPC 3 Polysorbate 80 1.2 Final mixing Magnesium stearate 3 Tableting Mini Tablet coating Opadry II 85F18422 white 2 Gross weight 551.65

Experimental Example 1 Stability Test

In order to evaluate the stability of the formulations prepared in Example 5 and Comparative Examples 1 to 3, each formulation was packaged with 1 g of silica gel in a HDPE bottle and then stored under long-term conditions (25 ° C. and 60% RH) to begin testing. After 3, 6, 9, 12, 18, 24 and 36 months later the amount of degradation product of atorvastatin (RRT 1.81) was measured.

<Analysis conditions for analogues of atorvastatin>

(1) Detector: ultraviolet absorbance photometer (wavelength 254 nm)

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

(3) Mobile phase: Mobile phase A: Acetonitrile: Tetrahydrofuran: Buffer 1 (31: 9: 60) (v / v)

Buffer 1; PH is adjusted with 0.05 M NH ₄ H ₂ PO ₄ (pH 5.0, ammonia water).

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 volume: 10 uL

(6) temperature: 35 ℃

(7) flow rate: 1.8 mL / min

In addition, each formulation was stored under accelerated conditions (40 ° C. and 75% RH) to determine the amount of degradation products of Ivesaltan (RRT 0.8) 1, 3 and 6 months after the start of the test.

<Conditions for the Analysis of Leading Materials in Ibesaltan>

(1) Detector: ultraviolet absorbance photometer (wavelength 220 nm)

(2) Column: A column filled with 5 μm C ₁₈ in a stainless tube about 4.6 mm in diameter and about 250 mm in length, or a similar column.

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

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

(4) Diluent: Methanol

(5) Injection volume: 15 uL

(6) temperature: 30 ℃

(7) flow rate: 1.2 mL / min

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

Atorvastatin Degradation Product (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 breakdown product (%) 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

Ivesaltan Degradation Product (RRT 0.8) after Accelerated Condition (40 ° C and 75% RH) Storage Acceleration condition (month) division 0 3 6 Ibersaltan
Decomposition product amount (%) 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 in Tables 5 and 6, it can be seen that the amount of atorvastatin degradation products (RRT1.81) and ibesaltan degradation products (RRT 0.8) increases over time. According to the analogues according to the ICH guideline, the ibesaltan and atorvastatin degradation products should be 0.2% or less by 6 months of acceleration or long term 24-36 months. The formulation according to the present invention was able to specifically improve the stability of the atorvastatin by including a basic additive, showing the most stable results compared to the formulations of Comparative Examples 1 to 3 was found to be effective as a product for more than three years. .

Experimental Example 2 Elution Evaluation of Ivesaltan

Example 5, Comparative Examples 1 to 3 and 150 mg of Aprobel (Sanopy-Aventis) as a control drug were subjected to the Ivesaltan elution test according to the following dissolution test conditions, and the results are shown in FIG. 3.

<Elution test condition>

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

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

(3) Eluent temperature: 37 ° C ± 0.5 ° C

(4) Eluent amount: 1000ml

(5) Speed: 50rpm

(6) Sampling: Eluate was taken every 5, 10, 15, 30 and 45 minutes and filtered using 0.45μm membrane filter to use as sample solution. After the eluate was taken, the same amount of new eluate was added to the dissolution test apparatus.

<Method of analysis>

(1) Analyzer: 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, pH adjusted with ammonia water)

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

(4) Column: Column about 4.6 in diameter and about 150 mm long, filled with octadecylsilylated 5 μm silica gel

(5) Flow rate: 1.8 ml / min

Experimental Example 3 Elution Evaluation of Atorvastatin Calcium

Example 5, Comparative Examples 1 to 3, and Lipitor 20 mg (control, Pfizer) as a control agent after the dissolution test of atorvastatin calcium in the analysis method and method of Experimental Example 2 according to the following dissolution test conditions, The results are shown in FIG.

<Elution test condition>

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

(2) Eluent: purified water

(3) Eluent temperature: 37 ° C ± 0.5 ° C

(4) Eluent amount: 900ml

(5) Speed: 50rpm

(6) Sampling: Eluate was taken every 5, 10, 15, 30 and 45 minutes and filtered using 0.45μm membrane filter to use as sample solution. After the eluate was taken, the same amount of new eluate was added to the dissolution test apparatus.

