WO2018199636A1

WO2018199636A1 - A combination formulation comprising hmg-coa reductase inhibitor and calcium channel blocker

Info

Publication number: WO2018199636A1
Application number: PCT/KR2018/004815
Authority: WO
Inventors: Si Beum Lee; Song Yi HA; Hye Suk Hong; Yoon Jung Lee
Original assignee: Alvogen Korea Co.,Ltd.
Priority date: 2017-04-26
Filing date: 2018-04-25
Publication date: 2018-11-01
Also published as: TWI674907B; CN110545801A; CN110545801B; KR20180120309A; KR101920996B1; TW201841623A

Abstract

The present invention relates to an oral combination formulation comprising a first composition comprising amlodipine or a pharmaceutically acceptable salt thereof, a disintegrant, and a sugar alcohol; and a second composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, and a stabilizer, and a preparation method thereof.

Description

A COMBINATION FORMULATION COMPRISING HMG-COA REDUCTASE INHIBITOR AND CALCIUM CHANNEL BLOCKER

The present invention relates to a combination formulation comprising a first composition comprising amlodipine or a pharmaceutically acceptable salt thereof, a disintegrant, and a sugar alcohol; and a second composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, and a stabilizer; and a preparation method thereof.

Hypertension is the most common cardiovascular disease, and damages blood vessels of the kidney, heart, and brain as blood pressure continually rises and elevates, thereby increasing the incidence of renal failure, coronary artery disease, heart failure, and stroke. Hypertension is divided into essential hypertension and secondary hypertension. Essential hypertension refers to high blood pressure of an unknown cause, that is, high blood pressure without a particular causative disease. Essential hypertension accounts for most (approximately 95%) of all hypertension cases, and for those in their 40s or older, most cases are related to essential hypertension. As there is no disease that causes essential hypertension, it is difficult to clearly investigate the cause thereof; however, genetic predisposition, salty eating habits, obesity, old age, stress, and excessive smoking and drinking can be problematic. Secondary hypertension refers to high blood pressure of a particular disease which secondarily increases blood pressure. Secondary hypertension accounts for 5% of all hypertension cases, and cases of hypertension in relatively young people are related to secondary hypertension. Nephritis, endocrine system abnormality, and pregnancy toxemia are primary causes, and blood pressure naturally lowers when the causative disease is treated.

Antihypertensive agents, which lower blood pressure, are broadly classified into three types―diuretics, antiadrenergic agents, and vasodilators―according to major regulatory sites or mechanisms, and are divided more specifically according to the sites on which each drug acts. Diuretics are drugs which excrete water and salt from the body by increasing an amount of urine, and they lower blood pressure by reducing the amounts of water and salt in the body. The sympathetic nervous system increases the number of contractions of the heart and strengthens the contractions, and also contracts the blood vessels, and sympathetic inhibitors are drugs that suppress the activities of the sympathetic nervous system, thereby lowering blood pressure. Sympatholytic agents include alpha blockers, which suppress the sympathetic nervous system that contracts blood vessels, beta blockers, which suppress the sympathetic nervous system that contracts the heart, and centrally acting sympatholytic agents, which act on the brain. Vasodilators are drugs which lower blood pressure by dilating blood vessels, and there are several types of vasodilators, such as ACE inhibitors, which suppress production of the vasoconstrictor angiotensin II, and angiotensin II receptor antagonists, which block angiotensin II activities. Additionally, as blood vessels contract and blood pressure elevates when intracellular calcium ion concentration increases, calcium channel blockers, which block the entry of the calcium ions and thereby lower blood pressure, are also a vasodilator.

It is important to prevent life-threatening complications of coronary artery diseases such as stroke, heart failure, myocardial infarction, etc.; and cardiovascular complications such as renal failure, rather than treating blood pressure itself, by maintaining the blood pressure within a normal range. Accordingly, it is important to steadily and patiently control the blood pressure. As antihypertensive medications require life-long administration, a therapeutic drug should be carefully selected. For continued treatment, therefore, it is necessary to obtain more excellent prophylactic and therapeutic effects by co-administering drugs having different mechanisms and reduce risks of side effects that can be caused by the long-term administration of a single drug by reducing an amount of its intake through the co-administration of drugs, rather than selecting a single drug. Hypertension Guidelines (The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; JNC7) recommends co-administration of drugs having different mechanisms in a case where there is no sufficient controlling effect of blood pressure by a single drug administration.

Meanwhile, hyperlipidemia means abnormally elevated levels of lipids in the blood, such as cholesterol, triglycerides, etc. In particular, hypercholesterolemia, by inducing coronary thrombosis, induces arteriosclerosis, in which an artery wall thickens as a result of accumulation of lipids, and causes ischemic heart disease, angina, and myocardial infarction by decreasing blood flow. Likewise, hyperlipidemia and arteriosclerosis are closely related, and thus, arteriosclerosis can be prevented by treating hyperlipidemia.

HMG-CoA reductase inhibitors inhibit mevalonate production to thereby interrupt cholesterol biosynthesis and show an effect of lowering levels of total cholesterol and LDL-cholesterol, and thus have been used in the treatment of hyperlipidemia (see Grundi S. M., NEngl J Med, 319(1): 24-32, 25-26, 31(1998)).

