TW201636022A - Pharmaceutical composition comprising PITAVASTATIN or a pharmaceutically acceptable salt thereof, and VALSARTAN or a pharmaceutically acceptable salt thereof - Google Patents

Abstract

Disclosed is a composite composition comprising pitavastatin or a pharmaceutically acceptable salt thereof, and valsartan or a pharmaceutically acceptable salt thereof and the composite pharmaceutical composition is more stable than simple formulations in combination, and is economically beneficial compared to a controlled-release formulation.

Description

a pharmaceutical composition comprising pitavastatin or a pharmaceutically acceptable salt thereof, and valsartan or a pharmaceutically acceptable salt thereof Technical field

The present invention relates to a pharmaceutical composition comprising, as an active ingredient, pitavastatin or a pharmaceutically acceptable salt thereof and versartan or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to a pharmaceutical composition for preventing or treating cardiovascular diseases and abnormal dyslipidemia, wherein pitavastatin or a pharmaceutically acceptable salt thereof and elsalazine or a pharmaceutically thereof thereof Acceptable salt blending.

Background skill

A statin (or HMG-CoA reductase inhibitor) class of drugs used to reduce cholesterol by competitively inhibiting HMG-CoA reductase (3-hydroxy-3-methyl-pentadiazine coenzyme A reductase). The HMG-CoA reductase is a rate controlling enzyme that catalyzes the conversion of HMG to the cholesterol biosynthetic pathway of mevalonate. Inhibition of this reductase by statins induces LDL in the liver Receptor performance, which in turn increases the catabolism of plasma LDL and lowers plasma cholesterol levels, resulting in a reduced risk of atherosclerosis. Pitavastatin, an adjuvant for diet therapy, is used to reduce the total cholesterol, LDL-cholesterol, apo-B protein, and the amount of elevated total cholesterol, mixed with dyslipidemia The amount of acid glycerin, and increase the amount of high density lipoprotein (HDL)-cholesterol.

Versartan is an angiotensin II receptor blocker known to be effective in lowering blood pressure without specificity depending on race or sex. Today, valsartan is indicated for the treatment of hypertension, septic heart failure, and myocardial infarction.

One patient with abnormal dyslipidemia is highly susceptible to high blood pressure. Because these two diseases coexist to further increase the risk of cardiovascular disease, an epidemiological strategy for treating and preventing abnormal dyslipidemia and hypertension is needed. A combination drug not only exerts a multiplier effect on the treatment of hypertension and abnormal dyslipidemia in patients with cardiovascular disease, but also increases the function of vascular endothelial cells to form a vascular protective layer. Insulin sensitivity plays a therapeutic role in diabetes. Even with these advantages, drug compliance is poor for these combination drugs, and the rate of drug absorption is 67% for one year and 50% for two years. One of the most important factors in determining drug compliance is the amount of drug that needs to be administered in a single dose. The need for a combination of an antihypertensive agent and an anti-dyslipidemic agent has been developed as it is expected to improve drug compliance compared to individual single agents. Patients with hypertension and abnormal dyslipidemia were simultaneously given a combination of antihypertensive agents and anti-dyslipidemic agents. However, it is low frequency because this combination drug has not been fully proven safe.

Korean Patent Application Unexamined Publication No. 2008-0039303 discloses a controlled release mismatch composition comprising losartan, an angiotensin-II-receptor blocker, and simvastatin ( Simvastatin), an HMG-CoA reductase inhibitor. When administered simultaneously, losartan and simvastatin are administered to the liver unless released in a controlled manner, during which the drugs compete competitively and therefore become hostile to each other. Therefore, a combination drug cannot be expected to exhibit optimal efficacy unless it is designed to be controlled release.

However, when a dual formulation consisting of a controlled release portion and an immediate release portion is applied to a combination of pitavastatin and valsartan, a Korean application such as a dual formulation is not used. Excipients such as enteric coated substrates for controlled release have a negative impact on pitavastatin stability as reviewed in the review of publication No. 2008-0039303. Furthermore, the formulations proposed in this patent, including two-phase matrix tablets, double tablets, core tablets, etc., are misaligned, requiring an expensive equipment to produce such formulations, increasing production costs. For a simple mixed formulation, it is highly likely that pitavastatin will be unevenly distributed due to its small content.

The present invention proposes a novel composite formulation which overcomes the above problems and overcomes the above problems and which overcomes the above problems, comprising pitavastatin or a pharmaceutically acceptable salt thereof, and versartan or a pharmaceutically acceptable salt thereof . The complex formulation of the present invention comprises verapartan of an angiotensin-II-receptor blocker and pitavastatin of an HMG-CoA reductase inhibitor, which are designed to be released in an immediate manner. In this formulation, pitavastatin or The pharmaceutically acceptable salt thereof is in a particle form such that it is highly miscible with versaltan or a pharmaceutically acceptable salt thereof and can be blocked from being treated with versaltan or its pharmacy The acceptable salt is in direct contact. This result ensures that the two components are mutually stable and improves the dissolution rate of both. In particular, the composite formulation contains a sodium-free (Na)-containing lubricant or stabilizer to stabilize the pintanstatin calcium component which is susceptible to instability under acidic conditions.

Expose

Accordingly, it is an object of the present invention to provide a pharmaceutical composition for preventing and treating cardiovascular diseases and abnormal dyslipidemia comprising, as an active ingredient, pitavastatin or a pharmaceutically acceptable salt thereof, and Versal Or a pharmaceutically acceptable salt thereof, wherein the pitavastatin component and the versalatin component are stable with minimal physical and chemical interactions therebetween, and wherein both of them can be released immediately.

To achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating cardiovascular diseases and abnormal dyslipidemia, comprising pitavastatin as an active ingredient or a pharmaceutically acceptable salt thereof, and versartan or Its pharmaceutically acceptable salts.

In another embodiment of the invention, pitavastatin or a pharmaceutically acceptable salt thereof is preferably separated from versalatin or a pharmaceutically acceptable salt thereof, or pitavastatin or a pharmaceutically acceptable salt thereof The acceptable salt may preferably be in the form of particles and may be admixed with versaltan or a pharmaceutically acceptable salt thereof. Hehe.