As can be seen in Figures 3 and 4, the capsules containing more than 3mm tablets (Comparative Example 2), not the mini tablets, the initial 5 minutes dissolution rate is low, and after 10 minutes it will be similar to the dissolution pattern of the control group Could. This is because of the influence of gelatin capsules, there is a lag time for the external gelatin capsules to disintegrate before dissolution of the internal tablets, and it has been observed that gelatin affects the disintegration of the internal tablets. In addition, in the case of the capsule containing no basic stabilizer (Comparative Example 1), it was found that the dissolution rate of atorvastatin was low until the second half.

On the other hand, the capsule formulation according to the present invention (Example 5) exhibited rapid disintegration by including mini tablets. Specifically, disintegration started immediately by the eluate introduced into the hole generated due to some disintegration of the gelatin capsule, and it was found that the dissolution was rapidly eluted out of the capsule due to the small particle size. In addition, the analysis of the active ingredient showed that the results were equivalent to the dissolution rate of each reference drug.

In addition, it can be seen that the capsule preparation according to the present invention exhibits an excellent dissolution rate even when the total weight of the preparation is smaller than that of the bilayer tablet (Comparative Example 3). Therefore, the capsule preparation according to the present invention is expected to improve the stability and dissolution rate, as well as to reduce the amount of excipients to increase the medication compliance to patients.

Experimental Example 4 Evaluation of Saturation Solubility of Ivesaltan

The saturated solubility of Ivesaltan was confirmed for the formulations prepared in Example 5 and Comparative Example 1. Ten tablets of each sample were prepared using 1000 mL of water and 1000 mL of pH 6.8 solution as the eluant according to the USP Elution Method 2 (Paddle Method) at a rotational speed of 50 rpm. Confirmed. The results are shown in FIG.

As can be seen in Figure 5, compared to the formulation of Comparative Example 1 does not contain a basic additive formulation of the present invention was found to increase significantly the solubility in water and pH 6.8 solution, through which the basic It was found that the additive plays a role of improving the solubility of poorly soluble ivesaltan.

Experimental Example 4 Evaluation of Bioavailability of Ivesaltan

The bioavailability of Ivesaltan was confirmed in beagle dogs for the formulations prepared in Example 5 and Comparative Example 1. The experimental method is as described in Table 7 below.

Evaluation method of bioavailability of ibesaltan title Biopharmacokinetic Study After Single Dose of Ivesaltan Composition in Beagle Dogs purpose To evaluate the effect of increasing the bioavailability of the increased solubility Ivesaltan composition Test system Animal: Beagle Dog
Gender: Male
Number of animals used: 6 animals per group, randomized crossover study Test group Test group: use of the formulation of Example 5
Control: Use of the formulation of Comparative Example 1 Test Methods 1) Maintain an empty stomach before 12 hours, supply only water
2) Oral administration of the formulation of Example 5 or Comparative Example 1
3) Blood collection after 0, 0.33, 0.66, 1, 2, 3, 8, 12, 24, 48 hours
4) Ibesaltan concentration measurement using LC / MS Statistical processing Pharmacokinetic parameters are measured using a data processing program (KE-Test).

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

Pharmacokinetic Parameters of Ibesaltan Ibersaltan parameter Example 1 Comparative Example 1 AUC _0-48 ( _nghr / 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 Figure 6, the formulation of the present invention showed a high bioavailability compared to the formulation of Comparative Example 1 does not contain a basic additive, through which the basic additive increases the bioavailability of Ivesaltan Sikkim was known.

Claims (21)