Hypertension is often prevalent in hyperlipidemia. Being considered as major risk factors for cardiovascular diseases, hypertension and hyperlipidemia ultimately lead to adverse cardiac symptoms. Such risk factors originate from potentially common mechanisms. Accordingly, it is advantageous for patients to receive a single prescription of a drug capable of treating all said diseases; however, when a cardiovascular disease patient co-administers an angiotensin II receptor antagonist and an HMG-CoA reductase inhibitor, not only are hypertension and hyperlipidemia treated, but also the function of endothelial cells as a blood vessel protective membrane is improved, as well as increased sensitivity to insulin, thereby also showing therapeutic effects on diabetes (see 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). Meanwhile, it is known that a large synergistic effect can be obtained by administering a calcium channel blocker, which is a therapeutic agent for hypertension, together with a lipid-lowering agent to treat arteriosclerosis (see Kramsch et al., Journal of Human Hypertention, Suppl.1, 53-59, 1995). It is also known that the calcium channel blocker can have an advantageous effect in the treatment of early atherosclerotic lesions (see Lichtlen P.R. et al., Lan et, 335, 1109-1139, 1990; and WatersD et. al., Circulation, 82, 1940-1953, 1990).

In particular, there is a recent study reporting that rosuvastatin, compared to atorvastatin, showed a more significant effect on atherosclerosis regression (Lee, C.W. et al, Am J Cardiol. 2012;109:1700-1704). Specifically, upon comparison of a treated group which was administered 10　mg of rosuvastatin and one which was administered 20　mg of atorvastatin for 6 months, rosuvastatin was found to show a significant reduction in atheroma.

Further, at the European Society of Cardiology (ESC) Congress 2014, LISTEN (LIpid lowering with highly potent Statins in hyperlipidemia with Type 2 diabetes patiENts), a study report on the effect of statin on the lipid regulation and glycometabolism, was presented, which revealed that rosuvastatin, in comparison with atorvastatin, would have a positive influence on a blood sugar level during an early treatment.

Meanwhile, a conventional oral combination formulation comprising amlodipine besylate and atorvastatin calcium is disclosed in KR　10-2006-0054495　A and KR　10-2009-0048023　A; however, there is no known combination formulation for administration comprising both amlodipine and rosuvastatin. As rosuvastatin and atorvastatin have completely different physicochemical properties, the stability of the formulation disclosed in the above-mentioned patents was confirmed to be significantly decreased when atorvastatin was substituted with rosuvastatin (Experimental Examples 6 and 7). Accordingly, there is a need for research on formulations comprising amlodipine and rosuvastatin which have high stability and a high dissolution rate.

Under such circumstances, the present inventors completed the present invention to prepare a combination formulation comprising rosuvastatin and amlodipine capable of obtaining stability and an excellent dissolution rate.

Stability of the oral combination formulation of the patents mentioned in Background Art was not secured due to the physicochemical properties of rosuvastatin when atorvastatin was simply substituted with rosuvastatin (Experimental Examples 6 and 7). Under such circumstances, the present invention is to provide a combination formulation comprising amlodipine and rosuvastatin capable of possessing an excellent dissolution rate and stability and a preparation method thereof.

In order to solve the problem, the present invention, as an aspect, provides an oral combination formulation comprising a first composition comprising amlodipine or a pharmaceutically acceptable salt thereof, a disintegrant, and a sugar alcohol; and a second composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, and a stabilizer.

As used herein, the term "amlodipine" is a compound represented by Formula 1 below, and is a calcium channel blocker used mainly in the treatment of hypertension and angina. Its chemical name is 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridine dicarboxylate.

[Formula 1]

It would be easy for one of ordinary skill in the art to chemically synthesize the amlodipine according to a known synthesis method, or purchase a commercially manufactured product thereof.

The oral combination formulation of the present invention may specifically contain 3.69　mg to 14　mg of amlodipine besylate (2.5　mg to 10　mg of amlodipine); and more specifically, 13.889　mg of amlodipine besylate (10　mg of amlodipine).

As used herein, the term "rosuvastatin" is a compound represented by Formula 2 below. As the type of statin which inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, rosuvastatin is used in the treatment of hypercholesteremia, hyperlipoproteinemia, atherosclerosis, etc. Its chemical name is (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhepten-6-oic acid).

[Formula 2]

It would be easy for one of ordinary skill in the art to chemically synthesize the rosuvastatin according to a known synthesis method, or purchase a commercially manufactured product thereof.

The oral combination formulation of the present invention may specifically contain 5.2　mg to 20.8　mg of rosuvastatin calcium (5　mg to 20　mg of rosuvastatin); and more specifically, 20.8　mg of rosuvastatin calcium (20　mg of rosuvastatin).

As used herein, the term "pharmaceutically acceptable salt" refers to a formulation which does not damage biological activities and properties of the administered amlodipine and rosuvastatin. The pharmaceutically acceptable salts include acid addition salts formed by an acid (e.g., an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.; an organic carboxylic acid such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.; etc.) which forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion. For example, the pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc.; amino acid salts such as lysine, arginine, guanidine, etc.; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc.; etc. Meanwhile, a commercially available besylic acid salt and a commercially available calcium salt are preferable for amlodipine and rosuvastatin, respectively.

In the oral combination formulation of the present invention, the "first composition" comprises amlodipine or a pharmaceutically acceptable salt thereof, a disintegrant, and a sugar alcohol, and "the second composition" comprises rosuvastatin or a pharmaceutically acceptable salt thereof.