In another embodiment of the invention, pitavastatin or a pharmaceutically acceptable salt thereof is preferably admixed with a sodium or Na-free lubricant or stability.

In another embodiment of the present invention, pitavastatin or a pharmaceutically acceptable salt thereof may be in the form of a granule, and may be combined with valsartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof. The additives are blended together.

In this regard, the granules of pitavastatin or a pharmaceutically acceptable salt thereof may contain, as an excipient, at least one selected from the group consisting of low-substituted hydroxypropylcellulose and lactose hydrate, as a lubricant or stabilizer. It is selected from at least one of magnesium aluminum metasilicate, magnesium aluminum silicate, magnesium carbonate, aluminum hydroxide, potassium dihydrogen phosphate, and aluminum chloride, and hydroxypropyl methylcellulose as a binder.

In another embodiment of the present invention, versartan or a pharmaceutically acceptable salt thereof may contain, as an excipient, at least one selected from the group consisting of low-substituted hydroxypropylcellulose and lactose hydrate.

In another embodiment of the present invention, the pharmaceutical composition may further comprise croscamellose sodium as a disintegration adjuvant, or magnesium stearate as a lubricant, or both.

In another embodiment of the invention, the pharmaceutical composition can include an outer film coating.

In another embodiment of the present invention, the outer film coating layer may contain at least one selected from the group consisting of polyvinyl alcohol, titanium oxide (TiO ₂ ), polyethylene glycol 3350 (PEG 3350), and talc, and is preferably And all of a substrate is made.

In another embodiment of the invention, pitavastatin or a pharmaceutically acceptable salt thereof may contain from 0.5 mg to 8 mg.

In another embodiment of the invention, versartan or a pharmaceutically acceptable salt thereof may contain an amount of from 20 mg to 240 mg.

In another embodiment of the present invention, the composition may contain low-substituted hydroxypropylcellulose in an amount of 20 mg to 200 mg, lactose hydrate in an amount of 2 mg to 20 mg, and magnesium in an amount of 0.5 mg to 10 mg. Aluminum metasilicate, and hydroxypropyl methylcellulose in an amount from 0.5 mg to 10 mg.

In another embodiment of the present invention, the composition may contain low-substituted hydroxypropylcellulose in an amount of from 20 mg to 200 mg, and lactose hydrate in an amount of from 30 mg to 300 mg.

In another embodiment of the invention, the composition may contain croscarmellose sodium in an amount of from 5 mg to 50 mg, and magnesium stearate in an amount of from 0.5 mg to 10 mg.

As described so far, the pharmaceutical composition of the present invention comprising pitavastatin or a pharmaceutically acceptable salt thereof and versartan or a pharmaceutically acceptable salt thereof is designed to simultaneously absorb such The drug, and the increase in therapeutic effect, accompanied by a decrease in negative effects. Therefore, the composition enables the patient to take such drugs with improved medication compliance, and can be used as an excellent preventive and therapeutic agent for cardiovascular diseases and abnormal blood lipids.

In the pharmaceutical composition of the present invention, pitavastatin or a pharmaceutically acceptable salt thereof is separated from versalatin or a pharmaceutically acceptable salt thereof, and these components exhibit immediate release. Therefore, this composite pharmaceutical group The adult system is more stable than the combined simple formulation and is economically advantageous compared to a controlled release formulation.

Invention mode

The present invention relates to a pharmaceutical composition for preventing and treating cardiovascular diseases and abnormal dyslipidemia, wherein the granules of pitavastatin or a pharmaceutically acceptable salt thereof and versartan or pharmaceutically acceptable thereof Salts are accepted for blending and are advantageous in terms of economy and stability over conventional formulations.

Hereinafter, a detailed description of the present invention will be provided.

The present invention provides a composition comprising, as an active ingredient, pitavastatin or a pharmaceutically acceptable salt thereof, and valsartan or a pharmaceutically acceptable salt thereof, wherein pitavastatin or a pharmaceutically thereof thereof Acceptable salts are separated from versartan or a pharmaceutically acceptable salt thereof.

More particularly, the present invention provides a pharmaceutical composition for preventing and treating cardiovascular diseases and abnormal dyslipidemia, comprising pitavastatin or pharmaceutically thereof mixed with versaltan or a pharmaceutically acceptable salt thereof Acceptable salts of the particles.

Any pharmaceutically acceptable salt of pitavastatin can be used in the present invention as long as it is readily available to those skilled in the art. The pharmaceutically acceptable salts of pitavastatin may be sodium salts, potassium salts, hemi-calcium salts, and magnesium salts, and are preferably hemi-calcium salts. The pitavastatin hemi-calcium salt is represented by the following chemical formula 1:

Likewise, any pharmaceutically acceptable salt of valsartan can be used in the present invention, as readily available to those skilled in the art. The pharmaceutically acceptable salt of valsartan can be a monosodium salt, a disodium salt, a monopotassium salt, a dipotassium salt, a magnesium salt, a calcium salt, a bisdiethylammonium salt, a bisdipropylammonium salt, Bis-dibutylammonium salt, mono-L-arginine, bis-L-arginine, mono-L-isoamine, bis-L-isoamine, or a combination thereof.

As used herein, the term "pharmaceutical composition" refers to a mixture of the active ingredient of the present invention with a chemical such as a diluent or carrier. Salts useful in pharmaceutical compositions can be prepared by reaction with acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

The term "separated" as used herein in connection with the relationship between pitavastatin or a pharmaceutically acceptable salt thereof and versalazine or a pharmaceutically acceptable salt thereof, means the active ingredient , pitavastatin or a pharmaceutically acceptable salt thereof, and valsartan or a pharmaceutically acceptable salt thereof, are limited to different individual fractions.