1) ibesaltan independent portion comprising ibesaltan or a pharmaceutically acceptable salt thereof; And
2) HMG-CoA reductase inhibitor independent portion comprising an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, and a basic additive
Contains in isolation,
The basic additive is included only in the HMG-CoA reductase inhibitor independent portion,
The Ivesaltan independent portion or HMG-CoA reductase inhibitor independent portion is in the form of granules or tablets, at least one of the Ivesaltan independent portion or HMG-CoA reductase inhibitor independent portion is in the form of a tablet, and the diameter of the tablet is 3 mm The thickness of the tablet is 3 mm or less, and the tablet further includes a coating layer,
Wherein the HMG-CoA reductase inhibitor is atorvastatin calcium, pharmaceutical capsule combination formulation. The method of claim 1,
The coating base used in the coating layer is selected from the group consisting of methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose and mixtures thereof, pharmaceutical capsules Combinations. The method of claim 2,
The pharmaceutical composition is 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 of claim 1,
The pharmaceutical capsule complex preparation, characterized in that the capsule is a hard capsule. The method of claim 4
A pharmaceutical capsule combination preparation, characterized in that the base of the capsule is selected from the group consisting of hypromellose, pullulan, gelatin and polyvinyl alcohol. The method of claim 1,
Said basic additives are NaHCO ₃ , CaCO ₃ , MgCO ₃ , KH ₂ PO ₄ , K ₂ HPO ₃ , calcium trichloride, arginine, lysine, histidine, meglumine, aluminum magnesium silicate, aluminum magnesium metasilicate, salts thereof, and A pharmaceutical capsule combination formulation, characterized in that selected from the group consisting of a mixture thereof. The method of claim 6,
The basic additive is NaHCO ₃ , MgCO ₃ or a mixture thereof, characterized in that the pharmaceutical capsule combination formulation. The method of claim 1,
The basic additive is characterized in that it comprises in an amount of 2 to 10 parts by weight based on 1 part by weight of the HMG-CoA reductase inhibitor, pharmaceutical capsule composite formulation. The method of claim 1,
The pharmaceutical capsule, characterized in that the Ivesaltan independent part further comprises a component selected from the group consisting of pharmaceutically acceptable binders, disintegrants, lubricants, diluents, colorants, anti-sticking agents, surfactants and mixtures thereof. Combinations. The method of claim 9,
The binder is selected from the group consisting of sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, gelatin, povidone and mixtures thereof. Capsule combinations. The method of claim 9,
The disintegrant is selected from the group consisting of corn starch, crospovidone, croscarmellose sodium, carboxymethyl cellulose calcium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and mixtures thereof, pharmaceutical capsule complex Formulation. The method of claim 9,
The lubricant is 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, characterized in that the pharmaceutical capsule combination formulation. The method of claim 9,
The pharmaceutical capsule complex preparation, characterized in that the surfactant is selected from the group consisting of sodium lauryl sulfate, poloxamer, polyethylene glycol and mixtures thereof. The method of claim 1,
Independent addition of the HMG-CoA reductase inhibitor water-soluble diluent, disintegrant, binder, carrier, filler, lubricant, flow regulator, crystallization retardant, solubilizer, colorant, pH regulator, surfactant, emulsifier, coating agent and mixtures thereof A pharmaceutical capsule complex preparation, further comprising a pharmaceutically acceptable additive selected from the group consisting of: The method of claim 14,
Wherein said water soluble diluent is selected from the group consisting of mannitol, sucrose, lactose, sorbitol, xylitol, glucose and mixtures thereof. The method of claim 1,
The pharmaceutical capsule complex preparation, characterized in that the co-formulation comprises ibesaltan or a pharmaceutically acceptable salt thereof in an amount of 8 mg to 600 mg per unit dosage form. The method of claim 1,
The pharmaceutical capsule combination preparation, characterized in that the co-formulation 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 of claim 1,
Wherein the combination formulation is characterized in that the release of ibesaltan and HMG-CoA reductase inhibitors at least 80% each 30 minutes, pharmaceutical capsule combination formulation. The method of claim 18,
Wherein the combination formulation is characterized in that the release of ibesaltan and HMG-CoA reductase inhibitors at least 80% each 15 minutes, pharmaceutical capsule combination formulation. The method of claim 1,
The combination preparation is used for the prevention or treatment of diseases selected from the group consisting of hypertension, hypercholesterolemia, hyperlipidemia, myocardial infarction, stroke, angiogenesis and chronic stable angina pectoris, pharmaceutical capsule combination formulation. 1) preparing ibesaltan granules or tablets comprising ibesaltan or a pharmaceutically acceptable salt thereof;
2) preparing a 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 ivesaltan granules or tablets prepared in step 1) and the HMG-CoA reductase inhibitor granules or tablets prepared in step 2) in a separated state,
The basic additive is included only in the HMG-CoA reductase inhibitor independent portion,
The product prepared in step 1) or step 2) is in the form of a tablet, the diameter of the tablet is 3mm or less, the thickness of the tablet is 3mm or less,
Coating the tablet;
The HMG-CoA reductase inhibitor is atorvastatin calcium, a method for producing a pharmaceutical capsule complex preparation according to claim 1.

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