There is no particular meaning in the order of the first and second compositions, and the order is merely to distinguish the two compositions.

The first composition may be provided in the form of a granule. The granule can be obtained according to a conventional granulation method; specifically, by mixing and sieving active ingredients and additives and dissolving the mixture in distilled water to prepare a binding solution, followed by mixing the binding solution in a high-speed mixer and drying the same.

The second composition in the form of a non-granulated mixture can be added to the granulated first composition to be compressed into a tablet. A preparation process of such combination formulation is simple and a preparation cost thereof can be reduced.

Due to a shortened disintegration time, the oral combination formulation releases rosuvastatin first, thereby decreasing a contact time between rosuvastatin and amlodipine. Accordingly, interactions between rosuvastatin and amlodipine can be minimized. According to an Experimental Example 1, there were interactions observed between rosuvastatin and amlodipine. Thus, it is important to minimize the contact between rosuvastatin and amlodipine.

Further, as the second composition of the oral combination formulation is not granulated, the stability of rosuvastatin, which is vulnerable to moisture and heat, can be increased.

The stability and uniformity of the formulation can be increased by having the second composition contain magnesium carbonate as an excipient, without being granulated.

The pharmaceutical composition of the present invention can be prepared in various types of formulations; for example, tablets such as uncoated tablets, film-coated tablets, single-layered tablets, double-layered tablets, multi-layer tablets, and core tablets; powders; and granules; capsules; etc. Preferably, the pharmaceutical composition of the present invention can be formulated in a single-layer tablet or double-layer tablet.

According to an exemplary embodiment, due to their excellent stability and dissolution rate compared to double-layer tablets, single-layer tablets can be prepared by a simple preparation process at a low cost.

As an alcohol derived from a sugar, the sugar alcohol in the first composition does not affect the stability of amlodipine and is capable of improving a dissolution profile of amlodipine. Any sugar alcohol can be used as long as it can be applied to medicine. The sugar alcohols include monosaccharide sugar alcohols such as tetritols (e.g., erythritol, D-threitol, L-threitol, etc.), pentitols (e.g., D-arabinitol, xylitol, etc.), hexitols (e.g., D-iditol, galactitol (dulcitol), D-glusitol (sorbitol), mannitol, etc.), cyclitols (e.g., inositol, etc.), etc.; disaccharide sugar alcohols such as maltitols, lactitols, reduced palatinoses (isomalt) etc.; and oligosaccharide sugar alcohols such as pentaerythritols, hydrogenated maltose starch syrup, etc., but are not limited thereto.

Specifically, mannitol, sorbitol, xylitol, erythritol, and inositol can be used; more specifically, mannitol can be used.

In an exemplary embodiment, when mannitol was included as the sugar alcohol, amlodipine and rosuvastatin exhibited an excellent dissolution rate as well as excellent stability (Experimental Examples 3 and 4).

The sugar alcohol can be included in an amount of 5　wt% to 20　wt% of the total weight of the oral combination formulation, specifically, 5　wt% to 15　wt%, more specifically, 5　wt% to 14　　wt%. When the sugar alcohol is included in an amount of less than 5　wt%, the dissolution rate may not be excellent, whereas when the sugar alcohol is included in an amount of greater than 20　wt%, the stability may be remarkably decreased. It was confirmed in an exemplary embodiment that when more than 20　wt% of the sugar alcohol is included in the first composition, the amlodipine and rosuvastatin contents were remarkably reduced when stored under an extreme condition (Experimental Example 5).

The disintegrants in the first composition may include sodium starch glycolate, crospovidone, sodium croscarmellose, or a mixture thereof. For example, the disintegrant may be sodium starch glycolate, and by selecting the same, excellent stability as well as an excellent dissolution rate may result.

The stabilizers in the second composition are included to prevent oxidation of rosuvastatin calcium. Magnesium carbonate, magnesium oxide, magnesium hydroxide, sodium bicarbonate, calcium hydrogen phosphate, calcium hydrogen phosphate, or a mixture thereof may be used as the stabilizer. For example, the stabilizer may be magnesium carbonate, and compared to the other stabilizers, magnesium carbonate may result in excellent stability of amlodipine and rosuvastatin (Experimental Example 8).

Specifically, the stabilizer is included in an amount of 1　wt% to 5　wt% of the total weight of the oral combination formulation. When the stabilizer is included in a larger amount, the stability of rosuvastatin as well as that of amlodipine may decrease, whereas when the stabilizer is included in a smaller amount, the stability of rosuvastatin may decrease.

The oral combination formulation of the present invention may have a film layer on an outer surface. The film layer may be formed with a water-soluble substance selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), cellulose acetate phthalate (CAP), ethyl cellulose (EC), methyl cellulose (MC), polymethacrylate, a polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol (PVA), and a mixture thereof.

The oral combination formulation of the present invention may have a lubricant to improve mobility. Specifically, the lubricant can be selected from the group consisting of light anhydrous silicic acid, talc, stearate, iron stearate, magnesium stearate, calcium stearate, polyethylene glycol, and a mixture thereof.

The first composition of the oral combination formulation of the present invention can be granulated by adding a binding agent. Specifically, the binding agent may be selected from the group consisting of polyvinyl povidone, hydroxypropyl cellulose, starch paste, gelatin, aluminum silicate, methyl cellulose, and a mixture thereof.