When the pharmaceutical composition of the present invention is prepared, wherein pitavastatin or a pharmaceutically acceptable salt thereof and valsartan or pharmaceutically acceptable thereof are prepared The salt is a simple blend of one of the compound formulations, which suffers from the following problems. First, pitavastatin is less likely to be distributed in the formulation because it is as low as 0.5 mg to 8 mg. Thus, when particles are formed, pitavastatin is evenly distributed throughout the formulation. Furthermore, pitavastatin needs to be stabilized against another ingredient, versartan. In this regard, the two components can be "separated" from each other such that they are blocked from contact with each other. Secondly, at a pH of 4.0 or less, valsartan has a low solubility and gelation causes its system to dissolve very slowly. This delayed dissolution inhibits the absorption of versartan in the small intestine. Furthermore, the curfartan gelation has a negative effect on the dissolution of pitavastatin and, therefore, interferes with the absorption of pitavastatin. In the present invention, the formulation is designed to isolate the active ingredients from each other, and therefore, vanesartan does not gel even at low pH.

Examples of the formulation in which the two active ingredients are "separated from each other" include, without limitation, a coated tablet containing versartan as an active ingredient or a pharmaceutically acceptable salt thereof. A lozenge having an overcoat layer containing pitavastatin as an active ingredient or a pharmaceutically acceptable salt thereof, or a pitavastatin or a pharmaceutically acceptable salt thereof as an active ingredient a lozenge having an outer coating comprising versartan as an active ingredient or a pharmaceutically acceptable salt thereof; a core tablet wherein versartan or a pharmaceutically acceptable compound thereof One of the salts is composed of a sheath material consisting of one of pitavastatin or a pharmaceutically acceptable salt thereof, or one of the core materials consisting of pitavastatin or a pharmaceutically acceptable salt thereof. Covered with a sheath consisting of one of versartan or a pharmaceutically acceptable salt thereof; a multi-compressed tablet, such as a bilayer tablet, wherein the pitavastatin or pharmaceutically acceptable thereof Salt, and Versartan or a pharmaceutically acceptable salt thereof is in a different individual layer.

As used herein, the term "abnormal dyslipidemia" refers to an abnormally elevated amount of lipids, including total cholesterol, LDL cholesterol, and triglycerides, or an abnormally reduced amount of HDL cholesterol. For example, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia fall within the scope of abnormal dyslipidemia. Hypercholesterolemia can be primary hypercholesterolemia (family and non-familial Fredrickson type IIa), or mixed dyslipidemia (Fred Krissen IIb) type).

The term "cardiovascular disease" refers to a disease involving the heart, an arterial tube, or both. Examples of cardiovascular diseases include, without limitation, hypertension, normal high blood, ischemic heart disease, coronary artery disease, angina pectoris, myocardial infarction, atherosclerosis, cerebrovascular disease, stroke, and arrhythmia.

Further, the pharmaceutical composition of the present invention can be used for the prevention and treatment of diabetes (N. Engl. J. med., 362; 16 April 22, 2010).

The pharmaceutical composition of the present invention, for example, pitavastatin or a pharmaceutically acceptable salt thereof, may be included in an amount of from 0.5 mg to 8 mg, and the amount range of versartan or a pharmaceutically acceptable salt thereof It is from 20 mg to 240 mg, but this is not a limitation of the present invention.

In addition to the particles of pitavastatin or a pharmaceutically acceptable salt thereof and versartan or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable additive.

As used herein, the term "pharmaceutically acceptable additives" It is defined as a carrier or a diluent that does not degrade the biological activity and physical properties of the composition.

In one embodiment of the invention, the particles of pitavastatin or a pharmaceutically acceptable salt thereof may further comprise a lubricant or stabilizer which does not contain sodium (Na). Lubricants or stabilizers containing sodium (Na) have a high affinity for water, allowing them to absorb water rapidly, reducing the dissolution rate of pitavastatin calcium and versaltan tablets. Therefore, the bioavailability of pitavastatin calcium that needs to be absorbed in the stomach is deteriorated, which is negatively affected by the bioavailability of valsartan. The sodium-free (Na) lubricant or stabilizer may be selected from the group consisting of magnesium aluminum metasilicate, magnesium aluminum silicate, magnesium aluminate, dried aluminum hydroxide, synthetic hydrotalcite, synthetic aluminum citrate, magnesium carbonate, Precipitated calcium carbonate, magnesium oxide, aluminum hydroxide, L-arginine, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, ammonium chloride, aluminum chloride, and combinations thereof.

Preferably, the particles of pitavastatin or a pharmaceutically acceptable salt thereof may further comprise, as an excipient, a low-substituted hydroxypropylcellulose and a lactose hydrate, and a hydroxypropylmethylcellulose as a binding agent. And at least one of magnesium aluminum bismuth citrate as a lubricant or stabilizer. More preferably, the granules may comprise low-substituted hydroxypropylcellulose in an amount of from 20 mg to 200 mg, lactose hydrate in an amount of from 2 mg to 20 mg, and magnesium aluminum hexanoic acid in an amount of from 0.5 mg to 10 mg. Salt, and 0.5 mg to 10 mg of hydroxypropyl methylcellulose.

In one embodiment, the elsalazine or a pharmaceutically acceptable salt portion thereof may further comprise at least one of a low-substituted hydroxypropylcellulose and a lactose hydrate as excipients, and a low-substituted hydroxypropyl group Cellulose and lactose The hydrate content is in the range of 20 mg to 200 mg, and 30 mg to 300 mg.

In another embodiment, the pharmaceutical composition of the present invention may further comprise crosslinked methylcellulose sodium as a disintegration adjuvant, or magnesium stearate as a lubricant, or both. In the composition, the crosslinked methylcellulose sodium may be included in an amount of from 5 mg to 50 mg, and the magnesium stearate is in an amount of from 0.5 mg to 10 mg, but this is not a limitation of the present invention.

In addition to the above diluents or excipients, the pharmaceutical composition for preventing or treating cardiovascular diseases and abnormal dyslipidemia according to the present invention may be in the form of pitavastatin or a pharmaceutically acceptable salt thereof and Versal Each of the stan or pharmaceutically acceptable salt moieties additionally comprises a typical carrier or additive.