As another aspect, the present invention provides a method for preparing an oral combination formulation, comprising:

granulating a first composition comprising amlodipine or a pharmaceutically acceptable salt thereof, a disintegrant, and a sugar alcohol (first step);

preparing a second composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, and a stabilizer (second step); and

mixing the second composition with the granulated first composition prepared in the first step followed by compressing the mixture (third step).

The terms used in the method for preparing the oral combination formulation are the same as those explained with respect to the oral combination formulation.

In the first step, a mixture containing amlodipine or a pharmaceutically acceptable salt thereof, a disintegrant, and a sugar alcohol is prepared and introduced to a fluidized bed granulator. By spraying a binding solution, the mixture can be granulated. The mixture can then be mixed in a high-speed mixer for 5 minutes.

In the second step, the second composition can be obtained by mixing rosuvastatin or a pharmaceutically acceptable salt thereof and a stabilizer without granulating.

In the third step, a lubricant can be further added into to compress the mixture.

The oral combination formulation of the present invention, which comprises a first composition comprising amlodipine or a pharmaceutically acceptable salt thereof, a disintegrant, and a sugar alcohol; and a second composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, and a stabilizer, can have an excellent dissolution rate and stability.

Further, the oral combination formulation of the present invention, prepared by mixing the first composition in the form of granule with the second composition and compressing the mixture, employs a simple preparation process, and thus, a preparation cost thereof can be reduced.

Figs.　1a to 1c are diagrams showing phase changes of amlodipine, rosuvastatin, and a mixture thereof stored under an extreme condition.

Figs.　2a and 2b are diagrams showing dissolution test results of the active ingredients of the double-layer combination formulation of Comparative Example 1 and those of the single-layer combination formulation of Example 4.

Figs.　3a and 3b are diagrams showing dissolution test results of the active ingredients of the formulation of Comparative Example 2, which does not contain a sugar alcohol, and those of the formulation of Example 3, which contains a sugar alcohol.

Hereinafter, the present invention will be described in more detail with reference to the following Examples. However, these Examples are for illustrative purposes only, and the invention is not intended to be limited by these Examples.

Experimental Example 1: Interaction between calcium rosuvastatin and amlodipine besylate

In order to determine whether a combination formulation of rosuvastatin calcium and amlodipine besylate can easily be developed, stability test was carried out for each of the two active pharmaceutical ingredients and the mixture thereof.

Specifically, as active pharmaceutical ingredients, rosuvastatin calcium (R), amlodipine besylate (A) , and a mixture of rosuvastatin calcium and amlodipine besylate(1:1 weight ratio) were prepared, respectively (see Table 1 below).

No.	Substances	Change in properties
1	Rosuvastatin Calcium (R)	●
2	Amlodipine Besylate (A)	○
3	Mixture of R and A at 1:1 weight ratio	●

(○: No change, ●: Change in properties)

Experimental Example 1-1. Observation of changes in properties under extreme condition

The properties of each of the two active ingredients and the mixture thereof were observed under an extreme condition. Specifically, stored for 4 weeks, the observations were performed at 60°C at the initial stage and after 2 and 4 weeks.

As shown in Figs.　1a to 1c, amlodipine besylate showed no significant change in properties, whereas rosuvastatin calcium was hardened and showed yellow discoloration. Meanwhile, the mixture of the two active ingredient, compared to rosuvastatin calcium, was further hardened and discolored.

Experimental Example 1-2. Observation of changes in contents of active pharmaceutical ingredients under extreme condition

Changes in the content of each active ingredient included in rosuvastatin calcium, amlodipine besylate, and a mixture thereof were observed under an extreme condition. Stored under the same condition as in Experimental Example 1-1., the changes in the content of each substance and mixture were calculated in wt% and are shown in Table 2 below.

○: content reduced to 5% or below, ●: content reduced to 5% or above)

As shown above, there was no reduction in the amlodipine besylate content, whereas there was a reduction of about 2% in the rosuvastatin content at 2 weeks and 4 weeks. Meanwhile, the mixture thereof showed a reduction of 28　wt% in the rosuvastatin content at 4 weeks and a reduction of 17　wt% in the amlodipine content. This indicates that when they are in contact, rosuvastatin calcium and amlodipine have an impact on each other, thereby changing each other's properties.

Experimental Example 1-3. Observation of impurity formation under extreme condition

Each of rosuvastatin calcium, amlodipine besylate, and a mixture thereof was observed with respect to the impurity formation under an extreme condition. Stored under the same condition as in Experimental Example 1-1., the amounts of impurities were measured, and the results are summarized in Table 3 below.