Diluents or excipients, such as fillers, thickeners, wetting agents, lubricants, binding agents, surfactants, and the like, are included within the scope of a pharmaceutically acceptable carrier or additive. Examples of the disintegration adjuvant include agar, starch, alginic acid or a sodium salt thereof, and anhydrous sodium monohydrogen phosphate. The lubricant may be exemplified by cerium oxide, talc, stearic acid or its magnesium or calcium, polyethylene glycol, and magnesium aluminum metasilicate. As a binding agent in the present invention, magnesium aluminosilicate, starch slurry, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low-substituted hydroxypropyl cellulose, or the like A combination of these can be used. Further, lactose, dextrose, sugar cane, mannitol, sorbitol, cellulose, glycine, and the like can be used as a diluent. A foaming salt, an absorbent, a coloring agent, a flavoring agent, a sweetener, or the like can be used as needed. The stabilizers useful in the present invention are sodium free (Na). Examples of sodium-free (Na) stabilizers include Alcoa citrate salt. , magnesium aluminosilicate, magnesium aluminate, dried aluminum hydroxide, synthetic hydrotalcite, synthetic aluminum silicate, magnesium carbonate, precipitated calcium carbonate, magnesium oxide, aluminum hydroxide, L-arginine, potassium phosphate, Dipotassium hydrogen phosphate, potassium dihydrogen phosphate, ammonium chloride, aluminum chloride, and combinations thereof.

The pharmaceutical composition of the present invention may have an outer film coating, the substrate of which may be at least one of polyvinyl alcohol, titanium oxide (TiO ₂ ), polyethylene glycol 3350 (PEG 3350), or talc, and preferably All of them are composed.

For external film coatings, a typical coating agent can be used. Opadry ^TM, hydroxypropylmethylcellulose or Eudragit series obtained as a coated substrate.

The pharmaceutical composition of the present invention facilitates administration of the active ingredient. There are various techniques for administering a pharmaceutical composition, including, oral, intrarectal, intravaginal, intranasal, intraocular, sublingual, subcutaneous, intramuscular, intravenous, intrathecal, intradermal, and epidural administration. . In the present invention, it is preferred to administer the drug orally.

The pharmaceutical composition of the present invention may be in the form of a lozenge, a powder, a dropping pill, a powder, a bolus, an elixir, or a paste. Preferred lozenges can be typical lozenges, coated lozenges, dispersible lozenges, or effervescent lozenges, and can be in the form of a plurality of compressed lozenges, such as a double lozenge, a core lozenge, Multi-layer tablets and the like. Further, enteric capsules and capsules of others are preferred.

The dosage of pitavastatin or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention may be varied depending on various factors, including the state of health and weight of the patient, Disease severity, route of administration, time of administration, etc. It is obvious to those skilled in the art that the total daily dose is suitable for the medical treatment of the attending physician. Within the scope of the decision.

For an adult, the total daily dose of statin and vanesartan can range from 1 mg to 640 mg, and preferably from 2 mg to 350 mg, for prophylactic or therapeutic effects on cardiovascular disease and hyperlipidemia.

According to another aspect thereof, the present invention relates to a method of preparing a pharmaceutical composition for preventing or treating cardiovascular diseases and abnormal blood lipids. The method may comprise a first step of granulating pitavastatin or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or additive; and providing versartan or a pharmaceutically acceptable salt thereof And a second step of admixing a pharmaceutically acceptable carrier or additive with pitavastatin or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, the pharmaceutically acceptable carrier or additive of the first step preferably comprises as an excipient low-substituted hydroxypropylcellulose and lactose hydrate, as a lubricant or stabilizer, magnesium aluminum. At least one of a metasilicate salt and a hydroxypropyl methylcellulose as a binder, but is not limited thereto.

Preferably, the particles may comprise pitvastatin or a pharmaceutically acceptable salt thereof in an amount of from 0.5 mg to 8 mg, and a low-substituted hydroxypropylcellulose in an amount of from 20 mg to 200 mg, from 2 mg to 20 A milligram of lactose hydrate, a magnesium aluminum metasilicate salt of 0.5 mg to 10 mg, and hydroxypropyl methylcellulose of 0.5 mg to 10 mg.

In another embodiment of the present invention, the pharmaceutically acceptable carrier or additive of the second step may preferably include at least one of low-substituted hydroxypropylcellulose, and lactose hydrate, but is not limited thereto.

In the second step, valsartan or a pharmaceutically acceptable salt thereof is preferably in the range of 20 mg to 240 mg, and 20 mg to 200 mg of the low-substituted hydroxypropylcellulose and 30 mg to 300 mg. The lactose hydrate is used together.

According to another embodiment of the present invention, the method further comprises adding at least one of croscarmellose sodium as a disintegration adjuvant and magnesium stearate as a lubricant to the blend of the second step The third step, and the fourth step of pressing the mixture of the third step into a tablet using a rotary tablet press, but not limited thereto.

After the fourth step, the method may further comprise the fifth step of coating the tablet with a coating substrate to form an outer film coating using a coating machine. The coated substrate for the outer film coating may be composed of at least one selected from the group consisting of polyvinyl alcohol, titanium oxide (TiO ₂ ), polyethylene glycol 3350 (PEG 3350), and talc. It is preferred to coat the substrate with one of the owners of the composition.

For outer film coatings, a typical coating agent can be suitable. E.g., Opadry ^TM, hydroxypropylmethylcellulose or Eudragit series available.

The croscarmellose sodium may be used in an amount of 5 mg to 50 mg, and the amount of magnesium stearate may be in the range of 0.5 mg to 10 mg, but is not limited thereto.

A better understanding of the present invention can be obtained by the following examples, which are set forth to illustrate, but not to limit the invention.

Example 1: Preparation of a composite formulation containing pitavastatin calcium and valsartan

The tablets were prepared as shown in Table 1 below for the ingredients and contents. The contents in Table 1 are based on a tablet.

<Step 1> Pitavastatin calcium granulation

Pitavastatin calcium in a mixer (V-mixer) with low-substituted hydroxypropyl cellulose (L-HPC, LH B1), lactose hydrate (lactose 200 mesh), and magnesium aluminum bismuth citrate mixing. Then, the mixture was agglomerated in a mixer (P-mixer) using 5% hydroxypropylmethylcellulose as a binder, after which the agglomerates were sieved through a sieve (20 mesh) to form granules. . This is then dried at 50 ° C for 8 hours to achieve a 3% to 5% LOD. Thereafter, the dried material was passed through a sieve (Osilator, 0.4 mm screen) to provide a uniform size of pitavastatin calcium.

<Step 2> Versaltan mixture

Versartan was mixed with low substituted hydroxypropylcellulose (L-HPC, LH B1) and lactose hydrate (Flowlac 100) using a mixer (V-mixer).

<Step 3> Preparation of pitavastatin calcium/Versaltan complex formulation

<Step 1> Pitavastatin granules, <Step 2> Versaltan mixture, and croscarmellose sodium are blended using a mixer (V-mixer), and then, with stearic acid Magnesium mixing produces a final blend. As used herein, a rotary press machine pressed into tablets, and to the coated substrate using a coater Opadry ^TM coated.

Example 2: Preparation of a composite formulation containing pitavastatin calcium and valsartan

The tablets were prepared in the same manner as in Example 1 except that magnesium aluminosilicate was used in place of magnesium aluminum metasilicate.

Example 3: Preparation of a composite formulation containing pitavastatin calcium and valsartan

The tablets were prepared in the same manner as in Example 1 except that magnesium carbonate was used instead of magnesium aluminum bismuth citrate.

Example 4: Preparation of a composite formulation containing pitavastatin calcium and valsartan

The tablets were prepared in the same manner as in Example 1, except that aluminum hydroxide was used instead of magnesium aluminum metasilicate.

Example 5: Preparation of a composite formulation containing pitavastatin calcium and valsartan

The tablets were prepared in the same manner as in Example 1 except that potassium dihydrogen phosphate was used in place of magnesium aluminum metatanning.

Example 6: Preparation of a composite formulation containing pitavastatin calcium and valsartan

The tablets were prepared in the same manner as in Example 1 except that aluminum chloride was used in place of magnesium aluminum metasilicate.

Comparative Example 1: Preparation of monomorphic ligand for pitavastatin calcium

Using two Livaro ^® lozenges (JW Pharmaceuticals), each containing 2 mg of the formulation as a single match of atorvastatin calcium salt.

Comparative Example 2: Preparation of a single formulation of valsartan

Used alone or containing 160 mg of the Van Ersha Tan Diovan 160 ^® lozenges (Novatis, Korea).

Comparative Example 3: Preparation of a composite formulation containing pitavastatin calcium and valsartan

The tablets were prepared in the same manner as in Example 1 except that sodium phosphate was used instead of magnesium aluminum bismuth citrate.

Comparative Example 4: Preparation of a composite formulation containing pitavastatin calcium and valsartan

The tablets were prepared in the same manner as in Example 1, except that sodium benzoate was used instead of magnesium aluminum bismuth citrate.

Comparative Example 5: Preparation of a composite formulation containing pitavastatin calcium and valsartan

The tablets were prepared in the same manner as in Example 1 except that sodium dihydrogen phosphate was used in place of magnesium aluminum metasilicate.

Comparative Example 6: Preparation of a composite formulation containing pitavastatin calcium and vanesartan

The tablets were prepared in the same manner as in Example 1, except that phosphorus was used. Disodium acid hydrogenate replaces magnesium aluminum bismuth citrate.

Comparative Example 7: Preparation of a composite formulation containing pitavastatin calcium and valsartan

The tablets were prepared in the same manner as in Example 1, except that sodium succinate was used instead of magnesium aluminum bismuth citrate.

Comparative Example 8: Preparation of a composite formulation containing pitavastatin calcium and versartan

The tablets were prepared in the same manner as in Example 1 except that sodium hydrogencarbonate was used instead of magnesium aluminum bismuth citrate.

Test Example 1: Dissolution analysis of pitavastatin

The complex formulation of Example 1 and the single formulation of Comparative Example 1 were analyzed for dissolution of pitavastatin calcium using a dissolution tester under the following conditions.

<Solution conditions>

Test method: second dissolution of Korean Pharmacopoeia

Solution method (paddle method)

Dissolved liquid: 900 ml

Device: USP paddle method, 50 rpm

The dissolution test results are summarized in Table 2 (Examples 1) and 3 (Comparative Example 1).

In Table 2, the dissolution rate of pitavastatin calcium of the formulation of Example 1 is shown in terms of pH.

Table 3 shows the dissolution rate of pitavastatin calcium by pH in the formulation of Comparative Example 1.

Test Example 2: Solubility analysis of versartan

The composite formulation of Example 1 and the single formulation of Comparative Example 1 were analyzed for dissolution of versaltan using the same conditions as Test Example 1 using a dissolution tester.

The dissolution test results are summarized in Table 4 (Example 1) and 5 (Comparative Example 2).

In Table 4, the rate of mediation of vanesartan of the formulation of Example 1 is shown in terms of pH.

Table 5 shows the dissolution rate of valsartan by pH of the formulation of Comparative Example 2.

Test Example 3: Biological Equivalence Analysis

(1) Drug use for clinical testing

The composite formulation of Example 1 and the single formulation of Comparative Examples 1 and 2 were analyzed for bioequivalence based on pharmacokinetic parameters. This clinical trial is an open-ended, single-dose, randomized, 2-treatment, 3-sequence, 3-stage crossover design (see Table 6 below).

This table shows the order of administration for clinical testing in a timely manner. R (reference): Comparative Example of a combined single dose 1 (Livaro ^® lozenges: pitavastatin 2 mg tablets x2) and Comparative Example 2 (Diovan 160 ^® lozenges: Where Ersha Tan 160 mg). T (test): Single dose single dose Example 1 (Pitavastatin 4 mg / Versaltan 160 mg).

The administration was carried out at 24:00 on the first day for the first period, 24:00 on the 15th day for the second period, and 24:00 on the 29th day for the third period. The drug was orally administered to the sequence group at 8:00 a.m. with 240 ml of water at a predetermined dose. Subjects were fasted from 10:00 p.m. on hospital day (only allowed to ingest water until 1 hour before administration). Subjects were fasted for 4 hours after administration, but only allowed to drink water 2 hours after administration. Four hours after administration, the lines were straight at 45 degrees or higher. The drug for clinical testing is administered directly by the attending physician.