No.		1	2	3
Substance		Rosuvastatin calcium (R)	Amlodipine besylate (A)	Mixture having R:A weight ratio of 1:1
Rosuvastatin content (%)	Initial	0.27	-	0.50
	2 weeks	0.91	-	21.20
	Δ (2 weeks -Initial)	0.6	-	20.7
	4 weeks	1.55	-	30.10
	Δ (4 weeks - Initial )	1.3	-	29.6
Result		●	-	●
Amlodipine content (%)	Initial	-	0.40	2.32
	2 weeks	-	0.46	12.46
	Δ(2 weeks - Initial)	-	0.1	10.1
	4 weeks	-	0.30	16.14
	Δ(4 weeks - Initial)	-	0.2	13.8
Result		-	○	●

(○: 1% or less impurity formed, ●: 1% or more impurity formed)

As described above, impurities were barely formed in amlodipine besylate, whereas about 1.3　wt% of impurities were formed in rosuvastatin at 4 weeks. Meanwhile, in the mixture thereof, 17　wt% and 28　wt% of impurities of amlodipine and rosuvastatin, respectively, were formed at 4 weeks. This indicates that when they are in contact, rosuvastatin calcium and amlodipine have an impact on each other, thereby forming excessive impurities.

Example 1

170　mg of microcrystalline cellulose, 76.8　mg of pregelatinized starch, 20　mg of sodium starch glycolate, and 20　mg of mannitol were added into 13.889　mg of amlodipine besylate through a No.　180 mesh sieve, and mixed in a high-speed mixer for 5 minutes to prepare a mixed solution. 10　mg of polyvinyl povidone was added to 45　mg of ethanol to prepare a binding solution. The mixed solution was introduced into a mobile phase granulator, and the binding solution was sprayed thereonto to prepare a granule. The granule was then dried.

Additionally, 20　mg of crospovidone, 8　mg of magnesium carbonate, and 2　mg of light anhydrous silicic acid were mixed with 20.8　mg of rosuvastatin to prepare a mixture.

The thus-prepared mixture and 4　mg of magnesium stearate (i.e., a lubricant) were further mixed with the amlodipine-containing granule and compressed into a tablet.

Example 2

A tablet was prepared by the same method as in Example 1, except that 190　mg of microcrystalline cellulose and 56.8　mg of pregelatinized starch were used.

Example 3

A tablet was prepared by the same method as in Example 1, except that 140　mg of microcrystalline cellulose and 50　mg of mannitol were used.

Example 4

A tablet was prepared by the same method as in Example 1, except that 140 mg of microcrystalline cellulose, 60 mg of mannitol, and 60 mg of ethanol were used when preparing the granule containing amlodipine; 16 mg of crospovidone and 4 mg of light anhydrous silicic acid were used, and 28.52 mg of microcrystalline cellulose and 20 mg of mannitol were further added to the mixture when preparing the non-granulated mixture containing rosuvastatin; and 8 mg of magnesium stearate was used as a lubricating agent.

Comparative Example 1 - A double-layer tablet of amlodipine and rosuvastatin

111　mg of microcrystalline cellulose, 55.9　mg of pregelatinized starch, 4　mg of sodium starch glycolate, and 8.1　mg of mannitol were mixed with 13.889　mg of amlodipine besylate. The mixture was dried and then granulated.

Further, 59.6　mg of microcrystalline cellulose, 89.5　mg of mannitol, 74.5　mg of Di-Tab, 21.8　mg of LH-11, and 15　mg of crospovidone were mixed with 20.8　mg of rosuvastatin calcium. The mixture was dried and then granulated.

The amlodipine-containing granule as the first layer and the rosuvastatin-containing granule as the second layer were further mixed with 2.2　mg and 3.8　mg of magnesium stearate, respectively, and compressed into a double-layer tablet.

The ingredients and the contents thereof in the double-layer tablet of Comparative Example 1 are shown in Table 4 below.

			Comparative Example 1
First granule(1^st layer)	Active ingredient	Amlodipine	13.889
	Excipient	Microcrystalline cellulose	111
	Excipient	Pregelatinized starch	55.9
	Disintegrant	Sodium starch glycolate	4
	Excipient	Mannitol	8.1
	Lubricant	Calcium stearate	2.2
Second granule(2^nd layer)	Active ingredient	Rosuvastatin	20.8
	Excipient	Microcrystalline cellulose	59.6
	Excipient	Mannitol	89.5
	Excipient	Di-Tab	74.5
	Excipient	LH-11	21.8
	Disintegrant	Crospovidone		15
Final mixture	Lubricant	Magnesium stearate	3.8
Total weight			480.089

(Unit: mg)

Comparative Example 2 - A single-layer tablet containing no sugar alcohol

A tablet was prepared by the same method as in Example 1, except that 190　mg of microcrystalline cellulose was used and mannitol was not used.

Comparative Example 3

A tablet was prepared by the same method as in Example 1, except that 110　mg of microcrystalline cellulose and 80　mg of mannitol were used.

Comparative Examples 4 to 6

Tablets were prepared by the same method as in Example 1, except that each of sodium bicarbonate, calcium hydrogen phosphate, and precipitated calcium carbonate was used instead of magnesium carbonate.

The ingredients and the contents thereof in the single-layer tablets of Examples 1 to 4, and Comparative Examples 2 to 6 are shown in Table 5 below.

(Unit: mg)

Comparative Example 7 - A formulation analogous to Caduet tablet

A tablet was prepared by substituting atorvastatin in the formulation disclosed in a patent directed to the Caduet tablet of Pfizer (Korean Laid-open Patent Publication No.　10-2006-0054495　A) with rosuvastatin. Contrary to Example 1, a rosuvastatin-containing granule and a a non-granulated mixture containing amlodipine were prepared, and the amlodipine mixture was then mixed with the rosuvastatin-containing granule. The specific contents thereof are shown in Table 6 below.