(2) Pharmacokinetic analysis

Plasma samples obtained from a total of 54 randomly selected subjects with an average age of 23.1 ± 1.9, 174.5 ± 5.7 cm height, and 68.3 ± 6.0 kg weight were evaluated for the amount of pitavastatin calcium and vanesartan.

<Step 1> Pharmacokinetic Analysis

For this analysis, the exact number of blood samples actually taken from individual subjects was used. "BQL" (below the quantifiable limit), "NA" (not applicable), and for the case where there is no detectable concentration (LLOQ) in the sample, no blood sample available, and no detectable concentration, and "ND" (not tested) is indicated individually in the drug concentration data. Blood volume-time data is presented in the graph as a linear or log/linear axis. The data obtained from, the following pharmacokinetic parameters using a non-chamber system (noncompartmental) verify the proper manner pharmacokinetic software (Phoenix WinNonlin ^®, 6.3 or higher version of, Pharsight, CA, USA)) assessed.

The area under the time of the serum drug concentration versus time curve (AUC) from time zero to the last quantifiable concentration ((AUC _0-∞ , AUC _t (t=48)) for the concentration increase period using a linear trapezoidal sum For the concentration reduction period, the logarithm/linear trapezoidal sum is used for the determination.

_Cmax means the maximum observed plasma concentration, and _Tmax means the time at which the plasma concentration reaches _Cmax after administration. The half-life (t _1/2β ) is calculated as ln(2)/λ _z , where λ _z is the exclusion rate constant calculated by linear regression of the log-transformed concentration of the drug at the end.

For pharmacokinetic parameters, descriptive statistical analysis (mean, standard deviation, intermediate, small, maximum) is based on the drug group and drug implementation. _Tmax was obtained by mean difference analysis.

The 90% confidence interval (CI) of the geometric mean ratio of the AUC _t to C _max values between treatments (test: reference drug) was calculated. The log-transformed data was analyzed using the ANOVA (variation analysis) model for the factors, the subjects in the sequence, the period, and the treatment group. The biological equivalence test range of the two treatments is 80-125% for the 90% confidence interval of the log conversion exposure test ratio. When the coefficient of variation of C _max of Comparative Examples 1 and 2 in the test subject exceeds 30% due to three or four repeated cross-tests, the bioequivalence is determined only when the following items are satisfied (however, The bioequivalence extension criteria based on the coefficient of variation are not applied to pitavastatin calcium).

For statistical analysis, the 90% confidence interval for AUC _t for the log-transform average difference needs to be within log 0.8 to log 1.25.

The average difference of C _max for its logarithmic transformation needs to fall between log 0.8 and log 1.25, and the 90% confidence interval of the log-transformed average difference means that the difference according to the range of the following equation is met. For coefficient of variation greater than 50%, the 90% confidence interval is required to be in the range of 0.6984 to log 1.4319.

In Table 7, the coefficient of variation of the 90% confidence interval of the logarithmic conversion average ratio of C _max is 30% or higher. [Upper limit, lower limit] = exp [±0.760 x (single mix of Comparative Example 1 or 2) The standard deviation of the logarithmic conversion C _max value in the test subject)); coefficient of variation (%) = equation exp [(the logarithmic conversion C _max value in the subject administered with the single formulation of Comparative Example 1 or 2) Standard deviation) ² ] The root value of -1.

If the 90% confidence in the average difference of the AUC _t of log-transformation and statistical processing does not fall between log 0.8 and log 1.25, the scaled bioequivalence criterion is applied to the data as a reference to establish for its Post-adjustment studies and the basis of the calculations of the subjects being tested.

<Step 2> Statistical Analysis

Considering the test characteristics, statistical assumptions do not need to be changed for safety and pharmacokinetic evaluation results. However, the following statistical analysis was performed with a significance of 0.05 if necessary. Continuous variables account for descriptive statistics (average, standard deviation, intermediate, minimum, number, etc.), and the frequency and ratio of each category is provided as a category variable. As demographic information, selected test subjects were analyzed. A safety analysis is performed on a test subject who has been administered one or more of the drugs for clinical testing, and a pharmaceutical analysis is performed only on test subjects who have completed the clinical test.

Regarding age, height, and weight, test subjects participating in clinical tests based on the sequence group were subjected to descriptive statistical analysis.

As a safety assessment, adverse reaction behavior was compared using a non-parametric approach between groups that were administered as a combined single formulation and administered separately as a composite formulation. The adverse reactions of each treatment group were analyzed using a descriptive statistical method for the frequency of accidents, the number of test subjects performing the adverse reactions, the severity, the significance, and the causal relationship with the compound formulation of Example 1. The clinical significance of individual subjects was determined by the overall results from the results obtained from vital signs, electrocardiography, clinical laboratory tests, and the like.

The pharmacokinetic properties of the foregoing tests are described below.

Pharmacokinetics of pitavastatin calcium contained in the formulations of Comparative Example 1 and Example 1.

A single formulation of Comparative Example 1 (Pitavastatin calcium 4 mg (2 mg x 2 tablets)) and 2 (Versaltan 160 mg), and the compound formulation of Example 1 (Pitavastatin calcium) 4 mg / versalamine 160 mg) were compared between groups of single administrations. The group of blood pititastatin reached a _Cmax at a median value of 0.76 hours (0.5 to 2.0 hours) in the group administered with the combination of the single formulations of Comparative Examples 1 and 2. When expressed in terms of arithmetic mean and standard deviation, _Cmax is 97.2 ± 40.0 ng/ml. After _Tmax , the concentration slowly decreased, and when expressed in terms of arithmetic mean and standard deviation, the AUC _t was 279.0 ± 86.0 hr ng/ml.

For the group administered with the compound formulation of Example 1, the blood pititastatin amount reached _Cmax at an intermediate value of 0.5 hours (0.25 to 1.5 hours). When expressed in terms of arithmetic mean and standard deviation, the _Cmax is 99.3 ± 34.4 ng/ml. After _Tmax , the concentration slowly decreased, and when expressed in terms of arithmetic mean and standard deviation, the AUC _t was 275.9 ± 79.7 hr ng/ml.

Table 8 shows the ratio of the least square mean of the early target parameters of the pitavastatin calcium after the combined Comparative Examples 1 and 2 or the single Example 1 administration, 90% CI (trust interval). C _max and AUC _t are expressed as arithmetic mean ± standard deviation, and T _max is expressed as an intermediate value [min] to maximum. Here, 90% CI is defined by the logarithmic transformation geometry ratio of Example 1 versus Comparative Example 1, which illustrates the logarithm of the difference between the means.

No statistical difference was detected between the treatment groups at AUC _inf , T _max , and t _1/2 when compared by nonparametric methods. Descriptive statistics for the pharmacokinetic parameters of pitavastatin calcium in the treatment group are compared in Table 9 below.

Table 9 summarizes descriptive statistics of the pharmacokinetic parameters of pitavastatin calcium in each treatment group. _Tmax is expressed as an intermediate value [minimum-maximum].

When compared with the combination of Comparative Example 1 (Pitavastatin 4 mg) and Comparative Example 2 (Versaltan 160 mg), a separate sample 1 (Pitavastatin 4 mg / Versaltan) was administered. 160 mg), the pitavastatin calcium, C _max and AUC _t of the geometric mean ratio of the valuation reviews and 90% confidence intervals are measured individually based 1.052 (0.958-1.154) and 0.996 (0.953-1.040).

For pitavastatin calcium, the arithmetic mean of the pharmacokinetic parameters _Cmax was calculated in the group administered with the compound formulation of Example 1 (test) by 99.3 ng/mL, and in a single formulation of Comparative Examples 1 and 2. The group (reference) used for the combination of the substances was 97.2 ng/mL. The arithmetic mean of AUC _{t (} t=48) was 275.9 hr ng/mL for the test group and 279.0 hr ng/mL for the reference group. Test group and reference group when assessing bioequivalence by pharmacokinetic parameters (C _max , AUC _{t (} t=48)) indicating drug exposure (WinNonlin ^® Pharsight, v.6.3, CA, USA) SAS 9.1 program) The geometric mean ratio (90% CI) is between 0.958 and 1.154 for _Cmax (90% CI) and 0.953 to 1.040 for AUC _{t (} t=48). Since 90% CI of _Cmax and AUC _t falls between 0.80 and 1.25, the two formulations are defined as being equal to each other.

Pharmacokinetics of pitavastatin calcium contained in the formulations of Comparative Example 2 and Example 1

A single formulation of the combined Example 1 (Pitavastatin calcium 4 mg (2 mg x 2 tablets)) and 2 (Versaltan 160 k mg), and the compound formulation of Example 1 (Pitavastatin calcium) 4 mg/Versaltan 160 mg) Comparison between groups administered once. For the group administered in a combination of the single formulations of Comparative Examples 1 and 2, the blood vanesartan amount reached _Cmax at an intermediate value of 2.5 hours (1.0 to 6.0 hours). When the type represented by the arithmetic mean and standard deviation, C _max based 4.4 ± 2.0 μ g / mL. After _Tmax , the concentration slowly decreased, and when expressed as an arithmetic mean and standard deviation, the AUC _t was 27.4 ± 11.4 hr ‧ μ g / mL.

For the group administered with the compound formulation of Example 1, the amount of blood pitavastatin reached _Cmax at an intermediate value of 2.5 hours (1.0 to 4.0 hours). When the type represented by the arithmetic mean and standard deviation, C _max based 4.8 ± 1.9 μ g / mL. After _Tmax , the concentration was slowly reduced, and when expressed as an arithmetic mean and standard deviation, the AUC _t was 28.4 ± 9.9 hr ‧ μ g / mL (Table 10).

Table 10 shows the least square mean ratio, 90% CI (trust interval), of the early target parameters of versartan after administration of the combined Comparative Examples 1 and 2 or Example 1 alone. C _max and AUC _t are expressed as arithmetic mean ± standard deviation, and T _max is expressed as i - intermediate value [min > maximum]. Here, 90% CI is defined by the log-transformation geometric ratio of Example 1 versus the combination of Comparative Examples 1 and 2, which is a logarithm of the difference between the means.

No statistical difference was detected between the treatment groups at AUC _inf , T _max , and t _1/2 when compared by nonparametric methods. Descriptive statistics for the pharmacokinetic parameters of pitavastatin calcium in the treatment group are compared in Table 11 below.

Table 11 summarizes descriptive statistics for the pharmacokinetic parameters of valsartan in each treatment group. _Tmax is expressed as an intermediate value [minimum-maximum].

In combination with the combination of pitavastatin 4 mg (2 mg x 2 tablets) and valsarsartan 160 mg, a separate Livaro complex lozenge (Pitavastatin 4 mg / Versaltan 160) was administered. The nominal estimate of the geometric mean ratio of C _max to AUC _t of vanesartan and the 90% confidence interval were measured for individual lines 1.153 (1.065 to 1.249) and 1.062 (0.987 to 1.143).

For all Ersha Tan, the pharmacokinetic parameters of the arithmetic mean C _max in the group in a complex formulation of Example 1 (test) is administered by the Department of Computing 4.8 μ g / mL, and in the order of Comparative Examples 1 and 2 group composition of a single administration of the formulation (reference) lines 4.4 μ g / mL. AUC _{t (t} = 48) of the arithmetic mean for what test group measured based 28.4hr‧ μ g / mL, and for the reference group based 27.3hr‧ μ g / mL. Bioequivalence is measured by the pharmacokinetic parameters (C _max , AUC _{t (} t=48)) of the drug exposure (WinNonlin ^® Pharsight, v.6.3, CA, USA) SAS 9.1 program), test group and reference group The geometric mean ratio (90% CI) is between 1.065 and 1.249 for _Cmax (90% CI) and between 0.987 and 1.143 for AUC _{t (} t=48). Since the 90% CI of C _max and AUC _t falls between 0.80 and 1.25, the dip system is defined as being equal to each other.