(Unit: mg)

Comparative Example 8 - A formulation analogous to that of Korean Laid-open Patent Publication No.　10-2009-0048023

A tablet was prepared by substituting atorvastatin in the formulation disclosed in Example 1 of Korean Laid-open Patent Publication No.　10-2006-0054495　A with rosuvastatin. Contrary to Example 1, a rosuvastatin-containing granule and an amlodipine -containing granule were separately prepared and were then mixed. The specific contents thereof are shown in Table 7 below.

(Unit: mg)

Experimental Example 2. Comparative dissolution test for single-layer tablet and double-layer tablet

A dissolution test was performed for the active ingredients of the combination formulation of Comparative Example 1 prepared in a double-layer tablet by granulating each of amlodipine and rosuvastatin and those of the tablet of Example 4 prepared in a single-layer tablet by further mixing the non-granulated mixture containing rosuvastatin with the amlodipine-containing granule. The dissolution test was performed according to a dissolution test of the Korean Pharmacopoeia, and the details thereof are as set forth below:

Test method: Dissolution Test 2 of the Korean Pharmacopoeia (paddle method)

Rotation speed: 50　rpm

Dissolution medium: 500　mL of a test solution having pH　6.8

The amlodipine and rosuvastatin showed the dissolution rates shown in Tables 8 and 9 below, respectively (see Figs.　2a and 2b).

	0　min	5　min	10　min	15　min	30　min	45　min	60　min
Example 1	0	11.3	42.9	51.5	60.2	65.1	68.2
SD	0	4.3	8.6	10.1	9.7	9.2	8.7
Example 4	0	74.9	86.3	89.2	89.6	90.1	90.6
SD	0	1.0	0.7	0.6	0.5	0.7	0.4

(Unit: wt%)

	0　min	5　min	10　min	15　min	30　min	45　min	60　min
Example 1	0	57.9	76.1	80.8	83.3	84.9	86.2
SD	0	3.6	3.5	3.3	3.6	3.7	3.4
Example 4	0	82.9	89.2	90.8	91.5	91.9	91.8
SD	0	3.3	1.3	0.8	0.6	0.3	0.6

(Unit: wt%)

As shown above, the combination formulation of Comparative Example 1 prepared in a double-layer tablet by granulating each of amlodipine and rosuvastatin showed a lower dissolution rated compared to the tablet of Example 4 prepared in a single-layer tablet by mixing the rosuvastatin mixed solution with the amlodipine-containing granule. This confirms that by changing the tablet from a double-layer tablet to a single-layer tablet, a more excellent dissolution rate can be obtained.

Experimental Example 3. Comparative dissolution test according to the presence of sugar alcohol

A dissolution test was performed for the active ingredients of the tablet of Comparative Example 2, which does not include a sugar alcohol in the amlodipine-containing granule, and those of the tablet of Example 3, which includes a sugar alcohol in the granule. The test was performed in the same manner as in Experimental Example 2.

Amlodipine and rosuvastatin showed the dissolution rates shown in Table 10 and 11 below, respectively (see Figs.　3a and 3b).

	0　min	5　min	10　min	15　min	30　min	45　min	60　min
Comp Ex
2	0	54.7	69.1	72.7	72.5	74.2	74.3
SD	0	0.5	1.5	0.9	1.4	0.7	1.3
Ex 3	0	42.8	82.0	93.9	96.5	96.5	96.7
SD	0	6.9	3.9	1.9	1.3	0.9	1.5

(Unit: wt%)

	0　min	5　min	10　min	15　min	30　min	45　min	60　min
Comp Ex
2	0	77.0	82.4	83.5	84.8	85.7	86.4
SD	0	1.1	0.7	1.0	1.2	1.0	1.2
Ex 3	0	57.8	87.9	94.3	95.1	95.5	95.7
SD	0	10.5	3.6	2.0	1.7	1.5	1.6

(Unit: wt%)

As shown above, the tablet of Comparative Example 2, which does not include a sugar alcohol in the amlodipine-containing granule, showed a lower dissolution rate compared to that of Example 3, which includes a sugar alcohol. This confirms that a better dissolution rate can be obtained by containing a sugar alcohol.

Experimental Example 4. Comparative stability tests according to the presence of sugar alcohol

The tablet of Comparative Example 2, which does not include a sugar alcohol in the amlodipine-containing granule, and the tablets of Examples 1 and 3, which include a sugar alcohol, were coated and were put in a vial packaged in aluminum. The vial was then stored under an extreme condition to examine chemical stability of their active ingredients; specifically, the vial was stored under the extreme conditions of 60°C and 80% relative humidity for 2 weeks, and the active ingredient contents (%) were measured via HPLC.

The condition used for HPLC analysis is as follows:

Detector: Ultraviolet Spectrophotometer (wavelengths: rosuvastatin - 242　nm, amlodipine - 237　nm)

Column: Thermo, Hypersil Gold, C18 (4.6 Х 250　mm, 5.0　μm)

Mobile phase: Mobile phase A - triethylamine buffer

Mobile phase B - acetonitrile

Mobile phase C - methanol

Flow rate: 1.0　mL/min

The changes in the amlodipine and rosuvastatin contents observed for 2 weeks are shown in Table 12 below.