When the combination of Comparative Example 1 (Pitavastatin calcium 4 mg) and 2 (Versaltan 160 mg), and Example 1 alone (Pitavastatin 4 mg / Versaltan 160 mg) were administered once, The 90% confidence interval for the log-to-digital conversion ratio of the AUC _t to C _max for both pravastatin calcium and van sartan was found to fall within 0.80-1.25. Therefore, the two formulations can be judged to meet the bioequivalence criteria.

Test Example 4: Security Analysis

The safety analysis was performed on a total of 54 subjects who had been administered the drug for clinical testing at least once. For this safety analysis, 54 subjects were randomly assigned.

All adverse drug reactions (ADRs) detected were found to be mild or moderate in severity and all subjects recovered without sequelae.

When causal relationships with test drugs are assessed as "probably related," "probably related," or "clearly related," they are all defined as adverse drug reactions (ADRs).

Test Example 5: Solubility analysis based on additive changes

The dissolution analysis was carried out on the composite formulations of Examples 1 to 6 and Comparative Examples 3 to 8, and the single formulations prepared in Comparative Examples 1 and 2. The dissolution analysis results are summarized in Table 12 for the composite formulations of Examples 1 to 6 and the single formulations of Comparative Examples 1 and 2, and Table 13 shows the results of Versaltan. Further, the dissolution analysis results are provided in Table 14 for the combination of the preparations prepared in Comparative Examples 3 to 8 and the single formulation prepared in Comparative Examples 1 and 2. Table 15 shows the results of valsartan.

<Solution conditions>

Test method: The second dissolution method of the Korean Pharmacopoeia (paddle method)

Dissolved liquid: 900 ml

Device: USP paddle method, 50 rpm

pH: 6.8

In Table 12, the dissolution rate of pitavastatin is shown.

In Table 13, the dissolution rate of van sartan is shown.

In Table 14, the dissolution rate of pitavastatin is shown.

In Table 15, the dissolution rate of pitavastatin is shown.

It is understood from the data that the compound formulation of pitavastatin calcium salt/Versaltan prepared in Examples 1 to 6 containing a lubricant or stabilizer without Na is disintegrated in about 1 minute and contains sodium residue. The stabilizers or lubricants prepared in Comparative Examples 3 to 7 were observed to disintegrate only after 5 minutes.

Therefore, a sodium or sodium-free lubricant or stabilizer is used to stabilize the acidic conditions and to ensure proper dissolution rates of pitavastatin and vanesartan. That is, the improvement in the stability of pitavastatin in acidic conditions results in an increase in the dissolution rate of both pravastatin and versartan, and thus also an increase in its bioavailability.

While the preferred embodiment of the present invention has been disclosed for the purposes of illustration, it will be understood by those skilled in the art And the substitution system is possible.

Claims (15)

A pharmaceutical composition for preventing or treating cardiovascular diseases and abnormal dyslipidemia, comprising pitavastatin as an active ingredient or a pharmaceutically acceptable salt thereof, and versartan or a pharmaceutically acceptable salt thereof . The pharmaceutical composition of claim 1, wherein the pitavastatin or a pharmaceutically acceptable salt thereof is separated from the versaartan or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 2, wherein the pitavastatin or a pharmaceutically acceptable salt thereof is mixed with a sodium-free (Na)-containing lubricant or stabilizer. The pharmaceutical composition according to claim 2, wherein the pitavastatin or a pharmaceutically acceptable salt thereof is in a particle form and is blended with the versaltan or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 4, wherein the pitavastatin or a pharmaceutically acceptable salt thereof is in a particle form, and is a vanesartan or a pharmaceutical thereof together with a pharmaceutically acceptable additive. Acceptable salt blending. The pharmaceutical composition of claim 5, wherein the particles of the pitavastatin or a pharmaceutically acceptable salt thereof comprise at least one selected from the group consisting of low-substituted hydroxypropylcellulose and lactose hydrate as excipients As a lubricant or stabilizer, at least one selected from the group consisting of magnesium aluminum metasilicate, magnesium aluminum silicate, magnesium carbonate, aluminum hydroxide, potassium dihydrogen phosphate, and aluminum chloride, and as a binder Hydroxypropylmethylcellulose. The pharmaceutical composition according to claim 5, wherein the vanesartan or a pharmaceutically acceptable salt thereof contains at least one selected from the group consisting of low-substituted hydroxypropylcellulose and lactose hydrate as an excipient. The pharmaceutical composition of claim 1, further comprising croscamellose sodium as a disintegration adjuvant, or magnesium stearate as a lubricant, or both. The pharmaceutical composition of claim 1 comprising an outer film coating. The pharmaceutical composition according to claim 9, wherein the outer film coating layer comprises one of at least one selected from the group consisting of polyvinyl alcohol, titanium oxide (TiO ₂ ), polyethylene glycol 3350 (PEG 3350), and talc. Made of substrate. The pharmaceutical composition according to claim 1, wherein the pitavastatin or a pharmaceutically acceptable salt thereof is contained in an amount of from 0.5 mg to 8 mg. The pharmaceutical composition according to claim 1, wherein the vanesartan or a pharmaceutically acceptable salt thereof is contained in an amount of from 20 mg to 240 mg. The pharmaceutical composition according to claim 6, wherein the composition contains the low-substituted hydroxypropylcellulose in an amount of from 20 mg to 200 mg, the lactose hydrate in an amount of from 2 mg to 20 mg, and 0.5 mg to 10 mg. The amount of the magnesium aluminum metasilicate, and the amount of the hydroxypropyl methylcellulose of 0.5 mg to 10 mg. The pharmaceutical composition according to claim 7, wherein the composition contains the low-substituted hydroxypropylcellulose in an amount of from 20 mg to 200 mg, and the lactose hydrate in an amount of from 30 mg to 300 mg. The pharmaceutical composition of claim 8, wherein the composition contains the croscarmellose sodium in an amount of from 5 mg to 50 mg, and 0.5 mg to The magnesium stearate is in an amount of 10 mg.