Extreme condition/Al-Al (60°C, 80%)		Amlodipine	SD	Rosuvastatin	SD
Initial	Comparative Example 2	99.5	0.1	100.6	0.7
	Example 1	99.5	0.3	99.1	0.8
	Example 3	100.7	0.3	100.3	0.2
1 week	Comparative Example 2	96.4	0.1	100.2	1
	Example 1	98.0	0.2	98.9	1.1
	Example 3	97.9	0.3	100.1	0.6
2 weeks	Comparative Example 2	95.5	0.3	97.8	0.6
	Example 1	98.2	0.2	98.7	0.4
	Example 3	96.1	0.1	100.1	0.5

(Unit: wt%)

In the case of the tablet of Comparative Example 2, which does not contain a sugar alcohol in the amlodipine-containing granule, the contents of the active ingredients decreased compared to those of Examples 1 and 3, which include mannitol. Based on the above result and the result of Experimental Example 1, it was confirmed that the formulation of the present invention has excellent stability as it contains a sugar alcohol in the amlodipine-containing granule and thus minimizes interactions between amlodipine and rosuvastatin.

Experimental Example 5. Comparative stability test according to sugar alcohol content

Chemical stability of the active ingredients was tested for the tablet of Comparative Example 3, which includes 21.9　wt% of a sugar alcohol in the amlodipine-containing granule, and that of Example 1, which includes 5.5　wt% of a sugar alcohol. The stability test was performed in the same manner as in Experimental Example 3.

The changes in the amlodipine and rosuvastatin contents observed for 2 weeks are shown in Table 13 below.

Extreme condition/Al-Al (60°C, 80%)		Amlodipine	Reduction	SD	Rosuvastatin	Reduction	SD
Initial	Example 1	99.5	-	0.3	99.1	-	0.8
Initial	Comparative Example 3	101.7	-	0.5	100.8	-	0.5
1 week	Example 1	98.0	1.5	0.2	98.9	0.2	1.1
1 week	Comparative Example 3	97.0	4.7	0.4	99.4	1.4	0.3
2 weeks	Example 1	98.2	1.3	0.2	98.7	0.4	0.4
2 weeks	Comparative Example 3	95.8	5.9	0.2	98.4	2.4	0.5

In the case of the tablet of Comparative Example 3 which includes 21.9　wt% of a sugar alcohol in the amlodipine-containing granule, the amlodipine content was 5.9　wt% at 2 weeks, and the rosuvastatin content was 2.4　wt%, indicating a significant decrease. Meanwhile, Example 1 showed almost no change in the amlodipine and rosuvastatin contents.

This result reveals an appropriate amount of sugar alcohol that would lead to the excellent stability of the present invention.

Experimental Example 6. Stability test of a formulation prepared by substituting atorvastatin in Caduet tablet with rosuvastatin

Stability was tested for the formulation of Comparative Example 7 prepared by substituting atorvastatin in the Caduet tablet, known as a combination formulation of amlodipine and atorvastatin, with rosuvastatin. The same test as in Experimental Example 4 was performed under the extreme condition for 1 week, and the observed changes in the amlodipine and rosuvastatin contents are shown in Table 14 below.

Extreme condition/Al-Al (60°C, 80%)		Amlodipine	Reduction	Rosuvastatin	Reduction
Initial	Example 1	99.5	-	99.1	-
Initial	Comp Ex 7	100.1	-	100.5	-
1 week	Example 1	98.0	1.5	98.9	0.2
1 week	Comp Ex 7	92.8	7.3	96.0	4.5

As shown above, in Comparative Example 7, the amlodipine and the rosuvastatin showed a reduction of 7.3　wt% and 4.5　wt%, respectively, at 1 week. In Example 1, which was performed at the same time, the amlodipine and the rosuvastatin showed a reduction of 1.5　wt% and 0.2　wt%, respectively. In comparison of the two results, Comparative Example 7 showed remarkably low stability.

This result shows that a combination formulation having excellent stability cannot be obtained simply by substituting atorvastatin with rosuvastatin in a conventionally known combination formulation of atorvastatin and amlodipine.

Experimental Example 7. Stability test for a formulation prepared by substituting atorvastatin in the formulation of Korean Laid-open Patent Publication No.　10-2009-0048023 with rosuvastatin

Stability was tested for the formulation of Comparative Example 3 prepared by substituting atorvastatin with rosuvastatin in the combination formulation of amlodipine and atorvastatin disclosed in Example 1 of Korean Laid-open Patent Publication No.　10-2009-0048023.

The stability was measured with respect to the amount of impurities formed under an extreme condition. Specifically, the formulations of Example 1 and Comparative Example 8 were put in a vial packaged in aluminum, and each packaged vial was stored at an extreme condition (60°C, 80% relative humidity) for 2 weeks to measure the amount of the impurities that are formed.

The contents of the formed impurities were measured according to the HPLC analysis method described in Experimental Example 4. The impurity contents of the amlodipine and the rosuvastatin formed after 2 weeks are shown in Table 15 below.

Extreme condition/Al-Al (60°C, 80%)		Amlodipine Impurity	Difference	Rosuvastatin Impurity	Difference
Initial	Example 1	0.02	-	0.09	-
Initial	Comp Ex 8	0.07	-	0.07	-
1 week	Example 1	0.56	0.54	0.58	0.49
1 week	Comp Ex 8	0.75	0.68	0.45	0.38
2 weeks	Example 1	0.8	0.72	0.8	0.71
2 weeks	Comp Ex 8	2.24	2.17	1.6	1.53

As shown above, in Comparative Example 8, 2.17　mg and 1.53　mg of the amlodipine and rosuvastatin impurities were formed, respectively, at 2 week. In Example 1, which was performed at the same time, 0.72　mg and 0.71　mg of the amlodipine and rosuvastatin impurities were formed, respectively. In comparison of the two results, Comparative Example 8 showed remarkably low stability.

Experimental Example 8. Comparative stability tests according to the type of stabilizer

Stability was tested for the formulations of Example 1 and Comparative Examples 4 to 6. Stability was examined by measuring the amount of the impurities formed disclosed in Experimental Example 7.

The amounts of each of the amlodipine and rosuvastatin impurities formed after 2 weeks are shown in Table 16 below.

Extreme conditions/Al-Al (60°C, 80%)		Amlodipine Impurity	Difference Δ	Rosuvastatin Impurity	Difference Δ
Initial	Example 1	0.02	-	0.09	-
	Comp Ex 4	0.03		0.03
	Comp Ex 5	0.03		0.03
	Comp Ex 6	0.03		0.03
1 week	Example 1	0.56	0.54	0.58	0.49
	Comp Ex 4	0.50	0.47	0.50	0.41
	Comp Ex 5	1.52	1.49	1.56	1.53
	Comp Ex 6	1.06	1.03	1.03	1.00
2 weeks	Example 1	0.8	0.72	0.8	0.71
	Comp Ex 4	1.37	1.34	1.35	1.32
	Comp Ex 5	2.70	2.67	2.72	2.69
	Comp Ex 6	2.85	2.82	2.70	2.67

As shown above, in Comparative Examples 4 to 6, 1.34　mg, 2.67　mg, and 2.82　mg of the amlodipine impurities were formed and 1.32　mg, 2.69　mg, and 2.67　mg of the rosuvastatin impurities were formed at 2 weeks. In comparison with 0.72　mg of the amlodipine impurities and 0.71　mg of the rosuvastatin impurities formed in Example 1, which was performed at the same time, it was confirmed that the stability measured in Comparative Examples 4 to 6 was remarkably low.

From such results, it can be understood that high stability is exhibited when magnesium carbonate is used as a stabilizer.

Those of ordinary skill in the art will recognize that the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. In this regard, the described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the present invention is therefore indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within the scope of the present invention.

Claims

An oral combination formulation comprising:

a first composition comprising amlodipine or a pharmaceutically acceptable salt thereof, a disintegrant, and a sugar alcohol; and

a second composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, and a stabilizer.
The oral combination formulation of claim 1, wherein the sugar alcohol is comprised in an amount of 5　wt% to 15　wt% of the total weight of the combination formulation.
The oral combination formulation of claim 2, wherein the sugar alcohol is selected from the group consisting of mannitol, sorbitol, xylitol, erythritol, and inositol.
The oral combination formulation of any of claims 1 to 3, wherein the disintegrant is sodium starch glycolate.
The oral combination formulation of any of claims 1 to 4, wherein the stabilizer is selected from the group consisting of magnesium carbonate, magnesium oxide, magnesium hydroxide, sodium hydrogen carbonate, calcium hydrogen phosphate, precipitated calcium carbonate, and a mixture thereof.
The oral combination formulation of claim 5, wherein the stabilizer is magnesium carbonate.
The oral combination formulation of any one of claims 1 to 6, wherein the stabilizer is comprised in an amount of 1　wt% to 5　wt% of the total weight of the formulation.
The oral combination formulation of any one of claims 1 to 7, wherein the first composition is in the form of a granule, and wherein the oral combination formulation is a single-layer tablet in which a mixture of the second composition and the granule are compressed.
The oral combination formulation of any of claims 1 to 8, further comprising a film layer on an outer surface of the formulation.
The oral combination formulation of claim 9, wherein the film layer is formed with a water-soluble substance selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), cellulose acetate phthalate (CAP), ethyl cellulose (EC), methyl cellulose (MC), polymethacrylate, a polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol (PVA), and a mixture thereof.
A method for preparing an oral combination formulation, comprising:

granulating a first composition comprising amlodipine or a pharmaceutically acceptable salt thereof, a disintegrant, and a sugar alcohol (first step);

preparing a second composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, and a stabilizer (second step); and

mixing the second composition with the granulated first composition prepared in the first step followed by compressing the mixture (third step).
The method of claim 11, wherein the sugar alcohol is comprised in an amount of 5　wt% to 15　wt% of the total weight of the oral combination formulation.
The method of claim 11 or 12, wherein the sugar alcohol is selected from the group consisting of mannitol, sorbitol, xylitol, erythritol, and inositol.
The method of any of claims 11 to 13, wherein the stabilizer is selected from the group consisting of magnesium carbonate, magnesium oxide, magnesium hydroxide, sodium bicarbonate, calcium hydrogen phosphate, precipitated calcium carbonate, and a mixture thereof.
The method of claim 14, wherein the stabilizer is magnesium carbonate.
The method of any of claims 11 to 15, wherein the stabilizer is comprised in an amount of 1　wt% to 5　wt% of the total weight of the formulation.
The method of any of claims 11 to 16, wherein the third step comprises further adding a lubricant into the mixture before compression.